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

Abstract

The present invention provides a method for obtaining a 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3, 4-dihydro-1H-pyrimidin-2-one of the formula (I), which is characterized in that the 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3, 4-dihydro-1H-pyrimidin-2-one has a general formula (I), wherein R is hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, an alkylthio group, a halogenated alkylthio group, an amino group, an alkylamino group, a dialkylamino group, an alkoxycarbonyl group, an alkylcarbonyl group, a hydroxyalkyl group, an ester, a haloid acid,-SH,-OH,-NH2,-NO2,-CN or CF3.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 454,125, filed March 23, 2023, the contents of which are hereby incorporated by reference.

[0002] Various publications have been cited throughout this application. The disclosures of these documents are hereby incorporated, in their entirety, into this application in order to provide a more complete description of the prior art to which this invention pertains. Technical Field

[0003] The subject of this invention relates to an efficient procedure for obtaining 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one. Background Technology

[0004] The compound 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one has the following structure:

[0005]

[0006] 5-Fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is a systemic fungicide that controls various pathogens in important economic crops, including but not limited to the pathogen of wheat leaf spot, SEPTTR.

[0007] Different manufacturing methods are known from the literature, including those described in WO 2015 / 103144 and WO 2015 / 103142.

[0008] There is a need to develop more efficient synthetic routes in terms of cost, yield, conversion rate and purity. Summary of the Invention

[0009] This invention provides a method for obtaining 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0010]

[0011] The method includes:

[0012] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0013]

[0014] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0015] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0016] The method includes using at least one water-immiscible solvent, wherein:

[0017] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0018] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0019] and

[0020] The reaction of the compound having formula (II) with DMS is carried out at a temperature between 10°C and below 25°C.

[0021] This invention provides a method for obtaining 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0022]

[0023] The method includes:

[0024] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0025]

[0026] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0027] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0028] The method includes using at least one water-immiscible solvent, wherein:

[0029] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0030] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0031] and

[0032] The one or more water-immiscible solvents wherein the solubility of the compound having formula (I) is greater than 33 mg / mL at room temperature.

[0033] This invention provides a method for improving the yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0034]

[0035] In the method, the method includes:

[0036] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0037]

[0038] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0039] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0040] The method includes using at least one water-immiscible solvent, wherein:

[0041] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0042] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0043] The method described herein includes reacting the compound having formula (II) with DMS at a temperature between 10°C and below 25°C.

[0044] This invention provides a method for improving the volumetric yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0045]

[0046] In the method, the method includes:

[0047] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0048]

[0049] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0050] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0051] The method includes using at least one water-immiscible solvent, wherein:

[0052] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0053] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0054] The method described herein includes using a water-immiscible solvent having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature. Detailed Implementation

[0055] Before elaborating on this topic in detail, it may be helpful to provide definitions for certain terms used herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this topic pertains.

[0056] Unless otherwise specified, the term "a / an" as used herein includes both the singular and the plural. Therefore, the terms "a / an" or "at least one" are used interchangeably in this application.

[0057] Throughout this application, the description of various embodiments uses the term "comprising"; however, those skilled in the art will understand that in certain specific cases, the language of "substantially consisting of" or "consisting of" may be used instead to describe embodiments. In each such case, the terms "comprising," "substantially consisting of," and "consisting of" are intended to have the same meaning as each such term when used as a transitional phrase in a patent claim.

[0058] In the embodiments, the term "about" as used herein specifically includes ±10% of the indicated value within the range. By example, about 15% therefore includes 13.5%, 13.6%, 13.7%, and so on up to 16.5%. The term "about" as used herein more specifically includes ±1% of the indicated value within the range. By example, about 100 mg / kg therefore includes 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9, 100, 100.1, 100.2, 100.3, 100.4, 100.5, 100.6, 100.7, 100.8, 100.9, and 101 mg / kg. Thus, in one embodiment, about 100 mg / kg includes 100 mg / kg.

[0059] Furthermore, the endpoints of all ranges referring to the same component or property herein are independent combinations and include all intermediate points and ranges. Where a range is given in the specification, it should be understood that the range includes all integers within that range and 0.1 units and any subranges thereof. For example, a range of “2%-18%” is the disclosure of 2.0%, 2.1%, 2.2%, 2.3%, etc., up to 18%.

[0060] As used herein, "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. Thus, as in "C1-C..." n C1-C in "alkyl" n Defined as a group comprising a linear or branched arrangement of 1, 2, ..., n-1 or n carbons, and specifically including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl, etc. One embodiment may be C1-C 12 Alkyl, C2-C 12 Alkyl, C3-C 12 Alkyl, C4-C 12 Alkyl groups, etc. One embodiment may be C1-C8 alkyl, C2-C8 alkyl, C3-C8 alkyl, C4-C8 alkyl, etc.

[0061] As used herein, “alkoxy” refers to an alkyl group as described above that is attached by an oxygen bridge.

[0062] As used in this article, "Ph" refers to phenyl.

[0063] As used in this article, the term "soluble" means that 1g of a substance dissolves in approximately 100ml of water.

[0064] In some embodiments, when used in relation to a solvent, the term "water immiscible" means that the solvent does not completely mix with water to form a single-phase solution.

[0065] As used in the description of the toluenesulfonation step, the term "polar solvent" means a solvent having a dielectric constant equal to or greater than 20. As used in the remaining applications, including in the description of sulfonation steps other than the toluenesulfonation, alkylation, and separation steps, the term "polar solvent" has the meaning commonly understood by one of ordinary skill in the art to which this subject belongs, and includes, but is not limited to, solvents having a dielectric constant equal to or greater than 20.

[0066] The polar solvents used in each of the sulfonation, alkylation, and separation steps can be the same or different. When the sulfonation step is a toluenesulfonation step, the polar solvent has a dielectric constant equal to or greater than 20.

[0067] As used herein, the term "Formula (II)" refers to the following structure:

[0068] Wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and their tautomers, including but not limited to their enamine tautomers.

[0069] As used herein, the term "formula (IIai)" refers to the following structure:

[0070] and their tautomers, including but not limited to their enamine tautomers. For example, compounds having the formula (IIai) include two of the following compounds:

[0071]

[0072] This invention provides a method for obtaining 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0073]

[0074] The method includes:

[0075] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0076]

[0077] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0078] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0079] The method includes using at least one water-immiscible solvent, wherein:

[0080] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0081] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0082] and

[0083] The reaction of the compound having formula (II) with DMS is carried out at a temperature between 10°C and below 25°C.

[0084] This invention provides a method for obtaining 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0085]

[0086] The method includes:

[0087] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0088]

[0089] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0090] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0091] The method includes using at least one water-immiscible solvent, wherein:

[0092] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0093] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0094] and

[0095] The one or more water-immiscible solvents wherein the solubility of the compound having formula (I) is greater than 33 mg / mL at room temperature.

[0096] An example of a water-immiscible solvent having a solubility greater than 33 mg / mL for a compound of formula (I) at room temperature is anisole. Other water-immiscible solvents having a solubility greater than 33 mg / mL for a compound of formula (I) at room temperature can be identified through routine experiments.

[0097] In some embodiments, the water-immiscible solvent has a solubility of greater than 33 mg / mL and up to 200 mg / mL for a compound of formula (I) at room temperature. In some embodiments, one or more water-immiscible solvents have a solubility of greater than 33 mg / mL and up to 150 mg / mL for a compound of formula (I) at room temperature. In some embodiments, one or more water-immiscible solvents have a solubility of greater than 33 mg / mL and up to 100 mg / mL for a compound of formula (I) at room temperature.

[0098] In some embodiments, after step (1), a mixture of two or more water-immiscible solvents is mixed with the reaction mixture. In some embodiments, after step (1), a mixture of two water-immiscible solvents is mixed with the reaction mixture. In some embodiments, after step (1), a mixture of three water-immiscible solvents is mixed with the reaction mixture. In some embodiments, after step (1), a mixture of four water-immiscible solvents is mixed with the reaction mixture.

[0099] In some embodiments, the mixture of water-immiscible solvents has a solubility of the compound having 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 having 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 having formula (I) greater than 33 mg / mL and up to 100 mg / mL at room temperature.

[0100] In some embodiments, one of the water-immiscible solvents or a plurality of water-immiscible solvents is anisole.

[0101] In some embodiments, anisole is mixed with the reaction mixture after step (1). In some embodiments, anisole is mixed with the reaction mixture only after step (1).

[0102] In some embodiments, the reaction of the compound having formula (II) in step (1) with DMS is carried out 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 (1).

[0103] This article describes suitable water-miscible and water-immiscible solvents.

[0104] In some embodiments, the reaction of the compound having formula (II) in step (1) with DMS is carried out in the presence of DMA, and anisole is mixed with the reaction mixture after step (1).

[0105] When mixing the water-immiscible solvent with the reaction mixture after step (1), the water-immiscible solvent can be mixed before step (2).

[0106] In some embodiments, the reaction mixture is added to an alkaline aqueous solution.

[0107] In some embodiments, an alkaline aqueous solution is added to the reaction mixture.

[0108] In some embodiments, R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3.

[0109] In some embodiments, the compound having formula (II) is (IIa), wherein R is an alkyl group.

[0110] In some embodiments, the compound having formula (IIa) is (IIai), where R is a methyl group.

[0111] In some embodiments, the compound having formula (I) is (Ia), where R is an alkyl group.

[0112] In some embodiments, the compound having formula (Ia) is (Iai), where R is a methyl group.

[0113] In some embodiments, the method forms a multiphase system. In some embodiments, a multiphase system is obtained at the end of step 2.

[0114] In some embodiments, the multiphase system comprises an organic phase and an aqueous phase. In some embodiments, the multiphase system is a slurry mixture comprising solids. The type of multiphase system formed depends on the volume and / or temperature of the water-immiscible solvent.

[0115] In some embodiments, the multiphase system comprises an organic phase and an aqueous phase, the organic phase comprising a water-immiscible solvent. In some embodiments, the method comprises heating the multiphase system to dissolve a compound having formula (I) in the organic phase. In some embodiments, the method comprises heating the multiphase system to 80°C to dissolve a compound having formula (I) in the organic phase.

[0116] In some embodiments, wherein the multiphase system comprises an organic phase and an aqueous phase, the method for separating a compound having formula (I) from the reaction mixture includes separating the organic phase from the aqueous phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals.

[0117] For example, compounds having formula (I) can be isolated from the reaction mixture according to the method described herein as pathway 2.

[0118] In some embodiments, step (1) is carried out in the presence of at least one water-immiscible solvent, and the reaction mixture comprises a compound having formula (I), DMS, and at least one water-immiscible solvent.

[0119] In some embodiments, a water-immiscible solvent is added after step (1) and before step (2), and the reaction mixture comprises a compound having formula (I), DMS, and at least one water-immiscible solvent.

[0120] In some embodiments, a water-immiscible solvent is added to the alkaline aqueous solution used in step (2).

[0121] In some embodiments, wherein the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, step (2) for separating the compound having formula (I) from the reaction mixture comprises (i) mixing the mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound having formula (I) from the organic phase and filtering the crystals.

[0122] In some embodiments, wherein the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, step (2) for separating the compound having formula (I) from the reaction mixture comprises (i) washing the mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound having formula (I) from the organic phase and filtering the crystals.

[0123] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) from the organic phase and filtering the crystals.

[0124] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) from the organic phase and filtering the crystals.

[0125] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) mixing at least one water-immiscible solvent with the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) from the reaction mixture and filtering the crystallized solid.

[0126] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing at least one water-immiscible solvent and an alkaline aqueous solution with the reaction mixture to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0127] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing at least one water-immiscible solvent with the reaction mixture and mixing with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0128] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with a mixture of an alkaline aqueous solution and at least one water-immiscible solvent to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0129] In some embodiments, the reaction mixture is added to a water-immiscible solvent.

[0130] In some embodiments, a water-immiscible solvent is added to the reaction mixture.

[0131] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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 alkaline aqueous solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3, NH4OH, NaOH, and any combination thereof. In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0132] In some embodiments, the concentration of the base in the alkaline aqueous solution is 2%-18% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 15% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 18% based on total weight (w / w).

[0133] In some embodiments, a compound having formula (I) is dissolved in a water-immiscible solvent or a mixture of a water-immiscible solvent and a water-miscible solvent to obtain an organic solution. In some embodiments, a compound having formula (I) in salt form is dissolved in a water-immiscible solvent or a mixture of a water-immiscible solvent and a water-miscible solvent to obtain an organic solution.

[0134] In some embodiments, the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is nonpolar. In some embodiments, the water-immiscible solvent is an organic polar solvent.

[0135] In some embodiments, the water-immiscible solvent includes, but is not limited to, cyclopentylmethyl ether (CPME), methyltetrahydrofuran (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.

[0136] In some embodiments, the water-immiscible solvent is selected from the group consisting of MeTHF, CPME, toluene, anisole, and any mixture thereof.

[0137] 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.

[0138] In some embodiments, a compound having formula (I) is crystallized from an organic phase by concentrating the organic phase. In some embodiments, a compound having formula (I) is crystallized from an organic phase by adding an antisolvent. In some embodiments, a compound having formula (I) is crystallized from an organic phase by crystallization initiation.

[0139] In some embodiments, the antisolvent is a C5-C11 alkane. In some embodiments, the antisolvent is hexane. In some embodiments, the antisolvent is heptane.

[0140] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0141] In some embodiments, a method for separating a compound having formula (I) includes (1) mixing an organic solution comprising a mixture of a polar water-immiscible solvent and compound (I) with DMS with an alkaline aqueous solution of 2%-18% w / w, (2) separating the organic phase from the aqueous phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[0142] In some embodiments, a method for separating a compound having formula (I) comprises: (1) washing an organic solution containing a polar water-immiscible solvent and a mixture of compound (I) and DMS with an alkaline aqueous solution of 2%-18% w / w; (2) separating the organic phase from the aqueous phase; and (3) concentrating the organic phase and filtering the precipitated solid.

[0143] In some embodiments, a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I) and DMS includes: (1) dissolving the mixture comprising a compound having formula (I) and DMS in an organic polar solvent to obtain an organic solution; (2) mixing the organic solution obtained in (1) with an alkaline aqueous solution of 2%-18% w / w; (3) separating the organic phase from the aqueous phase; and (4) concentrating the organic phase and filtering the precipitated solid.

[0144] In some embodiments, a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I) and DMS includes: (1) dissolving the mixture comprising a 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 an alkaline aqueous solution of 2%-18% w / w; (3) separating the organic phase from the aqueous phase; and (4) concentrating the organic phase and filtering the precipitated solid.

[0145] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20.

[0146] In some embodiments, the organic polar solvent is an organic polar water-immiscible solvent.

[0147] In some embodiments, the organic water-immiscible solvent has a dielectric constant of less than 20.

[0148] In some embodiments, organic water-immiscible solvents include, but are not limited to, methyltetrahydrofuran (MeTHF), cyclopentylmethyl ether (CPME), and mixtures thereof.

[0149] In some embodiments, the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, and any combination thereof.

[0150] In some embodiments, the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM, and any combination thereof.

[0151] 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.

[0152] In some embodiments, a compound having formula (I) is a compound having formula (Ia), wherein R is an alkyl group.

[0153] In some embodiments, a compound having formula (Ia) is a compound having formula (Iai), wherein R is a methyl group.

[0154] In some embodiments, the organic phase is cooled before and / or during filtration. In some embodiments, the organic phase is cooled to 0°C-5°C.

[0155] In some embodiments, an organic polar solvent is added after the reaction to obtain a compound having formula (I). In some embodiments, CPME is added after the reaction to obtain a compound having formula (I).

[0156] In some embodiments, a portion of the organic polar solvent is present from the reaction to obtain the compound having formula (I), and optionally, an additional amount of the organic polar solvent is mixed with the reaction mixture prior to the separation of the compound having formula (I). In some embodiments, a portion of CPME is present from the reaction to obtain the compound having formula (I), and optionally, an additional amount of CPME is mixed with the reaction mixture prior to the separation of the compound having formula (I).

[0157] In some embodiments, a portion of the organic polar solvent is present from the reaction that yields the compound having formula (I), and optionally an additional amount of the organic polar solvent is added prior to the separation of the compound having formula (I). In some embodiments, a portion of CPME is present from the reaction that yields the compound having formula (I), and optionally an additional amount of CPME is added prior to the separation of the compound having formula (I).

[0158] In some embodiments, prior to the separation step, the compound having formula (I) in the mixture is in salt form.

[0159] In some embodiments, the nonpolar solvent is a nonpolar water-immiscible solvent.

[0160] In some embodiments, a nonpolar water-immiscible solvent dissolves the compound of formula (I).

