Process for preparing 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1h-pyrimidin-2-one

Abstract

The present invention provides a process for obtaining 5-fluoro-4- imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-lH-pyrimidin-2- one having formula ( I ) : wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

Description

[0001] PROCESS FOR PREPARING 5-FLUORO-4-IMINO-3-METHYL-1- (TOLUENE-4- SULFONYL) -3 , 4-DIHYDRO-1H-PYRIMIDIN-2-ONE

[0002] Throughout this application various publications are referenced . The disclosures of these documents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains .

[0003] TECHNICAL FIELD

[0004] The present subj ect matter relates to an efficient procedure for obtaining 5-f luoro-4-imino-3-methyl-l- ( toluene-4-sulf onyl ) -3 , 4- dihydro-1H-pyrimidin-2-one .

[0005] BACKGROUND

[0006] The compound 5-f luoro-4-imino-3-methyl-l- ( toluene-4-sulf onyl ) -

[0007] 3 , 4-dihydro-1H-pyrimidin-2-one ( f lumetylsulf orim) has the structure : f lumetylsulf orim is a systemic fungicide which provides control of variety of pathogens in economically important crops including , but not limited to , the causal agent of leaf blotch in wheat , Septoria tri ti ci ( SEPTTR) .

[0008] Different manufacturing processes are known from the literature , including those described in WO 2015 / 103144 , WO 2015 / 103142 , WO 2021 / 059160 and WO 2021 / 181274 . There is a need to develop a more efficient synthesis pathway m terms of costs, yield, selectivity, conversion, and purity.

[0009] SUMMARY OF THE INVENTION

[0010] The present invention provides a process for obtaining 5-fluoro-4- imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2- one having formula (I) : comprising :

[0011] (a) reacting 5-f luorocytosine with compound having formula (III) : in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) (b) reacting the compound having formula (II) with dimethylsulphate

[0012] (DMS) ; wherein

[0013] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -N02, -CN or CF3; and

[0014] X is a halogen or -OSO2PhR; and

[0015] (c) isolating the compound having formula (I) from the reaction mixture .

[0016] The present invention also provides a process for obtaining the compound having formula (II) : (II) ,

[0017] Comprising reacting 5-f luorocytosine with compound having formula

[0018] (III) : in the presence of at least one polar solvent, at least one base and a metal agent. The present invention also provides a process for obtaining 5- f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H- pyrimidin-2-one having formula (I) : (I) , comprising : preparing the compound having formula (I) by reacting a compound having the formula (II) with dimethylsulphate (DMS) , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -N02, -CN or CF2, and

[0019] (b) isolating the compound having formula (I) from the reaction mixture by mixing an aqueous basic solution and an acid with the reaction mixture and obtaining the compound having formula (I) , wherein the process comprises use of at least one water immiscible solvent, wherein: step (a) is conducted in the presence of at least one water- immiscible solvent, and / or at least one water-immiscible solvent is mixed with the reaction mixture after step (a) .

[0020] The present invention also provides a process for obtaining 5- f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H- pyrimidin-2-one having formula (I) : comprising :

[0021] (a) reacting 5-f luorocytosine with compound having formula (III) : in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) wherein the molar ratio between the 5-f luorocytosine and the metal agent is 5:1 to 1.8:1,

[0022] (b) reacting the compound having the formula (II) with dimethylsulphate (DMS) , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF2, and

[0023] (c) isolating the compound having formula (I) from the reaction mixture by mixing an aqueous basic solution and an acid with the reaction mixture and obtaining the compound having formula (I) , wherein the acid is added to obtain a pH at a range between 7.8- 8.5, wherein the process comprises use of at least one water immiscible solvent, wherein: i) step (1) is conducted in the presence of at least one water- immiscible solvent, and / or ii) at least one water-immiscible solvent is mixed with the reaction mixture after step (1) , wherein the method comprises conducting the reaction of the compound having formula (II) with DMS at a temperature between 10 °C to below 25°C. The present invention further provides a process for obtaining 5- f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H- pyrimidin-2-one having formula (I) : comprising :

[0024] (a) reacting 5-f luorocytosine with compound having formula (III) : in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) wherein the molar ratio between the 5-f luorocytosine and the metal agent is 5:1 to 1.8:1, (b) reacting the compound having the formula (II) with dimethylsulphate (DMS) , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -N02, -CN or CF2, and

[0025] (c) isolating the compound having formula (I) from the reaction mixture by mixing an aqueous basic solution and an acid with the reaction mixture and obtaining the compound having formula (I) , wherein the acid is added to obtain a pH at a range between 7.8- 8.5, wherein the process comprises use of at least one water immiscible solvent, wherein: i) step (b) is conducted in the presence of at least one water- immiscible solvent, and / or ii) at least one water-immiscible solvent is mixed with the reaction mixture after step (b) , wherein the method comprises using a water immiscible solvent having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature.

[0026] The present invention also provides a method of improving yield of 5-f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4 -dihydro-1H- pyrimidin-2-one having formula (I) in a process as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0027] Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains.

[0028] The term "a" or "an" as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms "a," "an," or "at least one" can be used interchangeably in this application .

[0029] Throughout the application, descriptions of various embodiments use the term "comprising"; however, it will be understood by one of skill in the art, that in some specific instances, an embodiment can alternatively be described using the language "consisting essentially of" or "consisting of". In each such instance, the terms "comprising," "consisting essentially of," and "consisting of" are intended to have the same meaning as each such term would have when used as the transition phrase of a patent claim.

[0030] In an embodiment, use of the term "about" herein specifically includes ±10% from the indicated values in the range. By way of example, about 15% therefore includes 13.5%, 13.6%, 13.7%, etc. up to 16.5%. Use of the term "about" herein more specifically includes ±1% from the indicated values in the range. By way of example, about 100 mg / kg therefore includes 99, 99.1, 99.2, 99.3, 99.4,

[0031] 99.5, 99.6, 99.7, 99.8, 99.9, 100, 100.1, 100.2, 100.3, 100.4,

[0032] 100.5, 100.6, 100.7, 100.8, 100.9 and 101 mg / kg. Accordingly, about 100 mg / kg includes, in an embodiment, 100 mg / kg.

[0033] In addition, the endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. Where a range is given in the specification it is understood that the range includes all integers and 0.1 units within that range, and any sub-range thereof. For example, a range of "2-18%" is a disclosure of 2.0 %, 2.1 %, 2.2 %, 2.3% etc. up to 18%.

[0034] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cnas in "C1-Cnalkyl" is defined to include groups having 1, 2 , n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on. An embodiment can be C1-C8 alkyl, C2-C8 alkyl, C3-C8 alkyl, C4-C8 alkyl and so on.

[0035] As used herein, "alkoxy" represents an alkyl group as described above attached through an oxygen bridge.

[0036] As used herein, "Ph" is referring to phenyl group.

[0037] "metal agent" is a salt or compound comprising a metal atom. Without being bound to any theory, it is believed that the metal agent binds to functional group (s) to form a coordination complex.

[0038] In some embodiments, the metal agent binds one or more 5- f luorocytosine molecules. In some embodiments, the metal agent binds 1 to 3 molecules of 5-f luorocytosine . In some embodiments, 5-f luorocytosine forms a complex with the metal agent.

[0039] In some embodiments, the central metal of the metal agent is selected from a group consisting of Aluminum (Al) , Magnesium (Mg) , Calcium (Ca) , Titanium (Ti) , iron (Fe) , Zinc (Zn) , Zirconium (Zr) , Phosphate (P) , Ruthenium (Ru) , Nickle (Ni) , Tin (Sn) , Lead (Pb) , Mercury (Hg) , manganese (Mn) and Cobalt (Co) . In some embodiments, the metal agent is of Formula (v) M(Z)n, wherein :

[0040] M is selected from a group consisting of Aluminum (Al) , Magnesium (Mg) , Calcium (Ca) , Copper (Cu) , Titanium (Ti) , iron (Fe) , Zinc (Zn) , Zirconium (Zr) , Ruthenium (Ru) , Nickle (Ni) , Tin (Sn) , Lead (Pb) , Mercury (Hg) , manganese (Mn) and Cobalt (Co) ;

[0041] Z is selected from C1-C6 alkyl, phenyl, Aryl, Halogen such as Cl, Br, F and I, O-C1-C6-alkyl , pyridine, oxide, NO3, CN, sulfide, OH and sulfate, C1-6 alkyl acid; and n is an integer ranging from 1 to 6.

[0042] In some embodiments, the oxidation state of the metal is between + 2 to + 6.

[0043] In some embodiments, the oxidation state of aluminum is +2.

[0044] In some embodiments, the metal agent is selected from a group consisting of ALUMINUM (II) SULFATE, ALUMINUM (II) OXIDE, ALUMINUM (II) SULFIDE, ALUMINUM (II) PHOSPHATE.

[0045] In some embodiments, the oxidation state of aluminum is +3. In some embodiments, the metal agent is selected from a group consisting of ALUMINUM (III) OXIDE, ALUMINUM ( III ) PERCHLORATE, ALUMINUM ( III ) HYDROXIDE, ALUMINUM ( III ) CHLORIDE, ALUMINUM ( III ) SULFATE, ALUMINUM (III) BROMIDE, ALUMINUM ( III ) PHOSPHATE, ALUMINUM ( III ) IODIDE, ALUMINUM (III) CYANIDE, ALUMINUM ( III ) TERT-BUTOXIDE , ALUMINUM (III) 2, 4-PENTANEDIONATE, TRIMETHYLALUMINUM, TRIETHYLALUMINUM, ALUMINIUM ISOPROPOXIDE, TRIPROPYLALUMINUM, DIMETHYLALUMINUM I-PROPOXIDE

[0046] In some embodiments, the oxidation state of magnesium is +2. In some embodiments, the metal agent is selected from a group consisting of MAGNESIUM (II ) NITRATE, MAGNESIUM ( II ) OXIDE , MAGNESIUM (II) PHOSPHATE, MAGNESIUM (II ) CHLORIDE, MAGNESIUM (II) BROMIDE, MAGNESIUM ( II ) IODIDE , MAGNESIUM ( II ) ACETATE, MAGNESIUM (II) NITRIDE, MAGNESIUM ( II ) SULFIDE,

[0047] MAGNESIUM (II) HYDROXIDE, MAGNESIUM (II ) METHOXIDE, MAGNESIUM ( II ) N- PROPOXIDE, MAGNESIUM DI-TERT-BUTOXIDE, MAGNESIUM ( II ) OXIDE.

[0048] In some embodiments, the oxidation state of calcium is +2. In some embodiments, the metal agent is selected from a group consisting of CALCIUM (II) PHOSPHATE, CALCIUM (II ) CHLORIDE, CALCIUM ( II ) NITRATE, CALCIUM ( II ) OXIDE , CALCIUM (II) HYDROXIDE, CALCIUM ( II ) ACETATE , CALCIUM(II) FLUORIDE, CALCIUM ( II ) BROMIDE , CALCIUM (II ) IODIDE, CALCIUM(II) BIS (TRIFLUOROMETHANESULFONYL) IMIDE, CALCIUM(II) METHOXIDE, CALCIUM ( II ) ETHOXIDE , BIS (2, 4- PENTANEDIONATO) CALCIUM (II) .

[0049] In some embodiments, the oxidation state of copper is +2.

[0050] In some embodiments, the metal agent is selected from a group consisting of COPPER (II ) SULFATE, COPPER ( II ) CHLORIDE, COPPER (II) OXIDE, COPPER (II) NITRATE, COPPER ( II ) HYDROXIDE, COPPER (II) ACETATE, COPPER (II ) CYANURATE, COPPER ( II ) BROMIDE, COPPER (II) SULFIDE, COPPER (II) 2 -ETHYLHEXANOATE , COPPER (II) PHOSPHATE, COPPER (II) TRIFLUOROMETHANESULFONATE, COPPER (II) TRIFLATE, DI-N-PROPYL COPPER, COPPER ( II ) ACETYLACETONATE, COPPER (II) TRI FLUOROACETYLACETONATE, COPPER (II) NITRATE TRIHYDRATE, COPPER (II) ACETATE MONOHYDRATE, COPPER (II) CHLORIDE DIHYDRATE, COPPER (II) SULFATE ANHYDROUS, COPPER (II) SULFATE PENTAHYDRATE, COPPER (II) TRI FLUOROMETHANESULFONATE, COPPER ( II ) HYDROXIDE , COPPER (II) ACETATE, COPPER (II ) TERT-BUTYLACETOACETATE, COPPER(II) ETHYLACETOACETATE, COPPER (II ) ACETATE MONOHYDRATE, COPPER(II)D- GLUCONATE, COPPER ( II ) NITRATE HYDRATE, COPPER ( II ) PERCHLORATE HEXAHYDRATE, COPPER ( II ) ACETATE HYDRATE, COPPER (II ) FLUORIDE, COPPER (II) SULFATE HYDRATE, COPPER(II) HEXAFLUOROACETYLACETONATE HYDRATE, COPPER ( II ) NITRATE HEMI (PENTAHYDRATE) , COPPER (II) I- BUTYRATE, COPPER ( II ) TARTRATE HYDRATE, COPPER (II) TRIFLUOROMETHANESULFONIMIDE HYDRATE, TETRAKIS (PYRIDINE) COPPER (II) TRIFLATE, COPPER(II) TETRAFLUOROBORATE HYDRATE, COPPER (II ) HEPTADECANOATE PALMITATE, COPPER (II) PYROPHOSPHATE HYDRATE, COPPER ( II ) TRI FLUOROACETATE HYDRATE, PHTHALIC ACID COPPER (II) SALT, METHYL ACETOACETATE COPPER (II) , COPPER (II) DI ( 2 -NAPHTHOATE ) , BENZOIC ACID COPPER (II) SALT DIHYDRATE, COPPER (II ) 2 -ETHYLHEXANOATE, 8 -HYDROXYQUINOLINE COPPER (II) SALT, 3- (FLUOROSULFONYL) BENZOIC ACID COPPER (II) SALT.

[0051] In some embodiments, the oxidation state of titanium is +2. In some embodiments, the metal agent is selected from a group consisting of TITANIUM(II) CHLORIDE, TITANIUM (II) OXIDE, TITANIUM ( II ) ACETATE , TITANIUM (II) SULFIDE, TITANIUM (II ) SULFATE, TITANIUM (II ) HYDRIDE.

[0052] In some embodiments, the oxidation state of titanium is +3. In some embodiments, the metal agent is selected from a group consisting of TITANIUM (III) CHLORIDE, TITANIUM ISOPROPOXIDE, TITANIUM ( III ) BROMIDE, TITANIUM (III) SULFATE, TITANIUM ( III ) OXIDE , TITANIUM (III) CARBONATE, TITANIUM ( III ) ACETATE , TITANIUM (III )

[0053] FLUORIDE.

[0054] In some embodiments, the oxidation state of titanium is +4. In some embodiments, the metal agent is selected from a group consisting of TITANIUM (IV) OXIDE, TITANIUM ( IV) OXYACETYLACETONATE , TITANIUM (IV) CHLORIDE, TITANIUM (IV) ISOPROPOXIDE, TITANIUM ( IV) BROMIDE , TITANIUM(IV) FLUORIDE, TITANIUM ( IV) NITRATE, TITNAIUM ( IV) METHOXIDE , TITANIUM (IV) ETHOXIDE, TITANIUM ( IV) BUTOXIDE , TITANIUM (IV) OXYSULFATE, TITANIUM (IV) OXYACETYLACETONATE, TETRAKIS (DIMETHYLAMIDO) TITANIUM (IV) , TITANIUM ( IV) PROPOXIDE, TITANIUM (IV) IODIDE, BIS (CYCLOPENTADIENYL) TITANIUM (IV) DICHLORIDE, TITANIUM (IV) TERT-BUTOXIDE, TITANIUM (IV) 2 -ETHYLHEXYLOXIDE , CHLOROTRIISOPROPOXYTITANIUM (IV) .

[0055] In some embodiments, the oxidation state of iron is +2. In some embodiments, the metal agent is selected from a group consisting of IRON (II) OXIDE, IRON (II) CHLORIDE, IRON (II) BROMIDE, IRON (II) IODIDE, IRON (II) FLUORIDE, IRON ( II ) SULFIDE, IRON (II) SULFATE, IRON ( II ) NITRATE , IRON (II) TRIFLUOROMETHANESULFONATE, IRON (II ) ACETATE, IRON ( II ) PHOSPHATE, IRON (II) BICARBONATE, IRON ( II ) HYDROXIDE , I RON ( I I ) FUMARAT E , IRON (II) OXALATE, IRON ( II ) METHOXIDE , IRON ( II ) CHLORIDE TETRAHYDRATE, IRON(II) SULFATE HEPTAHYDRATE, AMMONIUM IRON ( II ) SULFATE HEXAHYDRATE, IRON (II) TITANATE, IRON ( II ) OXALATE DIHYDRATE, IRON (II) LACTATE HYDRATE, IRON ( II ) SULFATE HYDRATE, IRON (II) PERCHLORATE HYDRATE, (AMINOMETHYL ) -PHOSPHONIC ACID IRON (II) SALT.

[0056] In some embodiments, the oxidation state of iron is +3. In some embodiments, the metal agent is selected from a group consisting of IRON (III) OXIDE, IRON (III) NITRATE, IRON ( III ) CARBONATE, IRON (III) CHLORIDE, IRON (III) TERT-BUTOXIDE, IRON (III ) SULFATE, IRON (III) CITRATE, IRON ( III ) ETHOXIDE , IRON ( III ) BROMIDE , IRON (III) ACETYLACETONATE, AMMONIUM IRON (III) CITRATE, IRON (III) NITRATE NONAHYDRATE, IRON ( III ) CITRATE , IRON (III) PYROPHOSPHATE, IRON (III) PERCHLORATE HYDRATE, IRON (III) TARTRATE, IRON (III ) SULFATE HYDRATE, IRON (III) CHLORIDE HEXAHYDRATE, IRON (III) FLUORIDE, IRON (III) PHOSPHATE DIHYDRATE, LITHIUM IRON ( III ) OXIDE , AMMONIUM IRON (III) OXALATE TRIHYDRATE, IRON (III) PHOSPHATE TETRAHYDRATE, IRON (III) OXALATE HEXAHYDRATE, IRON (III ) CITRATE .

[0057] In some embodiments, the oxidation state of iron is +4. In some embodiments, the metal agent is selected from a group consisting of IRON (IV) SULFATE, IRON ( IV) PHOSPHATE .

[0058] In some embodiments, the oxidation state of iron is +6. In some embodiments, the metal agent is POTASSIUM FERRATE (K2FEO4) .

[0059] In some embodiments, the oxidation state of Zinc is +2. In some embodiments, the metal agent is selected from a group consisting of ZINC (II) CHLORIDE, ZINC ( II ) NITRATE , ZINC (II ) OXIDE, ZINC (II) IODIDE, ZINC (II) HYDROXIDE, ZINC ( II ) SULFIDE , ZINC (II) PHOSPHATE, ZINC (II ) SULFATE, ZINC ( II ) PERCHLORATE, ZINC (II) ACETYLACETONATE HYDRATE, ZINC (II) PIVALATE, ZINC ( II ) BROMIDE, ZINC (II) TRI FLUOROMETHANESULFONATE, ZINC TRI FLUOROACETATE HYDRATE, ZINC BIS [P-TOLUENESULPHINATE] , ZINC(II) N-HEXANOATE, DIMETHYLZINC, DIETHYL ZINC, ZINC ACETATE DIHYDRATE.

[0060] In some embodiments, the oxidation state of zirconium is +2. In some embodiments, the metal agent is ZIRCONIUM ( II ) HYDRIDE.

[0061] In some embodiments, the oxidation state of zirconium is +4. In some embodiments, the metal agent is selected from a group consisting of ZIRCONIUM (IV) PHOSPHIDE, ZIRCONIUM (IV) OXIDE, ZIRCONIUM (IV) SULFIDE, ZIRCONIUM (IV) CHLORIDE, ZIRCONIUM (IV) FLUORIDE, ZIRCONIUM ( IV) OXYNITRATE , ZIRCONIUM (IV) DICHROMATE, ZIRCONIUM ( IV) CARBONATE, ZIRCONIUM ( IV) ISOPROPOXIDE, ZIRCONIUM (IV) ETHOXIDE, ZIRCONIUM ( IV) ACETYLACETONATE, ZIRCONIUM ( IV) FLUORIDE, ZIRCONIUM ( IV) BUTOXIDE, ZIRCONIUM (IV) SELENATE, ZIRCONIUM ( IV) TRI FLUOROACETYLACETONATE , ZIRCONIUM (IV) OXYNITRATE HYDRATE, ZIRCONIUM ( IV) PROPOXIDE, ZIRCONIUM (IV) SULFATE HYDRATE, ZIRCONIUM ( IV) HYDROXIDE , ZIRCONIUM (IV) TERT-BUTOXIDE.

