Method for preparing 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide

Abstract

To provide a method for producing a compound which is a selective Janus kinase (JAK) inhibitor, and is therefore an intermediate for the production of a compound useful for the treatment of JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer.SOLUTION: A method for producing a compound represented by Formula (XIIb), comprises reacting a compound represented by Formula (VII) with an iridium catalyst and bis(pinacolato)diboron to yield a compound represented by Formula (VIII); and converting the compound represented by Formula (VIII) into the compound represented by Formula (XIIb).SELECTED DRAWING: None

Description

[Background technology]

[0001] WO2018 / 108969 is a selective Janus kinase (JAK) inhibitor, and Formula I is useful in treating JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer. The compounds that are represented are disclosed. Specifically, 1-[(3R,4S)-4-cyanothete [Lahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl) Mino]pyrazole-4-carboxamide(I) is disclosed. [ka]

[0002] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide(I) The known synthesis of 3-amino-1-[(3R,4S)-4-cyanotetrahedron This is clearly stated regarding dropyran-3-yl]pyrazole-4-carboxamide. See compound (XVI) in Scheme 4 below. This intermediate is soluble in organic solvents. Because the degree is low, the chiral separation of the parent racemic compound (XV) is performed using chiral supercritical fluid chromatography. It had to be done at Fee (SFC). Furthermore, 1-[(3R,4S)-4- [Cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyranyl] Further conversion to lysyl)amino]pyrazole-4-carboxamide(I) involves by-products. The formation process was involved, which made the production of the pure final product more difficult.

[0003] WO2013 / 041042 includes rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease (COPD). ) and pyrazole carboxamides as Janus kinase inhibitors useful for the treatment of cancer have been disclosed. The compounds of this disclosure are represented by the following formula

Chemical Formula

[0004] which is a compound represented by

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0010] To produce the compound represented by; and, b. Converting a compound represented by formula (XIII) to a compound represented by formula (I); The method, including the method described above.

[0011] Furthermore, a. A compound represented by formula (XIII) is a trialkylamine (preferably triethylamine). In the presence of luminamine, a lithium salt (preferably lithium bromide, lithium chloride, or hydroxyl) Reacting with lithium (Citrate), formula (XIV) [ka]

[0012] To produce the compound represented by; and, b. Converting a compound represented by formula (XIV) to a compound represented by formula (I); Includes.

[0013] The method further involves forming an active intermediate of the compound represented by formula (XIV), And then, ammonia or its equivalent (for example, ammonium chloride with a base) This includes reacting with ) to produce a compound represented by formula (I). [Modes for carrying out the invention]

[0014] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide(I) New access to has been detected. The main novelty is (i) WO2018 / 108969 Novel and more efficient synthesis of the bromopyridine intermediate (XIIb) shown, (ii) Synthesis and use of novel iodopyridine building blocks (XIIa), (iii) Pyrazole esters can be obtained in an enantiopurine form (VI) by ral separation. Synthesis and use of intermediate (V), and (iv) this advanced intermediate (VI) 1-[(3R ,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methyl To convert to toxic-4-pyridyl)amino]pyrazole-4-carboxamide (I) It is currently in the new synthesis stage. 1-[(3R,4S)-4-cyanotetrahydropyran-3 -yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole- Unlike the known synthesis of 4-carboxamide(I), the novel synthesis sequence is reasonably cost-effective. This offers the possibility of scaling up, and therefore a large amount of 1-[(3R,4S)-4-S Anotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyriol] Suitable for the manufacture of [zyl]amino]pyrazole-4-carboxamide(I).

[0015] Scheme 1 [ka]

[0016] The following describes the preparation of important intermediates in the novel synthesis.

[0017] 2-Fluoro-4-bromo-6-methyl methyl phosphate is disclosed in WO2018 / 108969. The synthesis of cy-pyridine (XIIb) is carried out by 3,5-dichloro-2,4,6-trifluoropyridine. It was based on a four-stage process starting from jinn. Several of the components of this process The synthesis stage proved to be unreliable and had a poor yield. Three specific examples of its shortcomings are: ,5-dichloro-2,4,6-trifluoropyridine Hydrogenation dechlorination reaction of ions (M. Schlosser et al. Chem. Eu) r. J. 2005,11, 1903) states that this can only be achieved in hydrophobic alcohols. This is possible, and the product undergoes partial hydrolysis. Furthermore, the obtained 2,4 Further conversion of ,6-trifluoropyridine to 2,6-difluoro-4-hydrazinylpyridine The resulting transformation was not regioselective. In this way, 2,6-difluoropyridine A novel and more efficient two-step synthesis based on iridium(I)-catalyzed borylation has been developed. (Scheme 2).