[0161] In some embodiments, water-immiscible solvents include, but are not limited to, ether-based solvents, aromatic solvents such as CPME, THF, anisole, toluene, and any mixture thereof.

[0162] In some embodiments, the nonpolar solvent is anisole. In some embodiments, the nonpolar solvent is toluene.

[0163] In some embodiments, an antisolvent is further added.

[0164] In some embodiments, the antisolvent is added in parallel to the water-immiscible solvent.

[0165] In some embodiments, the antisolvent is added dropwise.

[0166] In some embodiments, crystallization is carried out at a temperature below 0°C.

[0167] In some embodiments, the antisolvent is a C5-C11 alkane. In some embodiments, the antisolvent is hexane. In some embodiments, the antisolvent is heptane.

[0168] In some embodiments, the mixture of solvent and antisolvent is anisole and hexane.

[0169] In some embodiments, the mixture of solvent and antisolvent is toluene and hexane.

[0170] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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.

[0171] In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0172] In some embodiments, a compound having formula (I) is a compound having formula (Ia), wherein R is an alkyl group.

[0173] In some embodiments, a compound having formula (Ia) is a compound having formula (Iai), wherein R is a methyl group.

[0174] In some embodiments, the organic phase is cooled before and / or during filtration. In some embodiments, the organic phase is cooled to 0°C-5°C.

[0175] In some embodiments, crystallization is accomplished by concentrating the solvent.

[0176] In some embodiments, crystallization is accomplished using crystal seeding.

[0177] In some embodiments, the mixture is crystallized with 0.1%-1% of a compound of formula (I).

[0178] In some embodiments, a water-immiscible solvent is mixed with the reaction mixture after the reaction to obtain a compound having formula (I). In some embodiments, anisole and hexane are mixed with the reaction mixture after the reaction to obtain a compound having formula (I).

[0179] In some embodiments, a water-immiscible solvent is added after the reaction to obtain a compound having formula (I). In some embodiments, anisole and hexane are added after the reaction to obtain a compound having formula (I).

[0180] In some embodiments, a portion of the water-immiscible solvent from the reaction to obtain the compound having formula (I) is present, and optionally, an additional amount of the water-immiscible solvent is mixed with the reaction mixture prior to the separation of the compound having formula (I). In some embodiments, a portion of anisole from the reaction to obtain the compound having formula (I) is present, and optionally, an additional amount of anisole is mixed with hexane with the reaction mixture prior to the separation of the compound having formula (I).

[0181] In some embodiments, a portion of a water-immiscible solvent is present from the reaction that yields the compound having formula (I), and optionally an additional amount of a water-immiscible solvent is added prior to the separation of the compound having formula (I). In some embodiments, a portion of anisole is present from the reaction that yields the compound having formula (I), and optionally an additional amount of anisole, optionally together with hexane, is added prior to the separation of the compound having formula (I).

[0182] In some embodiments, the method for separating a compound having formula (I) includes contacting a mixture containing a compound having formula (I) with a water-immiscible solvent or a mixture of a solvent containing at least one water-immiscible solvent and water, separating the organic phase, crystallizing the compound having formula (I), and (3) filtering the crystals.

[0183] In some embodiments, where the multiphase system is a slurry containing solids, the method for separating a compound having formula (I) from the reaction mixture includes filtering the precipitated solids.

[0184] For example, compounds having formula (I) can be isolated from the reaction mixture according to the method described herein as pathway 3.

[0185] In some embodiments, step (1) is carried out in the presence of at least one water-immiscible solvent, and the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, and step (2) for separating the compound having formula (I) from the reaction mixture comprises: (i) mixing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0186] In some embodiments, step (1) is carried out in the presence of at least one water-immiscible solvent, and the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, and step (2) for separating the compound having formula (I) from the reaction mixture comprises: (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0187] In some embodiments, a water-immiscible solvent is added after step (1), and the reaction mixture comprises a compound having formula (I), DMS, and at least one water-immiscible solvent. Step (2) for separating the compound having formula (I) from the reaction mixture comprises: (i) mixing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0188] In some embodiments, a water-immiscible solvent is added after step (1), and the reaction mixture comprises a compound having formula (I), DMS, and at least one water-immiscible solvent. Step (2) for separating the compound having formula (I) from the reaction mixture comprises: (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0189] In some embodiments, step (1) is performed in the presence of at least one additional solvent.

[0190] In some embodiments, wherein (a) step (1) is carried out in the presence of at least one additional solvent, (b) step (1) is carried out in the presence of at least one water-immiscible solvent, and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent, and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) mixing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0191] In some embodiments, wherein (a) step (1) is carried out in the presence of at least one additional solvent, (b) step (1) is carried out in the presence of at least one water-immiscible solvent, and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent, and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0192] In some embodiments, wherein (a) step (1) is carried out in the presence of at least one additional solvent, (b) a water-immiscible solvent is added after step (1), and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent, and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) mixing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0193] In some embodiments, wherein (a) step (1) is carried out in the presence of at least one additional solvent, (b) a water-immiscible solvent is added after step (1), and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent, and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0194] In some embodiments, at least one additional solvent is mixed with the reaction mixture after step (1) and before step (2). In some embodiments, at least one additional solvent is added after step (1) and before step (2).

[0195] In some embodiments, wherein (a) after step (1) at least one additional solvent is mixed with the reaction mixture, (b) step (1) is carried out in the presence of at least one water-immiscible solvent, and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0196] In some embodiments, wherein (a) at least one additional solvent is added after step (1), (b) step (1) is carried out in the presence of at least one water-immiscible solvent, and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent, and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0197] In some embodiments, wherein (a) after step (1) at least one additional solvent is mixed with the reaction mixture, (b) after step (1) a water-immiscible solvent is added, and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0198] In some embodiments, wherein (a) at least one additional solvent is added after step (1), (b) a water-immiscible solvent is added after step (1), and (c) the reaction mixture comprises a compound having formula (I), DMS, at least one water-immiscible solvent, and at least one additional solvent, and step (2) for separating the compound having formula (I) comprises: (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0199] In some embodiments, step (2) is performed in the presence of at least one additional solvent.

[0200] In some embodiments, wherein step (1) is carried out in the presence of at least one water-immiscible solvent, and the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, step (2) for separating the compound having formula (I) comprises: (i) mixing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0201] In some embodiments, wherein step (1) is carried out in the presence of at least one water-immiscible solvent, and the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, and step (2) for separating the compound having formula (I) comprises: (i) washing the mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0202] In some embodiments, wherein after step (1) a water-immiscible solvent is mixed with the reaction mixture, and the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, step (2) for separating the compound having formula (I) comprises: (i) mixing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0203] In some embodiments, wherein a water-immiscible solvent is added after step (1), and the reaction mixture comprises a compound having formula (I), DMS and at least one water-immiscible solvent, step (2) for separating the compound having formula (I) comprises: (i) washing the mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0204] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent and at least one other solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0205] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent and at least one other solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0206] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) mixing at least one water-immiscible solvent and at least one additional solvent with the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0207] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) adding at least one water-immiscible solvent and at least one additional solvent to the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0208] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) mixing at least one water-immiscible solvent into the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0209] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) adding at least one water-immiscible solvent to the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0210] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) adding an alkaline aqueous 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.

[0211] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution, at least one water-immiscible solvent and at least one other solvent to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0212] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution and at least one water-immiscible solvent to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0213] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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 alkaline aqueous solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3, NH4OH, NaOH, and any combination thereof. In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0214] In some embodiments, the concentration of the base in the alkaline aqueous solution is 2%-18% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 15% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 18% based on total weight (w / w).

[0215] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0216] In some embodiments, the mixture contains a solvent. In some embodiments, the slurry mixture contains a solvent.

[0217] A mixture containing a compound having formula (I) may contain DMS and any or all solvents used during the method for preparing a compound having formula (I).

[0218] The additional solvent is used for the separation or auxiliary separation of compounds having formula (I). The additional solvent can be added directly to the mixture. Alternatively, it can be added together with an alkaline aqueous solution.

[0219] In some embodiments, the additional solvent is the same as one or more solvents used during the method for preparing a compound having formula (I).

[0220] In some embodiments, the additional solvent is different from one or more solvents used during the method for preparing a compound having formula (I).

[0221] In some embodiments, the additional solvent is a polar solvent.

[0222] In some embodiments, the additional solvent is a water-immiscible solvent.

[0223] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 4. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.

[0224] In some embodiments, the ratio of the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio of the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio of the additional solvent to the compound having formula (I) is about 1:1.

[0225] In some embodiments, the ratio of the additional solvent to the compound of formula (II) used to prepare the compound of formula (I) is greater than 0.5:1. In some embodiments, the ratio of the additional solvent to the compound of formula (II) used to prepare the compound of formula (I) is less than 2:1. In some embodiments, the ratio of the additional solvent to the compound of formula (II) used to prepare the compound of formula (I) is about 1:1.

[0226] In some embodiments, the additional solvent is a polar solvent and the polar solvent is CPME.

[0227] In some embodiments, the solvent used during the method for preparing a compound having formula (I) is DMA, and the other solvent is CPME.

[0228] In some embodiments, the ratio of CPME to a compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio of CPME to a compound having formula (I) is less than 2:1. In some embodiments, the ratio of CPME to a compound having formula (I) is about 1:1.

[0229] In some embodiments, the ratio of CPME to the compound of formula (II) used to prepare a compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio of CPME to the compound of formula (II) used to prepare a compound having formula (I) is less than 2:1. In some embodiments, the ratio of CPME to the compound of formula (II) used to prepare a compound having formula (I) is about 1:1.

[0230] In some embodiments, the slurry mixture is mixed for 30 minutes to 8 hours.

[0231] In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 60°C. In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 50°C. In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 35°C. In some embodiments, the slurry mixture is mixed at a temperature of about 30°C.

[0232] In some embodiments, a mechanical mixer is used to mix the slurry mixture.

[0233] In some embodiments, a high-shear mixer is used to mix the slurry mixture.

[0234] In some embodiments, both a mechanical mixer and a high-shear mixer are used to mix the slurry mixture.

[0235] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with 2%-18% of an alkaline aqueous solution.

[0236] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to a 2%-18% alkaline aqueous solution.

[0237] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with 11%-18% of an alkaline aqueous solution.

[0238] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to an 11%-18% alkaline aqueous solution.

[0239] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with 15% of an alkaline aqueous solution.

[0240] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with an 18% alkaline aqueous solution.

[0241] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to a 15% alkaline aqueous solution.

[0242] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to an 18% alkaline aqueous solution.

[0243] In some embodiments, the slurry mixture is obtained by adding 2%-18% alkaline aqueous solution to a mixture comprising a compound having formula (I), DMS, and optionally an organic solvent.

[0244] In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 15°C and 45°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 15°C and 20°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 20°C and 25°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 25°C and 30°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 30°C and 35°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 35°C and 40°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 40°C and 45°C.

[0245] In some embodiments, during the filtration process in step (2), the filter solids obtained in step (2) are mixed with an organic solvent. In some embodiments, during the filtration process in step (2), the filter solids obtained in step (2) are washed with an organic solvent. In some embodiments, the organic solvent is CPME.

[0246] In some embodiments, during the filtration process in step (2), the filtered solids obtained in step (2) are washed with water.

[0247] In some embodiments, the filtered solids are mixed with water and stirred for 1 to 3 hours and then filtered.

[0248] In some embodiments, the filtered solids are mixed with water and stirred and filtered at a temperature of 25°C-50°C.

[0249] In some embodiments, the organic solvent is the same organic solvent used to obtain the compound having formula (I).

[0250] In some embodiments, the alkaline aqueous solution is a 15% K2CO3 aqueous solution based on the total weight (w / w) of K2CO3 in the water.

[0251] In some embodiments, the alkaline aqueous solution is an 18% K2CO3 aqueous solution based on the total weight (w / w) of K2CO3 in the water.

[0252] In some embodiments, the organic phase is a solution obtained by reacting a compound having formula (II) with DMS.

[0253] In some embodiments, an organic phase is obtained by mixing an organic water-immiscible solvent with a mixture of a compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0254] In some embodiments, an organic phase is obtained by adding an organic water-immiscible solvent to a mixture of a compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0255] In some embodiments, the step of mixing the alkaline aqueous solution with the reaction mixture includes the additional use of a phase transfer catalyst (PTC), such as tetra-n-butylammonium bromide (TBAB).

[0256] In some embodiments, the step of adding an alkaline aqueous solution includes the additional use of a phase transfer catalyst (PTC), such as tetra-n-butylammonium bromide (TBAB).

[0257] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by mixing CPME and a compound having formula (I) at a weight ratio of 10:1 before mixing with an alkaline aqueous solution of 2%-18% w / w.

[0258] In some embodiments, a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) at a weight ratio of 10:1 before washing with an alkaline aqueous solution of 2%-18% w / w.

[0259] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by heating the combination of CPME and the compound having formula (I) to 65°C before mixing with a 2%-18% w / w alkaline aqueous solution.

[0260] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by heating the combination of CPME and the compound having formula (I) to 65°C before washing with a 2%-18% w / w alkaline aqueous solution.

[0261] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by heating the combination of CPME and the compound having formula (I) to about 50°C before mixing with a 2%-18% w / w alkaline aqueous solution.

[0262] In some embodiments, a solution of a compound having formula (I) in a CPME is obtained by heating the CPME and the combination of the compound having formula (I) to approximately 50°C before washing with a 2%–18% w / w alkaline aqueous solution. In some embodiments, the resulting mixture obtained by reacting a compound having formula (II) with DMS is dissolved in the CPME.

[0263] In some embodiments, the resulting mixture obtained by reacting a compound having formula (II) with DMS is dissolved in CPME and washed with an aqueous alkaline solution.

[0264] In some embodiments, the resulting mixture is a mixture of a compound having formula (I) and a solvent used in the reaction of a compound having formula (II) with DMS.

[0265] In some embodiments, the conversion of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one to 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%.

[0266] In some embodiments, the chemical yield of 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%. The purified 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one yields are greater than 50%, 60%, 70%, 80%, 90%, or 99%.

[0267] In some embodiments, the conversion of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one to 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%.

[0268] In some embodiments, the chemical yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%. The purified 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one yields are greater than 50%, 60%, 70%, 80%, 90%, or 99%.

[0269] In some embodiments, the mixture comprises a compound having formula (I), at least one water-immiscible solvent and at least one other solvent, and the method for separating the compound having formula (I) comprises (i) mixing the mixture with water to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0270] In some embodiments, the mixture comprises a compound having formula (I), at least one water-immiscible solvent and at least one other solvent, and the method for separating the compound having formula (I) comprises (i) washing the mixture with water to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0271] In some embodiments, the multiphase system comprises a liquid and a solid. In some embodiments, wherein the multiphase system comprises a liquid and a solid, a method for separating a compound having formula (I) from the reaction mixture includes filtering the solid.

[0272] For example, compounds having formula (I) can be separated from the reaction mixture according to the method described herein as pathway 1.

[0273] In some embodiments, the mixture comprises a compound having formula (I) and DMS, and a method for separating the compound having formula (I) from the reaction mixture comprises (1) mixing the mixture with at least one water-immiscible solvent and an alkaline aqueous solution to form a precipitated solid of the compound having formula (I) and (2) filtering the precipitated solid.

[0274] In some embodiments, the mixture comprises a compound having formula (I) and DMS, and a method for separating the compound having formula (I) from the reaction mixture comprises (1) adding at least one water-immiscible solvent and an alkaline aqueous solution to the mixture to form a precipitated solid of the compound having formula (I) and (2) filtering the precipitated solid.

[0275] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0276] In some embodiments, the water-immiscible solvent is polar.

[0277] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20.

[0278] In some embodiments, the polar solvent is an organic polar solvent.

[0279] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.

[0280] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, and any combination thereof.

[0281] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0282] In some embodiments, the method includes evaporating a polar solvent prior to filtration. In some embodiments, the method includes partially evaporating a polar solvent prior to filtration.

[0283] In some embodiments, the method includes cooling the reaction mixture prior to filtration.

[0284] In some embodiments, step (1) is performed in the presence of at least one water-immiscible solvent.

[0285] In some embodiments, after step (1) and before mixing the alkaline aqueous solution with the reaction mixture, a water-immiscible solvent is mixed with the reaction mixture.

[0286] In some embodiments, a water-immiscible solvent is added after step (1) and before adding an alkaline aqueous solution to the reaction mixture.

[0287] In some embodiments, a water-immiscible solvent is mixed with the reaction mixture while the alkaline aqueous solution is being mixed with the reaction mixture.