[0062] In some embodiments, the oxidation state of ruthenium is +2. In some embodiments, the metal agent is selected from a group consisting of RUTHENIUM (II) NITRATE, RUTHENIUM (II ) PEROXIDE, RUTHENIUM (II) PHOSPHATE, RUTHENIUM (II ) CHLORIDE, BIS (CYCLOPENTADIENYL) RUTHENIUM ( II ) ,BIS (TRIPHENYLPHOSPHINE) RUTHENI UM (II) DICARBONYL CHLORIDE, CARBONYLCHLOROHYDRIDOTRIS (TRIPHENYLPHOSPHINE) RUTHENIUM (II) , DIHYDR IDOTETRAKIS (TRIPHENYLPHOSPHINE) RUTHENIUM (II ) ,TRIS ( TRIPHENYLPHOSPI NE) RUTHENIUM (II) DICHLORIDE, BIS (CYCLOPENTADIENYL) RUTHENIUM (II ) , HEXAAMMINERUTHENIUM (II) CHLORIDE, RUTHENIUM ( IV) OXIDE , RUTHENIUM (III) ACETYLACETONATE.

[0063] In some embodiments, the oxidation state of ruthenium is +3. In some embodiments, the metal agent is selected from a group consisting of RUTHENIUM (III ) CHLORIDE HYDRATE, RUTHENIUM (III ) CHLORIDE, RUTHENIUM (III) CHLORIDE NITROSYL NITRATE, RUTHENIUM (III) ACETYLACETONATE, RUTHENIUM ( III ) CHLORIDE TRIHYDRATE.

[0064] In some embodiments, the oxidation state of ruthenium is +4. In some embodiments, the metal agent is selected from a group consisting of RUTHENIUM ( IV) OXIDE, RUTHENIUM ( IV) OXIDE HYDRATE.

[0065] In some embodiments, the oxidation state of nickel is +2. In some embodiments, the metal agent is selected from a group consisting of NICKEL (II) CHLORIDE, NICKEL (II) SULFATE HEXAHYDRATE, NICKEL (II) NITRATE HEXAHYDRATE, NICKEL (II) OXIDE, NICKEL (II) SULFATE HEXAHYDRATE, NICKEL ( II ) CHLORIDE HEXAHYDRATE, NICKEL (II) ACETYLACETONATE, NICKEL ( II ) ACETATE TETRAHYDRATE, NICKEL (II) BROMIDE, NICKEL (II) IODIDE, NICKEL (II) BROMIDE HYDRATE, NICKEL (II) SULFATE, BIS (CYCLOPENTADIENYL) NICKEL (II) , BIS (TRIPHENYLPHOSPHINE) NICKEL (II) DICHLORIDE, DICHLOROBIS (TRIMETHYL PHOSPHINE) NICKEL (II) , DIBROMOBIS (TRIPHENYLPHOSPHINE) NICKEL (II) , BIS (TRICYCLOHEXYLPHOSPHINE) NICKEL (II) DICHLORIDE, NICKEL (II) HEXAFLUOROACETYLACETONATE HYDRATE, NICKEL (II ) SULFATE HEPTAHYDRATE, NICKEL (II) HYDROXIDE, NICKEL (II) SULFAMATE TETRAHYDRATE, NICKEL(II) PERCHLORATE HEXAHYDRATE, BIS (METHYLCYCLOPENTADIENYL ) NICKEL ( II ) , NICKEL (II) CHLORIDE HYDRATE, NICKEL ( II ) BROMIDE TRIHYDRATE, NICKEL (II) CARBONATE HYDROXIDE TETRAHYDRATE, NICKEL ( II ) SULFATE HEXA- / HEPTAHYDRATE, NICKEL ( II ) CARBONATE BASIC HYDRATE, AMMONIUM NICKEL (II) SULFATE HEXAHYDRATE, BIS (ETHYLCYCLOPENTADIENYL) NICKEL (II) , NICKEL (II) BROMIDE ETHYLENE GLYCOL DIMETHYL ETHER COMPLEX, NICKEL (II) BIS ( 2 , 2 , 6 , 6-TETRAMETHYL- 3, 5-HEPTANEDIONATE) .

[0066] In some embodiments, the oxidation state of nickel is +4. In some embodiments, the metal agent is NICKEL (IV) OXIDE.

[0067] In some embodiments, the oxidation state of tin is +2. In some embodiments, the metal agent is selected from a group consisting of TIN (II) SULFATE, TIN (II) CHLORIDE, TIN (II) OXALATE, TIN (II) CHLORIDE DIHYDRATE, TIN (II) OXIDE, TIN (II) TRIFLUOROMETHANESULFONATE, TIN (II) PYROPHOSPHATE, TIN (II) PYROPHOSPHATE, TIN (II) 2 -ETHYLHEXANOATE , TIN (II) ACETYLACETONATE, TIN (II) BROMIDE, TIN (II) IODIDE, TIN (II) FLUORIDE, TIN (II) ACETATE, TIN(II) METHANESULFONATE, CITRIC ACID, TIN(II) SALT.

[0068] In some embodiments, the oxidation state of tin is +4. In some embodiments, the metal agent is selected from a group consisting of TIN (IV) OXIDE, TIN (IV) IODIDE, TIN (IV) BROMIDE, TIN (IV) CHLORIDE, TETRAKIS (DIMETHYLAMIDO) TIN (IV) , TIN (IV) CHLORIDE PENTAHYDRATE, TIN (IV) TERT-BUTOXIDE , TETRAKIS (DIETHYLAMIDO) TIN (IV) , TIN (IV) ACETATE, TIN (IV) BIS (ACETYLACETONATE) DICHLORIDE, TIN (IV) FLUORIDE, TETRACHLOROBIS (TRIPROPYLPHOSPHINE) TIN (IV) .

[0069] In some embodiments, the oxidation state of lead is +2. In some embodiments, the metal agent is selected from a group consisting of LEAD (II) NITRATE, LEAD (II) ACETATE TRIHYDRATE, LEAD (II) OXIDE, LEAD (II) PERCHLORATE HYDRATE, LEAD (II) THIOCYANATE, LEAD (II) CARBONATE BASIC.

[0070] In some embodiments, the oxidation state of lead is +4. In some embodiments, the metal agent is LEAD (IV) OXIDE.

[0071] In some embodiments, the oxidation state of mercury is +2. In some embodiments, the metal agent is selected from a group consisting of MERCURY (II) CHLORIDE, MERCURY (II) ACETATE, MERCURY (II) SULFATE, MERCURY (II) BROMIDE, MERCURY (II) IODIDE, MERCURY (II) OXIDE, MERCURY (II) THIOCYANATE, MERCURY (II) NITRATE MONOHYDRATE, MERCURY(II) AMIDOCHLORIDE, MERCURY (II) (N-HEPTYLSULFIDE) , MERCURY(II) (N-OCTYLSULFIDE) , CINNAMIC ACID MERCURY (II) SALT, 2- FURANACRYLIC ACID MERCURY (II) SALT.

[0072] In some embodiments, the oxidation state of manganese is +2. In some embodiments, the metal agent is selected from a group consisting of MANGANESE (II ) CHLORIDE, MANGANESE ( II ) SULFATE

[0073] MONOHYDRATE, MANGANESE (II ) NITRATE TETRAHYDRATE, MANGANESE ( II ) SULFATE TETRAHYDRATE, MANGANESE ( II ) CHLORIDE TETRAHYDRATE,

[0074] MANGANESE (II) BROMIDE, MANGANESE ( II ) ACETATE TETRAHYDRATE, MANGANESE (II) ACETATE, MANGANESE ( II ) IODIDE, MANGANESE ( II ) CHLORIDE, MANGANESE (II) OXIDE, MANGANESE (II ) PERCHLORATE HYDRATE, MANGANESE (II) ACETYLACETONATE, MANGANESE (II ) CARBONATE, MANGANESE (II) SULFIDE, MANGANESE ( II ) FLUORIDE, MANGANESE ( II )

[0075] CHLORIDE MONOHYDRATE, MANGANESE (II ) NITRATE HYDRATE, MANGANESE ( II ) CHLORIDE HYDRATE, MANGANESE ( II ) SULFATE HYDRATE, MANGANESE ( II ) CARBONATE HYDRATE, MANGANESE ( II ) BROMIDE TETRAHYDRATE,

[0076] MANGANESE (II) 4 -CYCLOHEXANEBUTYRATE, MANGANESE ( II ) CHLORIDE

[0077] BIS (LITHIUM CHLORIDE) , GLUCONIC ACID MANGANESE (II) SALT.

[0078] In some embodiments, the oxidation state of manganese is +3. In some embodiments, the metal agent is selected from a group consisting of MANGANESE ( III ) OXIDE, MANGANESE ( III ) ACETATE DIHYDRATE, MANGANESE ( III ) ACETYLACETONATE, MANGANESE ( III ) FLUORIDE, MANGANESE (III) METHANESULFONATE , TRIS ( 2 , 2 , 6 , 6- TETRAMETHYL-3, 5-HEPTANEDIONATO) MANGANESE (III) .

[0079] In some embodiments, the oxidation state of manganese is +4. In some embodiments , the metal agent is MANGANESE ( IV) OXIDE.

[0080] In some embodiments, the oxidation state of cobalt is +2. In some embodiments, the metal agent is selected from a group consisting of COBALT (II) NITRATE HEXAHYDRATE, COBALT (II) SULFATE HEPTAHYDRATE, COBALT (II) CHLORIDE HEXAHYDRATE, COBALT (II) PHTHALOCYANINE, COBALT (II) ACETYLACETONATE, COBALT (II) BROMIDE, COBALT (II) CHLORIDE, COBALT (II) OXIDE, COBALT (II) CHLORIDE ANHYDROUS, COBALT (II) CARBONATE HYDRATE, COBALT (II) THIOCYANATE, COBALT (II) ACETATE, COBALT (II) ACETATE TETRAHYDRATE, COBALT (II) SULFATE HYDRATE, DICHLOROBIS (TRIPHENYLPHOSPHINE) COBALT (II ) , COBALT(II) HEXAFLUOROACETYLACETONATE HYDRATE, COBALT (II) HYDROXIDE, COBALT(II) CHLORIDE HYDRATE, BIS (CYCLOPENTADIENYL) COBALT (II) , COBALT (II) PERCHLORATE HEXAHYDRATE, BIS (ETHYLCYCLOPENTADIENYL) COBALT (II) , AMMONIUM COBALT (II) SULFATE HEXAHYDRATE, COBALT (II) PHOSPHATE HYDRATE, COBALT (II) BROMIDE HYDRATE, COBALT (II) OXALATE DIHYDRATE.

[0081] In some embodiments, the oxidation state of cobalt is +3. In some embodiments, the metal agent is selected from a group consisting of COBALT (III) ACETYLACETONATE, HEXAMMINE COBALT (III) CHLORIDE, LITHIUM COBALT (III) OXIDE, COBALT (III) FLUORIDE, TRIS (ETHYLENEDIAMINE) COBALT (III) CHLORIDE DIHYDRATE, SODIUM HEXANITROCOBALTATE (III) , PENTAAMMINECHLOROCOBALT ( III ) CHLORIDE, HEXAAMMINECOBALT (III) CHLORIDE, POTASSIUM HEXACYANOCOBALTATE ( III ) .

[0082] As used herein, the term "soluble" means when 1g of substance is dissolved in the approximate volume of 100 ml.

[0083] In some embodiments, the term "water immiscible" when used in relation to a solvent means that the solvent does not completely mix with water to form a one phase solution.

[0084] As used in describing the tosylation step, the term "polar solvent" refers to solvent which has a dielectric constant equal to or above 20. As used in the remaining application, including in describing the sulfonation step other than tosylation step, the alkylation step and the isolation step, the term "polar solvent" has the meaning commonly understood by one of skill in the art to which this subject matter pertains, and includes, but is not limited to, solvent which has a dielectric constant equal to or above 20.

[0085] The polar solvent used in each of the sulfonation step, the alkylation step and isolation step may be the same or different. When the sulfonation step is a tosylation step, the polar solvent has a dielectric constant equal to or above 20.

[0086] As used herein, the term "formula (II)" refers to the following structure : wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF2, and tautomers thereof, including but not limited to enamine tautomers thereof.

[0087] As used herein, the term "formula (Ilai)" refers to the following structure : and tautomers thereof, including but not limited to an enamine tautomer thereof. For example, the compound having formula (Ilai) includes both of the following compounds :

[0088] Lack of selectivity in preparation of compound (II) refers to formation impurities such as compound having the formula [A] and compound having the formula [B] .

[0089] wherein

[0090] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid, halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0091] The present invention provides a process for obtaining 5-fluoro-4- imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2- one having formula (I) :

[0092] (I) , comprising :

[0093] (a) reacting 5-f luorocytosine with compound having formula (III) : in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II)

[0094] (b) reacting the compound having formula (II) with dimethylsulphate (DMS) ; wherein

[0095] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -N02, -CN or CF3; and

[0096] X is a halogen or -OSO2PhR; and

[0097] (c) isolating the compound having formula (I) from the reaction mixture .

[0098] Step (a) - reacting 5- luorocytosine with compound having formula

[0099] In some embodiments, the metal agent is useful for increasing the selectivity of step (a) .

[0100] In some embodiments, the metal agent is calcium chloride dihydrate.

[0101] In some embodiments, the purity of the compound obtained in step

[0102] (a) is higher than 95%. In some embodiments, the structural isomeric compounds obtained in step (a) are less than 1% .

[0103] In some embodiments, compound (A) obtained is step (a) is less than 1%

[0104] In some embodiments, compound (B) obtained is step (a) is less than 0.3%

[0105] In some embodiments, the compound having the formula (II) is (Ila) wherein R is alkyl.

[0106] In some embodiments, the compound having the formula (Ila) is

[0107] (Ilai) wherein R is methyl.

[0108] In some embodiments, the compound having the formula (I) is (la) wherein R is alkyl.

[0109] In some embodiments, the compound having the formula (la) is (lai) wherein R is methyl .

[0110] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) is carried out in the absence of protecting group.

[0111] In some embodiments, X is a halogen. In some embodiments, the halogen is Cl, Br or I. In some embodiments, the halogen is Cl.

[0112] In some embodiments, X is -OSO2PhR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3. In some embodiments, X is , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2,

[0113] -NO2, -CN or CF3.

[0114] In some embodiments, the compound having formula (III) is a compound having formula (Illb) wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3. In some embodiments, X is -OSO2PhR and R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0115] In some embodiments, R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -N02, -CN or CF3.

[0116] In some embodiments, R is alkyl.

[0117] In some embodiments, the compound having formula (III) is toluenesulfonyl anhydride. In some embodiments, the compound having the formula (III) may include but is not limited to 4-toluenesulf onyl chloride (TsCl) and toluenesulfonyl anhydride.

[0118] In some embodiments, the compound having the formula (III) is 4- toluenesulf onyl chloride (TsCl) . In some embodiments, the compound having the formula (III) is toluenesulfonyl anhydride.

[0119] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at a temperature between (-5)- 85°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-25°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-5°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)- 10 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-0°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between 0-5 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 5-25°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 25- 85 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 15-20°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between 15-25 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 15-30°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, a metal agent and at least one base.

[0120] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 0-30 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 0-25 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 0-20°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 15-30 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents, one base, a metal agent and at a temperature between 15-30°C.

[0121] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 15-25 °C.

[0122] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a polar solvent, at least one base, a metal agent and at a temperature between 15-20 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents, at least one base, a metal agent and at a temperature between 15-20 °C. In some embodiments , the reaction of 5-f luorocytosine with compound having the formula ( III ) is conducted in the presence of at least one polar solvent , at least one base , a metal agent and at a temperature between 15-20 °C .

[0123] In some embodiments , the polar solvent has a dielectric constant equal to or above 5 . In some embodiments , the polar solvent has a dielectric constant equal to or above 10 . In some embodiments , the polar solvent has a dielectric constant equal to or above 15 . In some embodiments , the polar solvent has a dielectric constant equal to or above 20 .

[0124] In some embodiments , wherein R is methyl in the compound having formula ( III ) , the sulfonation step is a tosylation step .

[0125] In the tosylation step, the polar solvent has a dielectric constant equal to or above 20 .

[0126] In some embodiments , the polar solvent having dielectric constant equal to or above 20 may include but is not limited to dimethyl acetamide (DMA) , N-methylpyrolidone (NMP) , acetonitrile (ACN or MeCN) , dimethylsul foxide ( DMSO) , dimethylformamide ( DMF) , water or any combination thereof .

[0127] In some embodiments , the polar solvent is selected from the group consisting of dimethyl acetamide (DMA) , N-methylpyrolidone (NMP ) , acetonitrile (ACN or MeCN) , dimethylsulfoxide ( DMSO) , dimethylformamide (DMF) , dimethylbenzylamine ( DMBA) , water and any combination thereof .

[0128] In some embodiments , the polar solvent is selected from the group consisting of dimethyl acetamide (DMA) , acetonitrile (ACN or MeCN) , dimethylbenzylamine ( DMBA) , water and any combination thereof .

[0129] In some embodiments the combination of polar solvent and base consist of one phase system . In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of one polar solvent.

[0130] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents .

[0131] In some embodiments, the two polar solvents are selected from the group consisting of dimethyl acetamide (DMA) , N-methylpyrolidone (NMP) , acetonitrile (ACN or MeCN) , dimethylsulfoxide (DMSO) , dimethylformamide (DMF) , dimethylbenzylamine (DMBA) , and water.

[0132] In some embodiments, the two polar solvents are selected from the group consisting of dimethyl acetamide (DMA) , acetonitrile (ACN or MeCN) , dimethyl aminopyridine (DMAP) , and water.

[0133] In some embodiments, the two polar solvents are DMA and water.

[0134] In some embodiments, the weight ratio between the two polar solvents is between 10:1 to 1:10.

[0135] In some embodiments, the weight ratio between the two polar solvents is between 2:1 to 1:2.

[0136] In some embodiments, the weight ratio between the two polar solvents is 1:1.

[0137] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of three polar solvents .

[0138] In some embodiments , the three polar solvents are DMA, water and

[0139] DMBA.

[0140] In some embodiments, at least one base is an organic base.

[0141] In some embodiments, at least one base is an inorganic base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of one base .

[0142] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two bases .

[0143] In some embodiments, the base may include but is not limited to K2CO3, Na2CO3, Li2CO3, NaHCO3, KHCO3, NaOH, KOH, Et3N, dimethyl aminopyridine (DMAP) , dimethylbenzylamine (DMBA) or any combination thereof.

[0144] In some embodiments, the base is selected from a group consisting of K2CO3, Na2CO3, Li2CO3, NaHCOs, KHCO3, Et2N, dimethyl aminopyridine (DMAP) and any combination thereof.

[0145] In some embodiments, the base is selected from the group consisting of K2CO2, Na2CO2, NaOH, KOH, Et2N, dimethyl aminopyridine (DMAP) , and any combination thereof.

[0146] In some embodiments, the base is K2CO3. In some embodiments, the base is Na2CO3. In some embodiments, the base is NaOH. In some embodiments, the base is KOH. In some embodiments, the base is Et2N. In some embodiments, the base is DMAP.

[0147] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, a metal agent and at least one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, calcium chloride dihydrate and NaOH.

[0148] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and at least one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and one NaOH. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, calcium chloride dihydrate and one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, calcium chloride dihydrate and NaOH.

[0149] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and two bases.

[0150] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, a metal agent and two bases.

[0151] In some embodiments, the metal agent is calcium chloride dihydrate.

[0152] In some embodiments, the two bases are Et3N and DMAP .

[0153] In some embodiments, the two bases are NaOH and DMAP.

[0154] In some embodiments, the two bases are dimethylbenzylamine and NaOH.

[0155] In some embodiments, the two bases are DMAP and Na2CO3.

[0156] In some embodiments, the two bases are DMAP and KOH.

[0157] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMA, water, calcium chloride dihydrate and K2CO3. In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMA, calcium chloride dihydrate and Et3N.

[0158] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of acetonitrile (ACN or MeCN) , calcium chloride dihydrate and triethylamine (Et3N) .

[0159] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMA, water , calcium chloride dihydrate and DMAP.

[0160] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMA, calcium chloride dihydrate and Na2CO3.

[0161] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, calcium chloride dihydrate and Na2CO3.

[0162] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of water , calcium chloride dihydrate and DMAP.

[0163] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, DMA, water , calcium chloride dihydrate and KOH.

[0164] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, DMA, water , calcium chloride dihydrate and NaOH.

[0165] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of a DMA, Et3N, calcium chloride dihydrate and DMAP . In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of a DMA, water , calcium chloride dihydrate , NaOH and DMAP .

