Pyrazole compounds and methods for their preparation

Abstract

The present invention provides a process for preparing substituted pyrazole compounds of Formula II, which are useful as intermediates for preparing substituted piperidine urea compounds useful for treating dilated cardiomyopathy (DCM).R 2 is independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl,R 3 is independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl,R 4 is C1-C4 alkyl,R 6 is H or a protecting group, andR 7 is selected from H, CI or trialkylsilyl.

Description

Technical Field

[0001] The present invention provides a method for preparing a substituted pyrazole compound of formula II, which can be used as an intermediate in the preparation of a substituted piperidine urea compound suitable for the treatment of dilated cardiomyopathy (DCM).

[0002]

[0003] R 2 Independently selected from F, C1-C4 alkyl, and C1-C4 haloalkyl; and R 3 Independently selected from H, F, C1-C4 alkyl, and C1-C4 haloalkyl.

[0004] R 4 It is a C1-C4 alkyl group, R 6 It is H or its protecting group or salt, and

[0005] R 7 Selected from H, Cl, or trialkylsilyl groups. Background Technology

[0006] The 4-methylsulfonyl-substituted piperidine urea compound of Formula I is being developed for the treatment of dilated cardiomyopathy (DCM), a disease that leads to heart failure and serious complications such as stroke, arrhythmia and sudden cardiac death.

[0007]

[0008] Where R 1 It is a 5- to 6-membered heteroaryl ring having at least one nitrogen atom, and optionally substituted with one or more of a halogroup, cyanogroup, hydroxyl group, C1-C4 alkyl group, C1-C4 haloalkyl group and C1-C4 alkoxy group.

[0009] WO2016 / 118774 discloses the preparation of 4-methylsulfonyl-substituted piperidine urea compounds using reagents such as N-fluorodiphenylsulfonylimide (NFSI), diethylaminosulfonium trifluoride, and lithium compounds. These reagents are potent and expensive and are not suitable for the commercial scaling-up of 4-methylsulfonyl-substituted piperidine urea compounds.

[0010] There is a need in the art to replace these reagents used in the preparation of 4-methylsulfonyl-substituted piperidine urea compounds of formula I. This invention provides a method for preparing substituted pyrazole compounds of formula II, which can be used as intermediates in the preparation of compounds of formula I.

[0011] Invention Objective

[0012] The present invention provides a method for preparing a substituted pyrazole compound of formula II, which can be used as an intermediate in the preparation of a substituted piperidine urea compound suitable for the treatment of dilated cardiomyopathy (DCM).

[0013]

[0014] R 2 Independently selected from F, C1-C4 alkyl, and C1-C4 haloalkyl; and R 3 Independently selected from H, F, C1-C4 alkyl, and C1-C4 haloalkyl.

[0015] R 4 It is a C1-C4 alkyl group, R 6 It is H or its protecting group or salt, and

[0016] R 7 Selected from H, Cl, or trialkylsilyl groups. Summary of the Invention

[0017] In one aspect, the present invention provides a method for preparing compounds of formula II.

[0018]

[0019] R 2 Independently selected from F, C1-C4 alkyl, C1-C4 haloalkyl, R 3 Independently selected from H, F, C1-C4 alkyl, and C1-C4 haloalkyl.

[0020] R 4 It is a C1-C4 alkyl group, R 6 H or its protecting group or salt, and R 7 It is a group selected from H, Cl, or trialkylsilyl groups;

[0021] The method includes the following steps:

[0022] a) React the compound of formula VII with elemental sulfur in the presence of a base, a catalyst and a reducing agent to obtain the compound of formula VI;

[0023]

[0024] Where R 3 R 4 and R 7 As defined above, L1 is a leaving group.

[0025] b) React the compound of formula VI with the compound of formula VIII to obtain the compound of formula V;

[0026]

[0027] Where L2 is a leaving group; R 6 As defined above;

[0028] c) Convert the compound of formula V into the compound of formula II.

[0029] In another aspect, the present invention provides a method for preparing compounds of formula II.

[0030]

[0031] R 2 Independently selected from F, C1-C4 alkyl, and C1-C4 haloalkyl; and R 3 Independently selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R 4 It is a C1-C4 alkyl group.

[0032] R 6 H or its protecting group or salt, and R 7 Selected from H, Cl, or trialkylsilyl groups;

[0033] The method includes the following steps:

[0034] a) React the compound of formula VII with elemental sulfur in the presence of a base and a catalyst to obtain the compound of formula VIB.

[0035]

[0036] Where R 3 and R 4 As defined above, n is 2-8; L1 is selected from leaving groups;

[0037] b) React the compound of formula VIB with the compound of formula VIII to obtain the compound of formula V.

[0038]

[0039] Where L2 is a leaving group;

[0040] c) Convert the compound of formula V into the compound of formula II.

[0041] In another aspect, the present invention provides a method for preparing a compound of formula II.

[0042]

[0043] Where R 2 R 3 R 4 R 6 and R 7As defined above;

[0044] The method includes the following steps:

[0045] a) Fluorinate the compound of formula V to obtain the compound of formula IV;

[0046]

[0047] b) Oxidize the compound of formula IV to obtain the compound of formula III.

[0048]

[0049] c) Convert the compound of formula III into the compound of formula II.

[0050] In another aspect, the present invention provides a method for preparing a compound of formula II, wherein the fluorination and oxidation steps are performed without separating the compound of formula IV.

[0051] In another aspect, the present invention provides a method for preparing a compound of formula IV.

[0052]

[0053]

[0054] The method includes the following steps:

[0055] a) Fluoride the compound of formula V.