[0018] Scheme 2: Novel access to compounds represented by formula (XIIb) [ka]

[0019] This process selectively targets the 4-position of 2,6-difluoropyridine(VII). Boration can be performed with a good yield (65%). In one embodiment of the present invention, the boration step The ligand is 4,4'-di-tert-butylbipyridine or N-benzyl-1 This is carried out in the presence of phenyl-N-(2-pyridylmethyleneamino)methaneamine. In another embodiment of the present invention, the boration step is tetrahydrofuran, cyclohexane, or This is carried out in an organic solvent such as dioxane. Then, the obtained boronic acid ester (VI The 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 accompanied by an oxidizing agent. In another embodiment of the present invention, the brominating agent is copper(II) bromide. 6-methoxy pyridine (XIIb) to obtain ruoro-4-bromo-6-methoxypyridine The introduction of a substitution group is alkaline methoxy such as potassium methoxide or sodium methoxide. This is achieved in the presence of sodium. In one embodiment of the present invention, alkali methoxide is sodium It is methoxide.

[0020] Newly developed 2-fluoro-4-bromo-6-methoxypyridine (XIIb) A cost-effective alternative to synthesis is 2-fluoro-4-iodo-6-methoxypyridine. This involves the synthesis and use of (XIIa) (Scheme 3).

[0021] Scheme 3: Novel access to compounds represented by formula (XIIa) [ka]

[0022] Thus, 2-fluoro-4-iodo-6-methoxypyridine (XIIa) is novel 2-fluoro-6-methoxypyridin via halogenation / halogenation dance protocol It can be obtained from (IX) in a single synthesis step with high purity and high yield. In one embodiment of the present invention, The halogenation / halogen dance step is performed in the presence of a lithium amide base. It is carried out under the present conditions. In a sub-embodiment of the present invention, the lithium amide base is lithium 2,2 Selected from 6,6-tetramethylpiperidide and lithium diisopropylamide. In a further sub-embodiment of the invention, the lithium amide base is lithium 2,2,6,6-teto It is lamethylpiperizide. In part of the present invention, the halogenation / halogenation dance step is This is carried out in the presence of 2 to 2.5 equivalents of lithium amide base. In a sub-part of the present invention The reaction is carried out in the presence of 2 to 2.1 equivalents of lithium amide base. One embodiment of the present invention In terms of morphology, halogenation / halogenation reactions are carried out at temperatures of -78 to -65°C. In a sub-embodiment of the present invention, the reaction is carried out at -75 to -70°C. Further embodiment of the present invention In the application method, the reaction is carried out using 15-20 volumes of solvent.

[0023] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide(I) The known synthesis of 3-amino-1-[(3R,4S)-4-cyanotetrahydr Regarding lopyran-3-yl]pyrazole-4-carboxamide (XVI), it is clearly shown that (WO2018 / 108969) (See Scheme 4). This intermediate has Because of its low solubility in the solvent, the chiral separation of the parent racemic compound (XV) is performed using chiral supercritical flow. It had to be performed by somatic chromatography (SFC). Furthermore, 1-[(3R ,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methyl Further transformation to toxic-4-pyridyl)amino]pyrazole-4-carboxamide(I) The exchange process 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-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide(I) This can be obtained from ethyl 3-amino-1H-pyrazole-4-carboxylate via a novel synthesis. 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3- It can be more conveniently prepared from [L]pyrazole-4-carboxylate ethyl(VI). This was discovered (Scheme 5).

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

[0027] This novel intermediate (V) is far less soluble in organic solvents compared to the parent amide (XV). Suku, and 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3- [(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxa It offers the advantage of readily undergoing clean conversion to mid(I). Because of its higher resolution, it is a novel chiral compound (V) that is expandable and extremely cost-effective and is suitable for racemic compounds. Separation is achieved.

[0028] 3-amino-1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyra Zol-4-carboxylate ethyl(VI) is 3-amino-1H-pyrazole-4-carb Ethyl(IV) phosphate is dissolved in an organic solvent in the presence of a base at high temperature, and then 3,6-dihydro-2H It is reacted with -pyran-4-carbonitrili(III), and then subjected to chiral separation. Therefore, it is prepared (Scheme 6).

