Process for the preparation of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide

Abstract

To provide an efficient process for synthesizing a halogenated pyridine derivative as a synthetic intermediate of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide, which is a selective Janus kinase (JAK) inhibitor.SOLUTION: The present invention provides a process for preparing a compound represented by the formula (XIIa). This process includes: reacting a pyridine derivative with iodine and a lithium amide base (preferably, lithium / TMP) to obtain iodide represented by the formula (X); and subjecting the compound represented by the formula (X) to a reaction in the presence of the lithium amide base (preferably, lithium / TMP), to form a compound represented by the formula (XIIa).SELECTED DRAWING: None

Description

[Background technology]

[0001] WO2018 / 108969 describes a selective Janus kinase (JAK) inhibitor, Thus, compounds of formula I are useful for the treatment of JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer. Specifically, the compound represented by the formula 1-[(3R,4S)-4-cyanotetradecanoate] is disclosed. [(2-fluoro-6-methoxy-4-pyridyl)-4-pyridyl-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)-4-pyrid ... [amino]pyrazole-4-carboxamide (I) is disclosed. [ka]

[0002] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) The known synthesis of 3-amino-1-[(3R,4S)-4-cyanotetrahydrofuran] is a key intermediate. dropyran-3-yl]pyrazole-4-carboxamide ( (See compound (XVI) in Scheme 4 below.) This intermediate can be dissolved in an organic solvent. Since the chirality is low, chiral separation of the parent racemate (XV) was performed using chiral supercritical fluid chromatography. Furthermore, 1-[(3R,4S)-4- cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyr Further conversion to [(lysyl)amino]pyrazole-4-carboxamide (I) can be achieved by the addition of the by-product The formation of methyltrimethylsilyl methylsilyl ether was also involved, which made the production of a pure final product more difficult.

[0003] WO2013 / 041042 describes a compound that is effective against rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease (COPD). Pyrazole carboxamides have been developed as Janus kinase inhibitors useful for the treatment of rhesus malabsorption and cancer. The compounds of this disclosure have the formula: [ka]

[0004] It is a compound represented by the formula: [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2018 / 108969 [Patent Document 2] WO2013 / 041042 Summary of the Invention [Means for solving the problem]

[0006] Formula (I) [ka]

[0007] A method for producing a compound represented by the formula: a. Formula (VI) [ka]

[0008] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. with a compound represented by formula (XII) [ka]

[0009] in the presence of a catalyst and, when R is I or Br, in the presence of a base. to form a compound of formula (XIII) [ka]

[0010] and b. converting a compound of formula (XIII) into a compound of formula (I); The method comprising:

[0011] The method further comprises: a. The compound represented by formula (XIII) is reacted with a trialkylamine (preferably, triethylamine). In the presence of a lithium salt (preferably lithium bromide, lithium chloride or lithium hydroxide), lithium chloride) to give a compound of formula (XIV) [ka]

[0012] and b. converting a compound of formula (XIV) into a compound of formula (I); Includes:

[0013] The method further comprises forming an activated intermediate of a compound of formula (XIV); and then ammonia or its equivalent (e.g., ammonium chloride with a base) ) to form a compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0014] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) The main novelties are (i) the access to the (ii) a new and more efficient synthesis of the bromo-pyridine intermediate (XIIb) shown; Synthesis and Use of Novel Iodo-Pyridine Building Blocks (XIIa), (iii) Pyrazole esters that can be obtained in enantiopure form (VI) by chromatographic separation (iv) synthesis and use of intermediate (V), and (iv) conversion of this advanced intermediate (VI) to 1-[(3R ,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methyl to form [(4-pyridyl)amino]pyrazole-4-carboxamide (I). This is a new synthetic step for the synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3 -yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole- Unlike known syntheses of 4-carboxamide (I), the new synthetic sequence is reasonably cost-effective. This offers the possibility of scaling up to large amounts of 1-[(3R,4S)-4- 2-fluoro-6-methoxy-4-pyri(2-methyl-2-pyr-4-yl)-3-[(2-fluoro-6-methoxy-4-pyr-4-yl)-2-(2-methyl-2-pyr-4-yl)-3-[(2-fluoro-6-methoxy-4 ... Suitable for the preparation of [(2- ...

[0015] Scheme 1 [ka]

[0016] A description of the preparation of key intermediates in the novel synthesis is provided below.

[0017] 2-fluoro-4-bromo-6-methoxamine disclosed in WO2018 / 108969 The synthesis of X-pyridine (XIIb) was carried out by 3,5-dichloro-2,4,6-trifluoropyridine. It was based on a four-step process that started with gin. The synthesis step proved to be unreliable and had poor yields. Illustrative drawbacks include: ,5-Dichloro-2,4,6-trifluoropyridine Hydrodechlorination to chlorine (M. Schlosser et al. Chem. Eu r. J. 2005,11, 1903) can only be achieved in hydrophobic alcohols. The resulting product can then be partially hydrolyzed. ,6-Trifluoropyridine to 2,6-difluoro-4-hydrazinylpyridine The conversion of 2,6-difluoropyridine to 2,6-difluoropyridine was not regioselective. A new and more efficient two-step synthesis based on iridium(I)-catalyzed borylation has been developed. (Scheme 2).

