Preparation method of 1-[(3R, 4S)-4-cyano tetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl) amino] pyrazole-4-carboxamide

Abstract

The present application relates to a process for the preparation of 1-[(3R, 4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl) amino] pyrazol-4-carboxamide (I), comprising (i) the synthesis of bromine and iodopyridine intermediates, (ii) the synthesis of pyrazolate intermediates that can be obtained in enantiomerically pure form and (iii) the combination of these intermediates to form the compound (I).

Description

[0001] This application is a divisional application of a patent application with an application date of December 12, 2019, application number 201980082538.2, and name “A method for preparing 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide”. Background Art

[0002] WO2018 / 108969 discloses a compound of formula I, which is a selective Janus kinase (JAK) inhibitor and is therefore useful for treating JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer. Specifically, 1-[(3R, 4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is disclosed.

[0003]

[0004] The known synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is centered around the key intermediate 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxamide (see compound (XVI) in Scheme 4 below). Since this intermediate has poor solubility in organic solvents, the chiral separation of the racemate (XV) must be performed by chiral supercritical fluid chromatography (SFC). In addition, its further conversion to 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is accompanied by the formation of by-products, which makes the preparation of a pure final product even more difficult.

[0005] WO2013 / 041042 discloses pyrazole carboxamides as Janus kinase inhibitors, which are useful for treating rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD) and cancer. The compounds in this disclosure are of the formula:

[0006] Summary of the invention

[0007] A method for preparing a compound of formula (I)

[0008]

[0009] It includes

[0010] a. Compound of formula (VI)

[0011]

[0012] Where R 1 It is C 1 -C 4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl; and a compound of formula (XII)

[0013]

[0014] Reaction in the presence of a catalyst and a base, wherein R is I or Br, to produce a compound of formula (XIII)

[0015] as well as

[0016] b. converting the compound of formula (XIII) into the compound of formula (I).

[0017] The method further comprises:

[0018] a. reacting a compound of formula (XIII) with a lithium salt, preferably lithium bromide, lithium chloride or lithium hydroxide, in the presence of a trialkylamine, preferably triethylamine, to produce a compound of formula (XIV)

[0019] as well as

[0020] b. converting the compound of formula (XIV) into the compound of formula (I).

[0021] The process further comprises forming a reactive intermediate of a compound of formula (XIV) which is then reacted with ammonia or its equivalent, such as ammonium chloride in combination with a base, to produce a compound of formula (I). DETAILED DESCRIPTION

[0022] A new method for obtaining 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is discovered. The main novelties are (i) a new and more efficient method for synthesizing bromo-pyridine intermediates (XIIb) is discovered in WO2018 / 108969; (ii) the synthesis and use of a new iodo-pyridine building block (XIIa); (iii) the synthesis and use of a pyrazole ester intermediate (V), which can be obtained by chiral separation to obtain an enantiopure form (VI); and (iv) a new synthetic step for converting the advanced intermediate (VI) to 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I). Unlike the known syntheses of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I), the new synthetic sequence offers the potential for scale-up at reasonable cost and is therefore compatible with large-scale production of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I).

[0023] Solution 1

[0024]

[0025] A description of the preparation of key intermediates in the new synthetic method is given below.

[0026] The synthesis of 2-fluoro-4-bromo-6-methoxy-pyridine (XIIb) is disclosed in WO2018 / 108969, which is based on a four-step method starting from 3,5-dichloro-2,4,6-trifluoropyridine. Some of the synthetic steps that make up the process have been proven to be unreliable and have low yields. As an illustrative disadvantage, the hydrodechlorination of 3,5-dichloro-2,4,6-trifluoropyridine to 2,4,6-trifluoropyridine (M.Schlosseretal.Chem.Eur.J.2005,11,1903) can only be achieved in hydrophobic alcohols and will suffer partial hydrolysis of the product. In addition, further conversion of the obtained 2,4,6-trifluoropyridine to 2,6-difluoro-4-hydrazinepyridine is not regioselective. A new and more efficient two-step synthesis of 2,6-difluoropyridine based on iridium (I) catalysis has been developed (Scheme 2).

[0027] Scheme 2: Method for novel compounds of formula (XIIb)

[0028]

[0029] This method allows the selective borylation of the 4-position of 2,6-difluoropyridine (VII) with high yield (65%). In one embodiment of the present invention, the borylation step is carried out in the presence of 4,4'-di-tert-butylbipyridine or N-benzyl-1-phenyl-N-(2-pyridylmethyleneamino)methylamine as a ligand. In another embodiment of the present invention, the borylation step is carried out in an organic solvent, such as tetrahydrofuran, cyclohexane or dioxane. The obtained boric acid ester (VIII) is then converted into the corresponding bromide (XI) in the presence of a brominating agent. In one embodiment of the present invention, the brominating agent is selected from copper (I) bromide or copper (II) bromide combined with an oxidant. In one embodiment of the present invention, the brominating agent is copper (II) bromide. The introduction of a 6-methoxy substituent to deliver the target 2-fluoro-4-bromo-6-methoxy-pyridine (XIIb) is achieved in the presence of an alkali metal methoxide (e.g., potassium methoxide or sodium methoxide). In one embodiment of the present invention, the alkali metal methoxide is sodium methoxide.