[0166] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMAP , calcium chloride dihydrate and Na2CO3.

[0167] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, calcium chloride dihydrate and KOH.

[0168] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, calcium chloride dihydrate and NaOH.

[0169] In some embodiments , the polar solvent has a dielectric constant equal to or above 20 is DMA, and the base is Et3N.

[0170] In some embodiment , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , and the base is K2CO3.

[0171] In some embodiment , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , and the base is NaOH.

[0172] In some embodiments , the polar solvent has a dielectric constant equal to or above 20 is water , the base is Et3N and the temperature is 15-20 °C .

[0173] In some embodiment , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , and the base is NaOH.

[0174] In some embodiments , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , the base is NaOH and the temperature is 15-20 °C . In some embodiments, the temperature is 15-20 °C, and the solvent is acetonitrile.

[0175] In another preferred embodiment, the temperature is 15-20 °C, the solvent is acetonitrile, and the base is Et3N.

[0176] In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5- f luorocytosine and the compound having formula (III) is between 1:10 to 10:1. In some embodiments, in the reaction of 5- f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:2 to 2:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is about 1:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is about 1:1.1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is 1:1.2.

[0177] In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5- f luorocytosine and the base is between 1:10 to 10:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is between 1:2 to 2:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5- f luorocytosine and the base is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is about 1:1. In some embodiments, in the reaction of 5- f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is 1:1.2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is 1:1.3.

[0178] In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:10 to 10:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:2 to 2:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is about 1:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is 1:1.2.

[0179] In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent varies between 5:1 to 1.8:1, respectively. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is between 5:1 and 2:1. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is between 5:1 and 3:1. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is between 4:1 and 2:1. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is about 3.3:1.

[0180] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield of at least 60%.

[0181] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield higher than 60%, 70%, 80%, 90%, 95% or 99%. In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield higher than 90%.

[0182] In some embodiments, the purity of the compound of Formula (II) in the reaction of 5-f luorocytosine with the compound having formula (III) is higher than 60%, 70%, 80%, 90% or 99%. In some embodiments, the purity of the compound of Formula (II) in the reaction of 5- f luorocytosine with the compound having formula (III) is higher than 95% .

[0183] In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 20% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 10% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 5% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 3% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 2% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 1% based on the conversion.

[0184] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain compound having the formula (II) further comprises a step of isolating the compound having formula (II) from the reaction mixture.

[0185] In some embodiments, isolation of the compound having formula (II) comprises (i) precipitation by adding a protic solvent to the reaction mixture, and (ii) filtration.

[0186] In some embodiments, the protic solvent is water, methanol or a combination thereof.

[0187] The present invention also provides a compound having formula (II) prepared using the process described herein.

[0188] The present invention also provides a compound having formula (Ilai) prepared using the process described herein.

[0189] The compound having formula (II) may be alkylated to prepare the compound having formula (I) using the alkylation step described herein below.

[0190] The compound having formula (II) may also be alkylated to prepare the compound having formula (I) using any suitable alkylation process known in the art including, but not limited to, the process described in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, 2021 / 181274, and WO / 2023 / 042126 the entire content of each of which is hereby incorporated by reference . In some embodiments, the compound having formula (lai) is prepared by contacting a compound having formula (Ilai) with an alkali carbonate and an alkylating agent and forming a compound having formula (lai ) .

[0191] In some embodiments, the contacting step is carried out between 22°C and 60°C. In some embodiments, the contacting step is carried out between 22 °C and 40 °C.

[0192] In some embodiments, the contacting step further includes a solvent selected from the group consisting of DMF, DMSO, DMA, NMP, and CH3CN, and any combination thereof.

[0193] In some embodiments, the alkali carbonate is selected from the group consisting of Na2CO3, K2CO3, CS2CO3, Li2CO3, and any combination thereof .

[0194] In some embodiments, the alkylating agent is selected from the group consisting of alkyl halides and benzyl halides. In some embodiments, the alkyl halide and benzyl halide are selected from the group consisting of methyl iodide (CH3I) , ethyl iodide (C2H5I) , benzyl bromide (BnBr) , and any combination thereof.

[0195] In some embodiments, the alkali carbonate base is CS2CO3, and the solvent is DMF.

[0196] In some embodiments, a molar ratio of the compound having formula (Ilai) to alkali carbonate base is from about 3:1 to about 1:1. In some embodiments, the molar ratio of the compound having formula (Ilai) to alkali carbonate base is about 2:1.

[0197] In some embodiments, the molar ratio between the compound having formula (Ilai) to alkylating agent is from about 1:1 to about 1:3. In some embodiments, the molar ratio between the compound having formula (Ilai) to alkylating agent is 1:3. In some embodiments, a molar ratio of the compound having formula (Ilai) to alkali carbonate base is from about 3:1 to about 1:1 and the molar ratio between the compound having formula (Ilai) to alkylating agent is from about 1:1 to about 1:3. In some embodiments, the molar ratio of the compound having formula (Ilai) to alkali carbonate base is about 2:1 and the molar ratio of the compound having formula (Ilai) to alkylating agent is 1:3.

[0198] In some embodiments, the process further includes the step of diluting a completed reaction mixture with CH3CN and 2.5% aqueous Na2S2O3. In some embodiments, the ratio of DMF to CH3CN is from about 1:1 to about 3:1 and the ratio of DMF to 2.5% aqueous Na2S2O3is from about 1:2 to about 2:1. In some embodiments, the ratio of DMF to CH3CN is about 2:1 and the ratio of DMF to 2.5% aqueous Na2S2O3is about 1:1.

[0199] In some embodiments, the compound having formula (lai) is prepared by contacting a compound having formula (Ilai) with a base, such as an alkali carbonate, e.g., sodium-, potassium-, cesium-, and lithium carbonate (Na2CO3, K2CO3, CS2CO3, and Li2CO3, respectively) and an alkylating agent, such as an alkyl halide of formula CH3-X, wherein X is a halogen, e.g., iodine, bromine, and chlorine, in a polar solvent, such as N, N-dimethylf ormamide (DMF) , dimethylsulfoxide (DMSO) , dimethylacetamide (DMA) , N- methylpyrrolidone (NMP) , acetonitrile (CH3CN) , and the like, at concentrations from about 0.1 molar (M) to about 3 M. In some embodiments, the reactions are conducted at temperatures between - 78°C and 90°C. In some embodiments, the reactions are conducted between 22°C and 60°C.

[0200] Step (b) - reacting the compound having formula (II) with dimethyl sulphate (DMS)

[0201] In some embodiments, the reaction of the compound having formula

[0202] (II) with DMS is conducted in the absence of base. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of at least one base.

[0203] In some embodiments, the base is selected from the group consisting of DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof.

[0204] In some embodiments, the base is selected from the group consisting of TBAB, NaOH, Na2CO3, Et3N, NaOMe, and any combination thereof.

[0205] In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 20-85°C. In some embodiments, the temperature is between 20-50°C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 35-50 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 15-30 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 15-25 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 20-25 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 10 and below 25 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at 20 °C.

[0206] In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:10. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:4. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:2.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:3. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:3.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is 1:3. In some embodiments, the molar ratio between the compound having formula (II) and DMS is 1:2.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is 1:2.

[0207] In some embodiments, the molar ratio between the compound having formula (II) and the base is 1:0.1 to 1:10. In some embodiments, the molar ratio between the compound having formula (II) and the base is 1:0.1 to 1:5.5.

[0208] In some embodiments, the base is added after 4 hours from the beginning of the reaction of compound (II) with DMS . Suitable bases include carbonates.

[0209] In some embodiments, the base is added after 4 hours from the beginning of the reaction of the compound having formula (II) with DMS and the temperature of the reaction is above 30 degrees Celsius.

[0210] In some embodiments, the base is added at the beginning of the reaction. Suitable bases include DABCO, NEt3, LiCO3, and KHCO3.

[0211] When the base is added at the beginning of the reaction of the compound having formula (II) with DMS, the temperature is preferably above 30 degrees Celsius.

[0212] In some embodiments, the compound having formula (I) reacts with DMS in the presence of a base having a pKa equal to or less than the pKa of the compound having formula (I) .

[0213] In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of at least one solvent. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of two solvents.

[0214] In some embodiments, the solvent is a polar solvent. In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0215] In some embodiments, the solvent is selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof. In some embodiments, the solvent in NMP.

[0216] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0217] In some embodiments, the solvent is MeTHF and the base is NEts .

[0218] In some embodiments, the solvent is a mixture of at least two solvents .

[0219] In some embodiments, the solvent is a mixture of DMA and Anisole.

[0220] In some embodiments, the solvent is a mixture of NMP and Anisole.

[0221] In some embodiments, the solvent is a mixture of DMA and CPME.

[0222] In some embodiments, the weight ratio between DMA and CPME is between 1:1 to 1:10. In some embodiments, the weight ratio between DMA and CPME is between 1:1 to 1:4. In some embodiments, the weight ratio between DMA and CPME is between 1:2 to 1:4. In some embodiments, the weight ratio between DMA and CPME is between 1:3 to 1:5. In some embodiments, the weight ratio between DMA and CPME is about 1:4.

[0223] In some embodiments, the solvent is a mixture of DMA and MeTHF.

[0224] In some embodiments, the solvent is a mixture of DMA and MeTHF in a weight ratio of 1:1 to 1:4. In some embodiments, the solvent is a mixture of DMA and MeTHF in a weight ratio of 1:2 to 1:4. In some embodiments, the alkylation process is conducted in the presence of a mixture of DMA and CPME in a weight ratio of 1:2 to 1:4. In some embodiments, the alkylation process is conducted in the presence of a mixture of DMA and CPME in a weight ratio of 1:4.

[0225] In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 30:1 and 1:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 20:1 and 5:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 15:1 and 10:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 14:1 to 12:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is about 13:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is 12.7:1.

[0226] In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is between 10:1 to 1:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is between 5:1 to 3:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is about 4:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is 3.9:1.

[0227] In some embodiments, the reaction of the compound having formula (II) with DMS further comprises neutralizing with an aqueous basic solution .

[0228] In some embodiments, the excess DMS is neutralized with an aqueous basic solution.

[0229] In some embodiments, the weight ratio of the DMA: CPME : compound having the formula (II) is 1.5:0:1 to 1:5:1.

[0230] In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 60%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 70%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 80%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 90%.

[0231] The compound having formula (II) may be prepared using the sulfonation process described herein.

[0232] In some embodiments, step (b) is conducted in the presence of at least one water-immiscible solvent.

[0233] In some embodiments, at least one water-immiscible solvent is mixed with the reaction mixture after step (b) .

[0234] In some embodiments, step (b) is conducted in the presence of at least one water-immiscible solvent and at least one water- immiscible solvent is mixed with the reaction mixture after step (b) . In some embodiments, the water immiscible solvent is mixed with the reaction mixture after step (b) and before step (c) .

[0235] In some embodiments, the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature .

[0236] An example of a water immiscible solvent having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature is anisole. Additional water immiscible solvents having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature may be identified through routine experimentation .

[0237] In some embodiments, the water immiscible solvent has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 200 mg / mL at room temperature. In some embodiments, the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 150 mg / mL at room temperature. In some embodiments, the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 100 mg / mL at room temperature.

[0238] In some embodiments, a mixture of two or more water immiscible solvents are mixed with the reaction mixture after step (b) . In some embodiments, a mixture of two water immiscible solvents is mixed with the reaction mixture after step (b) . In some embodiments, a mixture of three water immiscible solvents is mixed with the reaction mixture after step (b) . In some embodiments, a mixture of four water immiscible solvents is mixed with the reaction mixture after step (b) .

[0239] In some embodiments, the mixture of water immiscible solvents has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 200 mg / mL at room temperature. In some embodiments, the mixture of water immiscible solvents has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 150 mg / mL at room temperature. In some embodiments, the mixture of water immiscible solvents has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 100 mg / mL at room temperature.

[0240] In some embodiments, the water immiscible solvent or one of the water immiscible solvents is anisole.

[0241] In some embodiments, anisole is mixed with the reaction mixture after step (b) . In some embodiments, anisole is only mixed with the reaction mixture after step (b) .

[0242] In some embodiments, at the end of step (b) , a multi-phase system is obtained.

[0243] In some embodiment, step (b) is conducted in the presence of a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[0244] In some embodiments, step (b) is conducted in the presence of at least one water-immiscible solvent.

[0245] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THF, anisole, toluene, and any mixture thereof.

[0246] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0247] In some embodiments, step (b) is conducted in the presence of a solvent in addition to the water immiscible solvent.

[0248] In some embodiments, step (b) is conducted in the presence of a solvent and without a water immiscible solvent.

[0249] In some embodiments, the solvent is DMA. In some embodiments, step (b) is conducted in the presence of a mixture of solvents wherein at least one solvent is water immiscible and at least one solvent is water miscible.

[0250] In some embodiments, the mixture of solvents is a mixture of a polar water miscible solvent and a non-polar water-immiscible solvent .

[0251] In some embodiments, the mixture of solvents is DMA and anisole. In some embodiments, the weight ratio between DMA and anisole is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between anisole and the compound having formula (II) is from about 10:1 to about 1:1.

[0252] In some embodiments, the mixture of solvents is a mixture of DMA and toluene. In some embodiments, the weight ratio between DMA and toluene is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between toluene and the compound having formula (II) is from about 10:1 to about 1:1.

[0253] Step (c) - isolating the compound having formula (I)

[0254] In some embodiments, the process forms a multi-phase system. In some embodiments, in step (c) , a multi-phase system is obtained.

[0255] In some embodiments, the multi-phase system comprises an organic phase and a water phase. In some embodiments, the multi-phase system is a slurry mixture comprising solids. The type of multiphase system formed depends on the volume of the water-immiscible solvent and / or the temperature. In some embodiments, wherein the multi-phase system comprises an organic phase and a water phase, the organic phase comprises the water-immiscible solvent. In some embodiments, wherein the multiphase system comprises an organic phase and a water phase, the process comprises heating the multi-phase system for dissolution of the compound having formula (I) in the organic phase. In some embodiments, the process comprises heating the multi-phase system up to 80°C for dissolution of the compound having formula (I) in the organic phase.

[0256] In some embodiments, wherein the multi-phase system comprises an organic phase and a water phase, the process for isolating the compound having formula (I) from the reaction mixture comprises separating the organic phase from the water phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals.

[0257] For example, the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 2.

[0258] In some embodiments, wherein the reaction mixture comprises the compound having formula (I) , DMS and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0259] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0260] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the reaction mixture and filtering the crystallized solid, or

[0261] (1) reacting 5-f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (3) isolating the compound having formula (I) from the reaction mixture by (i) adding at least one water immiscible solvent and an aqueous basic solution to the reaction mixture to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.

[0262] In some embodiments, the aqueous basic solution comprises DABCO,

[0263] TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0264] In some embodiments, the concentration of the base in the aqueous basic solution is 2-20% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) .

[0265] In some embodiments, the isolation step further comprises the addition of an acid.

[0266] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0267] In some embodiments, the acid is added to obtain a pH between 7.8- 8.5.

[0268] In some embodiments, wherein the reaction mixture comprises the compound having formula (I) , DMS and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution and an acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0269] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the organic phase and filtering the crystals .

[0270] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the reaction mixture and filtering the crystallized solid, or

[0271] (1) reacting 5-f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (3) isolating the compound having formula (I) from the reaction mixture by (i) adding at least one water immiscible solvent, an aqueous basic solution and an acid to the reaction mixture to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.

[0272] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0273] In some embodiments, the acid is HC1.

[0274] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0275] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0276] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0277] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0278] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0279] In some embodiments, the compound having the formula (I) is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution. In some embodiments, the compound having the formula (I) in salt form is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution.

[0280] In some embodiments, the water immiscible solvent is polar. In some embodiments, the water immiscible solvent is non-polar. In some embodiments, the water immiscible solvent is an organic polar solvent . In some embodiments, the water immiscible solvent includes but not limited to cyclopentylmethylether (CPME) , methyl tetrahydrofuran (MeTHF) , DCM, toluene, anisole or any combination thereof. In some embodiments, the water immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene, anisole, and any combination thereof.

[0281] In some embodiments, the water immiscible solvent is selected from the group consisting of MeTHF, CPME, toluene, anisole, and any mixture thereof.

[0282] In some embodiments, the water immiscible solvent is CPME. In some embodiments, the water immiscible solvent is MeTHF. In some embodiments, the water immiscible solvent is DCM. In some embodiments, the water immiscible solvent is toluene. In some embodiments, the water immiscible solvent is anisole.

[0283] In some embodiments, the compound having the formula (I) is crystallized from the organic phase by concentrating the organic phase. In some embodiments, the compound having the formula (I) is crystallized from the organic phase by adding an -solvent. In some embodiments, the compound having the formula (I) is crystallized from the organic phase by seeding.

[0284] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane anti-solvent is cyclic. In some embodiments, the anti-solvent is cyclohexane. In some embodiments, the anti-solvent is methylcyclohexane .

[0285] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0286] In some embodiments, the process for isolating the compound having formula (I) comprises (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[0287] In some embodiments, the process for isolating the compound having formula (I) comprises (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution and an acid, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid .

[0288] In some embodiments, the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid .

[0289] In some embodiments, the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution followed by the addition of an acid, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[0290] In some embodiments, the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution, (3) separating the organic phase from the water phase, and (4) crystallizing the compound from the organic phase by adding an anti-solvent .

[0291] In some embodiments, the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution followed by the addition of an acid, (3) separating the organic phase from the water phase, and (4) crystallizing the compound from the organic phase by adding an anti-solvent.

[0292] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0293] In some embodiments, the acid is HC1.

[0294] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0295] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0296] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0297] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1. I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0298] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0299] In some embodiments, the organic polar solvent is an organic polar water immiscible solvent.

[0300] In some embodiments, the organic water immiscible solvent has a dielectric constant less than 20.

[0301] In some embodiments, organic water immiscible solvent includes but is not limited to methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , and a mixture thereof.

[0302] In some embodiments, the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof.

[0303] In some embodiments, the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM and any combination thereof .

[0304] In some embodiments, the organic polar solvent is DMA. In some embodiments, the organic polar solvent is CPME. In some embodiments, the organic polar solvent is MeTHF.

[0305] In some embodiments, the organic polar solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, the CPME is added after the reaction to obtain the compound having the formula (I) . In some embodiments, a partial amount of the organic polar solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the organic polar solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the CPME is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of CPME is added before isolation of the compound having formula (I) .

[0306] In some embodiments, the compound having the formula (I) in the mixture before the isolation step is in salt form.

[0307] In some embodiments, the non-polar solvent is a non-polar water immiscible solvent.

[0308] In some embodiments, a non-polar water immiscible solvent dissolves the compound of formula (I) .

[0309] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.

[0310] In some embodiments, the non-polar solvent is anisole. In some embodiments, the non-polar solvent is toluene.

[0311] In some embodiments, an anti-solvent is further added.

[0312] In some embodiments, the anti-solvent is added parallel to the to the water immiscible solvent.

[0313] In some embodiments, the anti-solvent is added dropwise.

[0314] In some embodiments, the crystallization is conducted at temperature between 0°C and 10 °C.

[0315] In some embodiments, the crystallization is conducted at temperature less than 0°C. In some embodiments, the crystallization is conducted at 10°C.

[0316] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[0317] In some embodiments, the mixture of solvent and anti-solvent are anisole and hexane.

[0318] In some embodiments, the mixture of solvent and anti-solvent is toluene and hexane .

[0319] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof.

[0320] In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0321] In some embodiments, the organic phase is cooled prior to and / or during the filtration. In some embodiments, the organic phase is cooled to 0-10 °C. In some embodiments, the organic phase is cooled to 0-5 °C. In some embodiments, the organic phase is cooled to 0°C. In some embodiments, the organic phase is cooled to 5 °C. In some embodiments, the organic phase is cooled to 10 °C.

[0322] In some embodiments, the crystallization is done by concentration of the solvent.

[0323] In some embodiments, the crystallization is done with crystal seeding . In some embodiments, the mixture is seeded with 0.1-1% of the compound of formula (I) .

[0324] In some embodiments, the water immiscible solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, anisole and hexane are added after the reaction to obtain the compound having the formula (I) .

[0325] In some embodiments, a partial amount of the water immiscible solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the water immiscible solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the anisole is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of anisole optionally with hexane are added before isolation of the compound having formula (I) •

[0326] In some embodiments, the process for isolating the compound having formula (I) comprises contacting the mixture comprising the compound having formula (I) with a water-immiscible solvent or a mixture of solvents comprising at least one water immiscible solvent and water, separating the organic phase, crystalizing the compound having the formula (I) , and filtering the crystals.