[0056]

[0057] To obtain compound of formula IV.

[0058] Where R 3 R 4 R 6 and R 7 As defined above.

[0059] In another aspect, the present invention provides a method for preparing compounds of formula III.

[0060]

[0061] The method includes the following steps:

[0062] a) Oxidation of the compound of formula IV

[0063]

[0064] To obtain compound of formula III;

[0065] Where R3 R 4 R 6 and R 7 As defined above.

[0066] In another aspect, the present invention provides a compound of formula VI,

[0067]

[0068] Where R 3 R 4 R 7 L1 is as defined above.

[0069] In another aspect, the present invention provides a method for preparing compound V.

[0070]

[0071] Where R 3 R 4 R 6 and R 7 As defined above;

[0072] The method includes the following steps:

[0073] a) React the compound of formula VI with the compound of formula VIII.

[0074]

[0075] Where R 3 R 4 and R 7 As defined above;

[0076] To obtain compound V.

[0077] In another aspect, the present invention provides a method for preparing compound V.

[0078]

[0079] Where R 3 R 4 R 6 and R 7 As defined above;

[0080] The method includes the following steps: reacting the compound of formula VIB with the compound of formula VIII.

[0081]

[0082] Where n is 2-8; R 3 R 4and R 7 As defined above;

[0083] To obtain compound V.

[0084] In another aspect, the present invention provides a compound of formula II and a salt thereof.

[0085]

[0086] Where R 6 It is H or its salt.

[0087] In another aspect, the present invention provides a pyrazole compound of formula III.

[0088]

[0089] Where R 3 R 4 and R 6 As defined above.

[0090] In another aspect, the present invention provides pyrazole compounds of formula IV.

[0091]

[0092] Where R 3 R 4 and R 6 As defined above. Detailed Implementation

[0093] In this invention, the term "C1-C4 alkyl" refers to methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0094] The term "C1-C4 haloalkyl" in this invention refers to an alkyl group substituted with one or more halogens. Examples of C1-C4 haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, etc.

[0095] The term "C1-C4 alkoxy" in this invention refers to alkoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.

[0096] In this invention, the term "ambient temperature" refers to a temperature in the range of 5°C to 35°C.

[0097] In this invention, the term "heteroaryl" refers to a 5- to 6-membered heteroaryl ring having at least one nitrogen atom as a ring member.

[0098] In this invention, the term "salt" refers to hydrochloride, hydrobromide, methanesulfonate, toluenesulfonate, etc.

[0099] The term "protecting group" as used in this invention refers to a group used in the art that serves to protect the amino moiety when reacting at other sites in the molecule. Examples of amino protecting groups include, but are not limited to, acyl, alkoxycarbonyl, alkenyloxycarbonyl, and arylalkoxycarbonyl groups, such as benzyloxycarbonyl, tert-butoxycarbonyl, triphenylmethyl, phthalyl, etc.

[0100] The term "deprotection" in this invention refers to the process of removing the protecting group. The deprotection step is carried out by procedures known in the art or as described in the Protecting Groups of Carey & Sundberg, which is included by reference. The step can be carried out using acids such as hydrochloric acid, hydrobromic acid, acetic acid, or trifluoroacetic acid, or bases such as sodium hydroxide or potassium hydroxide.

[0101] The term "leaving group" as used in this invention refers to an atom or group of atoms that can be substituted during the reaction. Leaving groups include, but are not limited to, organosulfonyl groups, acyloxy groups, alkoxy groups, alkoxycarbonyl groups (e.g., ethoxycarbonyl groups); halogens (e.g., iodine, bromine, chlorine, or fluorine); amide groups; azide groups; isocyanate groups; and substituted or unsubstituted thiolate groups (e.g., thiomethyl or thiophenyl). Examples of leaving groups include methanesulfonyl, toluenesulfonyl, bromo, iodo, etc.

[0102] The catalyst used in the step of forming the VI / VIB / VIC compound is selected from copper or iron salts. Catalysts include copper chloride (CuCl), copper bromide (CuBr), copper iodide (CuI), ferric chloride (FeCl3), ferric bromide (FeBr3), etc.

[0103] In this invention, the term "reducing agent" refers to zinc / acetic acid, zinc / alcoholic potassium hydroxide, sodium borohydride, potassium borohydride, lithium aluminum hydride, triphenylphosphine / HCl, and tri(2-carboxyethyl)phosphine, borane, triphenylphosphine, tributylphosphine, tri(2-carboxyethyl)phosphine, etc.

[0104] In this invention, the term "base" refers to an inorganic or organic base. Examples of inorganic bases include potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, potassium hydride, etc. Examples of organic bases include sodium ethoxide, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, n-butylamine, tert-butylamine, pyridine, methyllithium, n-butyllithium, diisopropylaminolithium, 2,2,6,6-tetramethylpiperidinelithium, sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diethylamino, etc.