[0030] As a cost-effective alternative to the newly developed synthesis of 2-fluoro-4-bromo-6-methoxy-pyridine (XIIb), the synthesis and use of 2-fluoro-4-iodo-6-methoxy-pyridine (XIIa) was performed (Scheme 3).

[0031] Scheme 3: New method for obtaining the compound of formula (XIIa)

[0032]

[0033] Therefore, high-purity 2-fluoro-4-iodo-6-methoxy-pyridine (XIIa) can be synthesized in high yield in one step from 2-fluoro-6-methoxy-pyridine (IX) by a new halogenation / halogen dance protocol. In one embodiment of the present invention, the halogenation / halogen dance reaction is carried out in the presence of an amide lithium base. In a sub-aspect of the present invention, the amide lithium base is selected from 2,2,6,6-tetramethylpyridine lithium and diisopropylamide lithium. In another sub-aspect of the present invention, the amide lithium base is 2,2,6,6-tetramethylpiperidinium lithium. In a part of the present invention, the halogenation / halogen dance reaction is carried out in the presence of 2 to 2.5 equivalents of an amide lithium base. In a sub-part of the present invention, the reaction is carried out in the presence of 2 to 2.1 equivalents of an amide lithium base. In one embodiment of the present invention, the halogenation / halogen dance reaction is carried out at a temperature between -78 and -65°C. In a sub-embodiment of the present invention, the reaction is carried out between -75 and -70°C. In another embodiment of the present invention, the reaction is carried out using 15 to 20 volumes of solvent.

[0034] The known synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is based on the key intermediate 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxamide (XVI) (WO2018 / 108969) (see Scheme 4). Due to the poor solubility of this intermediate in organic solvents, the chiral separation of the racemate (XV) must be performed by chiral supercritical fluid chromatography (SFC). In addition, its further conversion into 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is accompanied by the formation of by-products due to the presence of reactive amide groups.

[0035] Solution 4

[0036]

[0037] It was found that 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) can be more conveniently prepared from 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylic acid ethyl ester (VI), which can be obtained from 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester (IV) via a new synthetic method (Scheme 5).

[0038] Scheme 5: Synthesis of novel compounds of formula (I)

[0039]

[0040] This new intermediate (V) offers advantages over the parent amide (XV) in that it has higher solubility in organic solvents and can be cleanly converted to 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I). Due to its higher solubility in organic solvents, new scalable and more cost-effective chiral separations of racemic (V) can be achieved.

[0041] Ethyl 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (VI) is prepared by reacting ethyl 3-amino-1H-pyrazole-4-carboxylate (IV) with 3,6-dihydro-2H-pyran-4-carbonitrile (III) at elevated temperature in an organic solvent in the presence of a base, followed by chiral separation (Scheme 6).

[0042] Scheme 6: Preparation of the new synthetic intermediate formula (VI)

[0043]

[0044] In one embodiment of the present invention, the base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, tripotassium phosphate. In another embodiment of the present invention, the base is potassium carbonate or tripotassium phosphate.

[0045] In one embodiment of the present invention, the organic solvent is ethanol, 1,4-dioxane, N,N-dimethylformamide, toluene or acetonitrile. In a sub-aspect of the present invention, the organic solvent is toluene or acetonitrile. In one embodiment of the present invention, 1 to 2.5 equivalents of 3,6-dihydro-2H-pyran-4-carbonitrile (III) are reacted. In another embodiment of the present invention, 1.1 to 1.5 equivalents of 3,6-dihydro-2H-pyran-4-carbonitrile (III) are reacted.

[0046] The coupling step between 2-fluoro-4-bromo-6-methoxy-pyridine (XIIb) or 2-fluoro-4-iodo-6-methoxy-pyridine (XIIa) and the compound of formula (VI) is achieved in the presence of a palladium catalyst and a ligand (Scheme 7).

[0047] Scheme 7: Preparation of compounds of formula (XIII)

[0048]

[0049] In one embodiment of the invention, the palladium catalyst is selected from tris(dibenzylideneacetone)dipalladium(0), allylpalladium(II) chloride dimer, [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate and palladium(II) acetate and the ligand is selected from 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. In one part of the invention, the palladium-catalyzed coupling step is carried out in the presence of a base such as potassium acetate or tripotassium phosphate.

[0050] The resulting ester of formula (XIII) is hydrolyzed to the corresponding acid of formula (XIIV) in the presence of a lithium salt, a trialkylamine and a catalytic amount of water (Scheme 8).

[0051] Scheme 8: Preparation of compound of formula (XIV)

[0052]

[0053] In one embodiment of the present invention, the lithium salt is lithium bromide, lithium chloride or lithium hydroxide. In another embodiment of the present invention, the lithium salt is lithium bromide or lithium hydroxide. In another embodiment of the present invention, the trialkylamine base is triethylamine. In another embodiment of the present invention, the hydrolysis is carried out at an elevated temperature. In another embodiment of the present invention, the hydrolysis is carried out at a temperature of 60 to 100°C. In another embodiment of the present invention, the hydrolysis is carried out at a temperature between 65 and 85°C.