[0018] Scheme 2: New access to compounds of formula (XIIb) [ka]

[0019] This process allows selective cleavage at the 4-position of 2,6-difluoropyridine (VII). The boronation is possible in good yield (65%). In one embodiment of the present invention, the boronation step The ligands were 4,4'-di-tert-butylbipyridine or N-benzyl-1 -phenyl-N-(2-pyridylmethyleneamino)methanamine. In another embodiment of the present invention, the boronation step is carried out in a solvent selected from the group consisting of tetrahydrofuran, cyclohexane, or This is carried out in an organic solvent such as dioxane. The resulting boronic ester (VI) is then reacted with the resulting boronic acid ester (VI). Conversion of II) to the corresponding bromide (XI) is achieved in the presence of a brominating agent. In one embodiment, the brominating agent is selected from copper(I) bromide or copper(II) bromide together with an oxidizing agent. In another embodiment of the present invention, the brominating agent is copper(II) bromide. 6-Methoxy-4-bromo-6-methoxy-pyridine (XIIb) The introduction of the substituents is carried out using an alkali methoxide such as potassium methoxide or sodium methoxide. In one embodiment of the present invention, the alkali methoxide is sodium It is methoxide.

[0020] The newly developed 2-fluoro-4-bromo-6-methoxy-pyridine (XIIb) A cost-effective alternative for the synthesis is 2-fluoro-4-iodo-6-methoxy-pyridine The synthesis and use of (XIIa) (Scheme 3).

[0021] Scheme 3: New access to compounds of formula (XIIa) [ka]

[0022] Thus, 2-fluoro-4-iodo-6-methoxy-pyridine (XIIa) is a novel 2-Fluoro-6-methoxy-pyridinyl esters via halogenation / halogenation protocols In one embodiment of the present invention, the compound (IX) can be obtained in high purity and high yield in a single synthetic step. The halogenation / halogen dance step occurs in the presence of a lithium amide base. In a subembodiment of the present invention, the lithium amide base is a lithium 2,2, The compound is selected from 6,6-tetramethylpiperidide and lithium diisopropylamide. In a further subembodiment of the invention, the lithium amide base is lithium 2,2,6,6-tetramethyl-2, ... In some embodiments of the present invention, the halogenation / halogenation step is In a subsection of the present invention, the reaction is carried out in the presence of 2 to 2.5 equivalents of a lithium amide base. The reaction is carried out in the presence of 2 to 2.1 equivalents of a lithium amide base. In the present embodiment, the halogenation / halogenation reaction is carried out at a temperature of -78 to -65°C. In a subembodiment of the present invention, the reaction is carried out at -75 to -70°C. In an embodiment, the reaction is carried out using 15-20 volumes of solvent.

[0023] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) The known synthesis of 100% methylpyran-3-ylpyrazole-4-carboxamide (XVI) (WO2018 / 108969) (see Scheme 4). Due to its low solubility in organic solvents, chiral separation of the parent racemate (XV) was performed using chiral supercritical flow Furthermore, the 1-[(3R ,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methyl Further transformation to [(4-pyridyl)amino]pyrazole-4-carboxamide (I) The conversion was accompanied by the formation of by-products due to the presence of reactive amide groups.

[0024] Scheme 4 [ka]

[0025] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) can be obtained via a novel synthesis from ethyl 3-amino-1H-pyrazole-4-carboxylate 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl] It can be more conveniently prepared from ethyl [pyrazole-4-carboxylate (VI)] It was found that (Scheme 5).

[0026] Scheme 5: Novel synthesis of compounds of formula (I) [ka]

[0027] This new intermediate (V) is much more soluble in organic solvents than the parent amide (XV). and 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3- [(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide It offers the advantage of being readily amenable to clean conversion to the amide (I). Higher resolution allows for a scalable and highly cost-effective novel chiral synthesis of racemic compound (V) Separation is achieved.

[0028] 3-Amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyra Ethyl 3-amino-1H-pyrazole-4-carboxylate (VI) is a 3-amino-1H-pyrazole-4-carboxylate. Ethyl phosphate (IV) is reacted with 3,6-dihydro-2H in an organic solvent in the presence of a base at elevated temperature. -pyran-4-carbonitrile (III) followed by chiral separation. It is prepared by the following procedure (Scheme 6).

[0029] Scheme 6: Preparation of a novel synthetic intermediate of formula (VI) [ka]

[0030] In one embodiment of the present invention, the base is 1,8-diazabicyclo[5.4.0]undeca- In another embodiment of the present invention, the hydroxyl group is selected from the group consisting of 7-ene, potassium carbonate, and tripotassium phosphate. The base is potassium carbonate or tripotassium phosphate.

[0031] In one embodiment of the present invention, the organic solvent is ethanol, 1,4-dioxane, N,N-dioxane, In a sub-embodiment of the present invention, the organic solvent is methylformamide, toluene, or acetonitrile. The organic solvent is either toluene or acetonitrile. ~2.5 equivalents of 3,6-dihydro-2H-pyran-4-carbonitrile (III) reacts In another embodiment of the present invention, 1.1 to 1.5 equivalents of 3,6-dihydro- 2H-pyran-4-carbonitrile (III) is involved in the reaction.