[0288] In some embodiments, a water-immiscible solvent is added simultaneously with the addition of an alkaline aqueous solution to the reaction mixture.

[0289] In some embodiments, a water-immiscible solvent is mixed with the reaction mixture after the alkaline aqueous solution is mixed with the reaction mixture. In some embodiments, a water-immiscible solvent is mixed with the reaction mixture immediately after the alkaline aqueous solution is mixed with the reaction mixture.

[0290] In some embodiments, a water-immiscible solvent is added after the addition of an alkaline aqueous solution to the reaction mixture. In some embodiments, a water-immiscible solvent is added immediately after the addition of an alkaline aqueous solution to the reaction mixture.

[0291] In some embodiments, the water-immiscible solvent is an ether-based solvent, an aromatic solvent, or a mixture thereof.

[0292] In some embodiments, the water-immiscible solvent is CPME, THF, anisole, toluene, or any mixture thereof.

[0293] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0294] In some embodiments, a water-immiscible solvent and an alkaline aqueous solution are mixed sequentially with the reaction mixture.

[0295] In some embodiments, a water-immiscible solvent is gradually mixed with the reaction mixture.

[0296] In some embodiments, an alkaline aqueous solution is gradually mixed with the reaction mixture.

[0297] In some embodiments, a water-immiscible solvent and an alkaline aqueous solution are added sequentially.

[0298] In some embodiments, a water-immiscible solvent is gradually added.

[0299] In some embodiments, an alkaline aqueous solution is gradually added.

[0300] In some embodiments, step (1) is carried out in the presence of a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.

[0301] In some embodiments, step (1) is performed in the presence of at least one water-immiscible solvent.

[0302] In some embodiments, water-immiscible solvents include, but are not limited to, ether-based solvents, aromatic solvents such as CPME, THF, anisole, toluene, and any mixture thereof.

[0303] In some embodiments, the water-immiscible solvent is toluene, anisole, or a combination thereof.

[0304] In some embodiments, step (1) is performed in the presence of a solvent other than a water-immiscible solvent.

[0305] In some embodiments, step (1) is performed in the presence of a solvent and in the absence of a water-immiscible solvent.

[0306] In some embodiments, the solvent is DMA.

[0307] In some embodiments, step (1) is carried out in the presence of a mixture of solvents, wherein at least one solvent is water-immiscible and at least one solvent is water-miscible.

[0308] In some embodiments, the solvent mixture is a mixture of a polar water-miscible solvent and a non-polar water-immiscible solvent.

[0309] In some embodiments, the solvent mixture is DMA and anisole. In some embodiments, the weight ratio of DMA to anisole is between 100:1 and 1:1. In some embodiments, the weight ratio of DMA to anisole is about 1:1. In some embodiments, the weight ratio of DMA to a compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio of anisole to a compound having formula (II) is from about 10:1 to about 1:1.

[0310] In some embodiments, the solvent mixture is a mixture of DMA and toluene. In some embodiments, the weight ratio of DMA to toluene is between 100:1 and 1:1. In some embodiments, the weight ratio of DMA to toluene is about 1:1. In some embodiments, the weight ratio of DMA to a compound having formula (II) is from about 15:1 to about 0.5:1. In some embodiments, the weight ratio of toluene to a compound having formula (II) is from about 10:1 to about 1:1.

[0311] In some embodiments, a compound having formula (I) reacts with DMS in the presence of a base whose pKa is equal to or less than that of a compound having formula (I).

[0312] During the reaction and before water in any form (such as an alkaline aqueous solution) is mixed with the reaction mixture, the compound having formula (I) may be in salt form. During the reaction and before water in any form (such as an alkaline aqueous 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 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 monomethyl sulfate of the compound having formula (I).

[0313] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0314] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0315] In some embodiments, step (i) includes mixing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to form an organic phase and an aqueous phase.

[0316] In some embodiments, step (i) includes washing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to form an organic phase and an aqueous phase.

[0317] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) mixing at least one water-immiscible solvent with the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0318] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) adding at least one water-immiscible solvent to the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0319] In some embodiments, step (i) includes mixing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to form an organic phase and an aqueous phase.

[0320] In some embodiments, step (i) includes washing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to form an organic phase and an aqueous phase.

[0321] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing at least one water-immiscible solvent and an alkaline aqueous solution with the reaction mixture to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0322] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) adding at least one water-immiscible solvent and an alkaline aqueous solution to the reaction mixture to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid.

[0323] In some embodiments, the alkaline aqueous solution is an alkaline aqueous solution of 2%-18% w / w.

[0324] In some embodiments, a compound having formula (I) is crystallized by concentrating the organic phase, mixing with an antisolvent, and / or crystallizing.

[0325] In some embodiments, a compound having formula (I) is crystallized by concentrating the organic phase, adding an antisolvent, and / or crystallizing.

[0326] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent and at least one other solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0327] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent and at least one other solvent, and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0328] In some embodiments, step (i) includes mixing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to obtain a slurry mixture containing precipitated solids.

[0329] In some embodiments, step (i) includes washing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to obtain a slurry mixture containing precipitated solids.

[0330] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) mixing at least one water-immiscible solvent and at least one additional solvent with the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0331] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) adding at least one water-immiscible solvent and at least one additional solvent to the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0332] In some embodiments, step (i) includes mixing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to obtain a slurry mixture containing precipitated solids.

[0333] In some embodiments, step (i) includes washing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to obtain a slurry mixture containing precipitated solids.

[0334] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) mixing at least one water-immiscible solvent with the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0335] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), (2) adding at least one water-immiscible solvent to the reaction mixture, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) washing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing precipitated solids, and (ii) filtering the precipitated solids.

[0336] In some embodiments, step (i) includes mixing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to obtain a slurry mixture containing precipitated solids.

[0337] In some embodiments, step (i) includes washing the reaction mixture with a 2%-18% w / w alkaline aqueous solution to obtain a slurry mixture containing precipitated solids.

[0338] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution, at least one water-immiscible solvent and at least one other solvent to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

[0339] In some embodiments, the method includes (1) preparing a compound of formula (I) by reacting a compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) adding an alkaline aqueous 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.

[0340] In some embodiments, the alkaline aqueous solution is an alkaline aqueous solution of 2%-18% w / w.

[0341] In some embodiments, the alkaline aqueous solution is an aqueous solution comprising DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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 alkaline aqueous solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3, NH4OH, NaOH, and any combination thereof. In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0342] In some embodiments, the concentration of the base in the alkaline aqueous solution is 2%-18% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 15% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 18% based on total weight (w / w).

[0343] In some embodiments, the additional solvent is different from a water-immiscible solvent.

[0344] In some embodiments, the additional solvent is a polar solvent.

[0345] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5.

[0346] In some embodiments, the ratio between the additional solvent and the compound having formula (I) or formula (II) is about 1:1.

[0347] In some embodiments, the additional solvent is CPME.

[0348] In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 50°C.

[0349] In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 15°C and 45°C.

[0350] In some embodiments, the water-immiscible solvent is polar.

[0351] In some embodiments, the water-immiscible solvent is nonpolar.

[0352] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out in the absence of a base.

[0353] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out in the presence of at least one base.

[0354] In some embodiments, the alkali is selected from the group consisting of DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, and any combination thereof.

[0355] In some embodiments, the alkali is selected from the group consisting of TBAB, NaOH, Na2CO3, Et3N, NaOMe, and any combination thereof.

[0356] In some embodiments, when a base is present in the reaction of a compound having formula (II) with DMS and the pKa of the base is higher than that of a compound having formula (I), the compound having formula (I) does not exist in salt form.

[0357] In some embodiments, the reaction of the compound having formula (II) with DMS is carried out at a temperature between 10°C and 85°C. In some embodiments, the reaction of the compound having formula (II) with DMS is carried out at a temperature between 25°C and 85°C. In some embodiments, the temperature is between 25°C and 50°C. In some embodiments, the reaction of the compound having formula (II) with DMS is carried out at a temperature between 35°C and 50°C. In some embodiments, the temperature is between about 10°C and 50°C.

[0358] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 10°C and below 25°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 10°C and 24°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 10°C and 20°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 10°C and 15°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 15°C and 20°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature of about 10°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature of about 15°C. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature of about 20°C.

[0359] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature below 25°C, characterized by an increased yield, preferably in these embodiments, the solvent being DMA.

[0360] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between about 10°C and below 25°C, characterized by an optimized yield, preferably in these embodiments, the solvent being DMA.

[0361] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 10°C and below 25°C, and the amount of DMS is increased compared to the reaction of a compound having formula (II) with DMS at a temperature of 25°C or higher. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature between 10°C and 24°C, and the amount of DMS is increased compared to the reaction of a compound having formula (II) with DMS at a temperature of 25°C or higher. In some embodiments, the reaction of a compound having formula (II) with DMS is carried out at a temperature of about 20°C, and the amount of DMS is increased compared to the reaction of a compound having formula (II) with DMS at a temperature of 25°C or higher.

[0362] In some embodiments, the molar ratio of the compound having formula (II) to DMS is between 1:2 and 1:10. In some embodiments, the molar ratio of the compound having formula (II) to DMS is between 1:2 and 1:5. In some embodiments, the molar ratio of the compound having formula (II) to DMS is between 1:2 and 1:4. In some embodiments, the molar ratio of the compound having formula (II) to DMS is between 1:2 and 1:2.5. In some embodiments, the molar ratio of the compound having formula (II) to DMS is between 1:3 and 1:6. In some embodiments, the molar ratio of the compound having formula (II) to DMS is between 1:3 and 1:4. In some embodiments, the molar ratio of the compound having formula (II) to DMS is about 1:2. In some embodiments, the molar ratio of the compound having formula (II) to DMS is about 1:2. In some embodiments, the molar ratio of the compound having formula (II) to DMS is about 1:2.5. In some embodiments, the molar ratio of the compound having formula (II) to DMS is about 1:3. In some embodiments, the molar ratio of the compound having formula (II) to DMS is about 1:3.5. In some embodiments, the molar ratio between the compound having formula (II) and DMS is about 1:4.

[0363] In some embodiments, the compound having formula (II) and DMS are stirred for about 3-10 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 4-9 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 5-8 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 6-7 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 3 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 4 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 5 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 6 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 7 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 8 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 9 hours. In some embodiments, the compound having formula (II) and DMS are stirred for about 10 hours.

[0364] In some embodiments, when the reaction of the compound having formula (II) with DMS is carried out at a temperature of about 20°C, the molar ratio between the compound having formula (II) and DMS is between 1:3 and 1:4, and the compound having formula (II) and DMS are stirred for about 6-7 hours.

[0365] In some embodiments, when the reaction of a compound having formula (II) with DMS is carried out at a temperature between about 10°C and 20°C, the amount of DMS increases.

[0366] In some embodiments, when the reaction of the compound having formula (II) with DMS is carried out at a temperature between about 10°C and 20°C, the molar ratio between the compound having formula (II) and DMS is between 1:3 and 1:6.

[0367] In some embodiments, when the reaction of the compound having formula (II) with DMS is carried out at a temperature between about 10°C and 20°C, the molar ratio between the compound having formula (II) and DMS is between 1:3 and 1:4.

[0368] In some embodiments, when the reaction of the compound having formula (II) with DMS is carried out at a temperature between about 10°C and 20°C, the molar ratio between the compound having formula (II) and DMS is between 1:2 and 1:2.5.

[0369] In some embodiments, the compound having formula (II) and DMS are stirred at a temperature between 10°C and 20°C for about 5-7 hours, and the molar ratio between the compound having formula (II) and DMS is about 1:4.

[0370] In some embodiments, the compound having formula (II) and DMS are stirred at a temperature between 10°C and 20°C.

[0371] In some embodiments, the compound having formula (II) and DMS are stirred at a temperature between 10°C and 20°C for about 5-7 hours, and the molar ratio between the compound having formula (II) and DMS is about 1:4.

[0372] In some embodiments, the compound having formula (II) and DMS are stirred at a temperature between 10°C and 20°C for about 3 hours.

[0373] 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.

[0374] In some embodiments, the base is mixed with the reaction mixture 4 hours after the start of the reaction between compound (II) and DMS. Suitable bases include alkoxides and carbonates.

[0375] In some embodiments, a base is added 4 hours after the start of the reaction between compound (II) and DMS. Suitable bases include alkoxides and carbonates.

[0376] In some embodiments, the base is mixed with the reaction mixture at the start of the reaction. Suitable bases include DABCO, NEt3, LiCO3, and KHCO3.

[0377] In some embodiments, a base is added at the start of the reaction. Suitable bases include DABCO, NET3, LiCO3, and KHCO3.

[0378] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out in the presence of at least one solvent.

[0379] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out in the presence of two solvents.

[0380] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out in the presence of a solvent that is immiscible with water.

[0381] In some embodiments, the reaction of a compound having formula (II) with DMS is carried out in the presence of two or more solvents, and at least one of these solvents is water-immiscible. One or more other solvents may be water-immiscible or water-miscible.

[0382] In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is a nonpolar solvent.

[0383] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20.

[0384] In some embodiments, the solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.

[0385] In some embodiments, the solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, and any combination thereof.

[0386] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF. In some embodiments, the solvent is toluene. In some embodiments, the solvent is anisole.

[0387] In some embodiments, one or more solvents are solvents that completely dissolve the compound of formula (I).

[0388] In some embodiments, the solvent is MeTHF and the base is NET3.

[0389] In some embodiments, the solvent is a mixture of at least two solvents.

[0390] In some embodiments, the solvent is a mixture of DMA and CPME.

[0391] In some embodiments, the weight ratio of DMA to CPME is between 1:1 and 1:10. In some embodiments, the weight ratio of DMA to CPME is between 1:1 and 1:4. In some embodiments, the weight ratio of DMA to CPME is between 1:2 and 1:4. In some embodiments, the weight ratio of DMA to CPME is between 1:3 and 1:5. In some embodiments, the weight ratio of DMA to CPME is approximately 1:4.

[0392] In some embodiments, the solvent is a mixture of DMA and MeTHF.

[0393] 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.

[0394] In some embodiments, the alkylation process is carried out in the presence of a mixture of DMA and CPME in a weight ratio of 1:2 to 1:4.

[0395] In some embodiments, the solvent is a mixture of a polar water-miscible solvent and a non-polar water-immiscible solvent.

[0396] In some embodiments, the solvent is a mixture of DMA and anisole.

[0397] In some embodiments, the weight ratio of DMA to anisole is between 100:1 and 1:1. In some embodiments, the weight ratio of DMA to anisole is between 75:1 and 1:1. In some embodiments, the weight ratio of DMA to anisole is between 50:1 and 1:1. In some embodiments, the weight ratio of DMA to anisole is between 25:1 and 1:1. In some embodiments, the weight ratio of DMA to anisole is approximately 1:1.

[0398] In some embodiments, the solvent is a mixture of DMA and toluene.

[0399] In some embodiments, the weight ratio of DMA to toluene is between 100:1 and 1:1. In some embodiments, the weight ratio of DMA to toluene is between 75:1 and 1:1. In some embodiments, the weight ratio of DMA to toluene is between 50:1 and 1:1. In some embodiments, the weight ratio of DMA to toluene is between 25:1 and 1:1. In some embodiments, the weight ratio of DMA to toluene is approximately 1:1.

[0400] In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio between the solvent or a mixture of solvents and the compound having formula (II) is between 30:1 and 1:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio between the solvent or a mixture of solvents and the compound having formula (II) is between 20:1 and 5:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio between the solvent or a mixture of solvents and the compound having formula (II) is between 15:1 and 10:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio between the solvent or a mixture of solvents and the compound having formula (II) is between 14:1 and 12:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio between the solvent or a mixture of solvents and the compound having formula (II) is about 13:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio between the solvent or mixture of solvents and the compound having formula (II) is 12.7:1.

[0401] In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio of the solvent or solvent mixture to DMS is between 10:1 and 1:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio of the solvent or solvent mixture to DMS is between 5:1 and 3:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio of the solvent or solvent mixture to DMS is about 4:1. In some embodiments, in the reaction of a compound having formula (II) with DMS, the molar ratio of the solvent or solvent mixture to DMS is 3.9:1.

[0402] In some embodiments, the reaction of a compound having formula (II) with DMS further comprises neutralization with an alkaline aqueous solution.

[0403] In some embodiments, excess DMS is neutralized with an alkaline aqueous solution.

[0404] In some embodiments, the weight ratio of DMA:CPME:compound having formula (II) is 1.5:0:1 to 1:5:1.

[0405] 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.

[0406] 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.

