WO2017088819A1 - 调节激酶活性的化合物的中间体的制备方法 - Google Patents

调节激酶活性的化合物的中间体的制备方法 Download PDF

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WO2017088819A1
WO2017088819A1 PCT/CN2016/107274 CN2016107274W WO2017088819A1 WO 2017088819 A1 WO2017088819 A1 WO 2017088819A1 CN 2016107274 W CN2016107274 W CN 2016107274W WO 2017088819 A1 WO2017088819 A1 WO 2017088819A1
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compound
formula
group
prepare
halogen
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PCT/CN2016/107274
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English (en)
French (fr)
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李继军
朱岩
王虎庭
韩永信
黄体聪
李新路
赵锐
张喜全
Original Assignee
北京赛林泰医药技术有限公司
正大天晴药业集团股份有限公司
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Priority to US15/779,427 priority Critical patent/US20180346418A1/en
Priority to CN201680064207.2A priority patent/CN108349870B/zh
Publication of WO2017088819A1 publication Critical patent/WO2017088819A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom

Definitions

  • the present application relates to a process for the preparation of intermediates of compounds that modulate kinase activity.
  • Forma I is A compound that modulates kinase activity that can be used to treat diseases and conditions associated with modulation of kinase activity.
  • Example 9 of WO2013071865 discloses a compound of formula I and a process for its preparation.
  • the preparation of the compound of formula I involves the key intermediate 3-amino-6-chloro-2-fluorobenzoate compound of formula II, which is used to prepare the intermediate N-(3-amino group) of formula III. 4-chloro-2-fluorophenyl)-3-fluoropropane-1-sulfonamide, which is then combined with 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2 -Based - 9H-oxime reaction and removal of the protecting group to give a compound of formula I.
  • Scheme 4 of CN101808994A discloses a process for preparing ethyl 3-amino-6-chloro-2-fluorobenzoate, in which multiple steps are required to maintain the reaction temperature below -70 ° C, and the steps are cumbersome, and The chloroformate reaction takes up to 64 hours and requires purification of the product by column chromatography, so the process is not suitable for industrial production.
  • CN102858754A discloses a process for the preparation of a compound of formula III.
  • the yield of this method is only 46%, and the reaction reagent DPPA used is expensive and is not suitable for industrial production.
  • the application provides a method of preparing a compound of Formula II, which comprises the steps of:
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the above group is optionally selected from one or more selected from the group consisting of halogen, lower alkyl, halogen Substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di An alkylamino group, a cycloalkylamino group and an aryl or heteroaryl group optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio Substituent substitution;
  • R is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl and heteroaryl, wherein the above groups are optionally one or a plurality of low-grade selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen substituted An alkylthio group, a mono-alkylamino group, a di-alkylamino group, a cycloalkylamino group, and optionally one or more selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy, and lower alkylthio Substituent substitution of a substituted aryl or heteroaryl group;
  • R is selected from C 1 -C 4 alkyl and benzyl, wherein said group is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl, halogen-substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 An alkylthio group, a halogen-substituted C 1 -C 6 alkylthio group, and optionally one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 a substituent substituted with a aryl or heteroaryl group substituted with a C 6 alkylthio group;
  • R is selected from C 1 -C 4 alkyl and benzyl, wherein said group is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 Substituted by an alkyl group, a C 3 -C 6 cycloalkyl group, a halogen-substituted C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, and a halogen-substituted C 1 -C 6 alkoxy group.
  • R is selected from methyl, ethyl and benzyl, wherein said groups may be optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, substituted by halogen C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and halogen substituted C 1 -C 6 alkoxy Substituent substitution.
  • R is selected from the group consisting of methyl, ethyl, and benzyl, wherein the above groups are optionally selected from one or more selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, and trifluoro.
  • the substituents of the methyl and methoxy groups are substituted.
  • R is selected from ethyl or benzyl; in some more specific embodiments of the present application, the compound of formula II is a compound of formula II-0, and the compound of formula VI is a compound of formula VI-0
  • X is selected from halogen, preferably chlorine and bromine, and most preferably chlorine.
  • X may also be other groups as long as the compound of formula V is capable of reacting with a compound of formula VII to prepare a compound of formula VI.