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

[0030] In one embodiment of the present invention, the base is 1,8-diazabicyclo[5.4.0]undeca- Selected from 7-ene, potassium carbonate, and tripotassium phosphate. In another embodiment of the present invention 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-di It is methylformamide, toluene, or acetonitrile. In a sub-embodiment of the present invention, The solvent is either toluene or acetonitrile. In one embodiment of the present invention, 1 Approximately 2.5 equivalents of 3,6-dihydro-2H-pyran-4-carbonitrili(III) react. In another embodiment of the present invention, 1.1 to 1.5 equivalents of 3,6-dihydro- 2H-pyran-4-carbonitrili(III) is involved in the reaction.

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

[0033] Scheme 7: Preparation of the compound represented by formula (XIII) [ka]

[0034] In one embodiment of the present invention, the palladium catalyst is tris(dibenzylideneacetone) dipa Radium(0), allylpalladium(II) chloride dimer, [(2-di-tert-br Tylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1' -Biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) Selected from tansulfonates and palladium(II) acetate, and the ligand is 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, Selected from 9-dimethylxanthene. In part of the present invention, palladium is catalyzed. The coupling step is carried out in the presence of a base such as potassium acetate or tripotassium phosphate. It can be done.

[0035] The ester represented by the obtained formula (XIII) is converted to the corresponding acid represented by formula (XIV). Hydrolysis (Scheme 8) occurs in the presence of a lithium salt, a trialkylamine, and a catalytic amount of water. It will be implemented.

[0036] Scheme 8: Preparation of the compound represented by formula (XIV) [ka]

[0037] In one embodiment of the present invention, the lithium salt is lithium bromide, lithium chloride, or lithium hydroxide. It is lithium. In another embodiment of the present invention, the lithium salt is lithium bromide or lithium hydroxide. It is one of the following. In a further embodiment of the present invention, the trialkylamine base is tri It is ethylamine. In another embodiment of the present invention, hydrolysis is carried out at a high temperature. In an additional embodiment of the present invention, hydrolysis is carried out at a temperature of 60-100°C. In other embodiments, hydrolysis is carried out at a temperature of 65-85°C.

[0038] The second to last acid (XIV) is 1-[(3R,4S)-4-cyanotetrahydropyra [(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazo The conversion to 4-carboxamide (I) involves using an acid represented by formula (XIV) as an active intermediate. By converting and then reacting this intermediate with ammonia or its synthetic equivalent, Achieved (Scheme 9).

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

[0040] In one embodiment of the present invention, the active intermediate is an acid derived from an acid represented by formula (XIV). It is a chloride, and it chlorinates acid (XIV) with oxalyl chloride or thionyl chloride. It is obtained by reacting with an agent. In another embodiment of the present invention, the active intermediate is of formula ( The acid represented by XIV) may be hydroxybenzotriazole or cyano(hydroxybenzotriazole) In the presence of additives such as ethyl acetate (roxyimino), carbodiimide (DCC, DIC) ,EDC.HCl), O-(benzotriazol-1-yl-N,N,N',N'-teto Lamethyluronium salt (HBTU, TBTU), O-(7-azabenzotriazole-1) -yl)-N,N,N',N'-tetramethyluronium salt (HATU, TATU) reagent It is produced by reacting it with a coupling reagent such as the one shown.

[0041] definition Lithium tetramethylpiperizide (CAS number 38227-87-1) (in many cases, LiTMP (abbreviated as Li / TMP or LTMP) has the molecular formula C9H 18 Possesses LiN It is a compound that is used as a non-nucleophilic base.

[0042] Trimethylsilyl cyanide (CAS number 7677-24-9) (TMSCN) is a compound of the formula ( This is a compound represented as CH3)3SiCN. This volatile liquid has a trimethylsilyl group. It consists of bonded cyanide groups (i.e., CN). This molecule is used in organic synthesis, and cyanide It is used as an equivalent of hydrogen citrate.

[0043] 1,5-Cyclooctadiene (CAS No. 1552-12-1) (often referred to as COD) (abbreviated as ) is a compound used as a ligand in many metal complexes.

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

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

[0046] Dibenzylideneacetone (CAS No. 35225-79-7) (often referred to as dba and (abbreviated) is a compound used as a ligand in many metal complexes.

[0047] 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphen (CAS number 564483-19-8) (often t-Bu Xphos or te rt-Butyl Xphos (abbreviated as rt-Butyl Xphos) is a ligand in many metal complexes. These are the compounds used.

[0048] 4,5-Bis(diphenylphosphin)-9,9-dimethylxanthene (CAS No. 1 Xantphos (usually abbreviated as 61265-03-8) is found in many metal complexes. It is a compound that is used as a ligand.