[0105] The fluorination step in this invention is carried out in the presence of an electrophilic fluorinating agent. Examples of electrophilic fluorinating agents include N-fluoro-phthalimide, N-fluorobenzenesulfonide, 1-chloromethyl-4-fluoro-1,4-diazamonium bicyclo[2.2.2]octanebis(tetrafluoroborate), N-fluoropyridinium salts, such as 1-fluoropyridinium trifluoromethanesulfonate, 1-fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1 -Fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate, 1-fluoro-2,6-dichloropyridinium trifluoromethanesulfonate, 2,6-difluoro-1-fluoropyridinium tetrafluoroborate, 2-fluoro-1,3-dimethylpyridinium p-toluenesulfonate, 2-fluoro-1-methylpyridinium p-toluenesulfonate, N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate). Preferably, the fluorinating agent is selected from the group consisting of: 1-fluoropyridinium trifluoromethanesulfonate, 1-fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate, 1-fluoro-2,6-dichloropyridinium trifluoromethanesulfonate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, 1-fluoro-4-methylpyridinium trifluoromethanesulfonate, and 1-fluoro-4-methylpyridinium tetrafluoroborate. The oxidation step is carried out using an oxidizing agent, optionally in the presence of a catalyst, to oxidize the sulfide to a sulfone. Examples of oxidants optionally in the presence of catalysts such as ammonium molybdate or alkali metal tungstate include hydrogen peroxide / sodium tungstate, peracetic acid, benzyl hydroperoxide, ethylbenzene hydroperoxide, cumyl hydroperoxide, sodium hypochlorite, oxalate dihydrate / hydrogen peroxide (H2O2), m-chloroperoxybenzoic acid (mCPBA), urea-hydrogen peroxide adduct, permanganate / manganese dioxide, ruthenium chloride hydrate / sodium periodate, potassium peroxymonosulfate (oxone), etc.

[0106] The alkylation step is carried out using an alkylating agent in the presence of a base. Alkylating agents include, but are not limited to, bromoalkanes, chloroalkanes, iodoalkanes, diazonides, dialkyl carbonates, and dialkyl sulfonates.

[0107] In one embodiment, the present invention provides a method for preparing a compound of formula II.

[0108]

[0109] R 2 Independently selected from F, C1-C4 alkyl, and C1-C4 haloalkyl; and R 3 Selected from H, F, C1-C4 alkyl, C1-C4 haloalkyl, R 4 It is a C1-C4 alkyl group.

[0110] R 6 H or its protecting group or salt, and R 7Selected from H, Cl, or trialkylsilyl groups;

[0111] The method includes the following steps:

[0112] a) React the compound of formula VII with elemental sulfur in the presence of a base and a catalyst to obtain the compound of formula VIB.

[0113]

[0114] Where R 3 and R 4 As defined above, L1 is the leaving group, and n is 2-8;

[0115] b) React the compound of formula VIB with the compound of formula VIII to obtain the compound of formula V;

[0116]

[0117] Where R 6 As defined above, L2 is a leaving group.

[0118] c) Fluorinate the compound of formula V to obtain the compound of formula IV;

[0119] d) Oxidize the compound of formula IV to obtain the compound of formula III;

[0120] e) Alkylate the compound of formula III to obtain the compound of formula II.

[0121] In a specific embodiment, the present invention provides a method for preparing a compound of formula II, wherein R 2 and R 4 It represents methyl, and R 3 It represents difluoromethyl.

[0122] In a specific embodiment, the present invention provides a method for preparing a compound of formula II: converting a compound of formula VI or VIB into a compound of formula V; fluorinating the compound of formula V into a compound of formula IV; and then oxidizing the compound of formula IV into a compound of formula III, wherein in compounds of formulas II, V, IV, and III, R... 2 and R 4 It represents methyl, and R 3 The terms represent difluoromethyl groups, and they are represented as compounds of formulas IIA, VIA, VIC, VA, IVA, and IIIA, respectively.

[0123]

[0124] In another embodiment, the present invention provides compounds of formulas IIA, VIA, VIC, VA, IVA, and IIIA.

[0125] In another embodiment, the present invention provides a method for preparing 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidinecarboxylic acid tert-butyl ester, the method comprising the following steps:

[0126] a) Reacting 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole with elemental sulfur in the presence of a base, a catalyst and a reducing agent to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol;

[0127] b) Reaction of 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-thiol with 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester to give 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester;

[0128] c) Convert 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidinecarboxylic acid tert-butyl ester.

[0129] In another embodiment, the present invention provides a method for preparing 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidinecarboxylic acid tert-butyl ester, the method comprising the following steps:

[0130] a) Reacting 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole with elemental sulfur in the presence of a base and a catalyst to obtain 4,4'-dithionidinedimethylbis[3-(difluoromethyl)-1-methyl-1H-pyrazole];

[0131] b) React 4,4'-dithionylbis[3-(difluoromethyl)-1-methyl-1H-pyrazole] with 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester to give 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester;

[0132] c) Convert 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidinecarboxylic acid tert-butyl ester.

[0133] In another embodiment of the invention, step a) of reacting the compound of formula VII with sulfur is carried out in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, etc.

[0134] In another embodiment of the invention, step a) of reacting the compound of formula VII with sulfur is optionally carried out in the presence of an additive selected from the group consisting of potassium iodide, sodium iodide, or dimethylaminopyridine (DMAP), etc.

[0135] In another embodiment of the invention, step a) of reacting the compound of formula VII with sulfur is carried out in a solvent. Examples of solvents include dimethylformamide, dimethylacetamide, ethyl methyl ketone, acetone, methyl isopropyl ketone, methyl isobutyl ketone, methyl n-butyl ketone, methyl tert-butyl ketone, methyl isopentyl ketone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamine, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol, dimethyl ether, diethyl ether, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, ethyl acetate, acetonitrile, or mixtures thereof.

[0136] In another embodiment of the invention, step a) of reacting the compound of formula VII with sulfur is carried out in the presence of a reducing agent selected from the group consisting of: triphenylphosphine, tributylphosphine, tri(2-carboxyethyl)phosphine, etc.

[0137] In another embodiment of the invention, step b) of reacting the compound of formula VI / VIA / VIB with the compound of formula VIII is carried out in the presence of a base.