[0054] The conversion of the penultimate acid (XIV) to 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I) is achieved by converting the acid of formula (XIV) into a reactive intermediate and reacting the intermediate with ammonia or its synthetic equivalent (Scheme 9).

[0055] Scheme 9: Conversion of the intermediate of formula (XIV) into compound (I)

[0056]

[0057] In one embodiment of the present invention, the reactive intermediate is an acid chloride derived from an acid of formula (XIV) and is obtained by reacting the acid (XIV) with a chlorinating agent (such as oxalyl chloride or thionyl chloride). In another embodiment of the present invention, the reactive intermediate is obtained by reacting an acid of formula (XIV) with a coupling agent such as carbodiimide (DCC, DIC, EDC.HCl), O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium salt (HBTU, TBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium salt (HATU, TATU) reagent, optionally in the presence of additives such as hydroxybenzotriazole or ethyl cyano(hydroxyimino)acetate.

[0058] definition

[0059] Lithium tetramethylpiperidinium (CAS n°38227-87-1) (often abbreviated as LiTMP, Li / TMP or LTMP) is a 9 H 18 A chemical compound of LiN. It is used as a non-nucleophilic base.

[0060] Trimethylsilyl cyanide (CAS n°7677-24-9) (TMSCN) is a 3 ) 3 The chemical compound SiCN. This volatile liquid consists of a cyanide group (i.e. CN) attached to a trimethylsilyl group. The molecule is used in organic synthesis as an equivalent of hydrogen cyanide.

[0061] 1,5-Cyclooctadiene (CAS n°1552-12-1), commonly abbreviated as COD, is a chemical compound used as a ligand in numerous metal complexes.

[0062] Pinacol (CAS n°76-09-5), often abbreviated as pin, is a structural component of boron esters in organometallic coupling processes.

[0063] MTBE stands for methyl tert-butyl ester (CAS n°1634-04-4) and was used as the organic solvent.

[0064] Dibenzylideneacetone (CAS n° 35225-79-7), commonly abbreviated as dba, is a chemical compound used as a ligand in a variety of metal complexes.

[0065] 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (CAS n°564483-19-8), commonly abbreviated as t-BuXphos or tert-ButylXphos, is a compound used as a ligand complex for a variety of metals.

[0066] 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (CAS n°161265-03-8), commonly abbreviated as Xantphos, is a chemical compound used as a ligand in a variety of metal complexes.

[0067] 1,3-Dicyclohexylcarbodiimide (CAS n°538-75-0) is commonly abbreviated as DCC, 1,3-diisopropylcarbodiimide (CAS n°693-13-0) is commonly abbreviated as DIC, and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (CAS n°25952-53-8) is commonly abbreviated as EDC. HCl is a reagent used to convert carboxylic acids to the corresponding O-acylurea intermediates, which react rapidly with a variety of nucleophiles.

[0068] O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS n°94790-37-1) often abbreviated as HBTU and O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (CAS n°125700-67-6) often abbreviated as TBTU are reagents used to convert carboxylic acids to the corresponding 1-hydroxybenzotriazole esters, which react rapidly with a variety of nucleophiles.

[0069] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (CAS n°873798-09-5) is a reagent used to convert carboxylic acids to the corresponding 1-hydroxyazabenzotriazole esters and reacts rapidly with a variety of nucleophiles.

[0070] Ammonia equivalent is the synthetic equivalent of ammonia, such as ammonium chloride.

[0071] A brominating agent is a reagent used to introduce bromine into a reaction, such as copper(I) bromide or copper(II) bromide in combination with an oxidizing agent.

[0072] One embodiment of the present invention is a method for preparing a compound of formula (XII),

[0073]

[0074] Where R is I,

[0075] It includes

[0076] The compound of formula (IX)

[0077]

[0078] Reaction with iodine and lithium amide base, preferably lithium / TMP, to produce a compound of formula (X)

[0079]

[0080] In one embodiment, the method further comprises reacting the compound of formula (X) in the presence of a lithium amide base, preferably lithium / TMP, to produce a compound of formula (XII)

[0081]

[0082] In an alternative embodiment, the product of step a) is not isolated and purified before performing step b).

[0083] One embodiment of the present invention is a method for preparing a compound of formula (XII),

[0084]

[0085] Where R is Br,

[0086] It includes

[0087] The compound of formula (VII)

[0088]

[0089] Reaction with an iridium catalyst and bis(pinacol)diboron to produce a compound of formula (VIII)

[0090]

[0091] In one embodiment, the method further comprises reacting the compound of formula (VIII) with a brominating agent, preferably copper (II) bromide or copper (I) bromide in combination with an oxidizing agent, preferably copper (II) bromide, to produce a compound of formula (XI)

[0092]

[0093] In one embodiment, the method further comprises reacting the compound of formula (XI) with an alkali metal methoxide, preferably sodium methoxide or potassium methoxide, to produce a compound of formula (XIIb)

[0094]

[0095] One embodiment of the present invention is a method for preparing a compound of formula (VI)

[0096]

[0097] Where R 1 It is C 1 -C 4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl

[0098] It includes

[0099] The compound of formula (II)

[0100]

[0101] and

[0102] i. Hydrogen cyanide or its equivalent, such as TMSCN and

[0103] ii.POCl 3 orSOCl 2

[0104] Reaction to produce a compound of formula (III)

[0105]

[0106] In one embodiment, the method further comprises reacting the compound of formula (III) with the compound of formula (IV) in the presence of a base (eg, tripotassium phosphate or potassium acetate).