[0049] 1,3-Dicyclohexylcarbodiimide (CAS No. 538-75-0) (in many cases) (Abbreviated as DCC), 1,3-diisopropylcarbodiimide (CAS number 693- 13-0) (often abbreviated as DIC) and 1-ethyl-3-(3'-dimethylamide) Minopropyl carbodiimide hydrochloride (CAS number 25952-53-8) (usually ED) C.HCl (abbreviated as C.HCl) converts carboxylic acids into the corresponding O-acylurea intermediates. It is a reagent used for this purpose and promotes reactions with various nucleophiles.

[0050] O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Muhexafluorophosphate (CAS number 94790-37-1) (often HB) (Abbreviated as TU) and O-(benzotriazol-1-yl)-N,N,N',N'-te Tramethyluronium tetrafluoroborate (CAS No. 125700-67-6) Often abbreviated as TBTU, it is a compound that combines the carboxylic acid with the corresponding 1-hydroxybenzotriglycerides. It is a reagent used to convert to azole esters and is reactive with various nucleophiles. To promote a response.

[0051] O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl Uronium hexafluorophosphate (CAS number 148893-10-1) (many In this case, it is abbreviated as HATU) and O-(7-azabenzotriazol-1-yl)-N, N,N',N'-Tetramethyluronium tetrafluoroborate (CAS No. 8737) 98-09-5) is a carboxylic acid that corresponds to 1-hydroxyazabenzotriazole ester. It is a reagent used to convert to tel and promotes reactions with various nucleophiles. .

[0052] Ammonia equivalents are synthetic equivalents of ammonia, such as ammonium chloride.

[0053] Brominating agents are reagents used to introduce bromine into reactants, such as copper bromide. II) Or copper(I) bromide with an oxidizing agent.

[0054] One embodiment of the present invention is given by equation (XII) [ka]

[0055] [In the formula, R is I] A method for producing a compound represented by, wherein the method is Formula (IX) [ka]

[0056] The compound represented by iodine and lithium amide base (preferably lithium / TMP) And react to it, equation (X) [ka]

[0057] This includes producing a compound represented by [formula].

[0058] In one embodiment, the method further involves a compound represented by formula (X) as a lithium amide salt The reaction is carried out in the presence of a group (preferably lithium / TMP) to form formula (XIIa). [ka]

[0059] This includes producing a compound represented by [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 given by equation (XII) [ka]

[0062] [In the formula, R is Br] A method for producing a compound represented by, wherein the method is Formula (VII) [ka]

[0063] The compound represented by is reacted with an iridium catalyst and bis(pinacolate)diboron, Formula (VIII) [ka]

[0064] This includes producing a compound represented by [formula].

[0065] In one embodiment, the method further involves using a compound represented by formula (VIII) as a brominating agent. (Preferably copper(II) bromide or copper(I) bromide with an oxidizing agent, preferably copper(I) bromide) Reacting with I)) gives equation (XI) [ka]

[0066] This includes producing a compound represented by [formula].

[0067] In one embodiment, the method further involves alkali methoxyphosphate of the compound represented by formula (XI). Reacting with a side (preferably sodium methoxide or potassium methoxide), the formula ( XIIb) [ka]

[0068] This includes producing a compound represented by [formula].

[0069] One embodiment of the present invention is given by formula (VI) [ka]

[0070] [In the formula, R 1 It is a C1-C4 alkyl group, preferably a C1-C2 alkyl group. Most preferably, it is ethyl. A method for producing a compound represented by, wherein the method is Formula (II) [ka]

[0071] The compound represented by i. Hydrogen cyanide or equivalent (e.g., TMSCN); and, ii. POCl3 or SOCl2; And react to it, equation (III) [ka]

[0072] This includes producing a compound represented by [formula].

[0073] In one embodiment, the method further involves using a compound represented by formula (III) as a base (for example) If, in the presence of tripotassium phosphate or potassium acetate, formula (IV) [ka]

[0074] [In the formula, R 1 It is a C1-C4 alkyl group, preferably a C1-C2 alkyl group. Most preferably, it is ethyl. When reacted with a compound represented by formula (V), [ka]

[0075] [In the formula, R 1 It is a C1-C4 alkyl group, preferably a C1-C2 alkyl group. Most preferably, it is ethyl. This includes producing a compound represented by [formula].