[0138] In another embodiment of the invention, the reaction does not involve the separation of compounds of formula VI or VIA.

[0139] In another embodiment of the invention, the reaction does not involve the separation of compounds of formula VI or VIA.

[0140] In another embodiment, the fluorination step is carried out in the presence of an electrophilic fluorinating agent.

[0141] In another embodiment, the fluorination step is carried out in the presence of an N-fluoropyridinium salt.

[0142] In another embodiment of the invention, the compound of formula IVA may not be separated.

[0143] In another embodiment of the invention, the compound of formula IIIA may not be separated.

[0144] In another embodiment of the invention, the oxidation step may be performed before the fluorination step.

[0145] In another embodiment of the invention, a method for preparing 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester is provided, the method comprising the following steps:

[0146] a) Fluorination of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester in the presence of N-fluoropyridinium salt to obtain 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester;

[0147] b) Oxidize 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester.

[0148] c) Convert 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester.

[0149] In another embodiment of the invention, the invention provides a method for separating tert-butyl 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid ester or 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid ester.

[0150] In another embodiment of this aspect, the present invention provides a method for preparing 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester, wherein the fluorination and oxidation steps are carried out without separating 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester.

[0151] In one embodiment of the invention, a method for preparing a compound of formula IIA is provided.

[0152]

[0153]

[0154] Where R 6 and R7 As defined above, the method includes the following steps:

[0155] a) Methylating compound of formula IIIA.

[0156]

[0157] In another embodiment, the present invention relates to wherein R 7 Compounds of formula IIA that are C1 or alkylsilyl groups hydrolyze to form compounds where R 7 The steps for compounds of formula IIA containing hydrogen.

[0158] In another embodiment, the present invention relates to wherein R 6 Deprotection of a compound of formula IIA with a protecting group yields a compound where R is a protecting group. 6 The steps for compounds of formula IIA containing hydrogen.

[0159] In one embodiment, the present invention provides compounds of formula IIB and their salts with a purity of 95% to 99%.

[0160]

[0161] In another embodiment, the present invention provides 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine and its salts.

[0162] In one embodiment, the present invention provides a method for preparing a compound of formula I using a compound of formula IIB or a salt thereof.

[0163] In another embodiment, the present invention relates to separating a compound of formula IIC into a solid compound.

[0164]

[0165] Where R 6 It is tert-butyloxycarbonyl and R 7 It is hydrogen.

[0166] Compounds of formula IIC are isolated in crystalline and / or amorphous form. The isolation of compounds of formula IIC is carried out by crystallization in a suitable solvent or solvent mixture at a temperature of approximately -20°C to 30°C.

[0167] The solvent used in crystallization may be selected from the group consisting of: methanol, ethanol, propanol, 2-propanol, tetrahydrofuran, acetonitrile, cyclohexane, hexane, heptane, toluene, water, and mixtures thereof.

[0168] In one embodiment, the present invention provides a pyrazole compound of formula IIIA.

[0169]

[0170] Where R 6 As defined above.

[0171] In another embodiment, the present invention provides 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester.

[0172] In another embodiment, the present invention provides a method for preparing a compound of formula I using a compound of formula IIIA.

[0173] One aspect of the invention provides compounds of formulas II, IIA, IIB, IIC, III and / or IIIA as impurities in compounds of formula I.

[0174] Compounds of formula II and III can be converted into compounds of formula I using methods known or included in WO 2016118774, which are incorporated herein by reference.

[0175] In another embodiment, the present invention provides a method for preparing a compound of formula II, wherein the method does not involve the isolation of an intermediate of formula VIB.

[0176] The method of converting a compound of formula V into a compound of formula II involves a fluorination step, followed by oxidation and subsequent alkylation or permutation, as well as combinations of these steps, to obtain a compound of formula II.

[0177] In a specific instance, an electrophilic fluorinating agent is used to fluorinate 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester to give 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-(fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester, which, upon oxidation and subsequent methylation, yields 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester. 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester, after deprotection, yields 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine.

[0178] Compounds of formulas II, III, IV and V can be used to prepare compounds of formula I.

[0179] Compounds of formula V and VA can be converted into compounds of formula II by the methods taught in WO 2016118774, which is included by reference.

[0180] Compounds of Formula II can be converted to compounds of Formula I using methods known or included by reference in WO 2016118774. Compounds of Formulas VII and VIII, used as starting materials, are commercially available or can be prepared by methods as described in PCT Publication No. 2009 / 000442 and U.S. Publication No. 2010 / 29650. Compounds of Formula VIB are also commercially available or can be prepared by methods disclosed in Chinese Publication No. 105622469. Pyrazole carboxylic acid, used as a starting material, is commercially available or can be prepared by methods disclosed in U.S. Patent No. 9650345. These patent references are incorporated herein by reference.

[0181] In a particular embodiment, the present invention provides a method for preparing 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole, the method comprising the steps of decarboxylating 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid using Cu powder and Cu₂O in a polar aprotic solvent in the presence of an aliphatic amine, and subsequently iodinating 3-(difluoromethyl)-1-methyl-1H-pyrazole using iodine and potassium iodate in the presence of acetic acid and sulfuric acid. Examples of aliphatic amines include methylamine, ethylamine, triethylamine, diethylmethylamine, isopropylamine, diisopropylamine, diisopropylmethylamine, diisopropylethylamine, n-butylamine, tert-butylamine, tributylamine, etc.