[0107]

[0108] Where R 1 It is C 1 -C4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl

[0109] To produce a compound of formula (V)

[0110]

[0111] Where R 1 It is C 1 -C 4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl.

[0112] In one embodiment, the method further comprises separating the enantiomers of the compound of formula (V) to provide the compound of formula (VI).

[0113] In one embodiment, separation of enantiomers is achieved by chiral chromatography.

[0114] One embodiment of the present invention is a compound of formula (V)

[0115]

[0116] Where R 1 It is C 1 -C 4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl.

[0117] One embodiment of the present invention is a compound of formula (VI)

[0118] Where R 1 It is C 1 -C 4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl. One embodiment of the present invention is a compound of formula (XIII)

[0119] Where R 1 It is C 1 -C 4 Alkyl, preferably C 1 -C 2 Alkyl, most preferably ethyl. One embodiment of the present invention is a compound of formula (XIV)

[0120] Another embodiment of the present invention is a method for preparing a compound of formula (I)

[0121] It comprises the compound of formula (XVI)

[0122]

[0123] With the compound of formula (XIIa)

[0124]

[0125] Reaction to produce the compound of formula (I).

[0126] HPLC Method:

[0127] Method A

[0128] Agilent Technologies UHPLC / MSD6130B Series 1290 includes

[0129] Binary pump G7120A including degasser

[0130] Well Plate Sampler G4226A

[0131] Column thermostat G1316B

[0132] Diode Array Detector G4212A

[0133] Mass detector G6130B quadrupole LC / MS with ESI source

[0134] Column: Waters XP, 2.1x50mm Xbridge BEHC182.5μ, T=40℃;

[0135] Eluent: A: acetonitrile containing 0.05% (vol. / vol.) formic acid.

[0136] B: water containing 0.05% formic acid (vol / vol);

[0137] Flow rate: 0.8 mL / min;

[0138] Gradient: 2 to 100% eluent A in 1.2 min, 100% eluent A in 0.5 min;

[0139] Running time: 2.2 minutes;

[0140] Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z;

[0141] 254 and 210nm UV light;

[0142] Method B

[0143] Agilent Technologies UHPLC / MS1260 Series includes:

[0144] Binary Pump G7120A including Degasser

[0145] Well Plate Sampler G4226A

[0146] Column oven G7116B

[0147] Diode Array Detector G7117B

[0148] Mass detector G6150B quadrupole LC / MS with ESI jet stream source Column: Waters XP, 2.1x50mmXbridgeBEHC182.5μ, T=40°C;

[0149] Eluent: A: acetonitrile containing 0.05% (vol. / vol.) formic acid.

[0150] B: water containing 0.05% formic acid (vol / vol);

[0151] Flow rate: 0.8 mL / min;

[0152] Gradient: 2 to 100% eluent A in 1.2 min, 100% eluent A in 0.5 min;

[0153] Running time: 2.2 minutes;

[0154] Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z;

[0155] 254 and 210nm UV light;

[0156] Method C

[0157] Agilent Technologies UHPLC / MS1260 Series includes:

[0158] Binary Pump G4220A including Degasser

[0159] Well Plate Sampler G4226A

[0160] Column oven G7116B

[0161] Diode Array Detector G4212A

[0162] Mass detector G6130B Quadrupole LC / MS with ESI / APCI multimode source

[0163] Column: Waters XP, 2.1x50mm Xbridge BEHC182.5μ, T=40℃;

[0164] Eluent: A: acetonitrile containing 0.05% (vol. / vol.) formic acid.

[0165] B: water containing 0.05% formic acid (vol / vol);

[0166] Flow rate: 0.8 mL / min;

[0167] Gradient: 2 to 100% eluent A in 1.2 min, 100% eluent A in 0.5 min;

[0168] Running time: 2.2 minutes;

[0169] Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z;

[0170] 254 and 210nm UV light;

[0171] Example

[0172] Synthesis of ethyl 3-amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (III)

[0173]