[0076] In one embodiment, the method further comprises an enantiomer of a compound represented by formula (V) This includes separating the compounds to produce the compound represented by formula (VI).

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

[0078] One embodiment of the present invention is given by formula (V) [ka]

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

[0080] One embodiment of the present invention is given by formula (VI) [ka]

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

[0082] One embodiment of the present invention is given by equation (XIII) [ka]

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

[0084] One embodiment of the present invention is given by formula (XIV) [ka]

[0085] It is a compound represented by [formula].

[0086] A further embodiment of the present invention is given by formula (I) [ka]

[0087] A method for producing a compound represented by, wherein the method is Formula (XVI) [ka]

[0088] The compound represented by formula (XIIa) [ka]

[0089] This includes reacting a compound represented by (I) with another compound to produce a compound represented by formula (I).

[0090] HPLC method: Method A Agilent Technologies UHPLC / MSD 6130B Se ries 1290 consists of the following: Binary pump G7120A (containing 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℃; 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; Execution time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z; UV 254 and 210 nm.

[0091] Method B Agilent Technologies UHPLC / MS 1260 Series s, this consists of the following: Binary pump G7120A (containing degassing agent); Well plate sampler G4226A; Column oven G7116B; Diode array detector G7117B; Mass detector G6150B quadrupole LC / MS, with ESI-jetstream source; Column: Waters XP, 2.1 x 50 mm Xbridge BEH C18 2.5μ, T=40℃; 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; Execution time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z; UV 254 and 210 nm.

[0092] Method C Agilent Technologies UHPLC / MS 1260 Series s, this consists of the following: Binary pump G4220A (containing 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℃; 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; Execution time: 2.2 minutes; Detection: ESI / MS, positive and negative ion scan: 100-1000 m / z; UV 254 and 210 nm. [Examples]

[0093] 3-amino-1-[(trans)-4-cyanotetrahydropyran-3-yl]pyrzo Synthesis of ethyl(III) 4-carboxylate [ka]

[0094] Equipped with reflux condenser, mechanical stirrer, internal thermometer, and gas scrubber, and placed under a nitrogen atmosphere. In a jacketed glass reactor (10L), dry acetonitrile (2.55L) and Dihydro-2H-pyran-4(3H)-one(II) (365g, 3.65mol) Charge the solution. Stir the resulting mixture and adjust its temperature to -5 to 0°C. Add the warm water to the solution. While maintaining the temperature below 10°C, add zinc iodide (35g, 0.11mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (289 g, 2.6 mol). After adjusting the temperature to -5 to 0 °C and maintaining the temperature below 0 °C, trimethylsilylcarbonitrile (433 mL, 3.46 mol) is added dropwise over 80 minutes. After a reaction time of 3 hours at 0 °C, complete conversion of the starting material is observed, and pyridine (1.76 L, 21.9 mol) is added to the reaction mixture, followed by phosphoryl chloride (510 mL; 5.47 mol). The temperature is raised to 80 °C and the reaction mixture is stirred at this temperature for 16 hours. Then, the reaction mixture is cooled to room temperature and added to a solution of iron(II) sulfate heptahydrate (304 g, 1.09 mol) in water (7.3 L) adjusted to pH > 10 by the addition of aqueous 50% sodium hydroxide. While adding the reaction mixture to the basic iron(II) sulfate solution, the temperature is maintained below 20 °C and the pH is maintained at 10 or higher by the addition of 50% aqueous sodium hydroxide solution. The resulting mixture is extracted with methyl tert-butyl ether (3.5 L), the organic layer is collected, and the aqueous layer is diluted with water (6 L). The diluted aqueous layer is extracted with methyl tert-butyl ether (two 2.5 L portions). The combined organic layers are washed with saturated aqueous sodium hydrogen carbonate (1.83 L) and concentrated under reduced pressure at 40 °C. The crude residue is distilled under reduced pressure (0.5 mbar, bp about 45 °C) to give the desired product (III) as a colorless oil (​​​​​​​​​​​​​​​​​​​​​​​​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(pinacolate)diborone (68.8g, 0.27mol); 4,4'-di-te rt-butylbipyridine (2.10 g, 7.82 mmol) and (1,5-cycloocta Diene (methoxy)iridium(I) dimer (2.59 g, 3.91 mmol) Under an active atmosphere, 2,6-di ether is suspended in methyl tert-butyl ether (10 mL) and then 2,6-di Fluoropyridine (VII) (23.8 mL, 0.26 mol) was added. The temperature was slowly increased. The temperature was then raised to 45°C, and the reaction mixture was stirred at this temperature for 5 hours. Then, the reaction mixture... The solution was cooled to room temperature and concentrated under reduced pressure. Pentane was used as the eluent for the isolated residue. The desired product (VIII) was purified by filtration through a short silica gel column. It 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-methoxypyridine (XIIb) [ka]