  • a suitable catalyst may be selected as desired, examples of which include, but are not limited to, p-toluenesulfonic acid, montmorillonite, beta-cyclodextrin, 3,4-dihydroxy-3-cyclobutene-1,2-dione, sulfamic acid, trichloroacetic acid, alpha-amylase and various metal catalysts such as uranyl nitrate, cerium nitrate, zirconium tetrachloride Zirconium dioxide, zirconium oxychloride, magnesium iodide, titanium dioxide, antimony trichloride, lead oxide, indium triflate, antimony trichloride and triiron tetroxide.
  • the catalyst is preferably p-toluenesulfonic acid.
  • a suitable reaction solvent may be selected as needed, the solvent being selected from the group consisting of water, methanol, ethanol, propanol, isopropanol , n-butanol, isobutanol, tert-butanol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone
  • the reaction temperature is preferably from 0 ° C to the boiling point of the reaction system, more preferably the boiling point of the reaction system.
  • a compound of formula IV and 2,5-hexanedione in step (1) for preparing a compound of formula V, can be selected as appropriate, a compound of formula IV and 2,
  • the molar ratio of 5-hexanedione may be from 1:0.01 to 1:100, and may also be from 1:1 to 1:2.
  • the molar ratio of the compound of formula IV to 2,5-hexanedione is 1:0.9.
  • step (2) the compound of formula V and the compound of formula VII can be reacted in the presence of a base.
  • a suitable base may be selected as needed, and the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N, N.
  • -diisopropylethylamine triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide
  • sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate is preferably n-butyllithium.
  • a suitable reaction solvent may be selected as needed, the solvent being selected from the group consisting of methanol, ethanol, propanol, isopropanol, and positive Butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, butanone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran
  • the temperature at which the base is added is not more than 25 ° C, preferably not more than 0 ° C, and most preferably not more than -30 ° C. .
  • the compound of formula V can be contacted with a base prior to step (2) and the resulting mixture then contacted with a compound of formula VII.
  • step (2) can be carried out under the protection of nitrogen or argon.
  • a compound of formula V and a compound of formula VII in step (2) for the preparation of a compound of formula VI, can be selected to a suitable molar ratio as desired.
  • the molar ratio of the compound of the formula V to the compound of the formula VII may be from 1:0.01 to 1:100, and may also be from 1:1 to 1:5.
  • the molar ratio of the compound of Formula V to the compound of Formula VII is 1:2.
  • a suitable reaction solvent in the step (3) for preparing the compound of the formula II, can be selected as needed.
  • the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and One or more of a ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably It is a mixed solvent of ethanol and water.
  • a suitable reagent in step (3) for the preparation of a compound of formula II, may be added as needed.
  • the reagents include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine hydrochloride and a base, and hydrochloric acid and a base, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, Sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyl One or more of lithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbon
  • the reaction temperature is from 0 ° C to the boiling point of the reaction system, preferably 80 ° C.
  • the present application provides a process for the preparation of a compound of formula VIII, which comprises reacting a compound of formula II with 3-fluoro-1-propylsulfonyl chloride to prepare a compound of formula VIII,
  • R is as defined above.
  • 3-fluoro-1-propylsulfonyl chloride can be prepared by conventional methods in the art, for example by the following method:
  • the compound of formula VIII is preferably a compound of formula VIII-0,
  • the compound of formula II and 3-fluoro-1-propylsulfonyl chloride in the reaction to prepare a compound of formula VIII, can be selected as appropriate, for example, a compound of formula II and 3-fluoro.
  • Molar of 1-propylsulfonyl chloride The ratio may be 1:2-1:5; the molar ratio of the compound of the formula II to 3-fluoro-1-propylsulfonyl chloride is preferably 1:2.
  • a suitable base in the reaction to prepare the compound of formula VIII, can be selected as desired.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, Triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate,
  • One or more of sodium acetate, potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate is preferably triethylamine or pyridine.
  • a suitable solvent in the reaction to prepare the compound of Formula VIII, can be selected as needed.
  • the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and One or more of a ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably dichloromethane.
  • the reaction temperature is no greater than 40 ° C, preferably no greater than 30 ° C, and most preferably no greater than 20 ° C.
  • reaction of preparing a compound of formula VIII from a compound of formula II can be carried out under the protection of nitrogen or argon.