[0327] In some embodiments, wherein the multi-phase system is a slurry comprising solids, the process for isolating the compound having formula (I) form the reaction mixture comprises filtering the precipitated solids.

[0328] For example, the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 3.

[0329] In some embodiments, step (b) is conducted in the presence of at least one water-immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids .

[0330] In some embodiments, the water immiscible solvent is added after step (b) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0331] In some embodiments, step (b) is conducted in the presence of at least one additional solvent.

[0332] In some embodiments, wherein (I) step (b) is conducted in the presence of at least one additional solvent, (II) step (b) is conducted in the presence of at least one water-immiscible solvent and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0333] In some embodiments, wherein (I) step (b) is conducted in the presence of at least one additional solvent, (II) the water immiscible solvent is added after step (b) , and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids. In some embodiments, wherein (I) at least one additional solvent is added after step (b) , (II) step (b) is conducted in the presence of at least one water-immiscible solvent and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0334] In some embodiments, wherein (I) at least one additional solvent is added after step (b) , (II) the water immiscible solvent is added after step (b) , and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids .

[0335] In some embodiments, step (c) is conducted in the presence of at least one additional solvent.

[0336] In some embodiments, wherein step (b) is conducted in the presence of at least one water immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0337] In some embodiments, wherein the water immiscible solvent is added after step (b) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0338] In some embodiments, the isolation step further comprises the addition of an acid.

[0339] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0340] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0341] In some embodiments, the acid is HC1.

[0342] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0343] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0344] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0345] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0346] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0347] In some embodiments, step (b) is conducted in the presence of at least one water-immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0348] In some embodiments, the water immiscible solvent is added after step (b) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0349] In some embodiments, step (b) is conducted in the presence of at least one additional solvent.

[0350] In some embodiments, wherein (I) step (b) is conducted in the presence of at least one additional solvent, (II) step (b) is conducted in the presence of at least one water-immiscible solvent and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0351] In some embodiments, wherein (I) step (b) is conducted in the presence of at least one additional solvent, (II) the water immiscible solvent is added after step (b) , and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids. In some embodiments, wherein (I) at least one additional solvent is added after step (b) , (II) step (b) is conducted in the presence of at least one water-immiscible solvent and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0352] In some embodiments, wherein (I) at least one additional solvent is added after step (b) , (II) the water immiscible solvent is added after step (b) , and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0353] In some embodiments, step (c) is conducted in the presence of at least one additional solvent.

[0354] In some embodiments, wherein step (b) is conducted in the presence of at least one water immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0355] In some embodiments, wherein the water immiscible solvent is added after step (b) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (c) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0356] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0357] In some embodiments, the acid is HC1.

[0358] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0359] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0360] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0361] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0362] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0363] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids.

[0364] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2)preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .

[0365] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0366] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (3) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .

[0367] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0368] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) .

[0369] In some embodiments, the isolation step further comprises the addition of an acid.

[0370] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0371] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0372] In some embodiments, the acid is HC1.

[0373] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water. In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0374] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0375] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0376] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0377] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids .

[0378] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2)preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0379] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .

[0380] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (3) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution and an acid, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0381] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0382] In some embodiments, the acid is HC1. In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0383] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0384] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0385] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0386] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0387] In some embodiments, the mixture comprises a solvent. In some embodiments, the slurry mixture comprises a solvent.

[0388] The mixture comprising the compound having formula (I) may comprise DMS and any or all solvents used during the process for preparing the compound having formula (I) .

[0389] The additional solvent is a solvent used to isolate or assist in the isolation of the compound having formula (I) . The additional solvent may be added directly to the mixture. The additional solvent may also be added with the aqueous basic solution.

[0390] In some embodiments, the additional solvent is the same as the solvent (s) used during the process for preparing the compound having formula (I) .

[0391] In some embodiments, the additional solvent is different from the solvent (s) used during the process for preparing the compound having formula (I) . In some embodiments, the additional solvent is a polar solvent.

[0392] In some embodiments, the additional solvent is a water immiscible solvent. In some embodiments, the polar solvent has a dielectric constant equal to or above 4. In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.

[0393] In some embodiments, the ratio between the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is about 1:1.

[0394] In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.

[0395] In some embodiments, the additional solvent is a polar solvent, and the polar solvent is CPME .

[0396] In some embodiments, the solvent used during the process for preparing the compound having formula (I) is DMA and the additional solvent is CPME.

[0397] In some embodiments, the ratio between CPME to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (I) is about 1:1.

[0398] In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.

[0399] In some embodiments, the slurry mixture is mixed for 30 minutes to 8 hours. In some embodiments, the slurry mixture is mixed for 30 minutes. In some embodiments, the slurry mixture is mixed for 1, 2, 3, 4, 5, 6, 7 or 8 hours.

[0400] In some embodiments, the slurry mixture is mixed at temperature between 25 to 90 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 80 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 60 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 50 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 35 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 30 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 60 degrees Celsius.

[0401] In some embodiments, the slurry mixture is heated to reach the desired temperature for 30 minutes to 3 hours. In some embodiments, the slurry mixture is heated to reach the desired temperature for 30 minutes. In some embodiments, the slurry mixture is heated to reach the desired temperature for 1, 2 or 3 hours. In some embodiments, the reactor volume is IL to 500L. In some embodiments, the reactor volume is 10L to 500L. In some embodiments, the reactor volume is 25L to 500L. In some embodiments, the reactor volume is 50L to 500L. In some embodiments, the reactor volume is 100L to 500L. In some embodiments, the reactor volume is IL, 10L, 25L, 50L, 100L, 250L or 500L.

[0402] In some embodiments, the slurry mixture is mixed using mechanical stirrer .

[0403] In some embodiments, the slurry mixture is mixed using high shear stirrer .

[0404] In some embodiments, the slurry mixture is mixed using both mechanical stirrer and high shear stirrer.

[0405] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 2-18% of aqueous basic solution.

[0406] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 11-18% of aqueous basic solution.

[0407] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution.

[0408] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 18% of aqueous basic solution.

[0409] In some embodiments, the slurry mixture obtained by adding the 2- 18% aqueous basic solution into a mixture comprising the compound having formula (I) , DMS and optionally an organic solvent.

[0410] In some embodiments, the slurry further comprises an acid. In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0411] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution.

[0412] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 18% of aqueous basic solution.

[0413] In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 10 to 45 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 10 to 20 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 20 to 25 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 25 to 30 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 30 to 35 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 35 to 40 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 40 to 45 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature of 10 degrees Celsius.

[0414] In some embodiments, the filtered solid obtained in step (c) is washed with an organic solvent during filtration in step (c) . In some embodiments, the organic solvent is CPME.

[0415] In some embodiments, the filtered solid obtained in step (c) is washed with water during filtration in step (c) .

[0416] In some embodiments, the filtered solid is mixed with water and stirred for 1 to 3 hours and filtered. In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 25-50 degrees Celsius and filtered. In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 10-50 degrees Celsius and filtered. In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 10 degrees Celsius and filtered.

[0417] In some embodiments, the organic solvent is the same organic solvent as used in obtaining the compound having formula (I) .

[0418] In some embodiments, the aqueous basic solution is 15% of K2CO3in water based on the total weight (w / w) of K2CO3in water. In some embodiments, the aqueous basic solution is 18% of K2CO3in water based on the total weight (w / w) of K2CO3in water.

[0419] In some embodiments, the organic phase is the solution which is obtained in the reaction of compound having the formula (II) with DMS.

[0420] In some embodiments, the organic phase is obtained by adding an organic water immiscible solvent to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0421] In some embodiments, the organic phase is obtained by adding anisole to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0422] In some embodiments, the organic phase is obtained by adding anisole to the mixture of the compound having formula (I) , DMS and DMA obtained in the reaction of compound (II) and DMS.

[0423] In some embodiments, the step of adding an aqueous basic solution comprises additional use of a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB) . In some embodiments, a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) in weight ratio of 10:1 prior to washing with 2-18% w / w of aqueous basic solution.

[0424] In some embodiments, the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to 65 °C prior to washing with 2-18% w / w of aqueous basic solution.

[0425] In some embodiments, the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to about 50 °C prior to washing with 2-18% w / w of aqueous basic solution. In some embodiments, the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved in CPME.

[0426] In some embodiments, the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved with CPME and washed with water base solution.

[0427] In some embodiment the resultant mixture is a mixture of the compound having formula (I) with the solvent which was used in the reaction of the compound having formula (II) with DMS.

[0428] In some embodiments, the conversion of the 5-f luoro-4-imino-l- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one to 5-fluoro- 4 -imino- 3 -methyl -1- (toluene -4 -sulf onyl ) -3 , 4 -dihydro -IH-pyrimi di n- 2-one is higher than 50%.

[0429] In some embodiments, the chemical yield of 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one is higher than 50%. In some embodiments, the yield of the purified 5- f luoro-4-imino-3-methyl-l- (toluene-4-sulfonyl) -3, 4-dihydro-1H- pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%. In some embodiments, the conversion of the 5-f luoro-4-imino-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H- pyrimidin-2-one to 5-f luoro-4-imino-3-methyl-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 50%.

[0430] In some embodiments, the chemical yield of 5-f luoro-4-imino-3- methyl-1- (optionally substituted phenyl-4-sulf onyl ) -3, 4-dihydro- 1H-pyrimidin-2-one is higher than 50%. In some embodiments, the yield of the purified 5-f luoro-4-imino-3-methyl-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%.

[0431] In some embodiments, substituted phenyl means phenyl that is substituted with R which is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0432] In some embodiments, the mixture comprises the compound having formula (I) , at least one water immiscible solvent, and at least one additional solvent, and the process for isolating the compound having formula (I) comprises (i) washing the mixture with water to obtain slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0433] In some embodiments, the multi-phase system comprises a liquid and solids. In some embodiments, wherein the multi-phase system comprises a liquid and solids, the process for isolating the compound having formula (I) from the reaction mixture comprises filtering the solids.

[0434] For example, the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 1. In some embodiments, the mixture comprises the compound having formula (I) and DMS, and the process for isolating the compound having formula (I) from the reaction mixture comprises (1) adding at least one water immiscible solvent and an aqueous basic solution to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids.

[0435] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0436] In some embodiments, the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is non-polar.

[0437] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0438] In some embodiments, the polar solvent is an organic polar solvent.

[0439] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[0440] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof.

[0441] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0442] In some embodiments, the process comprises evaporation of the polar solvent prior to filtration. In some embodiments, the process comprises partial evaporation of the polar solvent prior to filtration . In some embodiments , the process comprises cooling the reaction mixture prior to filtration .

[0443] In some embodiments , step (b ) is conducted in the presence of at least one water-immiscible solvent .

[0444] In some embodiments , the water immiscible solvent is added after step (b) and before addition of the aqueous basic solution to the reaction mixture .

[0445] In some embodiments , the water immiscible solvent is added at the same time as addition of the aqueous basic solution to the reaction mixture .

[0446] In some embodiments , the water immiscible solvent is added after addition of the aqueous basic solution to the reaction mixture . In some embodiments , the water immiscible solvent is added immediately after addition of the aqueous basic solution to the reaction mixture .

[0447] In some embodiments , the water immiscible solvent is an ether-based solvent, an aromatic solvent , or a mixture thereof .

[0448] In some embodiments , the water immiscible solvent is CPME , THE, anisole , toluene , or any mixture thereof .

[0449] In some embodiments , the water-immiscible solvent is toluene , anisole , or a combination thereof .

[0450] In some embodiments , the water immiscible solvent and the aqueous basic solution are added sequentially .

[0451] In some embodiments , the water immiscible solvent is added gradually .

[0452] In some embodiments , the aqueous basic solution is added gradually . In some embodiment, step (b) is conducted in the presence of a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[0453] In some embodiments, step (b) is conducted in the presence of at least one water-immiscible solvent.

[0454] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.

[0455] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0456] In some embodiments, step (b) is conducted in the presence of a solvent in addition to the water immiscible solvent.

[0457] In some embodiments, step (b) is conducted in the presence of a solvent and without a water immiscible solvent.

[0458] In some embodiments, the solvent is DMA.

[0459] In some embodiments, step (b) is conducted in the presence of a mixture of solvents wherein at least one solvent is water immiscible and at least one solvent is water miscible.

[0460] In some embodiments, the mixture of solvents is a mixture of a polar water miscible solvent and a non-polar water-immiscible solvent .

[0461] In some embodiments, the mixture of solvents is DMA and anisole. In some embodiments, the weight ratio between DMA and anisole is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between anisole and the compound having formula (II) is from about 10:1 to about 1:1. In some embodiments, the mixture of solvents is a mixture of DMA and toluene. In some embodiments, the weight ratio between DMA and toluene is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between toluene and the compound having formula (II) is from about 10:1 to about 1:1.

[0462] In some embodiments, the compound having formula (I) reacts with DMS in the presence of a base having a pKa equal to or less than the pKa of the compound having formula (I) .

[0463] During the reaction and before water in any form, such as in the form of an aqueous basic solution, is added to the reaction mixture, the compound having formula (I) may be in salt form. In some embodiments, the compound having formula (I) is in salt form. In some embodiments, the compound having the formula (I) is in salt form during the reaction. In some embodiments, the compound having formula (I) is partially in salt form. In some embodiments, the compound having formula (I) is partially in salt form during the reaction. In some embodiments, the salt of the compound having formula (I) is a monomethylsulfate salt of the compound having formula ( I ) .

[0464] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystalized solid.

[0465] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to form an organic phase and a water phase.

[0466] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.

[0467] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to form an organic phase and a water phase.

[0468] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (3) isolating the compound having formula (I) from the reaction mixture by (i) adding at least one water immiscible solvent and an aqueous basic solution to the reaction mixture to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid. In some embodiments, the aqueous basic solution is a 2-18% w / w aqueous basic solution.

[0469] In some embodiments, the compound having the formula (I) is crystalized by concentrating the organic phase, adding an antisolvent, and / or seeding.

[0470] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids.

[0471] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.

[0472] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution to obtain a slurry mixture precipitated solids, and (ii) filtering the precipitated solids . In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.

[0473] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (3) adding at least one water immiscible solvent to the reaction mixture, and (4) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0474] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.

[0475] In some embodiments, the process comprises (1) reacting 5- f luorocytosine with compound having formula (III) in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II) , (2) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (3) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .

[0476] In some embodiments, the aqueous basic solution is a 2-18% w / w aqueous basic solution. In some embodiments, the aqueous basic solution is an aqueous solution comprising DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCOs, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0477] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) .

[0478] In some embodiments, the isolation step further comprises the addition of an acid.

[0479] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0480] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0481] In some embodiments, the acid is HC1.

[0482] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0483] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0484] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water. In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0485] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0486] In some embodiments, the additional solvent is different from the water immiscible solvent.

[0487] In some embodiments, the additional solvent is a polar solvent.

[0488] In some embodiments, the polar solvent has a dielectric constant equal to or above 5.

[0489] In some embodiments, the ratio between the additional solvent to the compound having formula (I) or formula (II) is about 1:1.

[0490] In some embodiments, the additional solvent is CPME.

[0491] In some embodiments, the slurry mixture is mixed at a temperature between 25 to 50 degrees Celsius.

[0492] In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 10 to 45 degrees Celsius.

[0493] In some embodiments, the water immiscible solvent is polar.

[0494] In some embodiments, the water immiscible solvent is non-polar.

[0495] The present invention provides a monomethylsulfate salt of the compound having formula (I) .

[0496] The present invention also provides a compound having formula (I) obtained using any one of the processes described herein. The present invention also provides a compound having formula (Tai) obtained using any one of the processes described herein.

[0497] Methods for isolating a compound having formula (I) from a mixture thereof, including routes 1-3, are described below.

[0498] The methods for isolating a compound having formula (I) may be applied to any mixture comprising the compound having formula (I) , including the reaction mixtures of the processes described herein for preparing the compound having formula (I) and the reaction mixtures of the processes described in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, and WO / 2021 / 181274 for preparing the compound having formula (I) .

[0499] The mixture, including reaction mixture resulting from the alkylation step of the process for preparing the compound having formula (I) , may comprise a non-salt form of the compound having the formula (I) , a salt form of the compound having the formula (I) , or a mixture thereof.

[0500] In some embodiments, the step after reacting compound having formula (II) with DMS to give the salt and / or non-salt form of the compound having the formula (I) is defined as the isolation step. In some embodiments, a salt form of the compound having formula (I) is formed prior to the isolation step. In some embodiments, a non-salt form of the compound having formula (I) is formed prior to the isolation step. In some embodiments, the non-salt form of compound having formula (I) is obtained by adding water after reaction with DMS with compound having formula (II) . In some embodiments, isolation includes neutralization of the salt form of the compound having the formula (I) .

[0501] Isolation of compound having the formula (I) , route 1

[0502] The present invention also provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, wherein the method comprises (1) adding at least one water immiscible solvent and an aqueous basic solution to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids .

[0503] In some embodiments, the method further comprises the addition of an acid.

[0504] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0505] In some embodiments, the method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, comprises (1) adding at least one water immiscible solvent, an aqueous basic solution and an acid to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids.

[0506] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0507] In some embodiments, the acid is HC1.

[0508] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0509] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0510] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0511] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about

[0512] 3:1. I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0513] In some embodiments, the compound having formula (I) is a compound having formula (lai

[0514] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0515] In some embodiments, the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is non-polar.

[0516] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0517] In some embodiments, the polar solvent is an organic polar solvent.

[0518] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[0519] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof. In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0520] In some embodiments, the method comprises evaporation of the polar solvent prior to filtration. In some embodiments, the method comprises partial evaporation of the polar solvent prior to filtration .

[0521] In some embodiments, the method comprises cooling the reaction mixture prior to filtration.

[0522] The method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015 / 103144 and W02015 / 103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in International Application Publication No. W02021 / 059160 and WO / 2021 / 181274. The entire content of each of W02015 / 103144, W02015 / 103142 , WO / 2021 / 181274 and W02021 / 059160 is hereby incorporated by reference.

[0523] Isolation of compound having the formula (I) , route 2

[0524] The present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0525] In some embodiments, the method comprises the addition of an acid. In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0526] In some embodiments, the method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, comprises (i) washing the mixture with an aqueous basic solution and an acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0527] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0528] In some embodiments, the acid is HC1.

[0529] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0530] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0531] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0532] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0533] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0534] In some embodiments, the compound having formula (I) is a compound having formula (lai) :

[0535] (lai)

[0536] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0537] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) .

[0538] In some embodiments, the compound having the formula (I) is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution. In some embodiments, the compound having the formula (I) in salt form is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution.

[0539] In some embodiments, the water immiscible solvent is polar. In some embodiments, the water immiscible solvent is non-polar. In some embodiments , the water immiscible solvent is an organic polar solvent .

[0540] In some embodiments, the water immiscible solvent includes but not limited to CPME, MeTHF, DCM, toluene, anisole or any combination thereof .

[0541] In some embodiments, the water immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene, anisole, and any combination thereof.

[0542] In some embodiments, the water immiscible solvent is selected from the group consisting of methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , toluene, anisole, and any mixture thereof .

[0543] In some embodiments, the water immiscible solvent is CPME. In some embodiments, the water immiscible solvent is MeTHF. In some embodiments, the water immiscible solvent is DCM. In some embodiments, the water immiscible solvent is toluene. In some embodiments, the water immiscible solvent is anisole.

[0544] In some embodiments, the compound having the formula (I) is crystalized from the organic phase. In some embodiments, the compound having the formula (I) is crystallized by concentrating the organic phase. In some embodiments, the compound having the formula (I) is crystallized by adding an anti-solvent. In some embodiments, the compound having the formula (I) is crystallized by seeding.

[0545] The present invention provides a method for isolating a compound having the formula (I) comprising (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid . In some embodiments, the method for isolating a compound having the formula (I) comprises (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution and 32% HC1, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[0546] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0547] The present invention provides a method for isolating the compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, wherein the method comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[0548] In some embodiments, the method for isolating the compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution and 32% HC1, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[0549] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0550] In some embodiments, the organic polar solvent is an organic polar water immiscible solvent.

[0551] In some embodiments, the organic water immiscible solvent has a dielectric constant less than 20.

[0552] In some embodiments, organic water immiscible solvent includes but is not limited to methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , and a mixture thereof.

[0553] In some embodiments, the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof.

[0554] In some embodiments, the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM and any combination thereof .

[0555] In some embodiments, the organic polar solvent is DMA. In some embodiments, the organic polar solvent is CPME. In some embodiments, the organic polar solvent is MeTHF.