[0407] In some embodiments, the alkali in the alkaline aqueous solution may include, but is not limited to, K₂CO₃, KHCO₃, Na₂CO₃, NaHCO₃, K₂CO₃, NH₄OH, NaOH, or any combination thereof. In some embodiments, the concentration of the alkali in the alkaline aqueous solution is 2%-18% based on the total weight (w / w).

[0408] In some embodiments, the base in the alkaline aqueous solution is K2CO3.

[0409] In some embodiments, the step of mixing the alkaline aqueous solution with the reaction mixture includes the additional use of a phase transfer catalyst (PTC), such as tetra-n-butylammonium bromide (TBAB).

[0410] In some embodiments, the step of adding an alkaline aqueous solution includes the additional use of a phase transfer catalyst (PTC), such as tetra-n-butylammonium bromide (TBAB).

[0411] In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of at least 60%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of at least 70%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of at least 80%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of at least 85%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of at least 90%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of 80%-90%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of 80%-85%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a yield of 80%. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has an 85% yield. In some embodiments, the reaction of a compound having formula (II) with DMS to obtain a compound having formula (I) has a 90% yield.

[0412] Compounds having formula (II) can be prepared using any method known in the art, including but not limited to the methods described in PCT International Application Publication Nos. WO 2015 / 103142 and WO 2015 / 103144, the entire contents of which are hereby incorporated by reference.

[0413] In some embodiments, compounds having formula (IIai) are used by making compounds having formula (IV):

[0414]

[0415] It is prepared by contacting bis-N,O-trimethylsilylacetamide (BSA) to form a compound having the formula (IIai).

[0416] 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 ranging from about 22°C to about 70°C.

[0417] In some embodiments, the contacting step further includes contacting a compound having formula (IV) with CH3CN.

[0418] In some embodiments, the method includes contacting the BSA-treated reaction mixture with arylsulfonyl chloride.

[0419] In some embodiments, the molar ratio between the compound having formula (IV) and the arylsulfonyl chloride is from about 1:2 to about 2:1. In some embodiments, the molar ratio between the compound having formula (IV) and the arylsulfonyl chloride is 1:1.1.

[0420] In some embodiments, the compound having formula (IIai) can be prepared by contacting the compound having formula (IV) with bis-N,O-trimethylsilylacetamide (BSA) at an elevated temperature (e.g., 70°C) for about 1 hour (h), followed by cooling and contacting a solution containing the protected pyrimidinol with CH3PhSO2Cl at about 20°C to 25°C. In some embodiments, the molar ratio between the compound having formula (IV) and BSA and sulfonyl chloride is about 1:3:1.1. In some embodiments, reducing the molar ratio of the reactants to about 1:1.1:1.1 provides an improved yield.

[0421] Compounds having formula (II) can be prepared using the method described in PCT International Application Publication No. WO / 2021 / 181274, the entire contents of which are hereby incorporated by reference.

[0422] In some embodiments, the compound having formula (II) is obtained by reacting 5-fluorocytosine with a compound having formula (III):

[0423]

[0424] It is prepared by reaction in the presence of at least one polar solvent and at least one base, wherein:

[0425] R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3; and

[0426] X is a halogen or -OSO2PhR.

[0427] In some embodiments, the compound having formula (II) is (IIa), wherein R is an alkyl group.

[0428] In some embodiments, the compound having formula (IIa) is (IIai), where R is a methyl group.

[0429] In some embodiments, the compound having formula (II) is a compound having formula (IIai).

[0430]

[0431] Furthermore, compounds having formula (IIai) can be obtained by reacting 5-fluorocytosine with compounds having formula (III):

[0432]

[0433] The compound is prepared by reacting a substance of formula (IIai) in the presence of at least one polar solvent and at least one base, where R is a methyl group and X is a halogen or -OSO2PhR.

[0434] The present invention also provides a method for obtaining the compound 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0435]

[0436] The method includes:

[0437] (a) Reacting 5-fluorocytosine with a compound having formula (III):

[0438]

[0439] The reaction is carried out in the presence of at least one polar solvent and at least one base to obtain a compound having formula (II).

[0440]

[0441] as well as

[0442] (b) Prepare a compound having formula (I) and isolate the compound having formula (I) from the reaction mixture according to any of the methods described herein.

[0443] In some embodiments, R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3.

[0444] In some embodiments, the compound having formula (I) is (Ia), where R is an alkyl group.

[0445] In some embodiments, the compound having formula (Ia) is (Iai), where R is a methyl group.

[0446] In some embodiments, the compound having formula (I) is a compound having formula (Iai):

[0447]

[0448] And the method includes:

[0449] (a) Reacting 5-fluorocytosine with a compound having formula (III):

[0450]

[0451] The reaction is carried out in the presence of at least one polar solvent and at least one base to obtain a compound having the formula (IIai).

[0452]

[0453] as well as

[0454] (b) Prepare a compound having formula (I) and isolate the compound having formula (I) from the reaction mixture according to any of the methods described herein.

[0455] Where R is a methyl group and X is a halogen or -OSO2PhR.

[0456] During the reaction and before water in any form is mixed with the reaction mixture, the compound having formula (I) may be in salt form. Water may be mixed with the reaction mixture in the form of an alkaline aqueous solution. During the reaction and before water in any form is added to the reaction mixture, the compound having formula (I) may be in salt form. Water may be added in the form of an alkaline aqueous solution. In some embodiments, the compound having formula (I) is in salt form. In some embodiments, the compound having 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 monomethyl sulfate of the compound having formula (I).

[0457] In some embodiments, after mixing DMS with the reaction mixture, a salt or salt mixture is optionally mixed with the reaction mixture. The salt or salt mixture is prepared in a prior alkylation reaction.

[0458] In some embodiments, after adding DMS to the reaction, a salt or a mixture of salts may optionally be added to the reaction mixture. The salt or mixture of salts is prepared in a prior alkylation reaction.

[0459] In some embodiments, the compound having formula (I) obtained in the alkylation is suspended in a solvent. In some embodiments, the compound having formula (I) obtained in the alkylation is soluble in a solvent. In some embodiments, a salt of the compound having formula (I) is suspended in a solvent. In some embodiments, the salt of the compound having formula (I) is soluble in a solvent. In some embodiments, the salt or salt solution is mixed with the alkylation reaction mixture after mixing dimethyl sulfate. In some embodiments, the salt or salt solution is added to the alkylation reaction after adding dimethyl sulfate.

[0460] The present invention provides a monomethyl sulfate having a compound of formula (I).

[0461] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the absence of a protecting group.

[0462] In some embodiments, X is a halogen. In some embodiments, the halogen is Cl, Br, or I. In some embodiments, the halogen is Cl.

[0463] In some embodiments, X is -OSO2PhR, where R is hydrogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3.

[0464] In some embodiments, X is Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3.

[0465] In some embodiments, the compound having formula (III) is a compound having formula (IIIb).

[0466]

[0467] Wherein R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -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, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3.

[0468] In some embodiments, R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3.

[0469] In some embodiments, R is an alkyl group.

[0470] In some embodiments, the compound having formula (III) is toluenesulfonic anhydride.

[0471] In some embodiments, compounds having formula (III) may include, but are not limited to, 4-toluenesulfonyl chloride (TsCl) and toluenesulfonic anhydride.

[0472] In some embodiments, the compound having formula (III) is 4-toluenesulfonyl chloride (TsCl). In some embodiments, the compound having formula (III) is toluenesulfonic anhydride.

[0473] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between -5°C and 85°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between -5°C and 25°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between -5°C and 5°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between -5°C and 0°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between 0°C and 5°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between 5°C and 25°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out at a temperature between 25°C and 85°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of at least one polar solvent and at least one base.

[0474] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of at least one polar solvent, at least one base, and at a temperature between 0°C and 5°C. In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of two polar solvents, one base, and at a temperature between 0°C and 5°C.

[0475] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of at least one polar solvent, at least one base, and at a temperature between 5°C and 25°C.

[0476] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in a polar solvent, in the presence of at least one base, and at a temperature between 25°C and 85°C.

[0477] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of at least one polar solvent, at least one base, and at a temperature between (-5°C) and 85°C.

[0478] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20.

[0479] In some embodiments, where R is methyl in the compound having formula (III), the sulfonation step is a toluenesulfonation step.

[0480] In the toluenesulfonation step, the polar solvent has a dielectric constant equal to or greater than 20.

[0481] In some embodiments, polar solvents having a dielectric constant equal to or greater than 20 may include, but are not limited to, dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile (ACN or MeCN), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), water, or any combination thereof.

[0482] In some embodiments, the polar solvent is selected from the group consisting of dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile (ACN or MeCN), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylbenzylamine (DMBA), water, and any combination thereof.

[0483] In some embodiments, the polar solvent is selected from the group consisting of dimethylacetamide (DMA), acetonitrile (ACN or MeCN), dimethylbenzylamine (DMBA), water, and any combination thereof.

[0484] In some embodiments, the combination of polar solvent and base consists of a single-phase system.

[0485] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of a polar solvent.

[0486] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of two polar solvents.

[0487] In some embodiments, the two polar solvents are selected from the group consisting of dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile (ACN or MeCN), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylbenzylamine (DMBA), and water.

[0488] In some embodiments, the two polar solvents are selected from the group consisting of dimethylacetamide (DMA), acetonitrile (ACN or MeCN), dimethylaminopyridine (DMAP), and water.

[0489] In some embodiments, the two polar solvents are DMA and water.

[0490] In some embodiments, the weight ratio between the two polar solvents is between 10:1 and 1:10.

[0491] In some embodiments, the weight ratio between the two polar solvents is between 2:1 and 1:2.

[0492] In some embodiments, the weight ratio between the two polar solvents is 1:1.

[0493] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of three polar solvents.

[0494] In some embodiments, the three polar solvents are DMA, water, and DMBA.

[0495] In some embodiments, at least one base is an organic base.

[0496] In some embodiments, at least one base is an inorganic base.

[0497] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of a base.

[0498] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of two bases.

[0499] In some embodiments, the base may include, but is not limited to, K2CO3, Na2CO3, Li2CO3, NaHCO3, KHCO3, NaOH, KOH, Et3N, dimethylaminopyridine (DMAP), dimethylbenzylamine (DMBA), or any combination thereof.

[0500] In some embodiments, the base is selected from the group consisting of K2CO3, Na2CO3, Li2CO3, NaHCO3, KHCO3, Et3N, dimethylaminopyridine (DMAP), and any combination thereof.

[0501] In some embodiments, the base is selected from the group consisting of K2CO3, Na2CO3, NaOH, KOH, Et3N, dimethylaminopyridine (DMAP), and any combination thereof.

[0502] 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 Et₃N. In some embodiments, the base is DMAP.

[0503] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA and at least one base.

[0504] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA, water, and at least one base.

[0505] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA, water, and two bases.

[0506] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA and two bases.

[0507] In some embodiments, the two bases are Et3N and DMAP.

[0508] In some embodiments, the two bases are NaOH and DMAP.

[0509] In some embodiments, the two bases are dimethylbenzylamine and NaOH.

[0510] In some embodiments, the two bases are DMAP and Na2CO3.

[0511] In some embodiments, the two bases are DMAP and KOH.

[0512] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA, water, and K2CO3.

[0513] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA and Et3N.

[0514] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of acetonitrile (ACN or MeCN) and triethylamine (Et3N).

[0515] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA, water, and DMAP.

[0516] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA and Na2CO3.

[0517] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMBA and Na2CO3.

[0518] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of water and DMAP.

[0519] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMBA, DMA, water, and KOH.

[0520] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMBA, DMA, water, and NaOH.

[0521] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA, Et3N, and DMAP.

[0522] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMA, water, NaOH, and DMAP.

[0523] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMAP and Na2CO3.

[0524] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMBA and KOH.

[0525] In some embodiments, the reaction of 5-fluorocytosine with a compound having formula (III) is carried out in the presence of DMBA and NaOH.

[0526] In some embodiments, the polar solvent with a dielectric constant equal to or greater than 20 is DMA, and the base is Et3N.

[0527] In some embodiments, the polar solvent with a dielectric constant equal to or greater than 20 is a mixture of DMA and water, and the base is K2CO3.

[0528] In some embodiments, the polar solvent with a dielectric constant equal to or greater than 20 is water, the alkali is Et3N, and the temperature is (-5°C) -5°C.

[0529] In some embodiments, the temperature is (-5°C) - 5°C, and the solvent is acetonitrile.

[0530] In another preferred embodiment, the temperature is (-5°C) - 5°C, the solvent is acetonitrile, and the base is Et3N.

[0531] In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the compound having formula (III) is between 1:10 and 10:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the compound having formula (III) is between 1:5 and 5:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the compound having formula (III) is between 1:2 and 2:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the compound having formula (III) is between 1:1 and 1:2. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the compound having formula (III) is about 1:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio between 5-fluorocytosine and the compound having formula (III) is about 1:1.1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio between 5-fluorocytosine and the compound having formula (III) is 1:1.2.

[0532] In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the base is between 1:10 and 10:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the base is between 1:5 and 5:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the base is between 1:2 and 2:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the base is between 1:1 and 1:2. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the base is about 1:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of 5-fluorocytosine to the base is 1:1.2. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio between 5-fluorocytosine and the base is 1:1.3.

[0533] In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of the compound having formula (III) to the base is between 1:10 and 10:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of the compound having formula (III) to the base is between 1:5 and 5:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of the compound having formula (III) to the base is between 1:2 and 2:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of the compound having formula (III) to the base is between 1:1 and 1:2. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio of the compound having formula (III) to the base is about 1:1. In some embodiments, in the reaction of 5-fluorocytosine with a compound having formula (III), the molar ratio between the compound having formula (III) and the base is 1:1.2.

[0534] In some embodiments, 5-fluorocytosine is reacted with a compound having formula (III) to obtain a compound having formula (II) in a yield of at least 61%.

[0535] In some embodiments, 5-fluorocytosine reacts with a compound having formula (III) to obtain a compound having formula (II) in a yield of more than 60%, 70%, 80%, 90%, or 99%. In some embodiments, 5-fluorocytosine reacts with a compound having formula (III) to obtain a compound having formula (II) in a yield of more than 90%.

[0536] In some embodiments, impurities (A) and (B) in the method of obtaining a compound having formula (II) disclosed herein are less than 20% based on a conversion rate. In some embodiments, impurities (A) and (B) in the method of obtaining a compound having formula (II) disclosed herein are less than 10% based on a conversion rate. In some embodiments, impurities (A) and (B) in the method of obtaining a compound having formula (II) disclosed herein are less than 5% based on a conversion rate. In some embodiments, impurities (A) and (B) in the method of obtaining a compound having formula (II) disclosed herein are less than 3% based on a conversion rate.

[0537] In some embodiments, reacting 5-fluorocytosine with a compound having formula (III) to obtain a compound having formula (II) further includes the step of separating the compound having formula (II) from the reaction mixture.

[0538] In some embodiments, the separation of a compound having formula (II) includes (i) mixing a protic solvent with the reaction mixture to precipitate the compound having formula (II) from the reaction mixture, and (ii) collecting the precipitated compound having formula (II).

[0539] In some embodiments, the separation of a compound having formula (II) includes (i) adding a protic solvent to the reaction mixture to precipitate the compound having formula (II) from the reaction mixture, and (ii) collecting the precipitated compound having formula (II).

[0540] In some embodiments, the proton solvent is water, methanol, or a combination thereof.

[0541] The present invention also provides a compound having formula (II) prepared using the method described herein.

[0542] The present invention also provides a compound having the formula (IIai), which is prepared using the method described herein.

[0543] In some embodiments, the compound having formula (I) is a compound having formula (Iai):

[0544]

[0545] Furthermore, the compound having formula (II) is a compound having formula (IIai).

[0546]

[0547] Where R is a methyl group and X is a halogen or -OSO2PhR.

[0548] The present invention also provides a compound having formula (I) which is obtained using any of the methods described herein.

[0549] The present invention also provides a compound having formula (Iai), which is obtained using any of the methods described herein.

[0550] The present invention also provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), wherein the method comprises (i) preparing a multiphase system comprising a compound having formula (I), a water-immiscible solvent and water, and (ii) obtaining and separating a solid of the compound having formula (I) from the multiphase system.

[0551] In some embodiments, water is mixed with the reaction mixture in the form of an alkaline aqueous solution.

[0552] In some embodiments, water is added in the form of an alkaline aqueous solution.

[0553] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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 alkaline aqueous solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3, NH4OH, NaOH, and any combination thereof. In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0554] In some embodiments, the concentration of the base in the alkaline aqueous solution is 2%-18% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 15% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 18% based on total weight (w / w).