  • the present application provides a process for the preparation of a compound of formula VIIIa which comprises reacting a compound of formula II with 3-fluoro-1-propylsulfonyl chloride to prepare a compound of formula VIIIa,
  • R is as defined above.
  • the compound of formula VIIIa is preferably a compound of formula VIIIa-0,
  • a compound of Formula II and 3-fluoro-1-propylsulfonyl chloride in the reaction to prepare a compound of Formula VIIIa, can be selected as appropriate, such as a compound of Formula II and 3-Fluorine.
  • the molar ratio of 1-propylsulfonyl chloride may be from 1:1 to 1:1.2; the molar ratio of the compound of formula II to 3-fluoro-1-propylsulfonyl chloride is preferably 1:1.2.
  • the reaction for preparing the compound of formula VIIIa in the reaction for preparing the compound of formula VIIIa, it may be selected as needed Suitable base.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, Triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate,
  • One or more of sodium acetate, potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate is preferably triethylamine or pyridine.
  • a suitable solvent in the reaction to prepare the compound of Formula VIIIa, can be selected as needed.
  • the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and One or more of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably dichloromethane.
  • the reaction temperature when 3-fluoro-1-propylsulfonyl chloride is added is not more than 40 ° C, preferably not more than 30 ° C, most preferably not More than 25 ° C.
  • reaction of preparing a compound of formula VIIIa from a compound of formula II can be carried out under the protection of nitrogen or argon.
  • the application provides a process for the preparation of a compound of formula IX, which comprises reacting a compound of formula VIII to produce a compound of formula IX,
  • a suitable base in the reaction to prepare a compound of formula IX from a compound of formula VIII, can be added as appropriate prior to the addition of the appropriate acid.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, Triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, One or more of sodium acetate, potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably sodium hydroxide or potassium hydroxide; the acid is selected from various organic and inorganic acids, such as hydroch
  • the reaction temperature at which the base is added is less than 20 ° C, preferably less than 0 ° C, and most preferably less than 10 ° C.
  • the reaction temperature at which the acid is added is less than 20 ° C, preferably less than 0 ° C, and most preferably less than 10 ° C.
  • the acid in the reaction to prepare a compound of formula IX from a compound of formula VIII, is added such that the pH of the reaction system is no greater than 7, preferably no greater than 5, and most preferably no greater than 3.
  • a suitable solvent in the reaction to prepare a compound of formula IX from a compound of formula VIII, can be selected as desired.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone One or more of hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably tetrahydrofuran.
  • the application provides a process for the preparation of a compound of formula IX, which comprises reacting a compound of formula VIIIa to produce a compound of formula IX,
  • a suitable base in the reaction to prepare a compound of formula IX from a compound of formula VIIIa, can be added as needed, followed by the addition of a suitable acid.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, Triethylamine, diethylamine, ethylenediamine, pyridine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, One or more of sodium acetate, potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably sodium hydroxide or potassium hydroxide; the acid is selected from various organic and inorganic acids, such
  • the reaction temperature at which the base is added is less than 20 ° C, preferably less than 0 ° C, and most preferably less than 10 ° C.
  • the reaction temperature at which the acid is added is less than 20 ° C, preferably less than 0 ° C, and most preferably less than 10 ° C.
  • the acid in the reaction to prepare a compound of formula IX from a compound of formula VIIIa, is added such that the pH of the reaction system is no greater than 7, preferably no greater than 5, and most preferably no greater than 3.
  • a suitable solvent in the reaction to prepare a compound of formula IX from a compound of formula VIIIa, can be selected as desired.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone One or more of hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably tetrahydrofuran.
  • the present application provides a method for preparing a compound of formula X, which comprises reacting a compound of formula IX and N, N'- carbonyldiimidazole imidazole (CDI) is reacted, followed by addition of NH 3 X preparation of compounds of formula,
  • a suitable solvent in the reaction to prepare the compound of formula X, can be selected as needed.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone One or more of hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably tetrahydrofuran.
  • reaction of the compound of formula in X, NH 3 may be added in the form of ammonia gas or aqueous ammonia.
  • the temperature of the compound of formula IX with N,N'-carbonyldiimidazole (CDI) is from 0 ° C to the boiling point of the reaction system, preferably a reaction. The boiling point of the system.