[0032] 2-Fluoro-4-bromo-6-methoxy-pyridine (XIIb) or 2-fluoro- Between 4-iodo-6-methoxy-pyridine (XIIa) and a compound represented by formula (VI) The coupling step is achieved in the presence of a palladium catalyst and a ligand (Scheme 7). .

[0033] Scheme 7: Preparation of compounds of formula (XIII) [ka]

[0034] In one embodiment of the present invention, the palladium catalyst is tris(dibenzylideneacetone)dipalladium. Radium(0), allylpalladium(II) chloride dimer, [(2-di-tert-butyl Thiophosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1' -biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) 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 some embodiments of the present invention, palladium-catalyzed The coupling step is carried out in the presence of a base such as potassium acetate or tripotassium phosphate. can be.

[0035] The resulting ester of formula (XIII) is converted into the corresponding acid of formula (XIV). Hydrolysis (Scheme 8) can be carried out in the presence of a lithium salt, a trialkylamine, and a catalytic amount of water. It will be implemented.

[0036] Scheme 8: Preparation of compounds of formula (XIV) [ka]

[0037] 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 a further embodiment of the present invention, the trialkylamine base is either In another embodiment of the present invention, the hydrolysis is carried out at elevated temperatures. In yet another embodiment, the hydrolysis is carried out at a temperature of 60 to 100° C. In a further embodiment, the hydrolysis is carried out at a temperature of 65 to 85°C.

[0038] 1-[(3R,4S)-4-cyanotetrahydropyridine] of the penultimate acid (XIV) 3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazo The conversion of the 4-amino-4-carboxamide (I) to the 4-amino-4-carboxamide (I) can be achieved by converting the acid of formula (XIV) into an activated intermediate. and reacting this intermediate with ammonia or its synthetic equivalent. This is achieved (Scheme 9).

[0039] Scheme 9: Conversion of intermediate of formula (XIV) to compound (I) [ka]

[0040] In one embodiment of the present invention, the activated intermediate is an acid derived from an acid of formula (XIV) chloride, and the acid (XIV) is chlorinated with a chlorinating agent such as oxalyl chloride or thionyl chloride. In another embodiment of the present invention, the activated intermediate is obtained by reacting with an agent of formula ( XIV), optionally with hydroxybenzotriazole or cyano(hydroxybenzotriazole). In the presence of an additive such as ethyl acetate (dihydroxyimino), carbodiimide (DCC, DIC , EDC.HCl), O-(benzotriazol-1-yl-N,N,N',N'-tet Tetramethyluronium salts (HBTU, TBTU), O-(7-azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium salt (HATU, TATU) reagent The compound is prepared by reacting the compound with a coupling reagent such as

[0041] definition Lithium tetramethylpiperidide (CAS number 38227-87-1) (often LiTMP, abbreviated as Li / TMP or LTMP, has the molecular formula CH 18 Contains LiN It is used as a non-nucleophilic base.

[0042] Trimethylsilyl cyanide (CAS number 7677-24-9) (TMSCN) has the formula ( The compound is represented by the formula CH3)3SiCN. This volatile liquid is This molecule is used in organic synthesis as a cyanide. It is used as an equivalent of hydrogen chloride.

[0043] 1,5-Cyclooctadiene (CAS number 1552-12-1) (often COD ), is a compound used as a ligand in many metal complexes.

[0044] Pinacol (CAS number 76-09-5), commonly abbreviated as pin, is a In many cases, it is a structural component of the boron esters involved in organometallic coupling processes.

[0045] MTBE stands for methyl tert-butyl ether (CAS number 1634-04-4) It is used as an organic solvent.

[0046] Dibenzylideneacetone (CAS number 35225-79-7) (often referred to as dba) (abbreviated as 'P') is a compound used as a ligand in many metal complexes.

[0047] 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (CAS number 564483-19-8) (often t-Bu Xphos or te rt-Butyl Xphos) is used as a ligand in many metal complexes. The compound used is:

[0048] 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS number 1 61265-03-8) (usually abbreviated as Xantphos) is found in many metal complexes. It is a compound used as a ligand in

[0049] 1,3-Dicyclohexylcarbodiimide (CAS number 538-75-0) (in many cases DCC), 1,3-diisopropylcarbodiimide (CAS number 693- 13-0) (often abbreviated as DIC) and 1-ethyl-3-(3'-dimethylaniline) (aminopropyl) carbodiimide hydrochloride (CAS number 25952-53-8) (usually ED C.HCl) is used to convert carboxylic acids to the corresponding O-acylurea intermediates. It is a reagent used for the synthesis of nucleophiles and promotes reactions with a variety of nucleophiles.