[0174] Anhydrous acetonitrile (2.55 L) and dihydro-2H-pyran-4(3H)-one (II) (365 g, 3.65 mol) were charged into a jacketed glass reactor (10 L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer, a gas scrubber and placed under a nitrogen atmosphere. The resulting mixture was stirred and the temperature was adjusted between -5 and 0°C. Zinc iodide (35 g, 0.11 mol) was added to the solution while keeping the temperature below 10°C. After the temperature was adjusted to between -5 and 0°C, trimethylsilanecarbonitrile (433 mL, 3.46 mol) was added dropwise over 80 minutes while keeping the temperature below 0°C. After reacting for 3 hours at 0°C, complete conversion of the starting material was observed, and then pyridine (1.76 L, 21.9 mol) and phosphoryl chloride (510 mL; 5.47 mol) were added to the reaction mixture. The temperature was raised to 80°C and the reaction mixture was stirred at this temperature for 16 hours. The reaction mixture was then cooled to room temperature and added to a solution of ferric sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) and adjusted to pH>10 by adding 50% aqueous sodium hydroxide solution. During the addition of the reaction mixture to the alkaline ferric sulfate solution, the temperature was kept below 20°C and the pH was kept above 10 by adding 50% aqueous sodium hydroxide solution. The resulting mixture was extracted with methyl-tert-butyl ether (3.5 L), the organic phase was collected and the aqueous phase was diluted with water (6 L). The diluted aqueous phase was extracted with methyl tert-butyl ether (2×2.5 L). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (1.83 L) and concentrated under reduced pressure at 40°C. The crude residue was distilled under reduced pressure (bp~45°C, 0.5 mbar) to obtain the desired product (III) as a colorless oil (289 g, 2.6 mol).

[0175] HPLC method A: retention time: 0.58 minutes; m / z 110

[0176] 1 HNMR (300MHz, CDCl 3 )δ(ppm):6.60–6.57(1H,m); 4.21–4.18(2H,m); 3.75(2H,J=5.52Hz,t); 2.31–2.25(2H,m)

[0177] Synthesis of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (VIII)

[0178]

[0179] Di(pinacol)diboron (68.8 g, 0.27 mol); 4,4'-di-tert-butyl bipyridine (2.10 g, 7.82 mmol) and (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (2.59 g, 3.91 mmol) were suspended in methyl-tert-butyl ether (10 mL was added under an inert atmosphere) and 2,6-difluoropyridine (VII) (23.8 mL, 0.26 mol) was added. The temperature was slowly raised to 45 ° C and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The separated residue was purified by filtering on a short silica gel column using pentane as an eluent to provide the desired product (VIII) (32.7 g, 0.14 mol) as a colorless solid.

[0180] HPLC method A: retention time: 0.68min; m / z 581

[0181] 1 HNMR (300MHz, CDCl 3 )δ(ppm):7.08(2H,m);1.28(12H,s)

[0182] Synthesis of 4-bromo-2-fluoro-6-methoxy-pyridine (XIIb)

[0183]

[0184] 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (VIII) (32 g, 133 mmol) was dissolved in methanol (380 mL) and a 1.1 M aqueous copper (II) bromide solution (104 g, 465 mmol) was added. The resulting mixture was heated to reflux and stirred at this temperature for 90 minutes. The heating was stopped and the reaction mixture was cooled to 0°C with an ice bath, and then a 10% aqueous ammonium hydroxide solution (300 mL) was added dropwise with stirring. The resulting mixture was extracted with pentane (3×200 mL), and the pentane solution of the desired product (XI) was used directly in the next step. Anhydrous methanol (160 mL) was added to the pentane solution of 4-bromo-2-fluoro-6-methoxy-pyridine (XI), and a solution of sodium methoxide (100 mmol) in anhydrous methanol (88.4 mL) was added with stirring at about 20°C. After 2.5 hours reaction time, the mixture was cooled to 0 ° C by using an ice bath, and the mixture was poured into a mixture of 2N aqueous hydrochloric acid solution (224 mL) and ice (224 g) stirred. After separation of the organic phase, the aqueous phase was extracted with pentane (100 mL). The combined organic layer was washed with brine (50 mL) and concentrated under reduced pressure (700 to 750 mbar) at about 38 ° C. In the presence of residual pentane (11% weight), the desired product (XIIb) (21.5 g, 92 mmol) was obtained as a light yellow solid.

[0185] HPLC method A: retention time: 1.11min

[0186] 1 HNMR (300MHz, CDCl 3 )δ(ppm):6.82(1H,m); 6.68–6.67(1H,m); 3.93(3H,s)

[0187] Synthesis of 2-Fluoro-6-methoxy-4-iodo-pyridine (XIIa)

[0188]

[0189] In an inert atmosphere, dry tetrahydrofuran (5.99 L) at 15 ° C was charged into a dry flask (20 L). 2,2,6,6-tetramethylpiperidine (1161 g, 8.22 mol) was added and the resulting solution was cooled to -30 ° C. A hexane solution of n-butyl lithium (2292 mL, 7.47 mol) was added dropwise over 30 minutes while maintaining the temperature at about -30 ° C. The resulting mixture was stirred at this temperature for 1 hour. The mixture was then reduced to -75 to -70 ° C, and a solution of 2-fluoro-6-methoxy-pyridine (IX) (500 g, 3.93 mol) in anhydrous tetrahydrofuran (1496 ml) was added over 30 minutes while maintaining a temperature of -75 to -70 ° C. The reaction mixture was stirred at this temperature for 90 minutes, and then a solution of iodine (998.4 g, 3.93 mol) in anhydrous tetrahydrofuran (2494 ml) was added at -75 to -70°C within 1 hour. The mixture was stirred between -75 and -70°C for 14 hours. Water (3.5 L) was added at -75 to -70°C within 30 minutes and the reaction mixture was allowed to reach room temperature. The organic layer was separated and the aqueous phase was extracted with methyl tert-butyl ether (2×2.5 L). The combined organic layers were concentrated to a total weight of 1250 g for 4 hours with 85% by weight aqueous phosphoric acid (2×4 L) at a temperature not exceeding 30°C. After steam distillation at 102°C and separation of the aqueous layer, a colorless oil was obtained. Heptane (390 mL) was added to the separated oil and the resulting mixture was stirred between -10 and -5°C for 30 minutes. The solid formed was collected by filtration and washed with a small amount of pre-cooled heptane (about 55 mL) to afford the desired product (XIIa) (530 g, 2.09 mol).