[0555] In some embodiments, the multiphase system is a mixture comprising liquid and solid, wherein the method includes filtering the solid. Preferred embodiments are described in the following pathway 1.

[0556] In some embodiments, the multiphase system comprises an organic phase and an aqueous phase, and the method includes separating the organic phase from the aqueous phase, crystallizing a compound having formula (I) from the organic phase, and filtering the crystals. Preferred embodiments are described in the following pathway 2.

[0557] In some embodiments, the multiphase system is a slurry mixture containing solids, and the method includes filtering the solids. Preferred embodiments are described in the following pathway 3.

[0558] In some embodiments, the compound having formula (I) is a compound having formula (Iai):

[0559]

[0560] The following describes methods for separating compounds having formula (I) from their mixtures, including routes 1-3.

[0561] The method for separating compounds having formula (I) can be applied to any mixture containing compounds having formula (I), including the reaction mixture of the method for preparing compounds having formula (I) described herein and the reaction mixture of the method described in PCT International Application Publications WO 2015 / 103142, WO 2015 / 103144 and WO / 2021 / 181274 for preparing compounds having formula (I).

[0562] The mixture, including the reaction mixture produced by the alkylation step of a method for preparing a compound having formula (I), may contain a non-salt form of a compound having formula (I), a salt form of a compound having formula (I), or a mixture thereof.

[0563] In some embodiments, the step following the reaction of a compound having formula (II) with DMS to obtain a salt and / or non-salt form of a compound having formula (I) is defined as a separation step. In some embodiments, the salt form of the compound having formula (I) is formed prior to the separation step. In some embodiments, the non-salt form of the compound having formula (I) is formed prior to the separation step. In some embodiments, the non-salt form of the compound having formula (I) is obtained by mixing water with the reaction mixture after reacting it with DMS. In some embodiments, the non-salt form of the compound having formula (I) is obtained by adding water after reacting it with DMS. In some embodiments, separation includes neutralizing the salt form of the compound having formula (I).

[0564] Separation of compounds having formula (I), route 1

[0565] The present invention also provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I) and DMS, wherein the method comprises (1) mixing the mixture with at least one water-immiscible solvent and an alkaline aqueous solution to form a solid precipitate of the compound having formula (I) and (2) filtering the solid precipitate.

[0566] The present invention also provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I) and DMS, wherein the method comprises (1) adding at least one water-immiscible solvent and an alkaline aqueous solution to the mixture to form a precipitated solid of the compound having formula (I) and (2) filtering the precipitated solid.

[0567] In some embodiments, the compound having formula (I) is a compound having formula (Iai):

[0568]

[0569] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0570] In some embodiments, the water-immiscible solvent is polar.

[0571] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20.

[0572] In some embodiments, the polar solvent is an organic polar solvent.

[0573] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, toluene, anisole, and any combination thereof.

[0574] In some embodiments, the mixture comprises a solvent selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, and any combination thereof.

[0575] In some embodiments, the solvent is DMA. In some embodiments, the solvent is CPME. In some embodiments, the solvent is MeTHF.

[0576] In some embodiments, the method includes evaporating a polar solvent prior to filtration. In some embodiments, the method includes partially evaporating a polar solvent prior to filtration.

[0577] In some embodiments, the method includes cooling the reaction mixture prior to filtration.

[0578] The method for separating a compound having formula (I) from a mixture thereof can be used to separate a compound having formula (I) from any mixture thereof, including but not limited to (i) the reaction mixture after preparing a compound having formula (I) using the method described herein, (ii) the reaction mixture after preparing a compound having formula (I) using the method described in PCT International Application Publications WO 2015 / 103144 and WO 2015 / 103142, and (iii) the reaction mixture after preparing a compound having formula (I) using the method described in PCT International Application Publication PCT / IB2020 / 058893. The entire contents of WO 2015 / 103144, WO 2015 / 103142 and PCT / IB2020 / 058893 are hereby incorporated by reference.

[0579] Separation of compounds having formula (I), via route 2

[0580] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS and at least one water-immiscible solvent, wherein the method comprises (i) mixing the mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound having formula (I) from the organic phase and filtering the crystals.

[0581] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS and at least one water-immiscible solvent, wherein the method comprises (i) washing the mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound having formula (I) from the organic phase and filtering the crystals.

[0582] In some embodiments, the compound having formula (I) is a compound having formula (Iai):

[0583]

[0584] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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 alkaline aqueous solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3, NH4OH, NaOH, and any combination thereof. In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0585] In some embodiments, the concentration of the base in the alkaline aqueous solution is 2%-18% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 15% based on total weight (w / w). In some embodiments, the concentration of the base in the alkaline aqueous solution is about 18% based on total weight (w / w).

[0586] In some embodiments, a compound having formula (I) is dissolved in a water-immiscible solvent or a mixture of a water-immiscible solvent and a water-miscible solvent to obtain an organic solution. In some embodiments, a compound having formula (I) in salt form is dissolved in a water-immiscible solvent or a mixture of a water-immiscible solvent and a water-miscible solvent to obtain an organic solution.

[0587] In some embodiments, the water-immiscible solvent is polar. In some embodiments, the water-immiscible solvent is nonpolar. In some embodiments, the water-immiscible solvent is an organic polar solvent.

[0588] In some embodiments, water-immiscible solvents include, but are not limited to, CPME, MeTHF, DCM, toluene, anisole, or any combination thereof.

[0589] In some embodiments, the water-immiscible solvent is selected from the group consisting of CPME, MeTHF, DCM, toluene, anisole, and any combination thereof.

[0590] In some embodiments, the water-immiscible solvent is selected from the group consisting of methyltetrahydrofuran (MeTHF), cyclopentylmethyl ether (CPME), toluene, anisole, and any mixture thereof.

[0591] 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.

[0592] In some embodiments, a compound having formula (I) is crystallized from an organic phase. In some embodiments, a compound having formula (I) is crystallized by concentrating the organic phase. In some embodiments, a compound having formula (I) is crystallized by mixing an antisolvent with a reaction mixture. In some embodiments, a compound having formula (I) is crystallized by adding an antisolvent. In some embodiments, a compound having formula (I) is crystallized by crystallization initiation.

[0593] The present invention provides a method for separating a compound having formula (I), comprising (1) mixing an organic solution comprising a polar water-immiscible solvent and a mixture of compound (I) and DMS with an alkaline aqueous solution of 2%-18% w / w, (2) separating the organic phase from the aqueous phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[0594] The present invention provides a method for separating a compound having formula (I), comprising (1) washing an organic solution containing a polar water-immiscible solvent and a mixture of compound (I) and DMS with an alkaline aqueous solution of 2%-18% w / w, (2) separating the organic phase from the aqueous phase, and (3) concentrating the organic phase and filtering the precipitated solid.

[0595] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0596] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a 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) mixing the organic solution obtained in (1) with an alkaline aqueous solution of 2%-18% w / w, (3) separating the organic phase from the aqueous phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[0597] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a 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 an alkaline aqueous solution of 2%-18% w / w, (3) separating the organic phase from the aqueous phase, and (4) concentrating the organic phase and filtering the precipitated solid.

[0598] In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20.

[0599] In some embodiments, the organic polar solvent is an organic polar water-immiscible solvent.

[0600] In some embodiments, the organic water-immiscible solvent has a dielectric constant of less than 20.

[0601] In some embodiments, organic water-immiscible solvents include, but are not limited to, methyltetrahydrofuran (MeTHF), cyclopentylmethyl ether (CPME), and mixtures thereof.

[0602] In some embodiments, the organic polar solvent is selected from the group consisting of DMA, CPME, MeTHF, DMA, DMF, DCM, and any combination thereof.

[0603] In some embodiments, the organic polar solvent is selected from the group consisting of CPME, MeTHF, DCM, and any combination thereof.

[0604] 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.

[0605] In some embodiments, a compound having formula (I) is a compound having formula (Ia), wherein R is an alkyl group.

[0606] In some embodiments, a compound having formula (Ia) is a compound having formula (Iai), wherein R is a methyl group.

[0607] In some embodiments, the organic phase is cooled before and / or during filtration. In some embodiments, the organic phase is cooled to 0°C-5°C.

[0608] In some embodiments, an organic polar solvent is mixed with the reaction mixture after the reaction to obtain a compound having formula (I). In some embodiments, CPME is mixed after the reaction to obtain a compound having formula (I).

[0609] In some embodiments, an organic polar solvent is added after the reaction to obtain a compound having formula (I). In some embodiments, CPME is added after the reaction to obtain a compound having formula (I).

[0610] In some embodiments, a portion of the organic polar solvent is present from the reaction to obtain the compound having formula (I), and optionally, an additional amount of the organic polar solvent is mixed with the reaction mixture prior to the separation of the compound having formula (I). In some embodiments, a portion of CPME is present from the reaction to obtain the compound having formula (I), and optionally, an additional amount of CPME is mixed prior to the separation of the compound having formula (I).

[0611] In some embodiments, a portion of the organic polar solvent is present from the reaction that yields the compound having formula (I), and optionally an additional amount of the organic polar solvent is added prior to the separation of the compound having formula (I). In some embodiments, a portion of CPME is present from the reaction that yields the compound having formula (I), and optionally an additional amount of CPME is added prior to the separation of the compound having formula (I).

[0612] In some embodiments, prior to the separation step, the compound having formula (I) in the mixture is in salt form.

[0613] In some embodiments, the nonpolar solvent is a nonpolar water-immiscible solvent.

[0614] In some embodiments, a nonpolar water-immiscible solvent dissolves the compound of formula (I).

[0615] In some embodiments, water-immiscible solvents include, but are not limited to, ether-based solvents, aromatic solvents such as CPME, THF, anisole, toluene, and any mixture thereof.

[0616] In some embodiments, the nonpolar solvent is anisole. In some embodiments, the nonpolar solvent is toluene.

[0617] In some embodiments, the antisolvent is further mixed with the reaction mixture.

[0618] In some embodiments, the antisolvent is mixed with a water-immiscible solvent in parallel with the reaction mixture.

[0619] In some embodiments, the antisolvent is mixed dropwise with the reaction mixture.

[0620] In some embodiments, an antisolvent is further added.

[0621] In some embodiments, the antisolvent is added in parallel to the water-immiscible solvent.

[0622] In some embodiments, the antisolvent is added dropwise.

[0623] In some embodiments, crystallization is carried out at a temperature below 0°C.

[0624] In some embodiments, the antisolvent is a C5-C11 alkane. In some embodiments, the antisolvent is hexane. In some embodiments, the antisolvent is heptane.

[0625] In some embodiments, the mixture of solvent and antisolvent is anisole and hexane.

[0626] In some embodiments, the mixture of solvent and antisolvent is toluene and hexane.

[0627] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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.

[0628] In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0629] In some embodiments, a compound having formula (I) is a compound having formula (Ia), wherein R is an alkyl group.

[0630] In some embodiments, a compound having formula (Ia) is a compound having formula (Iai), wherein R is a methyl group.

[0631] In some embodiments, the organic phase is cooled before and / or during filtration. In some embodiments, the organic phase is cooled to 0°C-5°C.

[0632] In some embodiments, crystallization is accomplished by concentrating the solvent.

[0633] In some embodiments, crystallization is accomplished using crystal seeding.

[0634] In some embodiments, the mixture is crystallized with 0.1%-1% of a compound of formula (I).

[0635] In some embodiments, a water-immiscible solvent is mixed with the reaction mixture after the reaction to obtain a compound having formula (I). In some embodiments, anisole and hexane are mixed with the reaction mixture after the reaction to obtain a compound having formula (I).

[0636] In some embodiments, a water-immiscible solvent is added after the reaction to obtain a compound having formula (I). In some embodiments, anisole and hexane are added after the reaction to obtain a compound having formula (I).

[0637] In some embodiments, a portion of the water-immiscible solvent from the reaction to obtain the compound having formula (I) is present, and optionally, an additional amount of the water-immiscible solvent is mixed with the reaction mixture prior to the separation of the compound having formula (I). In some embodiments, a portion of anisole from the reaction to obtain the compound having formula (I) is present, and optionally, an additional amount of anisole is mixed with hexane with the reaction mixture prior to the separation of the compound having formula (I).

[0638] In some embodiments, a portion of a water-immiscible solvent is present from the reaction that yields the compound having formula (I), and optionally an additional amount of a water-immiscible solvent is added prior to the separation of the compound having formula (I). In some embodiments, a portion of anisole is present from the reaction that yields the compound having formula (I), and optionally an additional amount of anisole, optionally together with hexane, is added prior to the separation of the compound having formula (I).

[0639] The method for separating a compound having formula (I) from a mixture thereof can be used to separate a compound having formula (I) from any mixture thereof, including but not limited to (i) the reaction mixture after preparing a compound having formula (I) using the method described herein, (ii) the reaction mixture after preparing a compound having formula (I) using the method described in PCT International Application Publications WO 2015 / 103144 and WO 2015 / 103142, and (iii) the reaction mixture after preparing a compound having formula (I) using the method described in PCT International Application Publication PCT / IB2020 / 058893. The entire contents of WO 2015 / 103144, WO 2015 / 103142 and PCT / IB2020 / 058893 are hereby incorporated by reference.

[0640] Separation of compounds having formula (I), via route 3

[0641] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS, at least one water-immiscible solvent and at least one other solvent, wherein the method comprises (i) mixing the mixture with an alkaline aqueous solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0642] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS, at least one water-immiscible solvent and at least one other solvent, wherein the method comprises (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0643] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS and at least one water-immiscible solvent, wherein the method comprises (i) mixing the mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0644] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS and at least one water-immiscible solvent, wherein the method comprises (i) washing the mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0645] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS and at least one solvent, wherein the method comprises (i) mixing the mixture with an alkaline aqueous solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0646] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), DMS and at least one solvent, wherein the method comprises (i) washing the mixture with an alkaline aqueous solution to obtain a slurry mixture comprising solids, and (ii) filtering the precipitated solids.

[0647] In some embodiments, the compound having formula (I) is a compound having formula (Iai):

[0648]

[0649] In some embodiments, the method includes mixing an additional solvent with the reaction mixture.

[0650] In some embodiments, the method includes adding an additional solvent.

[0651] In some embodiments, the alkaline aqueous solution comprises DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof. In some embodiments, the alkaline aqueous 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 alkaline aqueous solution is an aqueous solution of a base selected from the group consisting of K2CO3, KHCO3, Na2CO3, NaHCO3, K2CO3, NH4OH, NaOH, and any combination thereof. In some embodiments, the alkaline aqueous solution is an aqueous solution of K2CO3.

[0652] In some embodiments, the concentration of alkali in an alkaline aqueous solution is 2%-18% based on total weight (w / w).

[0653] In some embodiments, the compound having formula (I) in the mixture is in salt form.

[0654] In some embodiments, the mixture contains a solvent. In some embodiments, the slurry mixture contains a solvent.

[0655] A mixture containing a compound having formula (I) may contain DMS and any or all solvents used during the method for preparing a compound having formula (I).

[0656] The other solvent is used for the separation or auxiliary separation of compounds having formula (I). The other solvent can be mixed directly with the mixture. Alternatively, the other solvent can be mixed with a mixture containing an alkaline aqueous solution.

[0657] Other solvents can be added directly to the mixture. Alternatively, they can be added together with an alkaline aqueous solution.

[0658] In some embodiments, the additional solvent is the same as one or more solvents used during the method for preparing a compound having formula (I).

[0659] In some embodiments, the additional solvent is different from one or more solvents used during the method for preparing a compound having formula (I).

[0660] In some embodiments, the additional solvent is a polar solvent.

[0661] In some embodiments, the additional solvent is a water-immiscible solvent. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 4. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 5. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 10. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 15. In some embodiments, the polar solvent has a dielectric constant equal to or greater than 20. In some embodiments, the polar solvent has a dielectric constant of 4.7.

[0662] In some embodiments, the ratio of the additional solvent to the compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio of the additional solvent to the compound having formula (I) is less than 2:1. In some embodiments, the ratio of the additional solvent to the compound having formula (I) is about 1:1.

[0663] In some embodiments, the ratio of the additional solvent to the compound of formula (II) used to prepare the compound of formula (I) is greater than 0.5:1. In some embodiments, the ratio of the additional solvent to the compound of formula (II) used to prepare the compound of formula (I) is less than 2:1. In some embodiments, the ratio of the additional solvent to the compound of formula (II) used to prepare the compound of formula (I) is about 1:1.

[0664] In some embodiments, the additional solvent is a polar solvent and the polar solvent is CPME.

[0665] In some embodiments, the solvent used during the method for preparing a compound having formula (I) is DMA, and the other solvent is CPME.