[0182] The embodiments of the present invention are not mutually exclusive, but can be implemented in various combinations. The described embodiments and disclosed examples of the present invention are given for illustrative purposes and not for limiting the invention as set forth in the appended claims.

[0183] The following examples are given by way of illustration and should not be construed as limiting the scope of the invention.

[0184] Example

[0185] Example 1: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole

[0186] Tributylamine (90 gm, 0.48 mol) was added to a mixture of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (170 gm, 0.966 mol), Cu powder (10.8 gm, 0.176 mol), and Cu₂O (9.67 gm, 0.067 mol) in sulfolane (252 gm, 2.1 mol) at ambient temperature. The reaction mixture was stirred at 150 °C for six hours. After the reaction was complete, the product was distilled off from the reaction mixture under vacuum. The tributylamine was recycled back to the reactor.

[0187] Yield: 80% Purity: 95%

[0188] Example 2: Preparation of 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole

[0189] Sulfuric acid (98%; 64.37 g) was added dropwise to a mixture of 3-(difluoromethyl)-1-methyl-1H-pyrazole (73.5 g, 0.56 mol), iodine (67.5 g, 0.27 mol), potassium iodate (31 g, 0.14 mol), and acetic acid (816 g) over approximately 20 minutes at approximately 45 °C. The temperature of the reaction mixture was raised to approximately 60 °C and maintained at the same temperature for one hour. The reaction mixture was quenched with water (500 ml) at approximately 25 °C to approximately 30 °C, and the mixture was neutralized with an aqueous solution of sodium bisulfite (100 ml). The mixture was extracted with dichloromethane (200 ml). The layers were separated and washed twice with water (500 ml). The organic layers were combined and concentrated to give 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole.

[0190] Yield: 90%; Purity: 96%

[0191] Example 3: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol

[0192] Add 50 g of 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole to a mixture of potassium carbonate (52 g), copper iodide (3.56 g), and sulfur powder (18.2 g) in dimethylformamide (250 ml) over 10 to 20 minutes at approximately 50°C. Stir the reaction mixture at approximately 110°C for 4 to 5 hours. Cool the reaction mixture to approximately 20°C. Add a mixture of triphenylphosphine (125 g) in water (125 ml) and dioxane (325 ml) to the reaction mixture. Slowly add hydrochloric acid (35%; 42 ml) to the reaction mass while keeping the temperature of the reaction mixture below 30°C. After the addition is complete, stir the reaction mixture at approximately 40°C. Concentrate the reaction mixture at approximately 80°C to obtain a residue. Add water (700 ml) and dichloromethane (150 ml) to the residue and stir for approximately 15 minutes. Adjust the pH of the mixture to 4.5–5 and separate the layers. Extract the aqueous layer again with dichloromethane (60 ml). Combine the organic layers and filter, washing with water. Add a 20% potassium hydroxide solution (80 ml) to the organic layer. Wash the organic layer with water, pass it through a sodium sulfate bed, and concentrate to obtain the desired compound.

[0193] Yield: 65%; Purity: 93%

[0194] Example 4: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol

[0195] 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50 g) was added to a mixture of sodium carbonate (52 g), copper iodide (3.56 g), and sulfur powder (18.2 g) in dimethyl sulfoxide (250 ml) over 10 to 20 minutes at approximately 50°C. The reaction was then followed by a work-up process as described in Example 3.

[0196] Yield: 60%; Purity: 93%

[0197] Example 5: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol

[0198] 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50 g) was added to a mixture of sodium methoxide (30 g), copper iodide (3.56 g), and sulfur powder (18.2 g) in sulfolane (250 ml) over 10 to 20 minutes at approximately 50°C. The reaction mixture was stirred at approximately 110°C for 4 to 5 hours. Post-reaction treatment was continued according to Example 3.

[0199] Yield: 60%; Purity: 93%

[0200] Example 6: Preparation of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol

[0201] 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50 g) was added to a mixture of potassium carbonate (52 g), copper iodide (3.56 g), and sulfur powder (18.2 g) in sulfolane (250 ml) over 10 to 20 minutes at approximately 50°C. The reaction mixture was stirred at approximately 110°C for 4 to 5 hours. The reaction was continued according to Example 3.

[0202] Yield: 65%; Purity: 93%

[0203] Example 7: Preparation of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester)

[0204] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol (13 g) was added to a mixture of 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester (20 g) and potassium carbonate (20.6 g) in acetonitrile (200 ml). The reaction mixture was stirred at 60 °C for one hour. The progress of the reaction was monitored by gas chromatography. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The filtered material was washed with dichloromethane (100 ml). The organic layer was washed with dilute hydrochloric acid solution (1 N; 200 ml). The organic layer was concentrated to obtain the title compound.

[0205] Yield: 70%; Purity: 97%

[0206] Example 8: Preparation of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester)

[0207] 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol (13 g) was added to a mixture of 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester (20 g) and sodium methoxide (15 g) in acetonitrile (200 ml). The reaction mixture was stirred at 60 °C for one hour. The reaction was continued according to Example 8.