[0190] HPLC method A: retention time: 1.14min

[0191] 1 HNMR (300MHz, CDCl 3 )δ(ppm):7.03(1H,m); 6.88–6.86(1H,m); 3.93(3H,s)

[0192] Synthesis of ethyl 3-amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (V)

[0193]

[0194] Anhydrous acetonitrile (750 mL), tripotassium phosphate monohydrate (38.3 g, 0.16 mol) and ethyl 3-amino-1H-pyrazole-4-carboxylate (IV) (500 g, 3.19 mol) were charged into a jacketed glass reactor (5 L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under a nitrogen atmosphere. The resulting mixture was heated to 80°C and 3,6-dihydro-2H-pyran-4-carbonitrile (III) (462 g, 4.15 mol) was quickly added through an addition funnel. The addition funnel was rinsed with acetonitrile (250 mL) and acetonitrile was also added to the reaction mixture. The reaction mixture was reacted at 80°C under vigorous stirring for 6.5 hours, then the heating was stopped and the reaction mixture was further stirred overnight. After the reaction mixture was concentrated under reduced pressure, a yellow slurry was obtained. The obtained material was diluted with ethyl acetate (5L), and the obtained solution was extracted with 1M aqueous hydrochloric acid solution (3×1.5L), washed once with brine (1L), filtered through a filter filled with a magnesium pad, and concentrated under reduced pressure to obtain a yellow oil. The yellow oil was dissolved in methanol (1.36L), and the obtained mixture was warmed to 40°C under stirring to ensure homogenization. The solution was then cooled to 25°C, and 2.0g of pure crystal seeds were inoculated at this temperature, and then gently stirred overnight at -20°C. The precipitate formed was filtered out, washed with pre-cooled methanol (1L) and dried under reduced pressure at 40°C to obtain an off-white solid. The separated white solid was heated to reflux in 2-propanol (1L) for 1 hour, and the mixture was slowly brought to room temperature overnight under gentle stirring. The precipitate formed was filtered out, washed with 2-propanol (300mL) and dried under reduced pressure at 40°C to obtain the desired product (V) (347.2g, 1.20mol) as an off-white solid.

[0195] HPLC method A: retention time: 0.75min; m / z 265

[0196] 1 HNMR (600MHz, CDCl 3 )δ (ppm): 7.82 (s, 1H); 4.28 (2H, J = 7.1Hz, q); 4.14 (1H, J = 4.3, 9.0Hz, dt); 4.08 (1H, J = 4.2, 12.0Hz, dd); 4.00 (1H, J = 4.0, 12.1Hz, t d); 3.90(1H,J=8.7,12.0Hz,dd); 3.55-3.50(1H,m); 3.62-3.44(2H,m); 2.20-2.10(1H,m); 2.06-1.94(1H,m); 1.34(3H,J=7.1Hz,t)

[0197] Chiral separation of ethyl 3-amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate (V) to ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydro2H-pyran-3-yl]-1H-pyrazole-4-carboxylate (VI)

[0198]

[0199] Separation of the enantiomeric mixture (V) into the individual enantiomers (VI) is achieved by chiral chromatography.

[0200] Synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxylic acid ethyl ester (XIII)

[0201]

[0202] 3-Amino-1-[(3S,4R)-4-cyanotetrahydro-2H-pyran-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (VI) (50 g, 189 mmol), 4-bromo-2-fluoro-6-methoxy-pyridine (XIIb) (39 g, 189 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.57 g, 3.8 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (3.21 g, 7.6 mmol) and potassium acetate (37.1 g, 378 mmol) were placed under an inert atmosphere and 2-propanol (600 mL) was added. The resulting mixture was heated to 65 ° C and stirred at this temperature for 90 minutes. After cooling to room temperature, the mixture was concentrated under reduced pressure at 40 ° C. The resulting crude residue was stirred with acetonitrile (650 mL) at 50 ° C for 30 minutes. The hot solution was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 2-propanol (750 mL), the resulting mixture was heated to 100 ° C, and then slowly warmed to room temperature under gentle stirring. The formed precipitate was filtered out, the wet cake was rinsed with 2-propanol (50 mL), and then dried under reduced pressure at 40 ° C to obtain the desired product (XIII) (61.2 g, 149 mmol). Under reduced pressure, the filtrate was combined with the 2-propanol rinse to obtain a solid. The newly formed solid was washed with 2-propanol (2 × 50 mL) and dried under reduced pressure at 40 ° C to obtain a second batch of the desired product (XIII) (8.2 g, 19.5 mmol).