[0050] O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Hexafluorophosphate (CAS number 94790-37-1) (often referred to as HB TU) and O-(benzotriazol-1-yl)-N,N,N',N'-tetrahydrobenzotriazol-1-yl Tetramethyluronium tetrafluoroborate (CAS number 125700-67-6) (often abbreviated as TBTU) is a compound that converts carboxylic acids into the corresponding 1-hydroxybenzotriazoles. It is a reagent used to convert azole esters to azoles, and reacts with various nucleophiles. Promote response.

[0051] O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl Uronium hexafluorophosphate (CAS number 148893-10-1) (many (abbreviated as HATU in this case) and O-(7-azabenzotriazol-1-yl)-N, N,N',N'-Tetramethyluronium tetrafluoroborate (CAS number 8737 98-09-5) is a carboxylic acid converted to the corresponding 1-hydroxyazabenzotriazole ester. It is a reagent used to convert ethers to nucleophiles and promotes reactions with a variety of nucleophiles. .

[0052] An ammonia equivalent is a synthetic equivalent of ammonia, for example, ammonium chloride.

[0053] Brominating agents are reagents used to introduce bromine into a reaction, for example, copper bromide ( II) or copper(I) bromide with an oxidizing agent.

[0054] One embodiment of the present invention is a compound of formula (XII) [ka]

[0055] wherein R is I. wherein the method comprises: Formula (IX) [ka]

[0056] The compound represented by the formula: and reacting with the compound of formula (X) [ka]

[0057] The method includes producing a compound represented by the formula:

[0058] In one embodiment, the method further comprises reacting the compound of Formula (X) with a lithium amide salt. in the presence of a group (preferably lithium / TMP) to give a compound of formula (XIIa) [ka]

[0059] The method includes producing a compound represented by the formula:

[0060] In an alternative embodiment, the product of step (a) is isolated and purified before proceeding to step (b). I can't.

[0061] One embodiment of the present invention is a compound of formula (XII) [ka]

[0062] wherein R is Br. wherein the method comprises: Formula (VII) [ka]

[0063] with an iridium catalyst and bis(pinacolato)diboron, Formula (VIII) [ka]

[0064] The method includes producing a compound represented by the formula:

[0065] 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 with an oxidizing agent, preferably copper(I) bromide I)) to form a compound of formula (XI) [ka]

[0066] The method includes producing a compound represented by the formula:

[0067] In one embodiment, the method further comprises reacting the compound of formula (XI) with an alkali methoxide. methoxide (preferably sodium methoxide or potassium methoxide) to give a compound of formula ( XIIb) [ka]

[0068] The method includes producing a compound represented by the formula:

[0069] One embodiment of the present invention is a compound of formula (VI) [ka]

[0070] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. wherein the method comprises: Formula (II) [ka]

[0071] A compound represented by i. Hydrogen cyanide or its equivalent (e.g., TMSCN); and ii. POCl3 or SOCl2; to form a compound of formula (III) [ka]

[0072] The method includes producing a compound represented by the formula:

[0073] In one embodiment, the method further comprises reacting the compound of Formula (III) with a base, e.g. For example, tripotassium phosphate or potassium acetate) in the presence of a compound of formula (IV) [ka]

[0074] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. and reacting the compound represented by formula (V) [ka]

[0075] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. The method includes producing a compound represented by the formula:

[0076] In one embodiment, the method further comprises reacting an enantiomer of the compound of formula (V): and separating to produce a compound of formula (VI).

[0077] In one embodiment, separation of the enantiomers is achieved by chiral chromatography. can be.

[0078] One embodiment of the present invention is a compound of formula (V) [ka]

[0079] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. It is a compound represented by the formula:

[0080] One embodiment of the present invention is a compound of formula (VI) [ka]

[0081] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. It is a compound represented by the formula:

[0082] One embodiment of the present invention is a compound of formula (XIII) [ka]

[0083] [In the formula, R 1 is C1-C4 alkyl, preferably C1-C2 alkyl; Most preferably, it is ethyl. It is a compound represented by the formula:

[0084] One embodiment of the present invention is a compound of formula (XIV) [ka]

[0085] It is a compound represented by the formula:

[0086] An additional embodiment of the present invention is a compound of formula (I) [ka]

[0087] wherein the method comprises: Formula (XVI) [ka]

[0088] with a compound represented by formula (XIIa) [ka]

[0089] with a compound of formula (I) to produce a compound of formula (I):

[0090] HPLC method: Method A Agilent Technologies UHPLC / MSD 6130B Se ries 1290, which consists of: Binary pump G7120A (contains degassing agent); Well plate sampler G4226A; Column oven G1316B; Diode array detector G4212A; Mass detector G6130B quadrupole LC / MS with ESI source; Column: Waters XP, 2.1 x 50 mm Xbridge BEH C18 2.5μ, T = 40°C; Eluent: A: acetonitrile (containing 0.05% (vol. / vol.) formic acid); B: Water (containing 0.05% (vol. / vol.) formic acid); Flow rate: 0.8mL / min; Gradient: 2 → 100% eluent A 1.2 min, 0.5 min 100% eluent A; Run time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000m / z; UV 254 and 210nm.