[0666] In some embodiments, the ratio of CPME to a compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio of CPME to a compound having formula (I) is less than 2:1. In some embodiments, the ratio of CPME to a compound having formula (I) is about 1:1.

[0667] In some embodiments, the ratio of CPME to the compound of formula (II) used to prepare a compound having formula (I) is greater than 0.5:1. In some embodiments, the ratio of CPME to the compound of formula (II) used to prepare a compound having formula (I) is less than 2:1. In some embodiments, the ratio of CPME to the compound of formula (II) used to prepare a compound having formula (I) is about 1:1.

[0668] In some embodiments, the slurry mixture is mixed for 30 minutes to 8 hours.

[0669] In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 60°C. In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 50°C. In some embodiments, the slurry mixture is mixed at a temperature between 25°C and 35°C. In some embodiments, the slurry mixture is mixed at a temperature of about 30°C.

[0670] In some embodiments, a mechanical mixer is used to mix the slurry mixture.

[0671] In some embodiments, a high-shear mixer is used to mix the slurry mixture.

[0672] In some embodiments, both a mechanical mixer and a high-shear mixer are used to mix the slurry mixture.

[0673] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with 2%-18% of an alkaline aqueous solution.

[0674] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to a 2%-18% alkaline aqueous solution.

[0675] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with 11%-18% of an alkaline aqueous solution.

[0676] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to an 11%-18% alkaline aqueous solution.

[0677] In some embodiments, the slurry mixture is obtained by mixing a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent with 15% of an alkaline aqueous solution.

[0678] In some embodiments, the slurry mixture is obtained by adding a mixture comprising a compound having formula (I) and DMS and optionally an organic solvent to a 15% alkaline aqueous solution.

[0679] In some embodiments, the slurry mixture is obtained by mixing a 2%-18% alkaline aqueous solution with a mixture comprising a compound having formula (I), DMS, and optionally an organic solvent.

[0680] In some embodiments, the slurry mixture is obtained by adding 2%-18% alkaline aqueous solution to a mixture comprising a compound having formula (I), DMS, and optionally an organic solvent.

[0681] In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 15°C and 45°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 15°C and 20°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 20°C and 25°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 25°C and 30°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 30°C and 35°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 35°C and 40°C. In some embodiments, in step (2), the precipitated solid is filtered at a temperature between 40°C and 45°C.

[0682] In some embodiments, during the filtration process in step (2), the filtered solids obtained in step (2) are washed with an organic solvent. In some embodiments, the organic solvent is CPME.

[0683] In some embodiments, during the filtration process in step (2), the filtered solids obtained in step (2) are washed with water.

[0684] In some embodiments, the filtered solids are mixed with water and stirred for 1 to 3 hours and then filtered.

[0685] In some embodiments, the filtered solids are mixed with water and stirred and filtered at a temperature of 25°C-50°C.

[0686] In some embodiments, the organic solvent is the same organic solvent used to obtain the compound having formula (I).

[0687] In some embodiments, the alkaline aqueous solution is a 15% K2CO3 aqueous solution based on the total weight (w / w) of K2CO3 in the water. In some embodiments, the alkaline aqueous solution is an 18% K2CO3 aqueous solution based on the total weight (w / w) of K2CO3 in the water.

[0688] In some embodiments, the organic phase is a solution obtained by reacting a compound having formula (II) with DMS.

[0689] In some embodiments, an organic phase is obtained by mixing an organic water-immiscible solvent with a mixture of a compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0690] In some embodiments, an organic phase is obtained by adding an organic water-immiscible solvent to a mixture of a compound having formula (I) and DMS obtained in the reaction of compound (II) and DMS.

[0691] In some embodiments, the step of mixing the alkaline aqueous solution with the reaction mixture includes the additional use of a phase transfer catalyst (PTC), such as tetra-n-butylammonium bromide (TBAB).

[0692] In some embodiments, the step of adding an alkaline aqueous solution includes the additional use of a phase transfer catalyst (PTC), such as tetra-n-butylammonium bromide (TBAB).

[0693] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by mixing CPME and a compound having formula (I) at a weight ratio of 10:1 before mixing with an alkaline aqueous solution of 2%-18% w / w.

[0694] In some embodiments, a solution of the compound having formula (I) in CPME is obtained by mixing CPME and the compound having formula (I) at a weight ratio of 10:1 before washing with an alkaline aqueous solution of 2%-18% w / w.

[0695] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by heating the combination of CPME and the compound having formula (I) to 65°C before mixing with a 2%-18% w / w alkaline aqueous solution.

[0696] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by heating the combination of CPME and the compound having formula (I) to 65°C before washing with a 2%-18% w / w alkaline aqueous solution.

[0697] In some embodiments, a solution of a compound having formula (I) in CPME is obtained by heating the combination of CPME and the compound having formula (I) to about 50°C before mixing with a 2%-18% w / w alkaline aqueous solution.

[0698] In some embodiments, a solution of a compound having formula (I) in a CPME is obtained by heating the CPME and the combination of the compound having formula (I) to approximately 50°C before washing with a 2%–18% w / w alkaline aqueous solution. In some embodiments, the resulting mixture obtained by reacting a compound having formula (II) with DMS is dissolved in the CPME.

[0699] In some embodiments, the resulting mixture obtained by reacting a compound having formula (II) with DMS is dissolved in CPME and washed with an aqueous alkaline solution.

[0700] In some embodiments, the resulting mixture is a mixture of a compound having formula (I) and a solvent used in the reaction of a compound having formula (II) with DMS.

[0701] In some embodiments, the conversion of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one to 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%.

[0702] In some embodiments, the chemical yield of 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%. The purified 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one yields are greater than 50%, 60%, 70%, 80%, 90%, or 99%.

[0703] In some embodiments, the conversion of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one to 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%.

[0704] In some embodiments, the chemical yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one is greater than 50%. The purified 5-fluoro-4-imino-3-methyl-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one yields are greater than 50%, 60%, 70%, 80%, 90%, or 99%.

[0705] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), at least one water-immiscible solvent and at least one other solvent, wherein the method comprises (i) mixing the mixture with water to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0706] The present invention provides a method for separating a compound having formula (I) from a mixture comprising a compound having formula (I), at least one water-immiscible solvent and at least one other solvent, wherein the method comprises (i) washing the mixture with water to obtain a slurry mixture containing solids, and (ii) filtering the precipitated solids.

[0707] The method for separating a compound having formula (I) from a mixture thereof can be used to separate a compound having formula (I) from any mixture thereof, including but not limited to (i) the reaction mixture after preparing a compound having formula (I) using the method described herein, (ii) the reaction mixture after preparing a compound having formula (I) using the method described in PCT International Application Publications WO 2015 / 103144 and WO 2015 / 103142, and (iii) the reaction mixture after preparing a compound having formula (I) using the method described in PCT International Application Publication PCT / IB2020 / 058893. The entire contents of WO 2015 / 103144, WO 2015 / 103142 and PCT / IB2020 / 058893 are hereby incorporated by reference.

[0708] The present invention also provides a compound having formula (I) prepared using the method described herein.

[0709] The present invention also provides a compound having the formula (Iai), which is prepared using the method described herein.

[0710] This reaction occurs under reaction conditions sufficient to produce the desired compound. Those skilled in the art can modify such conditions, such as temperature, time, molar concentration, etc., according to the methods and procedures described herein.

[0711] The present invention also provides a method for crystallizing or recrystallizing a compound having formula (I), comprising (i) preparing a solution containing a compound having formula (I) and a solvent, and (ii) contacting the solution with an antisolvent.

[0712] In some embodiments, the antisolvent is a C5-C11 alkane. In some embodiments, the antisolvent is hexane. In some embodiments, the antisolvent is heptane.

[0713] In some embodiments, the solvent is a solvent in which the antisolvent can be dissolved.

[0714] The methods described herein for crystallizing or recrystallizing compounds having formula (I) can be used to crystallize or recrystallize compounds having formula (I) prepared by any method, including but not limited to the methods described herein and in PCT International Application Publications WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 059160 and WO / 2021 / 181274, the entire contents of which are hereby incorporated by reference.

[0715] In some embodiments, the method includes preparing a compound having formula (I) and crystallizing or recrystallizing the compound having formula (I), which includes (i) preparing a solution comprising the compound having formula (I) and a solvent, and (ii) contacting the solution with an antisolvent.

[0716] Compounds having formula (I) can be prepared by any method, including but not limited to the methods described herein and in PCT International Application Publications WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 059160 and WO / 2021 / 181274, the entire contents of which are hereby incorporated by reference.

[0717] The present invention also provides the use of antisolvents for crystallizing or recrystallizing compounds having formula (I) from their solutions.

[0718] In some embodiments, the antisolvent is a C5-C11 alkane. In some embodiments, the antisolvent is hexane. In some embodiments, the antisolvent is heptane.

[0719] In some embodiments, a compound having formula (I) is in a reaction mixture produced by preparing a compound having formula (I) using any of the methods described herein or any of the methods described in PCT International Application Publications WO 2015 / 103142, WO 2015 / 103144, WO / 2021 / 059160 and WO / 2021 / 181274, the entire contents of which are hereby incorporated by reference.

[0720] The present invention also provides a method for separating a compound having formula (II) from a mixture comprising a 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 having formula (II).

[0721] In some embodiments, the proton solvent is water, methanol, or a combination thereof.

[0722] The method for separating compounds having formula (II) can be applied to any mixture containing compounds having formula (II), including reaction mixtures of the methods described herein for preparing compounds having formula (II) and reaction mixtures of the methods described in PCT International Application Publications WO 2015 / 103142, WO 2015 / 103144 and WO / 2021 / 181274 for preparing compounds having formula (II), the entire contents of which are hereby incorporated by reference.

[0723] This invention provides a method for improving the yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0724]

[0725] In the method, the method includes:

[0726] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0727]

[0728] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0729] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0730] The method includes using at least one water-immiscible solvent, wherein:

[0731] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0732] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0733] The method described herein includes reacting the compound having formula (II) with DMS at a temperature between 10°C and below 25°C.

[0734] This invention provides a method for improving the volumetric yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I):

[0735]

[0736] In the method, the method includes:

[0737] (1) A compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS).

[0738]

[0739] Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and

[0740] (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained.

[0741] The method includes using at least one water-immiscible solvent, wherein:

[0742] i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or

[0743] ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture.

[0744] The method described herein includes using a water-immiscible solvent having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature.

[0745] In some embodiments, the water-immiscible solvent has a solubility of greater than 33 mg / mL and up to 200 mg / mL for a compound of formula (I) at room temperature. In some embodiments, the water-immiscible solvent has a solubility of greater than 33 mg / mL and up to 150 mg / mL for a compound of formula (I) at room temperature. In some embodiments, the water-immiscible solvent has a solubility of greater than 33 mg / mL and up to 100 mg / mL for a compound of formula (I) at room temperature.

[0746] In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 10°C and 85°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 25°C and 85°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 25°C and 50°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 35°C and 50°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between about 10°C and 50°C.

[0747] In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 10°C and below 25°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 10°C and 24°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 10°C and 20°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 10°C and 15°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature between 15°C and 20°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature of about 10°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature of about 15°C. In some embodiments, the method includes reacting a compound having formula (II) with DMS at a temperature of about 20°C.

[0748] This article describes examples of molar ratios between compounds of formula (II) and DMS. For example, the molar ratio between compounds of formula (II) and DMS is between 1:3 and 1:4. This article also describes examples of reaction times between compounds of formula (II) and DMS.

[0749] Each embodiment disclosed herein is contemplated to be applicable to every other disclosed embodiment. Therefore, all combinations of the various elements described herein are within the scope of this invention.

[0750] The invention will be better understood by referring to the experimental details below, but those skilled in the art will readily understand that the detailed experiments described in the following claims are merely illustrative of the invention.

[0751] Without limiting the scope of the invention, the invention will be illustrated by the following examples.

[0752] Example

[0753] Examples of sulfonation steps

[0754] Example 1: 5-Fluorocytosine is reacted with a compound having formula (III) in DMA and water and K2CO3 as a base.

[0755] 5-Fluorocytosine (99%, 80.1 g) was added to a 1 L glass reactor containing 200 g of water and 200 g of DMA. K₂CO₃ (solid, 114.9 g, 1.35 mol equivalent) was added, and the reactor was cooled to 0 °C. Toluenesulfonyl chloride (128 g, 1.05 mol equivalent) was added in a single addition at 0 °C, and the solution was mixed at 0 °C to 5 °C. The reaction was monitored using HPLC, and then 200 g of water was added, and the temperature was heated to 25 °C and mixed for 2 hours. The obtained solid was filtered off using a Buchner funnel. The filter cake was washed with water and dried in a vacuum oven at 55 °C to 65 °C. 178 g of the desired product was obtained with a purity of 90.9% and a yield of 93%.

[0756] The product contains impurity A (2.4%) and impurity B (0.2%).

[0757] Example 2: Reacting 5-fluorocytosine with a compound having formula (III) in DMA and using Et3N as a base.

[0758] Add 34.2 g of Et3N to 40 g of 99.2% 5-fluorocytosine in 120 g of DMA. Cool the mixture to 0 °C. Add 1.05 equivalents of TSCl and stir the reaction mixture at 3 °C for 4 hours. Monitor the reaction using HPLC. The conversion to the product was 94.5%.

[0759] Add 250 g of water to the mixture and heat to 15 °C. Filter off the solids and dry in a vacuum oven to obtain the desired product with a separation yield of 75%. Chemical yield = 77%. The product was obtained with a purity of 78.8% and contained impurity B (1%).

[0760] Example 3: Reacting 5-fluorocytosine with a compound having formula (III) in DMA and water with K2CO3 as a base.

[0761] 8.5 g of K₂CO₃ (1.6 equivalents) was added to 5 g of 99.2% 5-fluorocytosine in 20 g of water and 10 g of DMA. The reaction mixture was cooled to 5 °C, and 8.4 g of TSCl (1.1 equivalents) was added. The reaction mixture was stirred at 5 °C for 3 h. HPLC monitoring detected 92% of the desired product. The precipitate was filtered off and dried in a vacuum oven at 55 °C for 12 h to give a product as a white solid with a purity of 84% and a separation yield of 85%. The product contained impurity A (6%).

[0762] Example 4(a): Reaction of 5-fluorocytosine with a compound having formula (III) in ACN and Et3N as a base.

[0763] 30.4 g of Et3N (1.3 equivalents) was added to 30 g of 99.2% 5-fluorocytosine in 165 g of ACN. The mixture was cooled to 0 °C. Then, 50.6 g of TSCl (1.15 equivalents) was added in two portions at 0 °C. The reaction mixture was stirred for 4 hours. The reaction was monitored using HPLC. 310 g of water was added to the mixture, and the mixture was heated to 10 °C and stirred for 1 hour. The solids were filtered off and dried in a vacuum oven to obtain the desired product in a separation yield of 54%. The chemical yield was 63%. The product was obtained with a purity of 68.8% and contained impurity B (6.1%) and impurity A (0.7%).

[0764] Example 4(b): 5-fluorocytosine is reacted with a compound having formula (III) in ACN and Et3N as a base.

[0765] Add 4.7 g of Et3N to 5 g of 99.2% 5-fluorocytosine in 15 g of ACN. Cool the mixture to 5 °C. Then, add 8.1 g of TSCl and stir the reaction mixture at 5 °C for 2 hours. Monitor the reaction using HPLC. Add MeOH to the mixture, filter off the solids, and dry in a vacuum oven to obtain the desired product with a separation yield of 60.8%. Chemical yield = 74%. The product was obtained with a purity of 73.7% and contained impurity B (0.3%) and impurity A (0.5%).

[0766] Example 4(c): Reaction of 5-fluorocytosine with a compound having formula (III) in MeCN and NET3.

[0767] 5-Fluorocytosine (99%, 5 g) was added to a round-bottom flask containing 15 g of acetonitrile. Triethylamine (4.6 g, 1.2 mol equivalent) was added and the flask was cooled to 5 °C. Toluenesulfonyl chloride (8 g, 1.1 mol equivalent) was added in a single addition at 5 °C, and the solution was mixed at 5 °C. The reaction was monitored using HPLC, and methanol was then added, and the temperature was heated to 25 °C and mixed for 2 hours. The obtained solid was filtered off using a Buchner funnel. 9 g of the desired product was given with a purity of 74% and a yield of 61%. The product contained impurity A (0.5%) and impurity B (0.3%).

[0768] Example 5: Reacting 5-fluorocytosine with a compound having formula (III) in water and DMA, with DMAP as a base.