[0101] 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Rolan-2-yl)pyridine (VIII) (32g, 133 mmol) in methanol (3 Dissolve in 80 mL of a 1.1 M aqueous solution of copper(II) bromide (104 g, 465 mmol). The mixture was added. The resulting mixture was heated under reflux and stirred at this temperature for 90 minutes. Heating was stopped. After cooling the reaction mixture to 0°C in an ice bath, stir while maintaining a 10% ammonium hydroxide aqueous solution. (300 mL) was added dropwise. The resulting mixture was extracted with pentane (3 × 200 mL). The solution of the desired product (XI) in pentane was then used directly in the next step. A solution of 4-bromo-2-fluoro-6-methoxypyridine(XI) with dry methanol ( Add 160 mL and stir at approximately 20°C in dry methanol (88.4 mL) A solution of sodium methoxide (100 mmol) was added. After a reaction time of 2.5 hours... The mixture was cooled to 0°C by applying an ice bath, and the mixture was then mixed with 2N aqueous hydrochloric acid (224 mL). Pour the mixture of ) and ice (224g) into a stirring mixture. After the organic layer separated, the aqueous layer was separated into pentane (10 Extraction was performed under 0 mL. The combined organic layers were washed with brine (50 mL) and then under reduced pressure (700 mL). The solution was concentrated at approximately 38°C to a concentration of ~750 mbar. The desired product (XIIb) was found to contain residual pentane. In the presence of (11 wt%), it 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-iodopyridine (XIIa) [ka]

[0104] Under an inert atmosphere, dry tetrahydrofuran ( ) is added to a dry flask (20L) at 15°C. 5.99L) was added. 2,2,6,6-tetramethylpiperidine (1161g, 8. 22 mol) was added, and the resulting solution was cooled to -30°C. The solution (2292 mL, 7.47 mol) was dissolved dropwise over 30 minutes while maintaining the temperature at approximately -30°C. It was added after being grated. The resulting mixture was stirred at this temperature for 1 hour. Then the mixture was heated to -7 Lower the temperature to 5 to -70°C, and add 2-fluoro-6- Prepare a solution of methoxypyridine(IX) (500g, 3.93mol) at a temperature of -75°C to - The mixture was added over 30 minutes while maintaining the temperature at 70°C. After stirring the reaction mixture at this temperature for 90 minutes, Iodine (998.4 g, 3.93 mol) in dried tetrahydrofuran (2494 mL) The solution was added at -75 to -70°C for less than 1 hour. The mixture was then heated at -75 to -70°C. The mixture was stirred for 14 hours. Water (3.5 L) was added at -75 to -70°C for no more than 30 minutes, and the reaction was observed. The mixture was allowed to reach room temperature. The organic layer was separated, and the aqueous layer was converted to methyl tert-butyl ether. Extraction was performed using (2 x 2.5 L). The combined organic layer was washed with 85% by weight aqueous phosphoric acid (2 x 4 L). It was purified and concentrated at a temperature not exceeding 30°C for 4 hours to obtain a total weight of 1250g. After steam distillation and separation of the aqueous layer, a colorless oily substance was obtained. Hepburn was added to the isolated oily substance. Add 390 mL of tung, and stir the resulting mixture at -10 to -5°C for 30 minutes. The solid obtained was collected by filtration and washed with a small amount of pre-cooled heptane (about 55 mL) to obtain the desired product (XIIa) (530 g, 2.09 mol).

[0105] HPLC method A: Retention time: 1.14 minutes 1 1H NMR (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]pyrzo Synthesis of ethyl 4-carboxylate (V) [Chemical formula]