[0203] HPLC method B: retention time: 1.10min; m / z 390

[0204] 1 HNMR (600MHz, CDCl 3)δ(ppm):8.61(1H,s);7.95(1H,s);6.73(1H,s);6.68(1H,J=1.5Hz,d);4.33(2H,J=7 .1Hz,q); 4.25(1H,J=4.2,9.0Hz,dt); 4.16(1H,J=4.2,12.0Hz,dd); 4.06(1H,J=4.0,1 2.1Hz,td);3.98(1H,J=8.8,12.1Hz,dd);3.92(3H,s);3.70-3.62(1H,m);3.61-3.52 (1H,m);2.25-2.15(1H,m);2.06(1H,J=4.2,10.3,14.2Hz,dtd);1.38(3H,J=7.1Hz,t)

[0205] Synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxylic acid ethyl ester (XIII)

[0206]

[0207] 3-Amino-1-[(3S,4R)-4-cyanotetrahydro-2H-pyran-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (VI) (1 g, 3.78 mmol), 2-fluoro-4-iodo-6-methoxypyridine (XIIa) (1.15 g, 4.54 mmol), palladium diacetate (21 mg, 0.095 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (109 mg, 0.19 mmol) and tripotassium phosphate (2.41 g, 11.35 mmol) were placed under a nitrogen atmosphere and 1,4-dioxane (10 mL) was added. The resulting mixture was heated to 60 ° C and stirred at this temperature for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was diluted with 2-propanol (20 mL) and the resulting mixture was heated until a solution was obtained. The heating was stopped and the solution was allowed to slowly reach room temperature. The suspension was filtered to collect the precipitate formed. The wet cake was rinsed with 2-propanol (25 mL) and dried under reduced pressure at 40° C. to give the desired product (XIII) as an off-white solid (1.07 g, 2.75 mmol). The filtrate was concentrated under reduced pressure and the resulting residue was diluted in 2-propanol (5 mL) under reflux to provide a second crop of the desired product (XIII) (180 mg, 0.5 mmol) after filtering and drying the resulting precipitate.

[0208] Synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxylic acid (XIV)

[0209]

[0210] Lithium bromide (769 mg, 8.86 mmol) and triethylamine (380 μL, 2.66 mmol) were added to 1-[(3R, 4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxylic acid ethyl ester (XIII) (345 mg, 0.89 mmol) in acetonitrile (4.34 ml) and water (87 microliters), and the resulting mixture was stirred at 80 ° C for 20 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL) and extracted with saturated sodium bicarbonate aqueous solution (3×10 mL). The combined aqueous layer was acidified to pH 3 by adding 1M hydrochloric acid aqueous solution. The precipitate formed was separated by filtration and dried under reduced pressure at 40 ° C to provide the desired product (XIV) (308 mg, 0.85 mmol) as a colorless solid.

[0211] HPLC method C: retention time: 0.88min; m / z 362

[0212] Synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I)

[0213]

[0214] N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (245 mg,

[0215] 1.28 mmol), 1-hydroxybenzotriazole hydrate (131 mg, 0.85 mmol), ammonium chloride (91 mg, 1.71 mmol), triethylamine (238 μL, 1.71 mmol) and 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxylic acid

[0216] (XIV) (308 mg, 0.85 mmol) was stirred at room temperature in a mixture of tetrahydrofuran (3 mL) and N,N-dimethylformamide (1 mL) for 90 minutes. Saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude desired product (I) (276 mg, 0.77 mmol).

[0217] HPLC method A: retention time: 0.86min; m / z 361

[0218] 1 HNMR (600MHz, CDCl 3 )δ(ppm):9.70(1H,s);8.35(1H,s);7.83(1H,brs);7.32(1H,brs);7.03-6.68(2H,m);4.64(1H,J=4.4,10.2Hz,dt);4.04(1H,J=4.4 ,11.3Hz,dd);3.94-3.86(1H,m);3.79(3H,s);3.71-3.59(2H,m);3.49(1H,J=2.2,11.7Hz,dt);2.20-2.12(1H,m);2.04-1.93(1H,m)

[0219] Purification of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I)

[0220]

[0221] Crude product (I) (3.72kg, 10.32mol) and methanol (80.8L) were loaded into a 160L glass-lined container. The contents were heated to reflux (65°C) and the true seed of compound (I) (109g, 302.5mmol) was loaded into methanol (1.9L) to form a slurry. The mixture was stirred at 275rpm and aged for 14.5 hours. The slurry was cooled to 60°C and sampled for analytical purposes: pure compound (I) was obtained. The slurry was cooled from 65°C to 20°C within 12 hours and then aged at 20°C for 6 hours. The batch was filtered and the filter cake was washed with methanol (5.4L). The solid was dried in a vacuum oven at 40°C for 23 hours while passing nitrogen. The material was then ground together to break up any lumps and a white powdery compound (I) (2.21kg, 6.14mol) was obtained.