[0091] Method B Agilent Technologies UHPLC / MS 1260 Series s, which consists of: Binary pump G7120A (contains degassing agent); Well Plate Sampler G4226A; Column oven G7116B; Diode array detector G7117B; Mass detector G6150B quadrupole LC / MS with ESI-jet stream source; Column: Waters XP, 2.1 x 50 mm Xbridge BEH C18 2.5μ, T = 40°C; Eluent: A: acetonitrile (containing 0.05% (vol. / vol.) formic acid); B: Water (containing 0.05% (vol. / vol.) formic acid); Flow rate: 0.8mL / min; Gradient: 2 → 100% eluent A 1.2 min, 0.5 min 100% eluent A; Run time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000m / z; UV 254 and 210nm.

[0092] Method C Agilent Technologies UHPLC / MS 1260 Series s, which consists of: Binary pump G4220A (contains degassing agent); Well plate sampler G4226A; Column oven G7116B; Diode array detector G4212A; Mass detector G6130B quadrupole LC / MS with ESI / APCI-multimode source ; Column: Waters XP, 2.1 x 50 mm Xbridge BEH C18 2.5μ, T = 40°C; Eluent: A: acetonitrile (containing 0.05% (vol. / vol.) formic acid); B: Water (containing 0.05% (vol. / vol.) formic acid); Flow rate: 0.8mL / min; Gradient: 2 → 100% eluent A 1.2 min, 0.5 min 100% eluent A; Run time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000m / z; UV 254 and 210nm. [Example]

[0093] 3-Amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazo Synthesis of ethyl 4-aminobenzoate(III) [ka]

[0094] Equipped with a reflux condenser, mechanical stirrer, internal thermometer, gas scrubber, and placed under a nitrogen atmosphere. A jacketed glass reactor (10 L) was charged with dry acetonitrile (2.55 L) and and dihydro-2H-pyran-4(3H)-one (II) (365 g, 3.65 mol) The resulting mixture is stirred and its temperature is adjusted to -5 to 0°C. Add zinc iodide (35 g, 0.11 mol) while maintaining the temperature below 10°C. After adjusting the temperature to -5 to 0°C, add trimethylsilane carbohydrate while maintaining the temperature below 0°C. Add nitrile (433 mL, 3.46 mol) dropwise over 80 min. Stir at 0 °C for 3 h. After a reaction time of 10 min, complete conversion of the starting material was observed, and the reaction mixture was added with pyridine. HCl (1.76 L, 21.9 mol) was added, followed by phosphoryl chloride (510 mL; The temperature is raised to 80°C and the reaction mixture is stirred at this temperature for 16 hours. The reaction mixture is then cooled to room temperature and quenched by the addition of aqueous 50% sodium hydroxide. Iron sulfate heptahydrate (304 g, 1.09 mo) in water (7.3 L) adjusted to pH > 10 l) solution. While the reaction mixture is being added to the basic iron sulfate solution, the temperature is maintained at 2 The temperature is kept below 0°C, and the pH is maintained above 10 by adding 50% aqueous sodium hydroxide solution. The resulting mixture was extracted with methyl tert-butyl ether (3.5 L), and the organic layer The aqueous layer was collected and diluted with water (6 L). Extract with diethyl ether (2 x 2.5 L). The combined organic layers were washed with saturated aqueous sodium bicarbonate. (1.83 L) and concentrated under reduced pressure at 40° C. The crude residue is concentrated under reduced pressure (0.5 mbar Distillation at about 45°C yielded the desired product (III) as a colorless oil (289g). , 2.6 mol).

[0095] HPLC Method A: Retention time: 0.58 min; m / z 110.

[0096] 1 HNMR (300 MHz, CDCl3) δ (ppm): 6.60 - 6.57 (1H, m); 4.21 - 4.18 (2H, m); 3.7 5 (2H, J = 5.52 Hz, t); 2.31 - 2.25 (2H, m).

[0097] 2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Synthesis of (loran-2-yl)pyridine (VIII) [ka]

[0098] Bis(pinacolato)diboron (68.8 g, 0.27 mol); 4,4'-di-te rt-Butylbipyridine (2.10 g, 7.82 mmol) and (1,5-cyclooctadecane Diene)(methoxy)iridium(I) dimer (2.59 g, 3.91 mmol) was added to the Under an inert atmosphere, the mixture was suspended in methyl tert-butyl ether (10 mL) and 2,6-dichloromethane was added. Fluoropyridine (VII) (23.8 mL, 0.26 mol) was added. The temperature was gradually raised to 45°C and the reaction mixture was stirred at this temperature for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The isolated residue was purified by elution with pentane. The desired product (VIII) was obtained by filtration through a short silica gel column. was obtained as a colorless solid (32.7 g, 0.14 mol).

[0099] HPLC method A: Retention time: 0.68 min; m / z 581 1 HNMR (300 MHz, CDCl3) δ (ppm): 7.08 (2H, m); 1.28 (12H, s).