[0208] Yield: 70%; Purity: 97%

[0209] Example 9: Preparation of 4,4'-dithionylbis[3-(difluoromethyl)-1-methyl-1H-pyrazole]

[0210] 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50 g) was added to a mixture of potassium carbonate (52.6 g), copper iodide (3.56 g), and sulfur powder (18.25 g) in dimethylformamide (DMF, 400 g). The reaction mixture was heated to 110 °C and stirred at the same temperature for 3 to 4 hours. The progress of the reaction was monitored by gas chromatography (GC). The reaction mixture was concentrated at approximately 80 °C under reduced pressure of approximately 50 mbar to obtain the residue. Dichloromethane (150 ml) was added to the residue and filtered through a hyflo supercell. The filter cake was washed with dichloromethane (150 ml). The organic layer was washed with water (500 ml x 2). The organic layer was concentrated to obtain the desired product. GCMS 326+

[0211] Example 10: Preparation of 4,4'-dithionylbis-[3-(difluoromethyl)-1-methyl-1H-pyrazole]

[0212] 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole (50 g) was added to a mixture of potassium carbonate (52.6 g), copper iodide (3.56 g), and sulfur powder (18.25 g) in sulfolane (400 g). The reaction mixture was continued according to Example 9. GCMS 326+

[0213] Example 11: Preparation of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester using 4,4'-dithiodibis[3-(difluoromethyl)-1-methyl-1H-pyrazole]

[0214] Sodium borohydride (1.78 g) was slowly added to a mixture of 4,4'-dithionylbis[3-(difluoromethyl)-1-methyl-1H-pyrazole (7.4 g), 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester (9.7 g), and potassium carbonate (12.2 g) in acetonitrile (100 ml) at 20 °C. The reaction mixture was stirred at approximately 60 °C for 1 hour. The progress of the reaction was monitored using GC. After the reaction was complete, the reaction mixture was filtered. The residue was washed with dichloromethane (100 ml). The filtrate was concentrated to obtain the residue. Dichloromethane (100 ml) and water were added to the residue. The organic layer was washed with dilute hydrochloric acid solution (1 N, 200 ml). The organic layer was concentrated to give the desired product.

[0215] Example 12: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl](fluoro)methyl}piperidine-1-carboxylic acid

[0216] Under a nitrogen atmosphere, at approximately 30 to 35 °C, 0.8648 mmol of 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate was added to a solution of 0.8648 mmol of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidin-1-carboxylic acid tert-butyl ester (15 mL) in dichloromethane. The reaction mixture was refluxed at 40 °C for 10–11 h. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. At 0 °C, a solution of ruthenium chloride hydrate (0.012 mmol) in tetrahydrofuran (6 mL) was added to the reaction mixture. The progress of the reaction was monitored by HPLC. After the reaction was complete, the mixture was quenched with water. The layers were separated, filtered, and concentrated to isolate 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl](fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester. GCMS: 402 [M+Na] +

[0217] Yield: 85%; Purity: 95%

[0218] Example 13: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl](fluoro)methyl}piperidine-1-carboxylic acid

[0219] 2,6-Dichloro-1-fluoropyridinium tetrafluoroborate (0.9 mmol) was added to a solution of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidin-1-carboxylic acid tert-butyl ester (0.8648 mmol) in dichloromethane (15 ml) under a nitrogen atmosphere at a temperature of approximately 30 to 35 °C. The reaction mixture was refluxed at 40 °C for 10–11 h. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. A solution of ruthenium chloride hydrate (0.012 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture at 0 °C. The progress of the reaction was monitored by HPLC. After the reaction was complete, the mixture was quenched with water. The layers were separated, filtered, and concentrated to isolate 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl](fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester. GCMS: 402 [M+Na] +

[0220] Yield: 80%; Purity: 90%

[0221] Example 14: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid

[0222] Sodium periodate (3.44 mmol) in water was added to a reaction mixture containing 1.5 mmol of 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl](fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester in tetrahydrofuran (6 ml). The reaction mixture was stirred at 0 °C for 1–2 h. The reaction mixture was quenched with water (15 ml) and extracted with dichloromethane (10 ml). The resulting two-phase mixture was separated using a separatory funnel, and the aqueous layer was extracted twice with dichloromethane (10 ml). The organic layers were combined and washed with water (10 ml). The final organic layer was concentrated to give the title compound. The product was analyzed by HPLC. MS (ES, m / z): 434 [M+Na]+

[0223] Yield: 90%; Purity: 95%

[0224] Example 15: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid

[0225] Under a nitrogen atmosphere, at approximately 30 to 35 °C, 0.8648 mmol of 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate was added to a solution of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidin-1-carboxylic acid tert-butyl ester (0.8648 mmol) in dichloromethane (15 ml). The reaction mixture was refluxed at 40 °C for 10–11 hours. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. A solution of ruthenium chloride hydrate (0.012 mmol) in tetrahydrofuran (6 ml) was added to the reaction mixture at 0 °C. Sodium periodate in water (3.44 mmol) was added to the reaction mixture, and the temperature was maintained at 0 °C. The reaction mixture was stirred at 0 °C for 1–2 hours. The reactants were quenched with water (15 ml) and extracted with dichloromethane (10 ml). The resulting two-phase mixture was separated using a separatory funnel, and the aqueous layer was extracted twice with dichloromethane (10 ml). The organic layers were combined and washed with water (10 ml). The final organic layer was concentrated to give the title compound. The product was analyzed by HPLC. MS (ES, m / z): 434 [M+Na]+

[0226] Yield: 80%; Purity: 90%.