[0556] In some embodiments, the organic phase is cooled prior to and / or during the filtration. In some embodiments, the organic phase is cooled to 0-10 °C. In some embodiments, the organic phase is cooled to 0-5°C. In some embodiments, the organic phase is cooled to 0°C. In some embodiments, the organic phase is cooled to 5 °C. In some embodiments, the organic phase is cooled to 10 °C.

[0557] In some embodiments, the organic polar solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, the CPME is added after the reaction to obtain the compound having the formula (I) . In some embodiments, a partial amount of the organic polar solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the organic polar solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the CPME is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of CPME is added before isolation of the compound having formula (I) .

[0558] In some embodiments, the compound having the formula (I) in the mixture before the isolation step is in salt form.

[0559] In some embodiments, the non-polar solvent is a non-polar water immiscible solvent.

[0560] In some embodiments, the non-polar water immiscible solvent dissolves the compound of formula (I) .

[0561] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.

[0562] In some embodiments, the non-polar solvent is anisole. In some embodiments, the non-polar solvent is toluene.

[0563] In some embodiments, an anti-solvent is further added.

[0564] In some embodiments, the anti-solvent is added parallel to the to the water immiscible solvent.

[0565] In some embodiments, the anti-solvent is added dropwise.

[0566] In some embodiments, the crystallization is conducted at temperature less than 0°C. In some embodiments, the crystallization is conducted at 10°C.

[0567] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[0568] In some embodiments, the mixture of solvent and anti-solvent are anisole and hexane.

[0569] In some embodiments, the mixture of solvent and anti-solvent are toluene and hexane.

[0570] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof.

[0571] In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0572] In some embodiments, the compound having formula (I) is a compound having formula (la) wherein R is alkyl.

[0573] In some embodiments, the compound having formula (la) is a compound having formula (lai) wherein R is methyl.

[0574] In some embodiments, the organic phase is cooled prior to and / or during the filtration. In some embodiments, the organic phase is cooled to 0-10 °C. In some embodiments, the organic phase is cooled to 0-5°C. In some embodiments, the organic phase is cooled to 0°C. In some embodiments, the organic phase is cooled to 5 °C. In some embodiments, the organic phase is cooled to 10 °C.

[0575] In some embodiments, the crystallization is done by concentration of the solvent. In some embodiments , the crystallization is done with crystal seeding .

[0576] In some embodiments, the mixture is seeded with 0.1-1% of the compound of formula (I) .

[0577] In some embodiments, the water immiscible solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, anisole and hexane are added after the reaction to obtain the compound having the formula (I) .

[0578] In some embodiments, a partial amount of the water immiscible solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the water immiscible solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the anisole is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of anisole optionally with hexane are added before isolation of the compound having formula (I) •

[0579] The method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015 / 103144 and WO2015 / 103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication No. WC2021 / 059160 and WO / 2021 / 181274 The entire content of each of W02015 / 103144, W02015 / 103142 , WO / 2021 / 181274 and W02021 / 059160 is hereby incorporated by reference.

[0580] Isolation of compound having the formula (I) , route 3 In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0581] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution and at least one additional solvent to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0582] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, and at least one solvent wherein the method comprises (i) washing the mixture with an aqueous basic solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0583] In some embodiments, the method comprises the addition of an acid.

[0584] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0585] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0586] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, and at least one solvent wherein the method comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0587] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0588] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0589] In some embodiments, the acid is HC1.

[0590] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0591] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0592] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0593] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0594] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5. In some embodiments, the compound having formula (I) is a compound having formula (lai) :

[0595] In some embodiments, the method includes adding additional solvent.

[0596] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0597] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) .

[0598] In some embodiments, the compound having the formula (I) in the mixture is in salt form.

[0599] In some embodiments, the mixture comprises a solvent. In some embodiments, the slurry mixture comprises a solvent.

[0600] The mixture comprising the compound having formula (I) may comprise DMS and any or all solvents used during the process for preparing the compound having formula (I) .

[0601] The additional solvent is a solvent used to isolate or assist in the isolation of the compound having formula (I) . The additional solvent may be added directly to the mixture. The additional solvent may also be added with the aqueous basic solution.

[0602] In some embodiments, the additional solvent is the same as the solvent (s) used during the process for preparing the compound having formula (I) .

[0603] In some embodiments, the additional solvent is different from the solvent (s) used during the process for preparing the compound having formula (I) .

[0604] In some embodiments, the additional solvent is a polar solvent.

[0605] In some embodiments, the additional solvent is a water immiscible solvent. In some embodiments, the polar solvent has a dielectric constant equal to or above 4. In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.

[0606] In some embodiments, the ratio between the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is about 1:1.

[0607] In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.

[0608] In some embodiments, the additional solvent is a polar solvent, and the polar solvent is CPME.

[0609] In some embodiments, the solvent used during the process for preparing the compound having formula (I) is DMA and the additional solvent is CPME.

[0610] In some embodiments, the ratio between CPME to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (I) is about 1:1.

[0611] In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.

[0612] In some embodiments, the slurry mixture is mixed for 30 minutes to 8 hours .

[0613] In some embodiments, the slurry mixture is mixed at temperature between 25 to 90 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 80 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 60 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 50 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 35 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 30 degrees Celsius. In some embodiments, the slurry mixture is heated to reach the desired temperature for 30 minutes to 3 hours. In some embodiments, the slurry mixture is heated to reach the desired temperature for 30 minutes. In some embodiments, the slurry mixture is heated to reach the desired temperature for 1, 2 or 3 hours.

[0614] In some embodiments, the reactor volume is IL to 500L. In some embodiments, the reactor volume is 10L to 500L. In some embodiments, the reactor volume is 25L to 500L. In some embodiments, the reactor volume is 50L to 500L. In some embodiments, the reactor volume is 100L to 500L. In some embodiments, the reactor volume is IL, 10L, 25L, 50L, 100L, 250L or 500L.

[0615] In some embodiments, the slurry mixture is mixed using mechanical stirrer .

[0616] In some embodiments, the slurry mixture is mixed using high shear stirrer .

[0617] In some embodiments, the slurry mixture is mixed using both mechanical stirrer and high shear stirrer.

[0618] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 2-18% of aqueous basic solution.

[0619] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 2-18% of aqueous basic solution followed by the addition of 20-50% HC1 in water.

[0620] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 11-18% of aqueous basic solution. In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 11-18% of aqueous basic solution followed by the addition of 25-40% HC1.

[0621] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution.

[0622] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 18% of aqueous basic solution.

[0623] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution followed by the addition of 32% HC1.

[0624] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 18% of aqueous basic solution followed by the addition of 32% HC1.

[0625] In some embodiments, the slurry mixture obtained by adding the 2- 18% aqueous basic solution into a mixture comprising the compound having formula (I) , DMS and optionally an organic solvent.

[0626] In some embodiments, the slurry mixture obtained by adding the 2- 18% aqueous basic solution into a mixture comprising the compound having formula (I) , DMS and optionally an organic solvent, followed by the addition of 20-50% HC1 in water.

[0627] In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 15 to 45 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 15 to 20 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 20 to 25 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 25 to 30 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 30 to 35 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 35 to 40 degrees Celsius. In some embodiments, in step (c) , the precipitated solids are filtered at a temperature between 40 to 45 degrees Celsius.

[0628] In some embodiments, the filtered solid obtained in step (c) is washed with an organic solvent during filtration in step (c) . In some embodiments, the organic solvent is CPME.

[0629] In some embodiments, the filtered solid obtained in step (c) is washed with water during filtration in step (c) .

[0630] In some embodiments, the filtered solid is mixed with water and stirred for 1 to 3 hours and filtered.

[0631] In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 25-50 degrees Celsius and filtered.

[0632] In some embodiments, the organic solvent is the same organic solvent as used in obtaining the compound having formula (I) .

[0633] In some embodiments, the aqueous basic solution is 15% of K2CO3in water based on the total weight (w / w) of K2CO3in water.

[0634] In some embodiments, the aqueous basic solution is 18% of K2CO3in water based on the total weight (w / w) of K2CO3in water.

[0635] In some embodiments, the organic phase is the solution which is obtained in the reaction of compound having the formula (II) with DMS.

[0636] In some embodiments, the organic phase is obtained by adding an organic water immiscible solvent to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound

[0637] (II) and DMS.

[0638] In some embodiments, the organic phase is obtained by adding anisole to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0639] In some embodiments, the organic phase is obtained by adding anisole to the mixture of the compound having formula (I) , DMS and DMA obtained in the reaction of compound (II) and DMS.

[0640] In some embodiments, the step of adding an aqueous basic solution comprises additional use of a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB) .

[0641] In some embodiments, a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) in weight ratio of 10:1 prior to washing with 2-18% w / w of aqueous basic solution.

[0642] In some embodiments, the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to 65 °C prior to washing with 2-18% w / w of aqueous basic solution.

[0643] In some embodiments, the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to about 50 °C prior to washing with 2-18% w / w of aqueous basic solution.

[0644] In some embodiments, the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved in CPME.

[0645] In some embodiments, the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved with CPME and washed with water base solution. In some embodiment the resultant mixture is a mixture of the compound having formula (I) with the solvent which was used in the reaction of the compound having formula (II) with DMS .

[0646] In some embodiments, the conversion of the 5-f luoro-4-imino-l- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one to 5-fluoro-

[0647] 4 -imino- 3 -methyl -1- (toluene -4 -sulf onyl ) -3 , 4 -dihydro -IH-pyrimi di n- 2-one is higher than 50%.

[0648] In some embodiments, the chemical yield of 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one is higher than 50%. In some embodiments, the yield of the purified 5- f luoro-4-imino-3-methyl-l- (toluene-4-sulfonyl) -3, 4-dihydro-1H- pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%. In some embodiments, the chemical yield of 5-fluoro-4-imino-3-methyl- 1- (toluene-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 70%. In some embodiments, the chemical yield of 5-fluoro-4- imino-3-methyl-l- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2- one is higher than 80%. In some embodiments, the chemical yield of

[0649] 5-f luoro-4-imino-3-methyl-l- (toluene-4-sulf onyl ) -3, 4-dihydro-1H- pyrimidin-2-one is higher than 90%.

[0650] In some embodiments, the conversion of the 5-f luoro-4-imino-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H- pyrimidin-2-one to 5-f luoro-4-imino-3-methyl-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 50%.

[0651] In some embodiments, the chemical yield of 5-f luoro-4-imino-3- methyl-1- (optionally substituted phenyl-4-sulf onyl ) -3, 4-dihydro- 1H-pyrimidin-2-one is higher than 50%. In some embodiments, the yield of the purified 5-f luoro-4-imino-3-methyl-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%. In some embodiments, substituted phenyl means phenyl that is substituted with R which is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF2.

[0652] In some embodiments, the method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) at least one water immiscible solvent, and at least one additional solvent, comprises (i) washing the mixture with water to obtain slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0653] The method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015 / 103144 and WO2015 / 103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication No. WC2021 / 059160 and WO / 2021 / 181274. The entire content of each of W02015 / 103144, WO2015 / 103142 , WO2021 / 181274 and W02021 / 059160 is hereby incorporated by reference.

[0654] The present invention also provides a compound having formula (I) prepared using the process described herein.

[0655] The present invention also provides a compound having formula (lai) prepared using the process described herein.

[0656] The present reactions occur under reaction conditions sufficient to produce the desired compound. Such conditions, e.g., temperature, time, molarity, etc., may be varied by one of ordinary skill in the art based on the methods and protocols described herein .

[0657] In some embodiments, the method for crystallizing or recrystallizing a compound having formula (I) , comprising (i) preparing a solution comprising a compound having formula (I) and a solvent, and (ii) contacting the solution with an anti-solvent.

[0658] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[0659] In some embodiment, the solvent is one where the anti-solvent can be dissolved in.

[0660] The method for crystallizing or recrystallizing a compound having formula (I) described herein may be used for crystallizing or recrystallizing the compound having formula (I) prepared using any process, including but not limited to the processes described herein and in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 059160 , and WO / 2021 / 181274 , the entire content of each of which is hereby incorporated by reference .

[0661] In some embodiments, the method comprises preparing the compound having formula (I) and crystallizing or recrystallizing the compound having formula (I) comprising (i) preparing a solution comprising the compound having formula (I) and a solvent, and (ii) contacting the solution with an anti-solvent.

[0662] The compound of having formula (I) may be prepared using any process, including but not limited to the processes described herein and in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 059160 and WO / 2021 / 181274 , the entire content of each of which is hereby incorporated by reference .

[0663] The present invention also provides use of an anti-solvent to crystalize or recrystallize a compound having formula (I) from a solution thereof.

[0664] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[0665] In some embodiments, the compound having formula (I) is in a reaction mixture resulting from preparing the compound having formula (I) using any one of the processes described herein or any one of the processes described in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 059160 and WO / 2021 / 181274 , the entire content of each of which is hereby incorporated by reference.

[0666] The present invention also provides a method for isolating a compound having formula (II) from a mixture comprising the compound having formula (II) , wherein the method comprises (i) adding a protic solvent to the mixture to precipitate the compound having formula (II) from the mixture, and (ii) collecting the precipitated compound of formula (II) .

[0667] In some embodiments, the protic solvent is water, methanol, or a combination thereof.

[0668] The methods for isolating a compound having formula (II) may be applied to any mixture comprising the compound having formula (II) , Ill including the reaction mixtures of the processes described herein for preparing the compound having formula (II) and the reaction mixtures of the processes described in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, and WO / 2021 / 181274 for preparing the compound having formula (II) , the entire content of each of which is hereby incorporated by reference .

[0669] Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

[0670] The present invention further provides a process for obtaining the compound having formula (II) :

[0671] Comprising reacting 5-f luorocytosine with compound having formula (HI) : in the presence of at least one polar solvent, at least one base and a metal agent. In some embodiments, the metal agent is useful for increasing the selectivity of step (a) .

[0672] In some embodiments, the metal agent is calcium chloride dihydrate.

[0673] In some embodiments, the purity of the compound obtained in step (a) is higher than 95%.

[0674] In some embodiments, the structural isomeric compounds obtained in step (a) are less than 1% .

[0675] In some embodiments, compound (A) obtained is step (a) is less than 1%

[0676] In some embodiments, compound (B) obtained is step (a) is less than 0.3%

[0677] In some embodiments, the compound having the formula (II) is (Ila) wherein R is alkyl.

[0678] In some embodiments, the compound having the formula (Ila) is

[0679] (Ilai) wherein R is methyl.

[0680] In some embodiments, the compound having the formula (I) is (la) wherein R is alkyl.

[0681] In some embodiments, the compound having the formula (la) is (lai) wherein R is methyl .

[0682] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) is carried out in the absence of protecting group.

[0683] In some embodiments, X is a halogen. In some embodiments, the halogen is Cl, Br or I. In some embodiments, the halogen is Cl.

[0684] In some embodiments, X is -OSO2PhR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0685] In some embodiments, X is , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2,

[0686] -NO2, -CN or CF3.

[0687] In some embodiments, the compound having formula (III) is a compound having formula (Illb) wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3. In some embodiments, X is -OSO2PhR and R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0688] In some embodiments, R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0689] In some embodiments, R is alkyl. In some embodiments, the compound having formula (III) is toluenesulfonyl anhydride.

[0690] In some embodiments, the compound having the formula (III) may include but is not limited to 4-toluenesulf onyl chloride (TsCl) and toluenesulfonyl anhydride.

[0691] In some embodiments, the compound having the formula (III) is 4- toluenesulf onyl chloride (TsCl) . In some embodiments, the compound having the formula (III) is toluenesulfonyl anhydride.

[0692] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at a temperature between (-5)- 85°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-25°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-5°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)- 10 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between (-5)-0°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between 0-5 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 5-25°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 25- 85 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 15-20°C. In some embodiments, the reaction of 5- f luorocytosine with the compound having the formula (III) is conducted at temperature between 15-25 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted at temperature between 15-30°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, a metal agent and at least one base.

[0693] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 0-30 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 0-25 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 0-20°C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 15-30 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents, one base, a metal agent and at a temperature between 15-30°C.

[0694] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 15-25 °C.

[0695] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a polar solvent, at least one base, a metal agent and at a temperature between 15-20 °C. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents, at least one base, a metal agent and at a temperature between 15-20 °C. In some embodiments, the reaction of 5-f luorocytosine with compound having the formula (III) is conducted in the presence of at least one polar solvent, at least one base, a metal agent and at a temperature between 15-20°C.

[0696] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0697] In some embodiments, wherein R is methyl in the compound having formula (III) , the sulfonation step is a tosylation step.

[0698] In the tosylation step, the polar solvent has a dielectric constant equal to or above 20.

[0699] In some embodiments, the polar solvent having dielectric constant equal to or above 20 may include but is not limited to dimethyl acetamide (DMA) , N-methylpyrolidone (NMP) , acetonitrile (ACN or MeCN) , dimethylsulfoxide (DMSO) , dimethylformamide (DMF) , water or any combination thereof.

[0700] In some embodiments, the polar solvent is selected from the group consisting of dimethyl acetamide (DMA) , N-methylpyrolidone (NMP) , acetonitrile (ACN or MeCN) , dimethylsulfoxide (DMSO) , dimethylformamide (DMF) , dimethylbenzylamine (DMBA) , water and any combination thereof.

[0701] In some embodiments, the polar solvent is selected from the group consisting of dimethyl acetamide (DMA) , acetonitrile (ACN or MeCN) , dimethylbenzylamine (DMBA) , water and any combination thereof.

[0702] In some embodiments the combination of polar solvent and base consist of one phase system. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of one polar solvent.

[0703] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two polar solvents .

[0704] In some embodiments, the two polar solvents are selected from the group consisting of dimethyl acetamide (DMA) , N-methylpyrolidone (NMP) , acetonitrile (ACN or MeCN) , dimethylsulfoxide (DMSO) , dimethylformamide (DMF) , dimethylbenzylamine (DMBA) , and water.

[0705] In some embodiments, the two polar solvents are selected from the group consisting of dimethyl acetamide (DMA) , acetonitrile (ACN or MeCN) , dimethyl aminopyridine (DMAP) , and water.

[0706] In some embodiments, the two polar solvents are DMA and water.

[0707] In some embodiments, the weight ratio between the two polar solvents is between 10:1 to 1:10.

[0708] In some embodiments, the weight ratio between the two polar solvents is between 2:1 to 1:2.

[0709] In some embodiments, the weight ratio between the two polar solvents is 1:1.

[0710] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of three polar solvents .

[0711] In some embodiments , the three polar solvents are DMA, water and

[0712] DMBA.

[0713] In some embodiments, at least one base is an organic base.

[0714] In some embodiments, at least one base is an inorganic base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of one base .

[0715] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of two bases .

[0716] In some embodiments, the base may include but is not limited to K2CO3, Na2CO3, Li2CO3, NaHCO3, KHCO3, NaOH, KOH, Et3N, dimethyl aminopyridine (DMAP) , dimethylbenzylamine (DMBA) or any combination thereof.

[0717] In some embodiments, the base is selected from a group consisting of K2CO3, Na2CO3, Li2CO3, NaHCOs, KHCO3, Et2N, dimethyl aminopyridine (DMAP) and any combination thereof.

[0718] In some embodiments, the base is selected from the group consisting of K2CO2, Na2CO2, NaOH, KOH, Et2N, dimethyl aminopyridine (DMAP) , and any combination thereof.

[0719] In some embodiments, the base is K2CO3. In some embodiments, the base is Na2CO3. In some embodiments, the base is NaOH. In some embodiments, the base is KOH. In some embodiments, the base is Et2N. In some embodiments, the base is DMAP.

[0720] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, a metal agent and at least one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, calcium chloride dihydrate and NaOH.

[0721] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and at least one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and one NaOH. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, calcium chloride dihydrate and one base. In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, calcium chloride dihydrate and NaOH.

[0722] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, water, a metal agent and two bases.

[0723] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of a DMA, a metal agent and two bases.

[0724] In some embodiments, the metal agent is calcium chloride dihydrate.

[0725] In some embodiments, the two bases are Et3N and DMAP .

[0726] In some embodiments, the two bases are NaOH and DMAP.

[0727] In some embodiments, the two bases are dimethylbenzylamine and NaOH.

[0728] In some embodiments, the two bases are DMAP and Na2CO3.

[0729] In some embodiments, the two bases are DMAP and KOH.

[0730] In some embodiments, the reaction of 5-f luorocytosine with the compound having the formula (III) is conducted in the presence of DMA, water, calcium chloride dihydrate and K2CO3. In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMA, calcium chloride dihydrate and Et3N.

[0731] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of acetonitrile (ACN or MeCN) , calcium chloride dihydrate and triethylamine (Et3N) .

[0732] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMA, water , calcium chloride dihydrate and DMAP.

[0733] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMA, calcium chloride dihydrate and Na2CO3.

[0734] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, calcium chloride dihydrate and Na2CO3.