[0100] Synthesis of 4-bromo-2-fluoro-6-methoxy-pyridine (XIIb) [ka]

[0101] 2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Lorane-2-yl)pyridine (VIII) (32 g, 133 mmol) was dissolved in methanol (3 80 mL) and a 1.1 M aqueous solution of copper(II) bromide (104 g, 465 mmol) The resulting mixture was heated to reflux and stirred at this temperature for 90 minutes. The reaction mixture was cooled to 0°C in an ice bath, and then 10% aqueous ammonium hydroxide solution was added with stirring. (300 mL) was added dropwise, and the resulting mixture was extracted with pentane (3 x 200 mL). The solution of the desired product (XI) in pentane was used directly in the next step. A solution of 4-bromo-2-fluoro-6-methoxy-pyridine (XI) was added to dry methanol ( Add 160 mL of the ammonium hydroxide solution and add 160 mL of the ammonium hydroxide solution in dry methanol (88.4 mL) with stirring at about 20°C. A solution of sodium methoxide (100 mmol) was added. After 2.5 hours of reaction time The mixture was cooled to 0°C by applying an ice bath, and the mixture was diluted with 2N aqueous hydrochloric acid (224 mL The organic layer was separated and the aqueous layer was poured into a stirred mixture of pentane (10 The combined organic layers were washed with brine (50 mL) and extracted under reduced pressure (700 The desired product (XIIb) was obtained by condensing the remaining pentane (11 wt%) was obtained as a pale yellow solid (21.5 g, 92 mmol) .

[0102] HPLC method A: Retention time: 1.11 minutes 1 HNMR (300 MHz, CDCl3) δ (ppm): 6.82 (1H, m); 6.68 - 6.67 (1H, m); 3.93 (3H, s ).

[0103] Synthesis of 2-fluoro-6-methoxy-4-iodo-pyridine (XIIa) [ka]

[0104] Under an inert atmosphere, dry tetrahydrofuran ( 5.99 L). 2,2,6,6-Tetramethylpiperidine (1161 g, 8. 22 mol) was added and the resulting solution was cooled to -30°C. The solution (2292 mL, 7.47 mol) was added dropwise over 30 min while maintaining the temperature at approximately -30 °C. The resulting mixture was stirred at this temperature for 1 hour. The temperature was lowered to -5 to -70°C, and 2-fluoro-6- A solution of methoxypyridine (IX) (500 g, 3.93 mol) was heated to -75°C. The addition was carried out over 30 minutes while maintaining the temperature at 70° C. The reaction mixture was stirred at this temperature for 90 minutes, and then Iodine (998.4 g, 3.93 mol) in dry tetrahydrofuran (2494 mL) The mixture was heated at -75 to -70°C for 1 hour. The mixture was stirred for 14 hours. Water (3.5 L) was added at -75 to -70°C within 30 minutes, and the reaction mixture was stirred for 14 hours. The mixture was allowed to reach room temperature, the organic layer was separated, and the aqueous layer was diluted with methyl tert-butyl ether The combined organic layers were washed with 85 wt% aqueous phosphoric acid (2 x 4 L). The mixture was washed and concentrated for 4 hours at a temperature not exceeding 30°C to a total weight of 1250g. After steam distillation and separation of the aqueous layer, a colorless oil was obtained. Water (390 mL) was added, and the resulting mixture was stirred at -10 to -5°C for 30 minutes. The resulting solid was collected by filtration and washed with a small amount of pre-chilled heptane (approximately 55 mL) to give The desired product (XIIa) (530 g, 2.09 mol) was obtained.

[0105] HPLC method A: Retention time: 1.14 minutes 1 HNMR (300 MHz, CDCl3) δ (ppm): 7.03 (1H, m); 6.88 - 6.86 (1H, m); 3.93 (3H, s ).

[0106] 3-Amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazo Synthesis of ethyl 4-aminobenzoate (V) [ka]

[0107] A jacketed reactor equipped with a reflux condenser, mechanical stirrer, internal thermometer, and placed under a nitrogen atmosphere A glass reactor (5 L) was charged with dry acetonitrile (750 mL), potassium phosphate tribasic (100 mL), and Hydrate (38.3 g, 0.16 mol) and 3-amino-1H-pyrazole-4-carbohydrate Ethyl phosphate (IV) (500 g, 3.19 mol) was added. The resulting mixture was heated to 80°C. 3,6-dihydro-2H-pyran-4-carbonitrile (III) (462 g , 4.15 mol) was added quickly via the addition funnel. The addition funnel was filled with acetonitrile (2 The reaction mixture was heated to 80° C. with vigorous stirring. After 6.5 hours of reaction at RT, the heating was stopped and the reaction mixture was further stirred overnight. After concentrating the mixture under reduced pressure, a yellow slurry was obtained. The resulting material was extracted with ethyl acetate ( 5 L) and the resulting solution was extracted with 1 M aqueous hydrochloric acid (3 x 1.5 L) and brine (1 L), filtered through a filter filled with a pad of magnesium sulfate, and then filtered under reduced pressure. The yellow oil was dissolved in methanol (1.36 L) and concentrated at 200°C. The resulting mixture was heated to 40°C with stirring to ensure homogenization. The solution was cooled to 25°C and seeded with 2.0 g of pure seed crystals at this temperature. The mixture was stirred gently at 4°C overnight. The precipitate that formed was filtered off and washed with pre-chilled methanol (1 L). After washing and drying under vacuum at 40°C, an off-white solid was obtained. The solid was heated to reflux in 2-propanol (1 L) for 1 hour, and the mixture was gently stirred overnight. The mixture was allowed to slowly reach room temperature while stirring. The precipitate formed was filtered off and 2-propanol (3 00 mL) and dried under reduced pressure at 40 °C to give the desired product (V) was obtained as a solid (347.2 g, 1.20 mol).