[0227] Example 16: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid

[0228] 1-Fluoropyridium trifluoromethanesulfonate (0.9 mmol) was added to a solution of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidin-1-carboxylic acid tert-butyl ester (0.8648 mmol) in dichloromethane (15 ml) at a temperature of approximately 30 to 35 °C under a nitrogen atmosphere. The reaction mixture was refluxed at 40 °C for 10–11 hours. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). The reaction mixture was further oxidized according to Example 15. MS (ES, m / z): 434 [M+Na]+

[0229] Yield: 70%; Purity: 90%

[0230] Example 18: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid

[0231] 1-Fluoropyridium tetrafluoroborate (0.8648 mmol) was added to a solution of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidin-1-carboxylic acid tert-butyl ester (0.8648 mmol) in dichloromethane (15 ml) at a temperature of approximately 30 to 35 °C under a nitrogen atmosphere. The reaction mixture was refluxed at 40 °C for 10–11 hours. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. The reaction mixture was further oxidized according to Example 15. MS (ES, m / z): 434 [M+Na]+

[0232] Yield: 70%; Purity: 90%

[0233] Example 19: Preparation of tert-butyl 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid

[0234] 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (0.8648 mmol) was added to a solution of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidin-1-carboxylic acid tert-butyl ester (0.8648 mmol) in dichloromethane (15 ml) at a temperature of about 30 to 35 °C under a nitrogen atmosphere. The reaction mixture was refluxed at 40 °C for 10–11 hours. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC). The reaction mixture was cooled to 0 °C. The reaction mixture was further oxidized according to Example 15. MS: 434[M+Na]+

[0235] Yield: 70%; Purity: 85%

[0236] Example 20: Preparation of tert-butyl 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid

[0237] Potassium tert-butoxide (1M; 14.6 mL) was added dropwise to a solution of 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester (2 gm, 0.0048 mol) in THF (45 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -30 °C, and sodium hydride (0.28 gm, 0.0065 mol) was added to the reaction mixture, which was then stirred at -30 °C for 20 min. While maintaining the temperature at -30 °C, a solution of iodomethane (0.75 gm, 0.0053 mol) in THF (5 mL) was added to the reaction mixture over 10 min, and the mixture was then stirred at -30 °C for 30 min. The reaction was monitored using HPLC. After the reaction was complete, acetonitrile (50 mL) was added to the reaction mixture, and the pH of the reaction mixture was adjusted to 6 using acetic acid solution (2 mL). The reaction mixture was concentrated under reduced pressure to obtain the residue. Add 20 ml of dichloromethane to the residue and filter through a hyflo gel. Wash the residue with 4 x 10 ml of dichloromethane. Combine the filtrates and concentrate under reduced pressure to obtain the desired product. Recrystallize the crude product from ethanol and cyclohexane to obtain the pure product.

[0238] Purity: 99% (HPLC); Yield: 65%.

[0239] Example 20: Preparation of tert-butyl 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid

[0240] Under a nitrogen atmosphere, LiHMDS (1M; 14.6 mL) was added dropwise to a solution of 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid tert-butyl ester (2 gm, 0.0048 mol) in THF (45 mL). The reaction mixture was cooled to -78 °C and stirred for 20 min. While maintaining the temperature at -78 °C, a solution of iodomethane (0.75 gm, 0.0053 mol) in THF (5 mL) was added to the reaction mixture over 10 min, and then stirred at -78 °C for 30 min. The reaction was monitored using HPLC. After the reaction was complete, saturated ammonium chloride (20 mL) and dichloromethane (20 mL) were added. The layers were separated, the organic layer was washed with water and concentrated under reduced pressure to obtain the residue. The residue was crystallized using isopropanol and cyclohexane.

[0241] Yield: 75%; Purity: 99%; (HPLC).

[0242] Example 21: Preparation of 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine

[0243] An aqueous solution of the hydrochloride salt (3.5 N; 24 mL) was added to a solution of 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester (2.5 g) in acetonitrile (10 mL). The reaction mixture was stirred at 70 °C for one hour. The progress of the reaction was monitored by gas chromatography. After the reaction was complete, dichloromethane (15 mL) was added to the reaction mixture, and the layers were separated. The pH of the aqueous layer was maintained at 12–13 using 20% ​​NaOH (18 mL), and the layers were extracted twice with dichloromethane (25 mL). The organic layer was concentrated to obtain the given compound.

[0244] Purity: 99%; Yield: 95%.

Claims

1. A method for preparing compounds of formula II, Formula II in, R 2 It is F, C1-C4 alkyl or C1-C4 haloalkyl; R 3 It is H, F, C1-C4 alkyl or C1-C4 haloalkyl. R 4 C 1- C4 alkyl, R 6 It is H or its protecting group or salt, and R 7 It is H or Cl. The method includes the following steps: a) React the compound of formula VII with elemental sulfur in the presence of a base, a catalyst and a reducing agent to obtain the compound of formula VI; Where R 3 R 4 and R 7 As defined above, and L1 is a leaving group; b) React the compound of formula VI with the compound of formula VIII to obtain the compound of formula V; Where L2 is the leaving group, and R 3 R 4 R 6 and R 7 As defined above; c) Convert the compound of formula V into the compound of formula II.

2. A method for preparing compounds of formula II, Formula II in, R 2 F, C1-C4 alkyl, or C1-C4 haloalkyl, R 3 It is H, F, C1-C4 alkyl or C1-C4 haloalkyl. R 4 It is a C1-C4 alkyl group. R 6 It is H or its protecting group or salt, and R 7 It is H or Cl; The method includes the following steps: a) Reacting compound VII with elemental sulfur in the presence of a base and a catalyst to obtain compound VIB. R 3 R 4 and R 7 As defined above, L1 is a leaving group, and n is 2-8; b) React the compound of formula VIB with the compound of formula VIII to obtain the compound of formula V; Where R 6 As defined above, and L2 is a leaving group; and c) Convert the compound of formula V into the compound of formula II.