[0107] A jacketed glass reactor (5 L) equipped with a reflux condenser, a mechanical stirrer, and an internal thermometer and placed under a nitrogen atmosphere was charged with dry 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). The resulting mixture was heated to 80 °C, and 3,6-dihydro-2H-pyran-4-carbonitrile (III) (462 g, 4.15 mol) was rapidly added via an addition funnel. The addition funnel was rinsed with acetonitrile (250 mL), which was also added to the reaction mixture. The reaction mixture was stirred vigorously at 80 °C for 6.5 hours, after which heating was stopped and the reaction mixture was stirred for an additional overnight. The reaction mixture was concentrated under reduced pressure to obtain a yellow slurry. The resulting material was diluted with ethyl acetate (5 L), and the resulting solution was extracted with 1 M aqueous hydrochloric acid (3 × 1.5 L), brine (1 ​​​​​​​​​​​​​​​​​​Wash once with L), filter through a filter filled with a magnesium sulfate pad, and under reduced pressure. The mixture was concentrated to obtain a yellow oily substance. This yellow oily substance was then dissolved in methanol (1.36 L). The mixture was then stirred and heated to 40°C to ensure complete homogenization. Then, the solution is cooled to 25°C, and 2.0g of pure seed crystals are sown at this temperature, followed by -20 The mixture was gently stirred overnight at °C. The formed precipitate was filtered off, and the mixture was then heated with pre-cooled methanol (1 L). Washed and dried under reduced pressure at 40°C, an off-white solid was obtained. Isolated white The solid was heated under reflux in 2-propanol (1 L) for 1 hour, and the mixture was gently stirred overnight. It was slowly allowed to reach room temperature. The formed precipitate was filtered off and 2-propanol (3 Wash with 00 mL, dry under reduced pressure at 40°C, and if the desired product (V) is off-white, It 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]pyrzo 3-amino-1-[(3S,4R)-4-cyanoethyl(V)-4-carboxylate Trahydro-2H-pyran-3-yl]-1H-pyrazole-4-carboxylate ethyl(V I) Chiral separation

Chem.

[0110] The separation of the single enantiomer (VI) from the mixture of enantiomers (V) was achieved by chiral chromatography.

[0111] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxylate ethyl(X III) Synthesis

Chem.

[0112] Ethyl 3-amino-1-[(3S,4R)-4-cyanotetrahydro-2H-pyran-3-yl]-1H-pyrazole-4-carboxylate (VI) (50 g, 189 mmol), 4-bromo-2-fluoro-6-methoxypyridine (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 [[ID=4^5]]mixture was heated to 65 °C and stirred at this temperature for 90 minutes. After cooling to room temperature, the mixture was concentrated at 40 °C under reduced pressure. The resulting crude residue was stirred with acetonitrile (650 mL) at 50 °C for 30 minutes. The warm solution was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 2-propanol (750 mL), and the resulting mixture was 100 ml. The mixture was heated to °C, and then slowly allowed to reach room temperature while being gently stirred. Filter off the precipitate, rinse the moist cake with 2-propanol (50 mL), and then, under reduced pressure... The mixture was then dried at 40°C to obtain the desired product (XIII) (61.2 g, 149 mmol). The filtrate was combined with a 2-propanol rinse and concentrated under reduced pressure to obtain a solid. Wash the formed solid with 2-propanol (2 × 50 mL) and dry under reduced pressure at 40°C. This yields a second harvest (8.2 g, 19.5 mmol) of the desired product (XIII). It was done.

[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-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxylate ethyl(X III) Synthesis [ka]

[0115] 3-amino-1-[(3S,4R)-4-cyanotetrahydro-2H-pyran-3-i [L]-1H-pyrazole-4-carboxylate ethyl(VI) (1g, 3.78 mmol), 2-Fluoro-4-iodo-6-methoxypyridine (XIIa) (1.15g, 4.54 mmol), palladium diacetate (21 mg, 0.095 mmol), 4,5-bis(diph) (enylphosphino)-9,9-dimethylxanthene (109 mg, 0.19 mmol) and Tripotassium phosphate (2.41 g, 11.35 mmol) is placed under a nitrogen atmosphere, and 1,4 -Dioxane (10 mL) was added. The resulting mixture was heated to 60°C and at this temperature 1 The mixture was stirred for 8 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue 2- Diluted with propanol (20 mL), the resulting mixture was heated until a solution was obtained. The heat was stopped, and the solution was slowly allowed to reach room temperature. The suspension was filtered, and the resulting precipitate was removed. The sediment was collected. The moist cake was rinsed with 2-propanol (25 mL) and stored under reduced pressure at 40°C. Dry it, and the desired product (XIII) is an off-white solid (1.07 g, 2.75 g) It was obtained as mmol). The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to reflux to 2-propane Dilute with Nol (5 mL), filter and dry the resulting precipitate, and then obtain the desired product ( XIII) yielded a second harvest (180 mg, 0.5 mmol).