[0108] HPLC method A: Retention time: 0.75 min; m / z 265 1 HNMR (600 MHz, CDCl3) δ (ppm): 7.82 (s, 1H); 4.28 (2H, J = 7.1 Hz, q); 4.14 (1 H, J = 4.3, 9.0 Hz, dt); 4.08 (1H, J = 4.2, 12.0 Hz, dd); 4.00 (1H, J = 4.0, 12. 1 Hz, td); 3.90 (1H, J = 8.7, 12.0 Hz, 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 = 7.1 Hz, t).

[0109] 3-Amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrazo 3-amino-1-[(3S,4R)-4-cyanoethyl]-4-carboxylate (V) tetrahydro-2H-pyran-3-yl]-1H-pyrazole-4-carboxylate ethyl (V Chiral separation into I) [ka]

[0110] The separation of a mixture of enantiomers (V) into single enantiomers (VI) is a chiral This was achieved through chromatography.

[0111] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) Ethyl fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxylate (X Synthesis of III) [ka]

[0112] 3-amino-1-[(3S,4R)-4-cyanotetrahydro-2H-pyran-3-yl] ethyl]-1H-pyrazole-4-carboxylate (VI) (50 g, 189 mmol), 4-Bromo-2-fluoro-6-methoxy-pyridine (XIIb) (39 g, 189 mm ol), tris(dibenzylideneacetone)dipalladium(0) (3.57 g, 3.8 m mol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl Biphenyl (3.21 g, 7.6 mmol) and potassium acetate (37.1 g, 378 mmol) The resulting mixture was placed under an inert atmosphere and 2-propanol (600 mL) was added. The mixture was heated to 65°C and stirred at this temperature for 90 minutes. After cooling to room temperature, the mixture was The resulting crude residue was diluted with acetonitrile (650 mL) and concentrated under reduced pressure at 40° C. The mixture was stirred at 50° C. for 30 minutes. The warm solution was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 2-propanol (750 mL), and the resulting mixture was The temperature was raised to °C and then allowed to slowly reach room temperature with gentle stirring. The precipitate was removed by filtration, and the wet cake was rinsed with 2-propanol (50 mL) and then evaporated under reduced pressure. and drying at 40°C to give the desired product (XIII) (61.2 g, 149 mmol). The filtrate was combined with the 2-propanol rinse and concentrated under reduced pressure to give a solid. The solid formed was washed with 2-propanol (2 x 50 mL) and dried under reduced pressure at 40 °C. This gave a second crop of the desired product (XIII) (8.2 g, 19.5 mmol). was made.

[0113] HPLC method B: Retention time: 1.10 min; m / z 390 1 HNMR (600 MHz, CDCl3) δ (ppm): 8.61 (1H, s); 7.95 (1H, s); 6.73 (1H, s); 6.68 (1H, J = 1.5 Hz, d); 4.33 (2H, J = 7.1 Hz, q); 4.25 (1H, J = 4.2, 9.0 Hz, dt); 4 .16 (1H, J = 4.2, 12.0 Hz, dd); 4.06 (1H, J = 4.0, 12.1 Hz, td); 3.98 (1H, J = 8 .8, 12.1 Hz, 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, 14.2 Hz, dtd); 1.38 (3H, J = 7.1 Hz, t).

[0114] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) Ethyl fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxylate (X Synthesis of III) [ka]

[0115] 3-amino-1-[(3S,4R)-4-cyanotetrahydro-2H-pyran-3-yl] ethyl]-1H-pyrazole-4-carboxylate (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(difluoromethyl) (phenylphosphino)-9,9-dimethylxanthene (109 mg, 0.19 mmol) and and tripotassium phosphate (2.41 g, 11.35 mmol) were placed under a nitrogen atmosphere and -Dioxane (10 mL) was added. The resulting mixture was heated to 60 °C and stirred at this temperature for 1 The mixture was stirred for 8 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was 2- The mixture was diluted with propanol (20 mL) and warmed until a solution was obtained. The heat was turned off and the solution was allowed to slowly reach room temperature. The suspension was filtered to remove the precipitate that had formed. The precipitate was collected. The wet cake was rinsed with 2-propanol (25 mL) and heated under reduced pressure at 40°C. The desired product (XIII) was obtained as an off-white solid (1.07 g, 2.75 The filtrate was concentrated under reduced pressure, and the resulting residue was heated under reflux to obtain 2-propanol. After dilution with ethanol (5 mL), the resulting precipitate was filtered and dried to give the desired product ( A second crop of XIII) (180 mg, 0.5 mmol) was obtained.