[0735] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of water , calcium chloride dihydrate and DMAP.

[0736] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, DMA, water , calcium chloride dihydrate and KOH.

[0737] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, DMA, water , calcium chloride dihydrate and NaOH.

[0738] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of a DMA, Et3N, calcium chloride dihydrate and DMAP . In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of a DMA, water , calcium chloride dihydrate , NaOH and DMAP .

[0739] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMAP , calcium chloride dihydrate and Na2CO3.

[0740] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, calcium chloride dihydrate and KOH.

[0741] In some embodiments , the reaction of 5-f luorocytosine with the compound having the formula ( III ) is conducted in the presence of DMBA, calcium chloride dihydrate and NaOH.

[0742] In some embodiments , the polar solvent has a dielectric constant equal to or above 20 is DMA, and the base is Et3N.

[0743] In some embodiment , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , and the base is K2CO3.

[0744] In some embodiment , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , and the base is NaOH.

[0745] In some embodiments , the polar solvent has a dielectric constant equal to or above 20 is water , the base is Et3N and the temperature is 15-20 °C .

[0746] In some embodiment , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , and the base is NaOH.

[0747] In some embodiments , the polar solvent has a dielectric constant equal to or above 20 is mixture of DMA and water , the base is NaOH and the temperature is 15-20 °C . In some embodiments, the temperature is 15-20 °C, and the solvent is acetonitrile.

[0748] In another preferred embodiment, the temperature is 15-20 °C, the solvent is acetonitrile, and the base is Et3N.

[0749] In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5- f luorocytosine and the compound having formula (III) is between 1:10 to 10:1. In some embodiments, in the reaction of 5- f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:2 to 2:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is about 1:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is about 1:1.1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the compound having formula (III) is 1:1.2.

[0750] In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5- f luorocytosine and the base is between 1:10 to 10:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is between 1:2 to 2:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5- f luorocytosine and the base is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is about 1:1. In some embodiments, in the reaction of 5- f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is 1:1.2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between 5-f luorocytosine and the base is 1:1.3.

[0751] In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:10 to 10:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:5 to 5:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:2 to 2:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is between 1:1 to 1:2. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is about 1:1. In some embodiments, in the reaction of 5-f luorocytosine with the compound having formula (III) , the molar ratio between the compound having formula (III) and the base is 1:1.2.

[0752] In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent varies between 5:1 to 1.8:1, respectively. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is between 5:1 and 2:1. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is between 5:1 and 3:1. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is between 4:1 and 2:1. In some embodiments, the molar ratio between the 5-f luorocytosine and the metal agent is about 3.3:1.

[0753] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield of at least 60%.

[0754] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield higher than 60%, 70%, 80%, 90%, 95% or 99%. In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain the compound having formula (II) has a yield higher than 90%.

[0755] In some embodiments, the purity of the compound of Formula (II) in the reaction of 5-f luorocytosine with the compound having formula (III) is higher than 60%, 70%, 80%, 90% or 99%. In some embodiments, the purity of the compound of Formula (II) in the reaction of 5- f luorocytosine with the compound having formula (III) is higher than 95% .

[0756] In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 20% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 10% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 5% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 3% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 2% based on the conversion. In some embodiments, the impurities (A) and (B) in the invention process disclosed herein to obtain compound having the formula (II) is less than 1% based on the conversion.

[0757] In some embodiments, the reaction of 5-f luorocytosine with the compound having formula (III) to obtain compound having the formula (II) further comprises a step of isolating the compound having formula (II) from the reaction mixture.

[0758] In some embodiments, isolation of the compound having formula (II) comprises (i) precipitation by adding a protic solvent to the reaction mixture, and (ii) filtration.

[0759] In some embodiments, the protic solvent is water, methanol or a combination thereof.

[0760] The present invention also provides a compound having formula (II) prepared using the process described herein.

[0761] The present invention also provides a compound having formula (Ilai) prepared using the process described herein.

[0762] The compound having formula (II) may be alkylated to prepare the compound having formula (I) using the alkylation step described herein below.

[0763] The compound having formula (II) may also be alkylated to prepare the compound having formula (I) using any suitable alkylation process known in the art including, but not limited to, the process described in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 181274, and WO / 2023 / 042126 the entire content of each of which is hereby incorporated by reference . In some embodiments, the compound having formula (lai) is prepared by contacting a compound having formula (Ilai) with an alkali carbonate and an alkylating agent and forming a compound having formula (lai ) .

[0764] In some embodiments, the contacting step is carried out between 22°C and 60°C. In some embodiments, the contacting step is carried out between 22 °C and 40 °C.

[0765] In some embodiments, the contacting step further includes a solvent selected from the group consisting of DMF, DMSO, DMA, NMP, and CH3CN, and any combination thereof.

[0766] In some embodiments, the alkali carbonate is selected from the group consisting of Na2CO3, K2CO3, CS2CO3, Li2CO3, and any combination thereof .

[0767] In some embodiments, the alkylating agent is selected from the group consisting of alkyl halides and benzyl halides. In some embodiments, the alkyl halide and benzyl halide are selected from the group consisting of methyl iodide (CH3I) , ethyl iodide (C2H5I) , benzyl bromide (BnBr) , and any combination thereof.

[0768] In some embodiments, the alkali carbonate base is CS2CO3, and the solvent is DMF.

[0769] In some embodiments, a molar ratio of the compound having formula (Ilai) to alkali carbonate base is from about 3:1 to about 1:1. In some embodiments, the molar ratio of the compound having formula (Ilai) to alkali carbonate base is about 2:1.

[0770] In some embodiments, the molar ratio between the compound having formula (Ilai) to alkylating agent is from about 1:1 to about 1:3. In some embodiments, the molar ratio between the compound having formula (Ilai) to alkylating agent is 1:3. In some embodiments, a molar ratio of the compound having formula (Ilai) to alkali carbonate base is from about 3:1 to about 1:1 and the molar ratio between the compound having formula (Ilai) to alkylating agent is from about 1:1 to about 1:3. In some embodiments, the molar ratio of the compound having formula (Ilai) to alkali carbonate base is about 2:1 and the molar ratio of the compound having formula (Ilai) to alkylating agent is 1:3.

[0771] In some embodiments, the process further includes the step of diluting a completed reaction mixture with CH3CN and 2.5% aqueous Na2S2O3. In some embodiments, the ratio of DMF to CH3CN is from about 1:1 to about 3:1 and the ratio of DMF to 2.5% aqueous Na2S2O3is from about 1:2 to about 2:1. In some embodiments, the ratio of DMF to CH3CN is about 2:1 and the ratio of DMF to 2.5% aqueous Na2S2O3is about 1:1.

[0772] In some embodiments, the compound having formula (lai) is prepared by contacting a compound having formula (Ilai) with a base, such as an alkali carbonate, e.g., sodium-, potassium-, cesium-, and lithium carbonate (Na2CO3, K2CO3, CS2CO3, and Li2CO3, respectively) and an alkylating agent, such as an alkyl halide of formula CH3-X, wherein X is a halogen, e.g., iodine, bromine, and chlorine, in a polar solvent, such as N, N-dimethylf ormamide (DMF) , dimethylsulfoxide (DMSO) , dimethylacetamide (DMA) , N- methylpyrrolidone (NMP) , acetonitrile (CH3CN) , and the like, at concentrations from about 0.1 molar (M) to about 3 M. In some embodiments, the reactions are conducted at temperatures between - 78°C and 90°C. In some embodiments, the reactions are conducted between 22°C and 60°C.

[0773] The present invention further provides a process for obtaining 5- f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H- pyrimidin-2-one having formula (I) :

[0774] comprising :

[0775] (a) preparing the compound having formula (I) by reacting a compound having the formula (II) (II) with dimethylsulphate (DMS) , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF2, and

[0776] (b) isolating the compound having formula (I) from the reaction mixture by mixing an aqueous basic solution and an acid with the reaction mixture and obtaining the compound having formula (I) , wherein the process comprises use of at least one water immiscible solvent, wherein: i) step (a) is conducted in the presence of at least one water- immiscible solvent, and / or ii) at least one water-immiscible solvent is mixed with the reaction mixture after step (a) .

[0777] In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the absence of base.

[0778] In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of at least one base.

[0779] In some embodiments, the base is selected from the group consisting of DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof.

[0780] In some embodiments, the base is selected from the group consisting of TBAB, NaOH, Na2CO3, Et3N, NaOMe, and any combination thereof.

[0781] In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 10-85°C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 20-85 °C. In some embodiments, the temperature is between 20-50°C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 35-50 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 15-30 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 15-25 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 10 °C and below 25 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at a temperature between 20-25 °C. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted at 20°C. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:10. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:4. In some embodiments, the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:2.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:3. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:3.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is 1:3. In some embodiments, the molar ratio between the compound having formula (II) and DMS is 1:2.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is 1:2.

[0782] In some embodiments, the molar ratio between the compound having formula (II) and the base is 1:0.1 to 1:10. In some embodiments, the molar ratio between the compound having formula (II) and the base is 1:0.1 to 1:5.5.

[0783] In some embodiments, the base is added after 4 hours from the beginning of the reaction of compound (II) with DMS . Suitable bases include carbonates.

[0784] In some embodiments, the base is added after 4 hours from the beginning of the reaction of the compound having formula (II) with DMS and the temperature of the reaction is above 30 degrees Celsius.

[0785] In some embodiments, the compound having formula (I) reacts with DMS in the presence of a base having a pKa equal to or less than the pKa of the compound having formula (I) . In some embodiments, the base is added at the beginning of the reaction. Suitable bases include DABCO, NEt3, LiCO3, and KHCO3. When the base is added at the beginning of the reaction of the compound having formula (II) with DMS, the temperature is preferably above 30 degrees Celsius.

[0786] In some embodiments, the compound having formula (I) reacts with DMS in the presence of a base having a pKa equal to or less than the pKa of the compound having formula (I) .

[0787] In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of at least one solvent. In some embodiments, the reaction of the compound having formula (II) with DMS is conducted in the presence of two solvents.

[0788] In some embodiments, the solvent is a polar solvent.

[0789] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0790] In some embodiments, the solvent is selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof. In some embodiments, the solvent in NMP .

[0791] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0792] In some embodiments, the solvent is MeTHF and the base is NEts .

[0793] In some embodiments, the solvent is a mixture of at least two solvents .

[0794] In some embodiments, the solvent is a mixture of DMA and Anisole.

[0795] In some embodiments, the solvent is a mixture of NMP and Anisole. In some embodiments, the solvent is a mixture of DMA and CPME.

[0796] In some embodiments, the weight ratio between DMA and CPME is between 1:1 to 1:10. In some embodiments, the weight ratio between DMA and CPME is between 1:1 to 1:4. In some embodiments, the weight ratio between DMA and CPME is between 1:2 to 1:4. In some embodiments, the weight ratio between DMA and CPME is between 1:3 to 1:5. In some embodiments, the weight ratio between DMA and CPME is about 1:4.

[0797] In some embodiments, the solvent is a mixture of DMA and MeTHF.

[0798] In some embodiments, the solvent is a mixture of DMA and MeTHF in a weight ratio of 1:1 to 1:4. In some embodiments, the solvent is a mixture of DMA and MeTHF in a weight ratio of 1:2 to 1:4.

[0799] In some embodiments, the alkylation process is conducted in the presence of a mixture of DMA and CPME in a weight ratio of 1:2 to 1:4. In some embodiments, the alkylation process is conducted in the presence of a mixture of DMA and CPME in a weight ratio of 1:4.

[0800] In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 30:1 and 1:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 20:1 and 5:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 15:1 and 10:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is between 14:1 to 12:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is about 13:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to the compound having formula (II) is 12.7:1.

[0801] In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is between 10:1 to 1:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is between 5:1 to 3:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is about 4:1. In some embodiments, in the reaction of the compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents to DMS is 3.9:1.

[0802] In some embodiments, the reaction of the compound having formula (II) with DMS further comprises neutralizing with an aqueous basic solution .

[0803] In some embodiments, the excess DMS is neutralized with an aqueous basic solution.

[0804] In some embodiments, the weight ratio of the DMA: CPME : compound having the formula (II) is 1.5:0:1 to 1:5:1.

[0805] In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 60%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 70%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 80%. In some embodiments, the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 90%. The compound having formula (II) may be prepared using the sulfonation process described herein.

[0806] The compound having formula (II) may also be prepared using any process known in the art including, but not limited to, the process described in PCT International Application Publication Nos. WO 2015 / 103142 and WO 2015 / 103144, the entire content of each of which is hereby incorporated by reference.

[0807] In some embodiments, the compound having formula (Ilai) is prepared by contacting a compound having formula (IV) :

[0808] IV with bis-N, O-trimethylsilylacetamide (BSA) and forming a compound having formula (Ilai) , wherein the molar ratio of the compound having formula (IV) to bis- N, O-trimethylsilylacetamide (BSA) is 1:1.1 and the contacting step is carried out at a temperature from about 22 °C to about 70 °C.

[0809] In some embodiments, the contacting step further includes contacting the compound having formula (IV) with CH3CN.

[0810] In some embodiment, the process comprises contacting a BSA treated reaction mixture with an arylsulfonyl chloride.

[0811] In some embodiments, the molar ratio between the compound having formula (IV) to arylsulfonyl chloride is from about 1:2 to about 2:1. In some embodiments, the molar ratio between the compound having formula (IV) to arylsulfonyl chloride 1:1.1. In some embodiments, the compound having formula (Ilai) may be prepared by contacting a compound having formula (IV) with bis- N, O-trimethylsilylacetamide (BSA) at an elevated temperature, such as 70°C, for a period of about 1 hour (h) , followed by cooling and contacting the solution containing the protected pyrimidinol with CH3-PhSO2Cl at about 20°C - 25°C. In some embodiments, the molar ratio between the compound having formula (IV) to BSA and the sulfonyl chloride is about 1:3: 1.1, respectively. In some embodiments, reducing the molar ratio of the reactants to about 1:1.1:1.1 affords improved yields.

[0812] In some embodiments, step (a) is conducted in the presence of at least one water-immiscible solvent.

[0813] In some embodiments, at least one water-immiscible solvent is mixed with the reaction mixture after step (a) .

[0814] In some embodiments, step (a) is conducted in the presence of at least one water-immiscible solvent and at least one water- immiscible solvent is mixed with the reaction mixture after step (a) .

[0815] In some embodiments, the water immiscible solvent is mixed with the reaction mixture after step (a) and before step (b) .

[0816] In some embodiments, the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature .

[0817] An example of a water immiscible solvent having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature is anisole. Additional water immiscible solvents having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature may be identified through routine experimentation . In some embodiments, the water immiscible solvent has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 200 mg / mL at room temperature. In some embodiments, the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 150 mg / mL at room temperature. In some embodiments, the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 100 mg / mL at room temperature.

[0818] In some embodiments, a mixture of two or more water immiscible solvents are mixed with the reaction mixture after step (a) . In some embodiments, a mixture of two water immiscible solvents is mixed with the reaction mixture after step (a) . In some embodiments, a mixture of three water immiscible solvents is mixed with the reaction mixture after step (a) . In some embodiments, a mixture of four water immiscible solvents is mixed with the reaction mixture after step (a) .

[0819] In some embodiments, the mixture of water immiscible solvents has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 200 mg / mL at room temperature. In some embodiments, the mixture of water immiscible solvents has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 150 mg / mL at room temperature. In some embodiments, the mixture of water immiscible solvents has a solubility of the compound of formula (I) greater than 33 mg / mL and up to 100 mg / mL at room temperature.

[0820] In some embodiments, the water immiscible solvent or one of the water immiscible solvents is anisole.

[0821] In some embodiments, anisole is mixed with the reaction mixture after step (a) . In some embodiments, anisole is only mixed with the reaction mixture after step (a) .

[0822] In some embodiments, at the end of step (a) , a multi-phase system is obtained. In some embodiment, step (a) is conducted in the presence of a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof .

[0823] In some embodiments, step (a) is conducted in the presence of at least one water-immiscible solvent.

[0824] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THF, anisole, toluene, and any mixture thereof.

[0825] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0826] In some embodiments, step (a) is conducted in the presence of a solvent in addition to the water immiscible solvent.

[0827] In some embodiments, step (a) is conducted in the presence of a solvent and without a water immiscible solvent.

[0828] In some embodiments, the solvent is DMA.

[0829] In some embodiments, step (a) is conducted in the presence of a mixture of solvents wherein at least one solvent is water immiscible and at least one solvent is water miscible.

[0830] In some embodiments, the mixture of solvents is a mixture of a polar water miscible solvent and a non-polar water-immiscible solvent .

[0831] In some embodiments, the mixture of solvents is DMA and anisole. In some embodiments, the weight ratio between DMA and anisole is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between anisole and the compound having formula (II) is from about 10:1 to about 1:1. In some embodiments, the mixture of solvents is a mixture of DMA and toluene. In some embodiments, the weight ratio between DMA and toluene is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between toluene and the compound having formula (II) is from about 10:1 to about 1:1.

[0832] In some embodiments, the process forms a multi-phase system. In some embodiments, in step (b) , a multi-phase system is obtained.

[0833] In some embodiments, the multi-phase system comprises an organic phase and a water phase. In some embodiments, the multi-phase system is a slurry mixture comprising solids. The type of multiphase system formed depends on the volume of the water-immiscible solvent and / or the temperature.

[0834] In some embodiments, wherein the multi-phase system comprises an organic phase and a water phase, the organic phase comprises the water-immiscible solvent. In some embodiments, wherein the multiphase system comprises an organic phase and a water phase, the process comprises heating the multi-phase system for dissolution of the compound having formula (I) in the organic phase. In some embodiments, the process comprises heating the multi-phase system up to 80°C for dissolution of the compound having formula (I) in the organic phase.

[0835] In some embodiments, wherein the multi-phase system comprises an organic phase and a water phase, the process for isolating the compound having formula (I) from the reaction mixture comprises separating the organic phase from the water phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals. For example, the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 2.

[0836] In some embodiments, wherein the reaction mixture comprises the compound having formula (I) , DMS and at least one water immiscible solvent, step (b) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution an an acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0837] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution an acid to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the organic phase and filtering the crystals.

[0838] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) from the reaction mixture and filtering the crystallized solid, or

[0839] (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding at least one water immiscible solvent, an aqueous basic solution and an acid to the reaction mixture to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.

[0840] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0841] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) .

[0842] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0843] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0844] In some embodiments, the acid is HC1.

[0845] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water. In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0846] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0847] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0848] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0849] In some embodiments, the compound having the formula (I) is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution. In some embodiments, the compound having the formula (I) in salt form is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution.

[0850] In some embodiments, the water immiscible solvent is polar. In some embodiments, the water immiscible solvent is non-polar. In some embodiments, the water immiscible solvent is an organic polar solvent .

[0851] In some embodiments, the water immiscible solvent includes but not limited to cyclopentylmethylether (CPME) , methyl tetrahydrofuran (MeTHF) , DCM, toluene, anisole or any combination thereof. In some embodiments, the water immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene, anisole, and any combination thereof. In some embodiments, the water immiscible solvent is selected from the group consisting of MeTHF, CPME, toluene, anisole, and any mixture thereof.

[0852] In some embodiments, the water immiscible solvent is CPME. In some embodiments, the water immiscible solvent is MeTHF. In some embodiments, the water immiscible solvent is DCM. In some embodiments, the water immiscible solvent is toluene. In some embodiments, the water immiscible solvent is anisole.

[0853] In some embodiments, the compound having the formula (I) is crystallized from the organic phase by concentrating the organic phase. In some embodiments, the compound having the formula (I) is crystallized from the organic phase by adding an anti-solvent. In some embodiments, the compound having the formula (I) is crystallized from the organic phase by seeding.

[0854] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[0855] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0856] In some embodiments, the process for isolating the compound having formula (I) comprises (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution and an acid, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid .

[0857] In some embodiments, the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution and an acid, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid .

[0858] In some embodiments, the process for isolating the compound having formula (I) from a mixture comprising the compound having formula (I) and DMS comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution followed by the addition of an acid, (3) separating the organic phase from the water phase, and (4) crystallizing the compound from the organic phase by adding an anti-solvent.

[0859] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0860] In some embodiments, the acid is HC1.

[0861] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0862] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0863] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0864] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1. I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0865] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[0866] In some embodiments, the organic polar solvent is an organic polar water immiscible solvent.

[0867] In some embodiments, the organic water immiscible solvent has a dielectric constant less than 20.

[0868] In some embodiments, organic water immiscible solvent includes but is not limited to methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , and a mixture thereof.

[0869] In some embodiments, the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof.

[0870] In some embodiments, the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM and any combination thereof .