[0116] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxylic acid (XIV) synthesis [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) 1-[( [3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6 -Methoxy-4-pyridyl)amino]pyrazole-4-carboxylate ethyl(XIII) Add the solution (345 mg, 0.89 mmol) and stir the resulting mixture at 80°C for 20 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL), and saturated aqueous bicarbonate solution was prepared. Extraction was performed with sodium (3 x 10 mL). Add 1 M aqueous hydrochloric acid to the combined aqueous layer. The solution was acidified to pH 3. The formed precipitate was isolated by filtration and stored under reduced pressure for 40 minutes. Dry at °C until the desired product (XIV) is a colorless solid (308 mg, 0.85 mmol). ) was obtained as follows.

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

[0119] 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide(I) synthesis [ka]

[0120] N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (245m g, 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-cyanotetrahydro [Pyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyran-3-yl] Razole-4-carboxylic acid (XIV) (308 mg, 0.85 mmol) In a mixture of rofuran (3 mL) and N,N-dimethylformamide (1 mL), at room temperature, 9 Stirred for 0 minutes. Add saturated sodium bicarbonate (5 mL) to the reaction mixture and remove the aqueous layer. Extraction was performed with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (5 mL). Then, dehydrate with sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude desired product (I)( 276 mg (0.77 mmol) was obtained.

[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-fu Luoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide(I) Purification [ka]

[0123] Crude (I) (3.72 kg, 10.32 m³) in a 160L glass-lined container. 0.8L of 0.4L and methanol were added. The contents were heated under reflux (65°C) and the chemical mixture was added. A true seed crystal of substance (I) (109 g, 302.5 mmol) in methanol (1.9 L) The mixture was charged as a slurry. The mixture was stirred at 275 rpm and aged for 14.5 hours. The rally was cooled to 60°C and sampled for analysis. Pure compound (I) was obtained. The slurry is cooled from 65°C to 20°C over 12 hours, and then matured at 20°C for 6 hours. The batch was filtered, and the cake was washed with methanol (5.4 L). The solid was then nitrogen-filtered. The material was dried in a vacuum oven with a bleed valve at 40°C for 23 hours. Then, the material was treated with C The mass was crushed by passing it through an o-mill, and compound (I) (2.21 kg, 6.14 mol) turned white. It was obtained as a colored powder.

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

[0125] In the first container, N,N-dimethylacetamide (7.55 L) is subjected to subsurface nitrogen. Degassing was performed for 30 minutes. tBuBrettPhos (96.0g, 0.198mol) and Add allylpalladium(II) chloride dimer (36.2 g, 0.099 mol) The resulting mixture was stirred at 20°C for 100 minutes while purging with subsurface nitrogen. In a separate container 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 It was charged together with N,N-dimethylacetamide (17.55 L). The resulting mixture The mixture was stirred and degassed, and then the catalyst solution prepared in the first container was added. The mixture was rinsed with N,N-dimethylacetamide (0.5 L) and added to the reaction mixture. Next Then, the reaction mixture is stirred at room temperature and monitored with UV-HPLC until complete conversion is observed. The reaction mixture was filtered, and the moist cake was treated with N,N-dimethylacetamide (5 Washed with L). The filtrate was cooled to 0-5°C, and water (90L) was added while maintaining the temperature at 0-5°C. It was added over a period of 105 minutes. The resulting slurry was aged at this temperature for 1 hour. Then, The slurry is filtered, the cake is washed twice with water (10L and 20L), and then methanol is added. Washed four times with a 15L and 3 x 19L container. The wet cake was dried under a nitrogen stream. The desired compound (I) (3.14 kg, 0.154 mol) was obtained.

Claims

1. Equation (XII) 【Chemistry 1】 [In the formula, R is Br] A method for producing a compound represented by, a. Equation (VII) 【Chemistry 2】 The compound represented by is reacted with an iridium catalyst, which is a (1,5-cyclooctadiene)(methoxy)iridium(I) dimer, and bis(pinacolate)diborone in the presence of 4,4'-di-tert-butylbipyridine or N-benzyl-1-phenyl-N-(2-pyridylmethyleneamino)methaneamine. Formula (VIII) 【Transformation 3】 To produce a compound represented by ; b. The compound represented by formula (VIII) is reacted with a brominating agent, which is copper(II) bromide or copper(I) bromide with an oxidizing agent, to obtain formula (XI). 【Chemistry 4】 To produce a compound represented by ; c. Reacting a compound represented by formula (XI) with an alkali methoxide to produce a compound represented by formula (XII); Methods that include...

2. The method according to claim 1, wherein the alkali methoxide is sodium methoxide or potassium methoxide.

Images