[0769] Add 1.4 g of DMAP to 5 g of 99.2% 5-fluorocytosine in 15 g of water and 10 g of DMA. Cool the reaction mixture to 5 °C and add 9.15 g of TSCl. Adjust the pH of the reaction to 9–10 using a 20% NaOH solution. After reaching 86% product concentration on HPLC, heat the reaction mixture to 25 °C. Filter off the precipitate, wash with water, and dry in a vacuum oven to obtain the desired product with a separation yield of 59%.

[0770] The product was obtained with a purity of 79.6% and contained impurity B (0.75%) and impurity A (0.32%).

[0771] Example 6: Reaction of 5-fluorocytosine with a compound having formula (III) in MeCN and triethylamine as a base.

[0772] 30.4 g of Et3N (1.3 equivalents) was added to 30 g of 99.2% 5-fluorocytosine in 165 g of ACN. The mixture was cooled to 0 °C. Then, 50.6 g of TSCl (1.15 equivalents) was added in two portions at 0 °C. The reaction mixture was stirred for 4 hours. The reaction was monitored using HPLC. 310 g of water was added to the mixture, and the mixture was heated to 10 °C and stirred for 1 hour. The solids were filtered off and dried in a vacuum oven to obtain the desired product in a separation yield of 54%. The chemical yield was 63%. The product was obtained with a purity of 68.8% and contained impurity B (6.1%) and impurity A (0.7%).

[0773] Example 7: Reaction of 5-fluorocytosine with a compound having formula (III) in MeCN and triethylamine as a base.

[0774] Add 4.7 g of Et3N to 5 g of 99.2% 5-fluorocytosine in 15 g of MeCN. Cool the mixture to 5 °C. Then, add 8.1 g of TSCl and stir the reaction mixture at 5 °C for 2 hours. Monitor the reaction using HPLC. Add MeOH to the mixture, filter off the solids, and dry in a vacuum oven to obtain the desired product with a separation yield of 60.8%. Chemical yield = 74%. The product was obtained with a purity of 73.7% and contained impurity B (0.3%) and impurity A (0.5%).

[0775] Example 8: Reaction of 5-fluorocytosine with a compound having formula (III) in DMA and sodium carbonate as a base.

[0776] 6.38 g of Na₂CO₃ was added to 5 g of 99.2% 5-fluorocytosine in 35 g of DMA. The mixture was cooled to 5 °C. Then, 8.37 g of TSCl was added, and the reaction mixture was stirred at 5 °C for 3 hours. The reaction was sampled by HPLC. Partial conversion of the starting material was obtained. The product was not separated.

[0777] Example 9: Reacting 5-fluorocytosine with a compound having formula (III) in DMBA and sodium carbonate as a base.

[0778] 6.38 g of Na₂CO₃ was added to 5 g of 99.2% 5-fluorocytosine in 35 g of DMBA. The mixture was cooled to 5 °C. Then, 8.37 g of TSCl was added, and the reaction mixture was stirred at 5 °C for 3 hours. The reaction was sampled by HPLC. Partial conversion of the starting material was obtained. The product was not separated.

[0779] Example 10: Reaction of 5-fluorocytosine with a compound having formula (III) in water and DMAP as a base.

[0780] 2.35 g of 4-DMAP was added to 5 g of 99.2% 5-fluorocytosine in 40 g of water. 8.8 g of TSCl was added, and the reaction mixture was stirred at 25 °C for 4 hours. The reaction was sampled by HPLC. 50% of the desired product was obtained. The conversion of the starting material was 51%. No product separation was achieved.

[0781] Example 11: 5-Fluorocytosine was reacted with a compound having formula (III) in DMA, water, and DMBA with potassium hydroxide. It is an alkaline reaction

[0782] Add 15 g of water and 1.56 g of N,N-dimethylbenzylamine to 5 g of 99.2% 5-fluorocytosine in 15 g of DMA. Cool the mixture to 5 °C. Then, add 9.13 g of TSCl and stir the reaction mixture at 5 °C for 4 hours while maintaining the pH at 9–10 using 20% ​​potassium hydroxide in water. Sample the reaction mixture by HPLC. The product was obtained with partial selectivity and without separation.

[0783] Example 12: 5-Fluorocytosine was reacted with a compound having formula (III) in DMA, water, and DMBA, and then with sodium hydroxide. It is an alkaline reaction

[0784] Add 15 g of water and 1.56 g of N,N-dimethylbenzylamine to 5 g of 99.2% 5-fluorocytosine in 15 g of DMA. Cool the mixture to 5 °C. Then, add 9.13 g of TSCl and stir the reaction mixture at 5 °C for 4 hours while maintaining the pH at 9–10 using 20% ​​sodium hydroxide in water. Sample the reaction mixture by HPLC. 78.3% of the desired product was obtained, with a conversion of 82%. 3.8% of the product isomers were obtained. No product separation was achieved.

[0785] Example 13: 5-Fluorocytosine is reacted with a compound having formula (III) in DMA and water and K2CO3 as a base.

[0786] 5-Fluorocytosine (99%, 120 g) was added to a 1 L glass reactor containing 360 g of water and 160 g of DMA. K₂CO₃ (204 g, 1.6 mol equivalent) was added, and the reactor was cooled to -5 °C. Toluenesulfonyl chloride (192 g, 1.05 mol equivalent) was added in a single step over 1.5 hours at -5 °C to -3 °C, and the solution was mixed at -5 °C for 3.5 hours. The reaction was monitored using HPLC. 93% selectivity was observed. The reaction was heated to 15 °C, and the product was filtered off and dried in a vacuum oven at 55 °C. 329 g of product with a purity of 60% was obtained. The separation yield was 76%.

[0787] Examples of alkylation steps

[0788] Example 14: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in CPME and DMA in the absence of base. Response under circumstances

[0789] 4800 g of CPME, 1200 g of DMA, and 1700 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (IIai) (81% purity) were added to a 25 L reactor. The mixture was heated to 35 °C and dimethyl sulfate (2000 g, 3.5 mol equivalent) was added over 30 minutes. The reaction was stirred at 35-40 °C for 4 hours. 9000 g of CPME was added, and the mixture was heated to 50 °C until a clear solution was obtained. An aqueous solution of K₂CO₃ (10% w, 10 kg) was added, and the mixture was stirred for 30 minutes. The phases were separated, and the organic phase was mixed with another 5 kg of a 10% K₂CO₃ solution containing 85 g of TBAB for 1 hour, followed by phase separation, and the same procedure was repeated. The organic phase was washed with 9 kg of water, and then 10 kg of CPME was evaporated at 50 °C under 100 mbar.

[0790] The solution was cooled to 0°C–5°C, and the obtained solid was filtered off using a Buchner funnel. The filter cake was washed with 1 liter of cold water and dried in a vacuum oven at 65°C. 1222 g of product was obtained with a purity of 98.9% and a separation yield of 80%.

[0791] Example 15(a): Compounds having formula (IIai) react with dimethyl sulfate (DMS) in CPME and DMA and in TBAB The reaction in the presence of.

[0792] To a mixture of 40 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (IIai) with a purity of 86.8%, 200 g of CPME, 50 g of DMA, 5% TBAB, and 3 equivalents of dimethyl sulfate were added in a single step. The reaction mixture was heated to 40 °C for 6 hours. Then, 250 g of CPME was added, and the reaction mixture was heated to 50 °C and washed twice with 300 g of 10% K₂CO₃ solution. The final wash was performed at 50 °C with 300 g of water. The organic phase was concentrated under reduced pressure, and the residue was cooled to 5 °C. The solid formed was filtered off, washed with CPME, and dried in a vacuum oven at 65 °C to obtain the desired product with a purity of 94.5% and a separation yield of 80.4%.

[0793] Example 15(b): Compounds having formula (IIai) with dimethyl sulfate (DMS) in DMA and in the presence of NaOMe The reaction below.

[0794] To a mixture of 5 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (IIai) with a purity of 85.3%, 15 g of DMA, 0.2 equivalents of NaOMe, and 4 equivalents of dimethyl sulfate were added. The reaction mixture was heated to 35 °C for 5 hours. 45 g of CPME was added, and the mixture was heated to 50 °C. The organic phase was washed twice with 10% K₂CO₃ solution and a third time with 50 g of water. Phase separation was performed at 50 °C. The organic phase was concentrated under vacuum to obtain the desired product in a separation yield of 51%.

[0795] Example 16: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in CPME and DMA1:1 in the absence of reaction under alkaline conditions

[0796] 2000 g of CPME, 2000 g of DMA, and 2000 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (IIai) (81% purity) were added to a 25 L reactor. The mixture was heated to 35 °C and dimethyl sulfate (2200 g, 3 mol equivalent) was added over 60 minutes. The reaction was stirred at 35 °C–40 °C for 4 hours. 14000 g of CPME was added, and the mixture was heated to 50 °C until a clear solution was obtained. An aqueous solution of K₂CO₃ (15% w, 11.5 kg) was added, and the mixture was stirred at 60 °C for 60 minutes. The phases were separated, and the organic phase was mixed with another 6 kg of 10% K₂CO₃ solution for 0.5 hours, followed by phase separation. The organic phase was stirred with 6.3 kg of water for 30 minutes, and the phases were separated. 11 kg of CPME was evaporated at 50 °C under 100 mbar.

[0797] The solution was cooled to 0°C–5°C, and the obtained solid was filtered off using a Buchner funnel. The filter cake was washed with 1 liter of cold water and dried in a vacuum oven at 65°C. The product was obtained in a separation yield of 75%.

[0798] Example 17: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in DMA in the absence of base. reaction

[0799] 200 g of DMA and 100 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (IIai) (81% purity) were added to a 25 L reactor. The mixture was heated to 35 °C and dimethyl sulfate (110 g, 2.5 mol equivalent) was added over 60 minutes. The reaction was stirred at 35 °C–40 °C for 4 hours. 50 g of an aqueous solution of CPME and K₂CO₃ (15% w, 600 g) was added and the mixture was heated to 60 °C and stirred at 45 °C for 120 minutes.

[0800] The mixture was cooled to 0°C–5°C over 1 hour, and the obtained solids were filtered off using a Buchner funnel. The filter cake was mixed with 300 g of water at 40°C for 1 hour, cooled to 0°C, filtered, and the water slurry process was repeated. The product was dried in a vacuum oven at 65°C. The product was obtained with a separation yield of 80% and a purity of 99%.

[0801] Example 18: A compound having formula (IIai) reacts with 5 equivalents of dimethyl sulfate (DMS) in DMA and CPME without presence. The reaction occurs under alkaline conditions.

[0802] 28 g of CPME, 7 g of DMA, and 10 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (81% purity) were added to a round-bottom flask. The mixture was heated to 35 °C and dimethyl sulfate (18 g, 5 mol equivalent) was added over 30 minutes. The reaction was stirred at 39 °C for 5.5 hours. 53 g of CPME was added, and the mixture was heated to 58 °C until a clear solution was obtained. An aqueous solution of K₂CO₃ (10% w) was added, and the mixture was stirred for 30 minutes. The phases were separated, and the organic phase was mixed with another 176 g of a 10% K₂CO₃ solution containing 0.5 g of TBAB for 1 hour, followed by phase separation, and the same procedure was repeated again. The organic phase was washed with 300 g of water, and then 300 g of CPME was evaporated at 50 °C under 100 mbar.

[0803] The solution was cooled to 0°C–5°C, and the obtained solid was filtered off using a Buchner funnel. The filter cake was washed with 1 liter of cold water and dried in a vacuum oven at 65°C. The product was obtained with a purity of 99.5% and a separation yield of 81%.

[0804] Example 19: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in DMA and CPME in the presence of a base. The reaction.

[0805] 5.6 g of CPME, 1.4 g of DMA, and 2 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (81% purity) were added to a round-bottom flask. The mixture was heated to 35 °C and dimethyl sulfate (2.5 g, 3.5 mol equivalent) was added over 30 minutes. The reaction was stirred at 40 °C for 4 hours. After 4 hours, Na₂CO₃ (0.3 mol equivalent) was added and stirring was continued for another hour until the starting material was completely converted.

[0806] Add 10 g of CPME and heat the mixture to 56 °C until a clear solution is obtained. Add an aqueous solution of K₂CO₃ (10% w) and stir the mixture for 30 minutes. Separate the phases and mix the organic phase with another 35 g of 10% K₂CO₃ solution for 1 hour, followed by phase separation and repeating the same procedure again. Wash the organic phase with 60 g of water and then evaporate 60 g of CPME at 50 °C under 100 mbar.

[0807] The solution was cooled to 0°C–5°C, and the obtained solid was filtered off using a Buchner funnel. The filter cake was washed with 1 liter of cold water and dried in a vacuum oven at 65°C. The product was obtained with a purity of 97.5% and a separation yield of 74%.

[0808] Example 20: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in DMA and CPME in the presence of a base. The reaction.

[0809] 28 g of CPME, 7 g of DMA, and 10 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (81% purity) were added to a round-bottom flask. The mixture was heated to 35 °C and dimethyl sulfate (12.6 g, 3.5 mol equivalent) was added over 30 minutes. The reaction was stirred at 39 °C for 4 hours. After 4 hours, NaOMe (0.5 mol equivalent) was added and stirring was continued for another hour until the starting material was completely converted.

[0810] Add 53 g of CPME and heat the mixture to 58 °C until a clear solution is obtained. Add an aqueous solution of K₂CO₃ (10% w) and stir the mixture for 30 minutes. Separate the phases and mix the organic phase with another 176 g of a 10% K₂CO₃ solution containing 0.5 g of TBAB for 1 hour, followed by phase separation and repeating the same procedure again. Wash the organic phase with 300 g of water and then evaporate 300 g of CPME at 50 °C under 100 mbar.

[0811] The solution was cooled to 0°C–5°C, and the obtained solid was filtered off using a Buchner funnel. The filter cake was washed with 1 liter of cold water and dried in a vacuum oven at 65°C. The product was obtained with a purity of 98.8% and a separation yield of 77%.

[0812] Example 21: Compounds having formula (IIai) with dimethyl sulfate (DMS) in DMA / CPME under high shear stirring The reaction below.

[0813] 200 g of CPME, 200 g of DMA, and 200 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (81% purity) were added to a reactor. The mixture was heated to 35 °C and dimethyl sulfate (266 g, 3.5 mol equivalent) was added over 30 minutes. The reaction mixture was stirred at 35-40 °C for 5.5 hours. 1 / 10 of the reaction mixture was transferred to a 250 mL reactor equipped with a high-shear stirrer. 60 g of CPME was added and the mixture was heated to 60 °C. 120 g of a 15% aqueous solution of potassium carbonate was added over 10 minutes. The mixture was cooled to 50 °C and stirred for 2 hours, followed by stirring at 30 °C for an additional 2 hours. The mixture was cooled to 0 °C, filtered using a Buchner funnel, and the filter cake was dried overnight in a vacuum oven at 65 °C. The product was obtained with a purity of 97.7% and a yield of 62%.

[0814] Example 22: Reaction of a compound having formula (IIai) with dimethyl sulfate (DMS) in DMA and CPME.

[0815] 200 g of CPME, 200 g of DMA, and 200 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (81% purity) were added to a reactor. The mixture was heated to 35°C and dimethyl sulfate (266 g, 3.5 mol equivalent) was added over 30 minutes. The reaction mixture was stirred at 35°C–40°C for 5.5 hours. 193 g of the reaction mixture was transferred to a 1 L reactor equipped with a mechanical stirrer. 151 g of CPME was added and the mixture was heated to 60°C over 10 minutes. 300 g of a 15% aqueous solution of potassium carbonate was added over 20 minutes. The mixture was cooled to 30°C and stirred for 6 hours, followed by cooling to 0°C over 15 minutes. The product was filtered using a Buchner funnel, and the filter cake was washed with 200 g of water and dried overnight in a vacuum oven at 65°C. The product was obtained with a purity of 98.1% and a yield of 60%.

[0816] Example 23: Reaction of a compound having formula (IIai) with dimethyl sulfate (DMS) in DMA and CPME.

[0817] 200 g of CPME, 200 g of DMA, and 200 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (81% purity) were added to a reactor. The mixture was heated to 35 °C and dimethyl sulfate (266 g, 3.5 mol equivalent) was added over 30 minutes. The reaction was stirred at 35-40 °C for 5.5 hours. The mixture was heated to 60 °C over 10 minutes and added dropwise to a reactor containing a 15% potassium carbonate solution. The mixture was cooled to 30 °C and stirred for 3 hours, followed by cooling to 0 °C over 1.5 hours. The product was filtered using a Buchner funnel, and the filter cake was washed with 150 g of water and filtered again. The wet filter cake was mixed with 700 g of water for 3 hours, filtered, washed with 150 g of water, filtered again, and dried in a vacuum oven at 65 °C. The product was obtained with a purity of 97% and a yield of 65%.