[0222] Alternative Synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridinyl)amino]pyrazole-4-carboxamide (I)

[0223]

[0224] In the first container, N, N-dimethylacetamide (7.55L) was degassed with subsurface nitrogen for 30 minutes. tBuBrettPhos (96.0g, 0.198mol) and allylpalladium chloride (II) dimer (36.2g, 0.099mol) were added, and the resulting mixture was stirred at 20°C for 100 minutes while purging subsurface nitrogen. Another container was equipped with compound (XVI) (2.32kg, 9.88mol), compound (XIIa) (2.50kg, 9.88mol), tripotassium phosphate (4.19kg, 19.76mol) and N, N-dimethylacetamide (17.55L). The resulting mixture was stirred and degassed, and the catalyst solution prepared in the first container was added. The first container was rinsed with N, N-dimethylacetamide (0.5L), which was also added to the reaction mixture. The reaction mixture was then stirred at room temperature and monitored by UV-HPLC until complete conversion was observed. The reaction mixture was filtered and the wet cake was washed with N,N-dimethylacetamide (5 L). The filtrate was cooled to between 0 and 5 ° C and water (90 L) was added over 105 minutes while the temperature was maintained between 0 and 5 ° C. The resulting slurry was aged at this temperature for 1 hour. The slurry was then filtered and the filter cake was washed twice with water (10 and 20 L) and four times with methanol (15 and 3×19 L). The wet cake was dried under a stream of nitrogen to give the desired compound (I) (3.14 kg, 0.154 mol).

Claims

1. A method for preparing a compound of formula (I), It includes a. Compound of formula (VI) Where R 1 is C1-C4 alkyl, preferably C1-C2 alkyl, most preferably ethyl Reaction with a compound of formula (XII) in the presence of a catalyst and a base wherein R is I or Br, to produce a compound of formula (XIII) as well as b. converting the compound of formula (XIII) into the compound of formula (I).

2. The method of claim 1 further comprises a. reacting the compound of formula (XIII) with a lithium salt, preferably lithium bromide, lithium chloride or lithium hydroxide, in the presence of a trialkylamine, preferably trimethylamine to produce a compound of formula (XIV) as well as b. converting the compound of formula (XIV) into the compound of formula (I).

3. The method of claim 2 further comprises forming a reactive intermediate of a compound of formula (XIV), which is then reacted with ammonia or an ammonia equivalent, preferably ammonium chloride, in the presence of a base to obtain a compound of formula (I).

4. A method for preparing a compound of formula (XII), Where R is I, It includes a. Compound (IX) Reaction with iodine and lithium amide base, preferably lithium / TMP, to produce a compound of formula (X) as well as b. converting the compound of formula (X) into the compound of formula (XII).

5. The process of claim 4 further comprising reacting the compound of formula (X) in the presence of a lithium amide base, preferably lithium / TMP, to produce a compound of formula (XII)a 6. The process of claim 5, wherein the compound of formula (X) is not isolated and purified before being used in the compound of formula (XIIa).

7. A method for preparing a compound of formula (XII), Where R is Br, It includes a. Compound (VII) Reaction with an iridium catalyst and bis(pinacol)diboron to produce a compound of formula (VIII) as well as b. converting the compound of formula (VIII) into the compound of formula (XII).

8. The method of claim 7, further comprising a. reacting a compound of formula (VIII) with a brominating agent, preferably copper bromide (II) or copper bromide (I) combined with an oxidizing agent, preferably copper bromide (II), to obtain a compound of formula (XI) as well as b. converting the compound of formula (XI) into the compound of formula (XII).

9. The method of claim 8, further comprising reacting the compound of formula (XI) with an alkali metal methoxide, preferably sodium methoxide or potassium methoxide, to produce a compound of formula (XIIb) 10. A method for preparing a compound of formula (VI) Where R 1 is C1-C4 alkyl, preferably C1-C2 alkyl, most preferably ethyl It includes a. Compound of formula (II) and i. Hydrogen cyanide or its equivalent, such as TMSCN, and ii.POCl3 or SOCl2 Reaction to produce a compound of formula (III) as well as b. converting the compound of formula (III) into the compound of formula (VI).

11. The method of claim 10, further comprising a. reacting a compound of formula (III) with a compound of formula (IV) in the presence of a base such as tripotassium phosphate or potassium acetate Where R 1 is C1-C4 alkyl, preferably C1-C2 alkyl, most preferably ethyl To produce a compound of formula (V) Where R 1 is C1-C4 alkyl, preferably C1-C2 alkyl, most preferably ethyl; and b. converting the compound of formula (V) into the compound of formula (VI).

12. The process of claim 11, further comprising separating the enantiomers of the compound of formula (V) to obtain the compound of formula (VI).

13. The process of claim 12, wherein separation of enantiomers is achieved by chiral chromatography.

14. Compounds of formula (V) Where R 1 It is a C1-C4 alkyl group, preferably a C1-C2 alkyl group, and most preferably an ethyl group.

15. The compound of claim 14, wherein the compound is a compound of formula (VI) Where R 1 It is a C1-C4 alkyl group, preferably a C1-C2 alkyl group, and most preferably an ethyl group.

16. Compound of formula (XIII) Where R 1 It is a C1-C4 alkyl group, preferably a C1-C2 alkyl group, and most preferably an ethyl group.

17. Compound of formula (XIV)

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