[0116] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (Fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxylic acid (XIV) Synthesis of [ka]

[0117] Lithium bromide (769 mg, 8.86 mmol) and triethylamine (380 μL, 2.66 mmol) in acetonitrile (4.34 mL) and water (87 μL) 3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6 -Methoxy-4-pyridyl)amino]pyrazole-4-carboxylate ethyl (XIII) ( 345 mg, 0.89 mmol), 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 washed with saturated aqueous bicarbonate. The combined aqueous layers were extracted with 1 M aqueous hydrochloric acid (3 x 10 mL). The precipitate formed was isolated by filtration and diluted with water under reduced pressure for 40 minutes. After drying at 50° C., the desired product (XIV) was obtained as a colorless solid (308 mg, 0.85 mmol). ) was obtained.

[0118] HPLC Method C: Retention time: 0.88 min; m / z 362.

[0119] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) Synthesis of [ka]

[0120] N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (245m g, 1.28 mmol), 1-hydroxybenzotriazole hydrate (131 mg, 0. 85mmol), ammonium chloride (91mg, 1.71mmol), triethylamine (238 μL, 1.71 mmol) and 1-[(3R,4S)-4-cyanotetrahydro Pyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyran 4-Hydrazole-4-carboxylic acid (XIV) (308 mg, 0.85 mmol) was added to tetrahydrofuran. In a mixture of 3 mL of methylpropanol and 1 mL of N,N-dimethylformamide, 9 The reaction mixture was stirred for 10 minutes. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction mixture, and the aqueous layer was Extract with ethyl acetate (2 x 15 mL). Wash the combined organic layers with brine (5 mL). The resulting mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude desired product (I)( The yield was 276 mg, 0.77 mmol).

[0121] HPLC method A: Retention time: 0.86 min; m / z 361 1 HNMR (600 MHz, CDCl3) δ (ppm): 9.70 (1H, s); 8.35 (1H, s); 7.83 (1H, br s); 7. 32 (1H, br s); 7.03 - 6.68 (2H, m); 4.64 (1H, J = 4.4, 10.2 Hz, dt); 4.04 (1H, J = 4.4, 11.3 Hz, dd); 3.94 - 3.86 (1H, m); 3.79 (3H, s); 3.71 - 3.59 (2H, m); 3. 49 (1H, J = 2.2, 11.7 Hz, dt); 2.20 - 2.12 (1H, m); 2.04 - 1.93 (1H, m).

[0122] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) Refining into [ka]

[0123] In a 160 L glass-lined container, crude (I) (3.72 kg, 10.32 m The contents were heated to reflux (65°C) and the compound was added. A pure seed crystal of compound (I) (109 g, 302.5 mmol) was dissolved in methanol (1.9 L). The mixture was stirred at 275 rpm 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 over 12 hours and then aged at 20°C for 6 hours. The batch was filtered and the cake was washed with methanol (5.4 L). The solid was washed with nitrogen. The material was then dried in a vacuum oven equipped with a bleed at 40°C for 23 hours. The lumps were crushed through an o-mill to obtain compound (I) (2.21 kg, 6.14 mol). It was obtained as a colored powder.

[0124] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoromethyl) (fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) Alternative synthesis of [ka]

[0125] In the first vessel, N,N-dimethylacetamide (7.55 L) was heated under subsurface nitrogen. The mixture was degassed for 30 minutes. and allylpalladium(II) chloride dimer (36.2 g, 0.099 mol) were added. The resulting mixture was stirred at 20° C. for 100 minutes with a subsurface nitrogen purge. Compound (XVI) (2.32 kg, 9.88 mol) was added to compound (XIIa) (2. 50 kg, 9.88 mol), tripotassium phosphate (4.19 kg, 19.76 mol) and and N,N-dimethylacetamide (17.55 L). After stirring and degassing, the catalyst solution prepared in the first vessel was added. The mixture was rinsed with N,N-dimethylacetamide (0.5 L), which was also added to the reaction mixture. The reaction mixture was stirred at room temperature and monitored by UV-HPLC until complete conversion was observed. The reaction mixture was filtered and the wet cake was diluted with N,N-dimethylacetamide (5 The filtrate was cooled to 0-5°C and washed with water (90 L) while maintaining the temperature at 0-5°C. The resulting slurry was aged at this temperature for 1 hour. The slurry was filtered and the cake was washed twice with water (10 L and 20 L) and then with methanol. The wet cake was dried under a stream of nitrogen and washed four times with ethanol (15 L and 3 x 19 L). The desired compound (I) (3.14 kg, 0.154 mol) was obtained.

Claims

1. Formula (XII) 【Chemical 1】 wherein R is I. A method for producing a compound represented by the formula: Formula (IX) 【Chemistry 2】 with iodine and a lithium amide base to obtain a compound of formula (XII); A method comprising:

2. Formula (XII) 【Chemistry 3】 wherein R is I. A method for producing a compound represented by the formula: Formula (IX) 【Chemistry 4】 with iodine and a lithium amide base, followed by treating the resulting reaction mixture with water to obtain a compound of formula (XII); A method comprising:

3. The method described in claim 1 or 2, wherein the lithium amide base is lithium / TMP.

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