3. A method for preparing compounds of formula II, Formula II Where R 2 It is F, C1-C4 alkyl or C1-C4 haloalkyl. R 3 It is H, F, C1-C4 alkyl or C1-C4 haloalkyl. R 4 It is a C1-C4 alkyl group. R 6 It is H or its protecting group or salt, and R 7 It is H or Cl. The method includes the following steps: a) Fluorinate the compound of formula V to obtain the compound of formula IV; b) Oxidize the compound of formula IV to obtain the compound of formula III; and Formula III c) Convert the compound of formula III into the compound of formula II.

4. The method of claim 3, wherein the fluorination and oxidation steps are performed without separating the compound of formula IV.

5. A method for preparing compounds of formula III Formula III Where R 2 It is F, C1-C4 alkyl or C1-C4 haloalkyl. R 3 It is H, F, C1-C4 alkyl or C1-C4 haloalkyl. R 4 It is a C1-C4 alkyl group. R 6 It is H or its protecting group or salt, and R 7 It is H or Cl. The method includes the following steps: Oxidize the compound of formula IV Formula IV Where R 3 R 4 R 6 and R 7 As defined above, To obtain compound of formula III.

6. A method for preparing tert-butyl piperidine carboxylate, the method comprising the steps of: a) Reacting 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole with elemental sulfur in the presence of a base, a catalyst and a reducing agent to obtain 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiol; b) Reaction of 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-thiol with 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester to give 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester; and c) Convert 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidinecarboxylic acid tert-butyl ester.

7. A method for preparing tert-butyl piperidine carboxylate, the method comprising the steps of: a) Reacting 3-(difluoromethyl)-4-iodo-1-methyl-1H-pyrazole with elemental sulfur in the presence of a base and a catalyst to obtain 4,4'-dithionidinedimethylbis[3-(difluoromethyl)-1-methyl-1H-pyrazole]; b) Reaction of 4,4'-dithiodiylbis[3-(difluoromethyl)-1-methyl-1H-pyrazole] with 4-{[(methanesulfonyl)oxy]methyl}piperidine-1-carboxylic acid tert-butyl ester to give 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester; and c) Convert 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidinecarboxylic acid tert-butyl ester.

8. A method for preparing tert-butyl 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid, the method comprising the following steps: a) Fluorination of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester in the presence of N-fluoropyridinium salt to obtain 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester; b) Oxidation of 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester; and c) Convert 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester.

9. The method of claim 8, wherein the method does not involve the separation of 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester or 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid ester.

10. The method of claim 8, wherein the fluorination and oxidation steps are carried out without separating 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester.

11. A method for preparing 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester, the method comprising the following steps: a) Fluorination of 4-({[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester; b) Oxidation of 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester; and c) Convert 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester to 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoroethyl}piperidine-1-carboxylic acid tert-butyl ester.

12. The method of claim 11, wherein the method does not involve the separation of 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester or 4-{[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl](fluoro)methyl}piperidine-1-carboxylic acid ester.

13. The method of claim 11, wherein the fluorination and oxidation steps are carried out without separating 4-[{[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]thioalkyl}(fluoro)methyl]piperidine-1-carboxylic acid tert-butyl ester.

14. The method of any one of claims 1-2 and 6-7, wherein the alkali is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium bicarbonate.

15. The method of any one of claims 1-2 and 6-7, wherein the catalyst is selected from the group consisting of copper powder, copper chloride, copper bromide and copper iodide.

16. The method of claim 1 or 6, wherein the reducing agent is selected from the group consisting of: zinc / acetic acid, zinc / alcoholic potassium hydroxide, sodium borohydride, potassium borohydride, lithium aluminum hydride, triphenylphosphine / HCl, and tris(2-carboxyethyl)phosphine and borane.

17. The method of any one of claims 3, 4, and 8-10, wherein the fluorination step is carried out in the presence of a fluorinating agent selected from the group consisting of: 1-fluoropyridinium trifluoromethanesulfonate, 1-fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate, 1-fluoro-2,6-dichloropyridinium trifluoromethanesulfonate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, 1-fluoro-4-methylpyridinium trifluoromethanesulfonate, and 1-fluoro-4-methylpyridinium tetrafluoroborate.

18. The method of any one of claims 3-5 and 8-10, wherein the oxidation step is carried out in the presence of an oxidant selected from the group consisting of: hydrogen peroxide / sodium tungstate, peracetic acid, benzyl hydroperoxide, ethylbenzene hydroperoxide, cumyl hydroperoxide, sodium hypochlorite, oxalate dihydrate / hydrogen peroxide, m-chloroperoxybenzoic acid, urea-hydrogen peroxide adduct, permanganate / manganese dioxide, ruthenium chloride hydrate / sodium periodate, and potassium peroxymonosulfate.

19. The method of claim 3, wherein step c) of converting the compound of formula III to the compound of formula II is carried out using an alkylating agent selected from bromoalkane, chloroalkane, iodoalkane, diazonane, dialkyl carbonate, and dialkyl sulfonate in the presence of a base selected from: sodium hydride, potassium hydride, sodium ethoxide, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, n-butylamine, tert-butylamine, pyridine, methyllithium, n-butyllithium, diisopropylaminolithium, 2,2,6,6-tetramethylpiperidinelithium, sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and lithium diethylamino.

20. The method of claim 18, wherein the oxidant is ruthenium chloride hydrate / sodium periodate.

21. A compound, said compound being 4-{1-[3-(difluoromethyl)-1-methyl-1H-pyrazole-4-sulfonyl]-1-fluoromethyl}piperidine-1-carboxylic acid tert-butyl ester 。

Images