[0818] Example 24: The reaction of a compound having formula (IIai) with dimethyl sulfate (DMS) in CPME at 85°.

[0819] 15 g of CPME and 2 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (90.7% purity) were added to a round-bottom flask. Dimethyl sulfate (6 g, 7.4 mol equivalent) was added in a single addition. The reaction was stirred at 85 °C for 3 hours. HPLC analysis showed a selectivity of 53% and a conversion of 81% for the starting material. No product separation was observed.

[0820] Example 25: Reaction of a compound having formula (IIai) with dimethyl sulfate (DMS) in CPME / DMA at 25°C answer.

[0821] 6 g of CPME, 2 g of DMA, and 5 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (90.7% purity) were added to a round-bottom flask. Dimethyl sulfate (6 g, 3 mol equivalent) was added in a single addition. 2 g of 7% NaOH solution was added, and the reaction was stirred at room temperature for 6 hours. HPLC analysis showed 60% selectivity and 84% conversion of the starting materials. No product separation was observed.

[0822] Example 26: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in MeTHF using triethylamine as a base. reaction

[0823] 10 g of methyltetrahydrofuran, 5 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (90.7% purity), and 0.8 g of triethylamine were added to a round-bottom flask. Dimethyl sulfate (4 g, 5 mol equivalent) was added in a single addition. The reaction was stirred at 45 °C for 6 hours. HPLC analysis showed a selectivity of 73% and a conversion of 81% for the starting materials. No product separation was observed.

[0824] Example 27: Reaction of a compound having formula (IIai) with 10 mol equivalents of dimethyl sulfate (DMS) in MeTHF.

[0825] 15 g of methyltetrahydrofuran and 2 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (90.7% purity) were added to a round-bottom flask. Dimethyl sulfate (8 g, 10 mol equivalent) was added in a single addition. The reaction was stirred at 40 °C for 5 hours. HPLC analysis showed a 62% selectivity and 70% conversion of the starting material. No product separation was observed.

[0826] Example 28: Reaction of a compound having formula (IIai) with dimethyl sulfate (DMS) in DMA and anisole.

[0827] At room temperature, 50 g of DMAA and 50 g of anisole were added to 57.1 g of 4-amino-5-fluoro-1-[(4-methylphenyl)sulfonyl]-2(1H)-pyrimidinone (87.5% purity).

[0828] Heat the reaction mixture to Tr = 35°C.

[0829] Add dimethyl sulfate (55.7 g, 2.5 equivalents) dropwise over 30-60 minutes.

[0830] The reaction mixture was heated to Tr = 40°C and stirred for 3 hours.

[0831] Add 50 grams of n-hexane and 150 grams of anisole.

[0832] Add 50 grams of K2CO 3(S) Add to the reactor along with 300 grams of water.

[0833] The reactor mixture is heated to 60°C.

[0834] After stirring, the lower phase was discarded, and the upper phase was cooled to 30°C and crystallized with 1% of the compound of formula (I).

[0835] Mix the mixture at 30°C for 30 minutes, and then cool it to 0°C over a period of 3 hours.

[0836] Stir the reaction mixture overnight and then filter.

[0837] Wash the filter cake with 50 g of n-hexane and then with water.

[0838] The wet filter cake was dried under vacuum at 65°C.

[0839] Example 29: Compounds having formula (IIai) react with dimethyl sulfate (DMS) in DMA and anisole in the absence of base. Response in the case

[0840] 57.1 g of 5-fluoro-4-imino-1-(toluene-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one (IIai) (87.5% purity) and 100 g of DMA were added to a 1 L reactor. The mixture was stirred at room temperature and dimethyl sulfate (89.1 g, 4 equivalents) was added dropwise over 30–60 minutes. The reaction mixture was stirred at 20 °C for 6–7 hours. 150 g of anisole (3 w / w) was added to the reactor. The reaction mixture was added dropwise to 560 g of a 15% K₂CO₃ solution (560 g) at 20–30 °C. The reaction mixture was heated to 60 °C for 30 minutes and the phases were separated. 250 g of n-hexane (5 w / w) was added dropwise to the organic phase while maintaining the temperature between 57 °C and 62 °C. The reaction mixture was cooled to 50 °C and stirred at the same temperature for 30 minutes. The reaction mixture was cooled to 10°C for 3 hours, and the obtained solids were filtered off using a Buchner funnel. The filter cake was washed with 50 g of n-hexane and 100 g of water. The filter cake was dried in a vacuum oven at 60°C. 45.06 g of product was obtained with a purity of 98.9% and a separation yield of 85%.

[0841] discuss

[0842] An improved synthetic method is needed to produce 5-(fluoro-4-imino-3-methyl)-1-toluenesulfonyl-3,4-dihydropyrimidine-(1h)-one.

[0843] The claimed method is an improvement on the method for synthesizing 5-(fluoro-4-imino-3-methyl)-1-toluenesulfonyl-3,4-dihydropyrimidine-(1h)-one as described in WO 2015 / 103144 and / or WO 2015 / 103142.

[0844] This invention provides an efficient route for synthesizing compound I via a two-step reaction, wherein each step is a one-step reaction without additional protecting groups and / or without using alkylation reactions as described in WO 2015 / 103144 and / or WO 2015 / 103142.

[0845] This method is designed to address the problems of non-selective sulfonation and alkylation steps as described in previous methods.

[0846] Furthermore, it was found that higher yields (e.g., 80%-85%) could be achieved when the reaction of the compound having formula (II) with dimethyl sulfate (DMS) was carried out at temperatures between 10°C and below 25°C. It may be necessary to adjust the molar ratio between the compound having formula (II) and DMS, as well as the reaction time. In particular, the reaction time can be reduced when more DMS is used, and increased when less DMS is used to achieve a given yield.

[0847] References

[0848] WO 2015 / 103144, published on July 9, 2015 (AdamaMakhteshim Ltd.)

[0849] WO 2015 / 103142, published on July 9, 2015 (Adama Maxim Ltd).

Claims

1. A method for obtaining 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I): The method includes: (1) Compound of formula (I) is prepared by reacting a compound of formula (II) with dimethyl sulfate (DMS). Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained. The method includes using at least one water-immiscible solvent, wherein: i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture. and The reaction of the compound having formula (II) with DMS is carried out at a temperature between 10°C and below 25°C.

2. The method as described in claim 1, wherein, The reaction was carried out at a temperature between 10°C and 24°C.

3. The method as described in claim 1 or 2, wherein, The reaction was carried out at a temperature of about 20°C.

4. The method according to any one of claims 1-3, wherein, The reaction of the compound having formula (II) in step (1) with DMS is carried out 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 (1).

5. The method according to any one of claims 1-4, wherein, The water-immiscible solvent is anisole.

6. The method according to any one of claims 1-5, wherein, The reaction of the compound having formula (II) in step (1) with DMS is carried out in the presence of DMA, and anisole is mixed with the reaction mixture after step (1).

7. The method according to any one of claims 1-6, wherein, R is alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN, or CF3.

8. The method according to any one of claims 1-7, wherein, Obtain a multiphase system.

9. The method of claim 8, wherein, The multiphase system comprises an organic phase and an aqueous phase, and the method for separating the compound having formula (I) from the reaction mixture comprises separating the organic phase from the aqueous phase, crystallizing the compound having formula (I) from the organic phase, and filtering the crystals.

10. The method of claim 9, wherein, The compound having formula (I) is crystallized by concentrating the organic phase, mixing the reaction mixture with an antisolvent, and / or crystallizing.

11. The method of claim 8, wherein, The multiphase system is a slurry containing solids, and the method for separating the compound having formula (I) from the reaction mixture includes filtering the precipitated solids.

12. The method of claim 8, wherein, The multiphase system comprises a liquid and a solid, and the method for separating the compound having formula (I) from the reaction mixture comprises filtering the solid.

13. The method according to any one of claims 1-4 and 7-12, wherein, The water-immiscible solvent is an ether-based solvent, an aromatic solvent, or a mixture thereof.

14. The method according to any one of claims 1-4 and 7-13, wherein, The water-immiscible solvent is toluene, anisole, or a mixture thereof.

15. The method according to any one of claims 1-14, wherein, The reaction is carried out in the presence of at least one water-immiscible solvent.

16. The method according to any one of claims 1-3, 5 and 7-14, wherein: a. After step (1) and before mixing the alkaline aqueous solution with the reaction mixture, the water-immiscible solvent is mixed with the reaction mixture. b. While mixing the alkaline aqueous solution with the reaction mixture, the water-immiscible solvent is mixed with the reaction mixture, or c. After mixing the alkaline aqueous solution with the reaction mixture, the water-immiscible solvent is mixed with the reaction mixture.

17. The method according to any one of claims 1-16, wherein, The reaction is carried out in the presence of a mixture of solvents, wherein at least one solvent is water-immiscible and at least one solvent is water-miscible.

18. The method of claim 17, wherein, The solvent mixture is DMA and anisole.

19. The method according to any one of claims 1-18, wherein, The compound having formula (I) is in salt form.

20. The method of claim 19, wherein, The salt is a monomethyl sulfate of the compound having formula (I).

21. The method of claim 1, wherein, The method includes: (a)(1) The compound having formula (I) is prepared by reacting the compound having formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent, and (2) The compound having formula (I) is separated from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound having formula (I) from the organic phase and filtering the crystals. (b)(1) To prepare the compound of formula (I) by reacting the compound of formula (II) with dimethyl sulfate (DMS), (2) to mix the reaction mixture with at least one water-immiscible solvent, and (3) to separate the compound of formula (I) from the reaction mixture by the following steps: (i) to mix the reaction mixture with an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) to separate the organic phase from the aqueous phase, and (iii) to crystallize the compound of formula (I) from the reaction mixture and to filter the crystallized solid. (c)(1) Preparing the compound of formula (I) by reacting the compound of formula (II) with dimethyl sulfate (DMS), and (2) Separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with at least one water-immiscible solvent and an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid. (d)(1) Preparing the compound of formula (I) by reacting the compound of formula (II) with dimethyl sulfate (DMS), and (2) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with at least one water-immiscible solvent and an alkaline aqueous solution to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound of formula (I) and filtering the crystallized solid, or (e)(1) The compound having formula (I) is prepared by reacting a compound having formula (II) with dimethyl sulfate (DMS), and (2) The compound having formula (I) is separated from the reaction mixture by the following steps: (i) mixing the reaction mixture with a mixture of an alkaline aqueous solution and at least one water-immiscible solvent to form an organic phase and an aqueous phase, (ii) separating the organic phase from the aqueous phase, and (iii) crystallizing the compound having formula (I) and filtering the crystallized solid.

22. The method of claim 1, wherein, The method includes: (a)(1) The compound having formula (I) is prepared by reacting the compound having formula (II) with dimethyl sulfate (DMS) in the presence of at least one water-immiscible solvent and at least one other solvent, and (2) The compound having formula (I) is separated from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid. (b)(1) The compound having formula (I) is prepared by reacting the compound having formula (II) with dimethyl sulfate (DMS), (2) the reaction mixture is mixed with at least one water-immiscible solvent and at least one other solvent, and (3) the compound having formula (I) is separated from the reaction mixture by the following steps: (i) the reaction mixture is mixed with an alkaline aqueous solution to obtain a slurry mixture containing a precipitated solid, and (ii) the precipitated solid is filtered. (c)(1) preparing the compound of formula (I) by reacting the compound of formula (II) with dimethyl sulfate (DMS), (2) mixing the reaction mixture with at least one water-immiscible solvent, and (3) separating the compound of formula (I) from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution and at least one additional solvent to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid, or (d)(1) The compound having formula (I) is prepared by reacting the compound having formula (II) with dimethyl sulfate (DMS), and (2) The compound having formula (I) is separated from the reaction mixture by the following steps: (i) mixing the reaction mixture with an alkaline aqueous solution, at least one water-immiscible solvent and at least one other solvent to obtain a slurry mixture containing a precipitated solid, and (ii) filtering the precipitated solid.

23. The method according to any one of claims 1-22, wherein, The alkaline aqueous solution contains DABCO, TBAB, NaOH, K2CO3, KHCO3, Na2CO3, Et3N, NaOMe, NaOEt, or any combination thereof.

24. The method according to any one of claims 1-23, wherein, The alkaline aqueous solution is an aqueous solution of K2CO3.

25. The method according to any one of claims 1-24, wherein, Based on total weight (w / w), the concentration of the alkali in the alkaline aqueous solution is 2%-18%.

26. The method according to any one of claims 1-25, wherein, The molar ratio between the one or more solvents and the compound having formula (II) is between 30:1 and 1:

1.

27. The method according to any one of claims 1-26, wherein, The molar ratio between the one or more solvents and DMS is between 10:1 and 1:

1.

28. The method according to any one of claims 1-27, wherein, The molar ratio between the compound having formula (II) and DMS is between 1:2 and 1:

10.

29. The method according to any one of claims 1-28, wherein, The molar ratio between the compound having formula (II) and DMS is between 1:3 and 1:

4.

30. The method according to any one of claims 1-29, wherein, The compound having formula (II) was stirred with DMS for about 3-10 hours.

31. The method according to any one of claims 1-30, wherein, The compound having formula (II) was stirred with DMS for about 6-7 hours.

32. The method according to any one of claims 1-31, wherein, The compound having formula (II) is reacted with DMS to obtain the compound having formula (I) in a yield of at least 80%.

33. The method according to any one of claims 1-32, wherein, The compound having formula (I) is a compound having formula (Iai): Furthermore, the compound having formula (II) is a compound having formula (IIai). Where R is a methyl group and X is a halogen or -OSO2PhR.

34. A compound having formula (I) obtained using the method described in any one of claims 1-33.

35. A method for obtaining a compound having formula (I) 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one: The method includes: (a) Reacting 5-fluorocytosine with a compound having formula (III): The reaction is carried out in the presence of at least one polar solvent and at least one base to obtain a compound having formula (II). as well as (b) Prepare the compound having formula (I) and separate the compound having formula (I) from the reaction mixture by the method according to any one of claims 1-33.

36. The method of claim 35, wherein, The reaction of 5-fluorocytosine with the compound having formula (III) to obtain the compound having formula (II) further includes the step of separating the compound having formula (II) from the reaction mixture, the step comprising (i) adding a protic solvent to the mixture to precipitate the compound having formula (II) from the mixture, and (ii) filtering the precipitated solid.

37. The method of claim 36, wherein, The proton solvent is water, methanol, or a combination thereof.

38. A method for obtaining 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I): The method includes: (1) Compound of formula (I) is prepared by reacting a compound of formula (II) with dimethyl sulfate (DMS). Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained. The method includes using at least one water-immiscible solvent, wherein: i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture. and The one or more water-immiscible solvents wherein the solubility of the compound having formula (I) is greater than 33 mg / mL at room temperature.

39. The method of claim 38, wherein, One of the water-immiscible solvents is anisole.

40. The method of claim 38 or 39, wherein, The reaction of the compound having formula (II) with DMS is carried out at a temperature between 10°C and 85°C.

41. The method of claim 38 or 39, wherein, The reaction of the compound having formula (II) with DMS is carried out at a temperature between 10°C and below 25°C.

42. A method for improving the yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I): In the method, the method includes: (1) Compound of formula (I) is prepared by reacting a compound of formula (II) with dimethyl sulfate (DMS). Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained. The method includes using at least one water-immiscible solvent, wherein: i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture. The method described herein includes reacting the compound having formula (II) with DMS at a temperature between 10°C and below 25°C.

43. A method for improving the volumetric yield of 5-fluoro-4-imino-3-methyl-1-(phenyl-4-sulfonyl)-3,4-dihydro-1H-pyrimidin-2-one having formula (I): In the method, the method includes: (1) Compound of formula (I) is prepared by reacting a compound of formula (II) with dimethyl sulfate (DMS). Where R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino, alkoxycarbonyl, alkylcarbonyl, hydroxyalkyl, ester, hydrogen halide, -SH, -OH, -NH2, -NO2, -CN or CF3, and (2) The compound having formula (I) is separated from the reaction mixture by mixing an alkaline aqueous solution with the reaction mixture and the compound having formula (I) is obtained. The method includes using at least one water-immiscible solvent, wherein: i) Step (1) is carried out in the presence of at least one water-immiscible solvent, and / or ii) After step (1), at least one water-immiscible solvent is mixed with the reaction mixture. The method described herein includes using a water-immiscible solvent having a solubility of the compound of formula (I) greater than 33 mg / mL at room temperature.

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