  • the reaction temperature at which NH 3 is added is not more than 25 ° C, preferably not more than 5 ° C, and most preferably not more than 0 ° C. In some embodiments of the present application, the temperature at which NH 3 is added is 0 °C.
  • the method of preparing a compound of formula X further comprises the step of adding an acid after a period of time in which the NH 3 is added, the acid being selected from various organic and inorganic acids, such as hydrochloric acid, sulfuric acid, Nitric acid, phosphoric acid, maleic acid or citric acid or the like is preferably hydrochloric acid.
  • the acid is added such that the pH of the reaction system is no greater than 7, preferably no greater than 5, and most preferably no greater than 3.
  • the application provides a process for the preparation of a compound of formula III, which comprises reacting a compound of formula X to produce a compound of formula III,
  • the method of preparing a compound of Formula III preferably comprises the steps of:
  • a suitable solvent in the method of preparing the compound of Formula III, can be selected as needed.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone One or more of pentanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO, preferably one of tetrahydrofuran and water One or two, most preferably a mixed solvent of tetrahydrofuran and water.
  • a suitable base in step i of the method of preparing a compound of formula III, can be selected as desired.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, Triethylamine, diethylamine, ethylenediamine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, sodium acetate
  • potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate is preferably sodium hydroxide or potassium hydroxide.
  • step i of the process for the preparation of a compound of formula III the compound of formula X is contacted with a base and then with hypochlorite.
  • the reaction temperature upon contact with hypochlorite is no greater than 25 °C, preferably no greater than 5 °C.
  • the reaction temperature is raised after contact with hypochlorite; for example, the reaction temperature is raised to 25 °C.
  • the reaction temperature at which the thiosulfate is added is 25 °C.
  • the hypochlorite is preferably sodium hypochlorite or potassium hypochlorite;
  • the thiosulfate is preferably sodium thiosulfate or potassium thiosulfate.
  • the acid is selected from the group consisting of various organic and inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid or citric acid. Etc., preferably hydrochloric acid.
  • step iii of the process for preparing a compound of formula III the acid is added such that the pH of the reaction system is no greater than 7, preferably no greater than 6, more preferably 5-6.
  • the temperature of the reaction system is maintained no greater than 40 ° C, preferably no greater than 30 ° C, and most preferably no greater than 20 ° C.
  • the method of preparing a compound of Formula III further comprises the step of adding ethanol or isopropanol after step iii.
  • the application provides a method of preparing a compound of formula III, which comprises the steps of:
  • a suitable solvent in the method of preparing the compound of Formula III, can be selected as needed.
  • the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone One or more of hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC or DMSO.
  • the solvent in the step (a) is preferably tetrahydrofuran.
  • the solvent in the step (b) is preferably one or two of tetrahydrofuran and water, and most preferably a mixed solvent of tetrahydrofuran and water.
  • the steps of the method for preparing a compound of formula III (a) in, NH 3 may be added in the form of ammonia gas or aqueous ammonia.
  • step (a) of the method of preparing a compound of formula III the compound of formula IX is reacted with N,N'-carbonyldiimidazole (CDI) at a temperature of from 0 ° C to the reaction system.
  • CDI N,N'-carbonyldiimidazole
  • the boiling point is preferably the boiling point of the reaction system.
  • the reaction temperature at which NH 3 is added is not more than 25 ° C, preferably not more than 5 ° C, more preferably not more than 0. °C, most preferably 0 °C.
  • step (a) of the method of preparing a compound of formula III further comprises the step of adding an acid selected from the group consisting of various organic and inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid , maleic acid or citric acid, etc., preferably hydrochloric acid.
  • an acid selected from the group consisting of various organic and inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid , maleic acid or citric acid, etc., preferably hydrochloric acid.
  • the acid in the method of preparing a compound of Formula III, is added such that the pH of the reaction system is no greater than 7, preferably no greater than 5, and most preferably no greater than 3.
  • step (b) of the method of preparing a compound of formula III comprises the steps of:
  • a suitable base in step i, can be selected as desired.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, N,N-diisopropylethylamine, Triethylamine, diethylamine, ethylenediamine, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, n-butyllithium, lithium t-butoxide, lithium diisopropylamide, sodium carbonate, potassium carbonate, sodium acetate
  • potassium acetate, sodium hydrogencarbonate or potassium hydrogencarbonate is preferably sodium hydroxide or potassium hydroxide.