[0871] In some embodiments, the organic polar solvent is DMA. In some embodiments, the organic polar solvent is CPME. In some embodiments, the organic polar solvent is MeTHF.

[0872] In some embodiments, the organic polar solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, the CPME is added after the reaction to obtain the compound having the formula (I) . In some embodiments, a partial amount of the organic polar solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the organic polar solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the CPME is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of CPME is added before isolation of the compound having formula (I) .

[0873] In some embodiments, the compound having the formula (I) in the mixture before the isolation step is in salt form.

[0874] In some embodiments, the non-polar solvent is a non-polar water immiscible solvent.

[0875] In some embodiments, a non-polar water immiscible solvent dissolves the compound of formula (I) .

[0876] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.

[0877] In some embodiments, the non-polar solvent is anisole. In some embodiments, the non-polar solvent is toluene.

[0878] In some embodiments, an anti-solvent is further added.

[0879] In some embodiments, the anti-solvent is added parallel to the to the water immiscible solvent.

[0880] In some embodiments, the anti-solvent is added dropwise.

[0881] In some embodiments, the crystallization is conducted at temperature between 0°C and 10 °C.

[0882] In some embodiments, the crystallization is conducted at temperature less than 0°C. In some embodiments, the crystallization is conducted at 10°C.

[0883] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[0884] In some embodiments, the mixture of solvent and anti-solvent are anisole and hexane.

[0885] In some embodiments, the mixture of solvent and anti-solvent is toluene and hexane

[0886] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof.

[0887] In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0888] In some embodiments, the organic phase is cooled prior to and / or during the filtration. In some embodiments, the organic phase is cooled to 0-10°C. In some embodiments, the organic phase is cooled to 0-5 °C. In some embodiments, the organic phase is cooled to 0°C. In some embodiments, the organic phase is cooled to 5 °C. In some embodiments, the organic phase is cooled to 10 °C.

[0889] In some embodiments, the crystallization is done by concentration of the solvent.

[0890] In some embodiments, the crystallization is done with crystal seeding . In some embodiments, the mixture is seeded with 0.1-1% of the compound of formula (I) .

[0891] In some embodiments, the water immiscible solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, anisole and hexane are added after the reaction to obtain the compound having the formula (I) .

[0892] In some embodiments, a partial amount of the water immiscible solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the water immiscible solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the anisole is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of anisole optionally with hexane are added before isolation of the compound having formula (I) •

[0893] In some embodiments, the process for isolating the compound having formula (I) comprises contacting the mixture comprising the compound having formula (I) with a water-immiscible solvent or a mixture of solvents comprising at least one water immiscible solvent and water, separating the organic phase, crystalizing the compound having the formula (I) , and filtering the crystals.

[0894] In some embodiments, wherein the multi-phase system is a slurry comprising solids, the process for isolating the compound having formula (I) form the reaction mixture comprises filtering the precipitated solids.

[0895] For example, the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 3.

[0896] In some embodiments, step (a) is conducted in the presence of at least one water-immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (b) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0897] In some embodiments, the water immiscible solvent is added after step (a) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (b) for isolating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0898] In some embodiments, step (a) is conducted in the presence of at least one additional solvent.

[0899] In some embodiments, wherein (I) step (a) is conducted in the presence of at least one additional solvent, (II) step (a) is conducted in the presence of at least one water-immiscible solvent and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (b) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0900] In some embodiments, wherein (I) step (a) is conducted in the presence of at least one additional solvent, (II) the water immiscible solvent is added after step (a) , and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (b) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids. In some embodiments, wherein (I) at least one additional solvent is added after step (a) , (II) step (a) is conducted in the presence of at least one water-immiscible solvent and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (b) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0901] In some embodiments, wherein (I) at least one additional solvent is added after step (a) , (II) the water immiscible solvent is added after step (a) , and (III) the reaction mixture comprises the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, step (b) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0902] In some embodiments, step (b) is conducted in the presence of at least one additional solvent.

[0903] In some embodiments, wherein step (a) is conducted in the presence of at least one water immiscible solvent and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (b) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0904] In some embodiments, wherein the water immiscible solvent is added after step (a) and the reaction mixture comprises the compound having formula (I) , DMS, and at least one water immiscible solvent, step (b) for isolating the compound having formula (I) comprises (i) washing the mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0905] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0906] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0907] In some embodiments, the acid is HC1.

[0908] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0909] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0910] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0911] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[0912] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0913] In some embodiments, step (b) is conducted in the presence of at least one additional solvent.

[0914] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids .

[0915] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0916] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .

[0917] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution and an acid, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0918] In some embodiments, the aqueous basic solution comprises DABCO,

[0919] TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[0920] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) .

[0921] In some embodiments, the acid is added after the addition of the aqueous basic solution.

[0922] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[0923] In some embodiments, the acid is HC1.

[0924] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[0925] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[0926] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[0927] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about

[0928] 3:1.

[0929] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[0930] In some embodiments, the compound having the formula (I) in the mixture is in salt form.

[0931] In some embodiments, the mixture comprises a solvent. In some embodiments, the slurry mixture comprises a solvent.

[0932] The mixture comprising the compound having formula (I) may comprise DMS and any or all solvents used during the process for preparing the compound having formula (I) .

[0933] The additional solvent is a solvent used to isolate or assist in the isolation of the compound having formula (I) . The additional solvent may be added directly to the mixture. The additional solvent may also be added with the aqueous basic solution.

[0934] In some embodiments, the additional solvent is the same as the solvent (s) used during the process for preparing the compound having formula (I) .

[0935] In some embodiments, the additional solvent is different from the solvent (s) used during the process for preparing the compound having formula (I) .

[0936] In some embodiments, the additional solvent is a polar solvent.

[0937] In some embodiments, the additional solvent is a water immiscible solvent. In some embodiments, the polar solvent has a dielectric constant equal to or above 4. In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.

[0938] In some embodiments, the ratio between the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (I) is about 1:1.

[0939] In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between the additional solvent to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.

[0940] In some embodiments, the additional solvent is a polar solvent, and the polar solvent is CPME .

[0941] In some embodiments, the solvent used during the process for preparing the compound having formula (I) is DMA and the additional solvent is CPME.

[0942] In some embodiments, the ratio between CPME to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (I) is about 1:1.

[0943] In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is less than 2:1. In some embodiments, the ratio between CPME to the compound having formula (II) used for preparing the compound having formula (I) is about 1:1.

[0944] In some embodiments, the slurry mixture is mixed for 30 minutes to 8 hours. In some embodiments, the slurry mixture is mixed for 30 minutes. In some embodiments, the slurry mixture is mixed for 1, 2, 3, 4, 5, 6, 7 or 8 hours.

[0945] In some embodiments, the slurry mixture is mixed at temperature between 25 to 90 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 80 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 60 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 50 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature between 25 to 35 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 30 degrees Celsius. In some embodiments, the slurry mixture is mixed at temperature of about 60 degrees Celsius.

[0946] In some embodiments, the slurry mixture is mixed using mechanical stirrer .

[0947] In some embodiments, the slurry mixture is mixed using high shear stirrer .

[0948] In some embodiments, the slurry mixture is mixed using both mechanical stirrer and high shear stirrer.

[0949] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 2-18% of aqueous basic solution, followed by the addition of 20-50% HC1 in water.

[0950] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 11-18% of aqueous basic solution, followed by the addition of 25-40% HC1 in water.

[0951] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 15% of aqueous basic solution, followed by the addition of 32% HC1 in water.

[0952] In some embodiments, the slurry mixture is obtained by adding the mixture comprising the compound having formula (I) and DMS and optionally organic solvent into a 18% of aqueous basic solution, followed by the addition of 32% HC1 in water.

[0953] In some embodiments, the slurry mixture obtained by adding the 2- 18% aqueous basic solution and 32% HC1 in water into a mixture comprising the compound having formula (I) , DMS and optionally an organic solvent.

[0954] In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 10 to 45 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 10 to 20 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 20 to 25 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 25 to 30 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 30 to 35 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 35 to 40 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 40 to 45 degrees Celsius. In some embodiments, in step (b) , the precipitated solids are filtered at a temperature of 10 degrees Celsius. In some embodiments, the filtered solid obtained in step (b) is washed with an organic solvent during filtration in step (b) . In some embodiments, the organic solvent is CPME.

[0955] In some embodiments, the filtered solid obtained in step (b) is washed with water during filtration in step (b) .

[0956] In some embodiments, the filtered solid is mixed with water and stirred for 1 to 3 hours and filtered.

[0957] In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 25-50 degrees Celsius and filtered. In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 10-50 degrees Celsius and filtered. In some embodiments, the filtered solid is mixed with water and stirred at a temperature of 10 degrees Celsius and filtered.

[0958] In some embodiments, the organic solvent is the same organic solvent as used in obtaining the compound having formula (I) .

[0959] In some embodiments, the aqueous basic solution is 15% of K2CO3in water based on the total weight (w / w) of K2CO3in water. In some embodiments, the aqueous basic solution is 18% of K2CO3in water based on the total weight (w / w) of K2CO3in water.

[0960] In some embodiments, the organic phase is the solution which is obtained in the reaction of compound having the formula (II) with DMS.

[0961] In some embodiments, the organic phase is obtained by adding an organic water immiscible solvent to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0962] In some embodiments, the organic phase is obtained by adding anisole to the mixture of the compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS. In some embodiments, the organic phase is obtained by adding anisole to the mixture of the compound having formula (I) , DMS and DMA obtained in the reaction of compound (II) and DMS.

[0963] In some embodiments, the step of adding an aqueous basic solution comprises additional use of a phase transfer catalyst (PTC) such as tetra-n-butylammonium bromide (TBAB) .

[0964] In some embodiments, a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) in weight ratio of 10:1 prior to washing with 2-18% w / w of aqueous basic solution and an acid.

[0965] In some embodiments, the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to 65 °C prior to washing with 2-18% w / w of aqueous basic solution and an acid.

[0966] In some embodiments, the solution of the compound having formula (I) in CPME is obtained by warming the combination of CPME and the compound having formula (I) up to about 50 °C prior to washing with 2-18% w / w of aqueous basic solution and an acid. In some embodiments, the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved in CPME.

[0967] In some embodiments, the resultant mixture obtained from the reaction of the compound having formula (II) with DMS is dissolved with CPME and washed with water base solution followed by the addition of an acid.

[0968] In some embodiment the resultant mixture is a mixture of the compound having formula (I) with the solvent which was used in the reaction of the compound having formula (II) with DMS.

[0969] In some embodiments, the conversion of the 5-f luoro-4-imino-l- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one to 5-fluoro- 4 -imino- 3 -methyl -1- (toluene -4 -sulf onyl ) -3 , 4 -dihydro -IH-pyrimi di n- 2-one is higher than 50%.

[0970] In some embodiments, the chemical yield of 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one is higher than 50%. The yield of the purified 5-f luoro-4-imino-3- methyl-1- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%. In some embodiments, the chemical yield of 5-f luoro-4-imino-3-methyl-l- (toluene-4- sulfonyl) -3, 4-dihydro-1H-pyrimidin-2-one is higher than 70%. In some embodiments, the chemical yield of 5-fluoro-4-imino-3-methyl- 1- (toluene-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 80%. In some embodiments, the chemical yield of 5-fluoro-4- imino-3-methyl-l- (toluene-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2- one is higher than 90%.

[0971] In some embodiments, the conversion of the 5-f luoro-4-imino-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H- pyrimidin-2-one to 5-f luoro-4-imino-3-methyl-l- (optionally substituted phenyl-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one is higher than 50%.

[0972] In some embodiments, the chemical yield of 5-f luoro-4-imino-3- methyl-1- ( optionally substituted phenyl -4-sulf onyl ) -3 , 4-dihydro- 1H-pyrimidin-2-one is higher than 50%. The yield of the purified 5-f luoro-4-imino-3-methyl-l- (optionally substituted phenyl-4- sulfonyl) -3, 4-dihydro-1H-pyrimidin-2-one is higher than 50%, 60%, 70%, 80%, 90% or 99%.

[0973] In some embodiments, substituted phenyl means phenyl that is substituted with R which is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3. In some embodiments, the mixture comprises the compound having formula (I) , at least one water immiscible solvent, and at least one additional solvent, and the process for isolating the compound having formula (I) comprises (i) washing the mixture with water to obtain slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0974] In some embodiments, the multi-phase system comprises a liquid and solids. In some embodiments, wherein the multi-phase system comprises a liquid and solids, the process for isolating the compound having formula (I) from the reaction mixture comprises filtering the solids.

[0975] For example, the compound having formula (I) may be isolated from the reaction mixture in according with the process described herein as route 1.

[0976] In some embodiments, the mixture comprises the compound having formula (I) and DMS, and the process for isolating the compound having formula (I) from the reaction mixture comprises (1) adding at least one water immiscible solvent, an aqueous basic solution, and an acid to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids .

[0977] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0978] In some embodiments, the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is non-polar.

[0979] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20. In some embodiments, the polar solvent is an organic polar solvent.

[0980] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[0981] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof.

[0982] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0983] In some embodiments, the process comprises evaporation of the polar solvent prior to filtration. In some embodiments, the process comprises partial evaporation of the polar solvent prior to filtration .

[0984] In some embodiments, the process comprises cooling the reaction mixture prior to filtration.

[0985] In some embodiments, step (a) is conducted in the presence of at least one water-immiscible solvent.

[0986] In some embodiments, the water immiscible solvent is added after step (a) and before addition of the aqueous basic solution to the reaction mixture.

[0987] In some embodiments, the water immiscible solvent is added at the same time as addition of the aqueous basic solution to the reaction mixture .

[0988] In some embodiments, the water immiscible solvent is added after addition of the aqueous basic solution to the reaction mixture. In some embodiments, the water immiscible solvent is added immediately after addition of the aqueous basic solution to the reaction mixture . In some embodiments, the water immiscible solvent is an ether-based solvent, an aromatic solvent, or a mixture thereof.

[0989] In some embodiments, the water immiscible solvent is CPME, THF, anisole, toluene, or any mixture thereof.

[0990] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0991] In some embodiments, the water immiscible solvent and the aqueous basic solution are added sequentially.

[0992] In some embodiments, the water immiscible solvent is added gradually .

[0993] In some embodiments, the aqueous basic solution is added gradually.

[0994] In some embodiment, step (a) is conducted in the presence of a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[0995] In some embodiments, step (a) is conducted in the presence of at least one water-immiscible solvent.

[0996] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THF, anisole, toluene, and any mixture thereof.

[0997] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0998] In some embodiments, step (a) is conducted in the presence of a solvent in addition to the water immiscible solvent.

[0999] In some embodiments, step (a) is conducted in the presence of a solvent and without a water immiscible solvent.

[1000] In some embodiments, the solvent is DMA. In some embodiments, step (a) is conducted in the presence of a mixture of solvents wherein at least one solvent is water immiscible and at least one solvent is water miscible.

[1001] In some embodiments, the mixture of solvents is a mixture of a polar water miscible solvent and a non-polar water-immiscible solvent .

[1002] In some embodiments, the mixture of solvents is DMA and anisole. In some embodiments, the weight ratio between DMA and anisole is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and anisole is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between anisole and the compound having formula (II) is from about 10:1 to about 1:1.

[1003] In some embodiments, the mixture of solvents is a mixture of DMA and toluene. In some embodiments, the weight ratio between DMA and toluene is between 100:1 to 1:1. In some embodiments, the weight ratio between DMA and toluene is about 1:1. In some embodiments, the weight ratio between DMA and the compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio between toluene and the compound having formula (II) is from about 10:1 to about 1:1.

[1004] In some embodiments, the compound having formula (I) reacts with DMS in the presence of a base having a pKa equal to or less than the pKa of the compound having formula (I) .

[1005] During the reaction and before water in any form, such as in the form of an aqueous basic solution, is added to the reaction mixture, the compound having formula (I) may be in salt form. In some embodiments, the compound having formula (I) is in salt form. In some embodiments, the compound having the formula (I) is in salt form during the reaction. In some embodiments, the compound having formula (I) is partially in salt form. In some embodiments, the compound having formula (I) is partially in salt form during the reaction. In some embodiments, the salt of the compound having formula (I) is a monomethylsulfate salt of the compound having formula ( I ) .

[1006] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to from an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystalized solid.

[1007] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to form an organic phase and a water phase.

[1008] In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1009] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid . In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to form an organic phase and a water phase.

[1010] In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1011] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding at least one water immiscible solvent, an aqueous basic solution and an acid to the reaction mixture to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystalizing the compound having the formula (I) and filtering the crystallized solid.

[1012] In some embodiments, the aqueous basic solution is a 2-18% w / w aqueous basic solution.

[1013] In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1014] In some embodiments, the compound having the formula (I) is crystalized by concentrating the organic phase, adding an antisolvent, and / or seeding.

[1015] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) in the presence of at least one water immiscible solvent and at least one additional solvent, and (2) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to obtain a slurry mixture comprising precipitated solids, and (ii) filtering the precipitated solids . In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.

[1016] In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1017] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent and at least one additional solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution and an acid to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[1018] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids.

[1019] In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1020] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , (2) adding at least one water immiscible solvent to the reaction mixture, and (3) isolating the compound having formula (I) from the reaction mixture by (i) washing the reaction mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids .

[1021] In some embodiments, step (i) comprises washing the reaction mixture with 2-18% w / w of aqueous basic solution to obtain a slurry mixture comprising precipitated solids. In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1022] In some embodiments, the process comprises (1) preparing the compound having formula (I) by reacting the compound having the formula (II) with dimethylsulphate (DMS) , and (2) isolating the compound having formula (I) from the reaction mixture by (i) adding an aqueous basic solution and an acid, at least one water immiscible solvent and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[1023] In some embodiments, the aqueous basic solution is a 2-18% w / w aqueous basic solution.

[1024] In some embodiments, step (i) comprises addition of 20-50% HC1 in water .

[1025] In some embodiments, the aqueous basic solution is an aqueous solution comprising DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCOs, K2CO3NH4OH, NaOH, and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[1026] In some embodiments, the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments, the concentration of the base in the aqueous basic solution is about 18% based on the total weight (w / w) . In some embodiments, the concentration of the acid is 20-50% HC1 in water. In some embodiments, the concentration of the acid is 25-40% HC1 in water. In some embodiments, the concentration of the acid is 32% HC1 in water.

[1027] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[1028] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[1029] In some embodiments, the additional solvent is different from the water immiscible solvent.

[1030] In some embodiments, the additional solvent is a polar solvent.

[1031] In some embodiments, the polar solvent has a dielectric constant equal to or above 5.

[1032] In some embodiments, the ratio between the additional solvent to the compound having formula (I) or formula (II) is about 1:1.

[1033] In some embodiments, the additional solvent is CPME.

[1034] In some embodiments, the slurry mixture is mixed at a temperature between 25 to 50 degrees Celsius.

[1035] In some embodiments, in step (b) , the precipitated solids are filtered at a temperature between 10 to 45 degrees Celsius.

[1036] In some embodiments, the water immiscible solvent is polar.

[1037] In some embodiments, the water immiscible solvent is non-polar.

[1038] The present invention provides a monomethylsulfate salt of the compound having formula (I) . In some embodiments, the compound having formula (II) is prepared in a reaction of 5-f luorocytosine with the compound having formula (III) that is carried out in the absence of protecting group.

[1039] The present invention also provides a compound having formula (I) obtained using any one of the processes described herein.

[1040] The present invention also provides a compound having formula (Tai) obtained using any one of the processes described herein.

[1041] Methods for isolating a compound having formula (I) from a mixture thereof, including routes 1-3, are described below.

[1042] The methods for isolating a compound having formula (I) may be applied to any mixture comprising the compound having formula (I) , including the reaction mixtures of the processes described herein for preparing the compound having formula (I) and the reaction mixtures of the processes described in PCT International Application Publication Nos. WO 2015 / 103142, WO 2015 / 103144, and WO / 2021 / 181274 for preparing the compound having formula (I) .

[1043] The mixture, including reaction mixture resulting from the alkylation step of the process for preparing the compound having formula (I) , may comprise a non-salt form of the compound having the formula (I) , a salt form of the compound having the formula (I) , or a mixture thereof.

[1044] In some embodiments, the step after reacting compound having formula (II) with DMS to give the salt and / or non-salt form of the compound having the formula (I) is defined as the isolation step. In some embodiments, a salt form of the compound having formula (I) is formed prior to the isolation step. In some embodiments, a non-salt form of the compound having formula (I) is formed prior to the isolation step. In some embodiments, the non-salt form of compound having formula (I) is obtained by adding water after reaction with DMS with compound having formula (II) . In some embodiments, isolation includes neutralization of the salt form of the compound having the formula (I) .

[1045] Isolation of compound having the formula (I) , route 1

[1046] The present invention also provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, wherein the method comprises (1) adding at least one water immiscible solvent, an aqueous basic solution and an acid to the mixture to form precipitated solids of the compounds having formula (I) and (2) filtering the precipitated solids .

[1047] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[1048] In some embodiments, the acid is HC1.

[1049] In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[1050] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[1051] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[1052] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[1053] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[1054] In some embodiments, the compound having formula (I) is a compound having formula (lai) :

[1055] (lai)

[1056] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[1057] In some embodiments, the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is non- polar.

[1058] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[1059] In some embodiments, the polar solvent is an organic polar solvent.

[1060] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM, toluene, anisole, and any combination thereof.

[1061] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof.

[1062] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[1063] In some embodiments, the method comprises evaporation of the polar solvent prior to filtration. In some embodiments, the method comprises partial evaporation of the polar solvent prior to filtration .

[1064] In some embodiments, the method comprises cooling the reaction mixture prior to filtration.

[1065] The method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015 / 103144 and W02015 / 103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in International Application Publication No. W02021 / 059160 and WO / 2021 / 181274. The entire content of each of W02015 / 103144, W02015 / 103142 , WO / 2021 / 181274 and W02021 / 059160 is hereby incorporated by reference.

[1066] Isolation of compound having the formula (I) , route 2

[1067] The present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution and ana acid to form an organic phase and a water phase, (ii) separating the organic phase from the water phase, and (iii) crystallizing the compound having the formula (I) from the organic phase and filtering the crystals.

[1068] In some embodiments, the acid is selected from HC1, H2SO4 and H2PO4.

[1069] In some embodiments, the acid is HC1. In some embodiments the acid is 20-50% HC1 in water. In some embodiments the acid is 25-40% HC1 in water. In some embodiments the acid is 32% HC1 in water.

[1070] In some embodiments, the acid is 50%-98% H2SO4 in water. In some embodiments the acid is 98% H2SO4 in water.

[1071] In some embodiments, the acid is 50%-98% H3PO4 in water. In some embodiments the acid is 98% H3PO4 in water.

[1072] In some embodiments, the acid is 32% HC1, and the molar ratio between the base and the acid is 5-2:1. In some embodiments, the molar ratio between the base and the acid is 5-2.2:1. In some embodiments, the molar ratio between the base and the acid is about 3:1.

[1073] I some embodiments, the acid is added to obtain a pH between 7.8 and 8.5.

[1074] In some embodiments, the compound having formula (I) is a compound having formula (lai

[1075] (lai)

[1076] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3NH4OH, NaOH, and any combination thereof . In some embodiments , the aqueous basic solution is an aqueous solution of K2CO3.

[1077] In some embodiments , the concentration of the base in the aqueous basic solution is 2-18 % based on the total weight (w / w) . In some embodiments , the concentration of the base in the aqueous basic solution is about 15% based on the total weight (w / w) . In some embodiments , the concentration of the base in the aqueous basic solution is about 18 % based on the total weight (w / w) .

[1078] In some embodiments , the compound having the formula ( I ) is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution . In some embodiments , the compound having the formula ( I ) in salt form is dissolved in the water immiscible solvent or a mixture of a water immiscible solvent with a water miscible solvent to obtain an organic solution .

[1079] In some embodiments , the water immiscible solvent is polar . In some embodiments , the water immiscible solvent is non-polar . In some embodiments , the water immiscible solvent is an organic polar solvent .

[1080] In some embodiments , the water immiscible solvent includes but not limited to CPME , MeTHF, DCM, toluene , anisole or any combination thereof .

[1081] In some embodiments , the water immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene , anisole , and any combination thereof .

[1082] In some embodiments , the water immiscible solvent is selected from the group consisting of methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME ) , toluene , anisole , and any mixture thereof . In some embodiments, the water immiscible solvent is CPME. In some embodiments, the water immiscible solvent is MeTHF. In some embodiments, the water immiscible solvent is DCM. In some embodiments, the water immiscible solvent is toluene. In some embodiments, the water immiscible solvent is anisole.

[1083] In some embodiments, the compound having the formula (I) is crystalized from the organic phase. In some embodiments, the compound having the formula (I) is crystallized by concentrating the organic phase. In some embodiments, the compound having the formula (I) is crystallized by adding an anti-solvent. In some embodiments, the compound having the formula (I) is crystallized by seeding.

[1084] The present invention provides a method for isolating a compound having the formula (I) comprising (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution and an acid, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[1085] In some embodiments, the method for isolating a compound having the formula (I) comprises (1) washing of an organic solution comprising a polar water immiscible solvent and a mixture of compound (I) and DMS with 2-18% w / w of aqueous basic solution and 20-50% HC1 in water, (2) separating the organic phase from the water phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[1086] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[1087] The present invention provides a method for isolating the compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, wherein the method comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution and an acid, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[1088] In some embodiments, the method for isolating the compound having the formula (I) from a mixture comprising the compound having formula (I) and DMS, comprises (1) dissolving the mixture comprising the compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution, (2) washing the organic solution obtained from (1) with 2-18% w / w of aqueous basic solution and 20-50% HC1, (3) separating the organic phase from the water phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[1089] In some embodiments, the polar solvent has a dielectric constant equal to or above 5. In some embodiments, the polar solvent has a dielectric constant equal to or above 10. In some embodiments, the polar solvent has a dielectric constant equal to or above 15. In some embodiments, the polar solvent has a dielectric constant equal to or above 20.

[1090] In some embodiments, the organic polar solvent is an organic polar water immiscible solvent.

[1091] In some embodiments, the organic water immiscible solvent has a dielectric constant less than 20.

[1092] In some embodiments, organic water immiscible solvent includes but is not limited to methyl tetrahydrofuran (MeTHF) , cyclopentylmethylether (CPME) , and a mixture thereof.

[1093] In some embodiments, the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMF, DCM and any combination thereof. In some embodiments, the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM and any combination thereof .

[1094] In some embodiments, the organic polar solvent is DMA. In some embodiments, the organic polar solvent is CPME. In some embodiments, the organic polar solvent is MeTHF.

[1095] In some embodiments, the organic phase is cooled prior to and / or during the filtration. In some embodiments, the organic phase is cooled to 0-10°C. In some embodiments, the organic phase is cooled to 0-5°C. In some embodiments, the organic phase is cooled to 0°C. In some embodiments, the organic phase is cooled to 5 °C. In some embodiments, the organic phase is cooled to 10 °C.

[1096] In some embodiments, the organic polar solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, the CPME is added after the reaction to obtain the compound having the formula (I) .

[1097] In some embodiments, a partial amount of the organic polar solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the organic polar solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the CPME is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of CPME is added before isolation of the compound having formula (I) .

[1098] In some embodiments, the compound having the formula (I) in the mixture before the isolation step is in salt form.

[1099] In some embodiments, the non-polar solvent is a non-polar water immiscible solvent. In some embodiments, the non-polar water immiscible solvent dissolves the compound of formula (I) .

[1100] In some embodiments, the water immiscible solvent includes but is not limited to ether-based solvent, aromatic solvent such as CPME, THE, anisole, toluene, and any mixture thereof.

[1101] In some embodiments, the non-polar solvent is anisole. In some embodiments, the non-polar solvent is toluene.

[1102] In some embodiments, an anti-solvent is further added.

[1103] In some embodiments, the anti-solvent is added parallel to the to the water immiscible solvent.

[1104] In some embodiments, the anti-solvent is added dropwise.

[1105] In some embodiments, the crystallization is conducted at temperature less than 0°C. In some embodiments, the crystallization is conducted at 10°C.

[1106] In some embodiments, the anti-solvent is a C5-C11 alkane. In some embodiments, the anti-solvent is hexane. In some embodiments, the anti-solvent is heptane. In some embodiments, the C5-C11 alkane is cyclic. In some embodiments, the anti-solvent is cyclohexane . In some embodiments, the anti-solvent is methylcyclohexane .

[1107] In some embodiments, the mixture of solvent and anti-solvent are anisole and hexane.

[1108] In some embodiments, the mixture of solvent and anti-solvent are toluene and hexane.

[1109] In some embodiments, the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof. In some embodiments, the aqueous basic solution is an aqueous solution of a base selected from the group consisting of DABCO, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt and any combination thereof.

[1110] In some embodiments, the aqueous basic solution is an aqueous solution of K2CO3.

[1111] In some embodiments, the acid is an aqueous solution of HC1.

[1112] In some embodiments, the compound having formula (I) is a compound having formula (la wherein R is alkyl.

[1113] In some embodiments, the compound having formula (la) is a compound having formula (lai) wherein R is methyl.

[1114] In some embodiments, the organic phase is cooled prior to and / or during the filtration. In some embodiments, the organic phase is cooled to 0-10°C. In some embodiments, the organic phase is cooled to 0-5°C. In some embodiments, the organic phase is cooled to 0°C. In some embodiments, the organic phase is cooled to 5 °C. In some embodiments, the organic phase is cooled to 10 °C.

[1115] In some embodiments, the crystallization is done by concentration of the solvent.

[1116] In some embodiments, the crystallization is done with crystal seeding .

[1117] In some embodiments, the mixture is seeded with 0.1-1% of the compound of formula (I) .

[1118] In some embodiments, the water immiscible solvent is added after the reaction to obtain the compound having the formula (I) . In some embodiments, anisole and hexane are added after the reaction to obtain the compound having the formula (I) .

[1119] In some embodiments, a partial amount of the water immiscible solvent is present from the reaction to obtain the compound having formula (I) and optionally additional amount of the water immiscible solvent is added before isolation of the compound having formula (I) . In some embodiments, a partial amount of the anisole is present from the reaction to obtain the compound having formula (I) and optionally an additional amount of anisole optionally with hexane are added before isolation of the compound having formula (I) •

[1120] The method for isolating a compound having formula (I) from a mixture thereof may be used to isolate a compound having formula (I) from any mixture thereof, including, but not limited to, (i) the reaction mixture after preparing the compound having formula (I) using the processes described herein, (ii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application Publication Nos. W02015 / 103144 and WO2015 / 103142 , and (iii) the reaction mixture after preparing the compound having formula (I) using the processes described in PCT International Application publication No. WC2021 / 059160 and WO / 2021 / 181274. The entire content of each of W02015 / 103144, W02015 / 103142 , WO / 2021 / 181274 and W02021 / 059160 is hereby incorporated by reference.

[1121] Isolation of compound having the formula (I) , route 3

[1122] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS, at least one water immiscible solvent, and at least one additional solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution and an acid to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[1123] In some embodiments, the present invention provides a method for isolating a compound having the formula (I) from a mixture comprising the compound having formula (I) , DMS and at least one water immiscible solvent, wherein the method comprises (i) washing the mixture with an aqueous basic solution, an acid and at least one additional solvent to obtain slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[1124] In some embodiments, the present invention provides...

Claims

Claims1. A process for obtaining 5-f luoro-4-imino-3-methyl-l- (phenyl -4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one having formula (I) :comprising :(a) reacting 5-f luorocytosine with compound having formula (III) :in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II)(b) reacting the compound having formula (II) with dimethylsulphate(DMS) ;whereinR is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF3; andX is a halogen or -OSO2PhR; and(c) isolating the compound having formula (I) from the reaction mixture .

2. The process of claim 1, wherein the reaction of step (a) is conducted at a temperature of about 15-20 °C.

3. The process of claim 1 or 2 , wherein the metal agent is a salt or compound comprising a metal atom.

4. The process of any one of claims 1-3, wherein the molar ratio between the 5-f luorocytosine and the metal agent is 5:1 to 1.8:1, respectively .

5. The process of any one of claims 1-4, wherein: i) step (b) is conducted in the presence of at least one water- immiscible solvent, and / or ii) at least one water-immiscible solvent is mixed with the reaction mixture after step (b) .

6. The process of any one of claims 1-5, wherein the reaction of the compound having formula (II) with DMS is conducted at a temperature between 10°C to below 25°C.

7. The process of claim 6, wherein the reaction is conducted at a temperature between 10-24 °C.

8. The process of claim 6 or 7, wherein the reaction is conducted at a temperature of about 20 °C.

9. The process of any one of claims 6-8, wherein the reaction of the compound having formula (II) with DMS of step (b) is conducted in the presence of at least one water miscible solvent and the at least one water immiscible solvent is mixed with the reaction mixture after step (b) .

10. The process of any one of claims 6-9, wherein the water immiscible solvent is anisole.

11. The process of any one of claims 6-10, wherein the reaction of the compound having formula (II) with DMS of step (b) is conducted in the presence of DMA and anisole is mixed with the reaction mixture after step (b) .

12. The process of any one of claims 6-11, wherein a multi-phase system is obtained.

13. The process of claim 12, wherein the multi-phase system comprises an organic phase and a water phase and the process of isolating the compound having formula (I) from the reaction mixture comprises separating the organic phase from the water phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals.

14. The process of claim 13, wherein the compound having the formula (I) is crystalized by concentrating the organic phase, mixing the reaction mixture with an anti-solvent, and / or seeding.

15. The process of claim 12, wherein the multi-phase system is a slurry comprising solids, the process for isolating the compound having formula (I) form the reaction mixture comprises filtering the precipitated solids.

16. The process of claim 12, wherein the multi-phase system comprises a liquid and solids and the process for isolating the compound having formula (I) from the reaction mixture comprises filtering the solids.

17. The process of any one of claims 6-9 and 12-16, wherein the water immiscible solvent is an ether-based solvent, an aromatic solvent, or a mixture thereof.

18. The process of any one of claims 6-9 and 12-16, wherein the water-immiscible solvent is toluene, anisole, or a mixture thereof.

19. The process of any one of claims 6-18, wherein the reaction is conducted in the presence of at least one water-immiscible solvent .

20. The process of any one of claims 6-8, 10, and 12-19, wherein: i) the water immiscible solvent is mixed with the reaction mixture after step (b) and before step (c) , ii) the water immiscible solvent is mixed with the reaction mixture in step (c) .

21. The process of any one of claims 6-20, wherein the reaction is conducted in the presence of a mixture of solvents wherein at least one solvent is water immiscible and at least one solvent is water miscible.

22. The process of claim 21, wherein the mixture of solvents is DMA and anisole.

23. The process of any one of claims 1-22, wherein the compound having formula (I) is in salt form.

24. The process of claim 23, wherein the salt is a monomethylsulfate salt of the compound having formula (I) .

25. The process of any one of claims 1-24, wherein in step (c) the compound having formula (I) is isolated from the reaction mixture by mixing the reaction mixture with an aqueous basic solution for obtaining the compound having formula (I) .

26. The process of claim 25, wherein the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof.

27. The process of claim 25 or 26, wherein the aqueous basic solution is an aqueous solution of K2CO3.

28. The process of any one of claims 25-27, wherein the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) .

29. The process of any one of claims 25-28, wherein step (c) further comprises addition of an acid.

30. The process of claim 29, wherein the acid is selected from HC1, H2SO4 and H2PO4.

31. The process of claim 29 or 30, wherein the acid is added to obtain a pH in a range between 7.8-8.5.

32. The process of any one of claims 29-31, wherein the acid isHC1 the molar ratio between the base and the acid is 5-2:1.

33. The process of claim 32, wherein the molar ratio between the base and the acid is 5-2.2 :1.

34. The process of claim 33, wherein the molar ratio between the base and the acid is about 3:1.

35. The process of any one of claims 1-34, wherein the molar ratio between the solvent (s) to the compound having formula (IT) is between 30:1 and 1:1.

36. The process of any one of claims 1-35, wherein the molar ratio between the solvent (s) to DMS is between 10:1 to 1:1.

37. The process of any one of claims 1-36, wherein the molar ratio between the compound having formula (II) and DMS is between 1:2 to 1:10.

38. The process of any one of claims 1-37, wherein the molar ratio between the compound having formula (II) and DMS is between 1:3 to1:4.

39. The process of any one of claims 1-38, wherein the compound having formula (II) and DMS are stirred for about 3-10 hours.

40. The process of any one of claims 1-39, wherein the compound having formula (II) and DMS are stirred for about 6-7 hours.

41. The process of any one of claims 1-40, wherein the reaction of the compound having formula (II) with DMS to obtain the compound having formula (I) has a yield of at least 80%.

42. The process of any one of claims 1-41, wherein the compound having formula (I) is a compound having formula (lai) :(lai) and the compound having formula (II) is a compound having formula(Ilai)wherein R is methyl and X is a halogen or -OSO2PhR.

43. A compound having formula (I) obtained using the process of any one of claims 1-42.

44. A process for obtaining the compound having formula (II) :comprising :(a) reacting 5-f luorocytosine with compound having formula (III) :in the presence of at least one polar solvent, at least one base and a metal agent.

45. The process of claim 44, wherein the metal agent is a salt or compound comprising a metal atom.

46. The process of claim 44 or 45, wherein the reaction of step(a) is conducted at a temperature of about 15-20 °C.

47. The process of any one of claims 44-46, wherein the molar ratio between the 5-f luorocytosine and the metal agent is 5:1 to 1.8:1, respectively.

48. The process of any one of claims 44-47, wherein the reaction of 5-f luorocytosine with the compound having formula (ITT) to obtain compound having formula (II) further comprises a step of isolating the compound having formula (II) from the reaction mixture comprising (i) adding a protic solvent to the mixture to precipitate the compound having formula (II) from the mixture, and (ii) filtering the precipitated solids .

49. The process of claim 48, wherein the protic solvent is water, methanol, or a combination thereof.

50. A process for obtaining 5-fluoro-4-imino-3-methyl-l-(phenyl- 4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one having formula (I) :comprising :(a) preparing the compound having formula (I) by reacting a compound having the formula (II)with dimethylsulphate (DMS) , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF2, and(b) isolating the compound having formula (I) from the reaction mixture by mixing an aqueous basic solution and an acid with the reaction mixture and obtaining the compound having formula (I) , wherein the process comprises use of at least one water immiscible solvent, wherein: i) step (a) is conducted in the presence of at least one water- immiscible solvent, and / or ii) at least one water-immiscible solvent is mixed with the reaction mixture after step (a) .

51. The process of claim 50, wherein the water immiscible solvent (s) has a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature.

52. The process of claim 50 or 51, wherein the water immiscible solvent or one of the water immiscible solvents is anisole.

53. The process of any one of claims 50-52, wherein the reaction of the compound having formula (II) with DMS is conducted at a temperature between 10°C-85°C.

54. The process of any one of claims 50-53, wherein the reaction of the compound having formula (II) with DMS is conducted at a temperature between 10°C to below 25°C.

55. The process of any one of claims 50-54, wherein the aqueous basic solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt or any combination thereof.

56. The process of any one of claims 50-55, wherein the aqueous basic solution is an aqueous solution of K2CO3.

57. The process of any one of claims 50-56, wherein the concentration of the base in the aqueous basic solution is 2-18% based on the total weight (w / w) .

58. The process of any one of claims 50-57, wherein the acid is selected from HC1, H2SO4 and H2PO4.

59. The process of any one of claims 50-58, wherein the acid is added to obtain a pH in a range between 7.8-8.5.

60. The process of any one of claims 50-59, wherein the acid is HC1, and the molar ratio between the base and the acid is 5-2:1.

61. The process of claim 60, wherein the molar ratio between the base and the acid is 5-2.2 :1.

62. The process of claim 61, wherein the molar ratio between the base and the acid is about 3:1.

63. A process for obtaining 5-f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3 , 4-dihydro-1H-pyrimidin-2-one having formula (I) :comprising :(a) reacting 5-f luorocytosine with compound having formula (III) :in the presence of at least one polar solvent, at least one base and a metal agent to obtain the compound having formula (II)wherein the molar ratio between the 5-f luorocytosine and the metal agent is 5:1 to 1.8:1, respectively,(b) reacting the compound having the formula (II) with dimethylsulphate (DMS) , wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkyl carbonyl, hydroxyalkyl, ester, acid halogen, -SH, -OH, -NH2, -NO2, -CN or CF2, and(c) isolating the compound having formula (I) from the reaction mixture by mixing an aqueous basic solution and an acid with the reaction mixture and obtaining the compound having formula (I) , wherein the acid is added to obtain a pH at a range between 7.8- 8.5, and wherein the process comprises use of at least one water immiscible solvent, wherein: i) step (1) is conducted in the presence of at least one water- immiscible solvent, and / or ii) at least one water-immiscible solvent is mixed with the reaction mixture after step (1) , and wherein the method comprises conducting the reaction of the compound having formula (II) with DMS at a temperature between 10 °C to below 25°C.

64. A method of improving yield of 5-f luoro-4-imino-3-methyl-l- (phenyl-4-sulf onyl ) -3, 4-dihydro-1H-pyrimidin-2-one having formula (I)in a process according to any one of claims 1-63.

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