  • the compound of formula X is first contacted with a base and then with hypochlorite in step i.
  • the reaction temperature upon contact with hypochlorite is no greater than 25 °C, preferably no greater than 5 °C.
  • step i the reaction temperature is raised after contact with hypochlorite; for example, the reaction temperature is raised to 25 °C.
  • the reaction temperature when thiosulfate is added in step ii is 25 °C.
  • the hypochlorite is sodium hypochlorite or potassium hypochlorite.
  • the thiosulfate is sodium thiosulfate or potassium thiosulfate.
  • the acid in step iii, is selected from the group consisting of various organic and inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid or citric acid, and the like, preferably hydrochloric acid.
  • step iii the acid is added such that the pH of the reaction system is no greater than 7, preferably no greater than 6, more preferably 5-6.
  • step iii the temperature of the reaction system is maintained no greater than 40 °C, preferably no greater than 30 °C, and most preferably no greater than 20 °C.
  • the preparation of the compound of Formula III further includes the step of adding ethanol or isopropanol after step iii.
  • the application provides a method of preparing a compound of formula III, which comprises the steps of:
  • the application provides a method of preparing a compound of formula III, comprising the steps of:
  • the invention provides a compound of formula VI, or a salt or solvate thereof,
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the above group is optionally selected from one or more selected from the group consisting of halogen, lower alkyl, halogen Substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di An alkylamino group, a cycloalkylamino group and an aryl or heteroaryl group optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio Substituent substitution;
  • R is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl and heteroaryl, wherein the above groups are optionally one or a plurality of low-grade selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen substituted An alkylthio group, a mono-alkylamino group, a di-alkylamino group, a cycloalkylamino group, and optionally one or more selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy, and lower alkylthio Substituent substitution of a substituted aryl or heteroaryl group;
  • R is selected from C 1 -C 4 alkyl and benzyl, wherein said group is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 Alkyl, C 3 -C 6 cycloalkyl, halogen-substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 An alkylthio group, a halogen-substituted C 1 -C 6 alkylthio group, and optionally one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 a substituent substituted with a aryl or heteroaryl group substituted with a C 6 alkylthio group;
  • R is selected from C 1 -C 4 alkyl and benzyl, wherein said group is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 a substituent substituted with an alkyl group, a C 3 -C 6 cycloalkyl group, a halogen-substituted C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, and a halogen-substituted C 1 -C 6 alkoxy group;
  • R is selected from methyl, ethyl and benzyl, wherein said groups may be optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, substituted by halogen C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and halogen substituted C 1 -C 6 alkoxy Substituent substitution.
  • R is selected from the group consisting of methyl, ethyl, and benzyl, wherein the above groups are optionally selected from one or more selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, and trifluoro. A substituent of a methyl group or a methoxy group is substituted.
  • R is selected from the group consisting of ethyl and benzyl.
  • the application provides a compound of Formula VIII, Formula VIIIa, or a salt or solvate thereof,
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the above group is optionally selected from one or more selected from the group consisting of halogen, lower alkyl, halogen Substituted lower alkyl, cycloalkyl, halogen substituted cycloalkyl, lower alkoxy, halogen substituted lower alkoxy, lower alkylthio, halogen substituted lower alkylthio, mono-alkylamino, di Substituted with a substituent of an alkylamino group, a cycloalkylamino group and a heteroaryl group optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy and lower alkylthio .
  • R is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, aryl and heteroaryl, wherein the above groups are optionally one or a plurality of low-grade selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cycloalkyl, halogen-substituted cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkylthio, halogen substituted An alkylthio group, a mono-alkylamino group, a di-alkylamino group, a cycloalkylamino group, and optionally one or more selected from the group consisting of halogen, hydroxy, amino, lower alkyl, lower alkoxy, and lower alkylthio Substituent substitution of a heteroaryl group substituted with a group.
  • R is selected from C 1 -C 4 alkyl group, wherein said group is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halo-substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen-substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, halogen-substituted C 1 -C 6 alkoxy, C 1 -C 6 alkylthio a halogen-substituted C 1 -C 6 alkylthio group and optionally one or more selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 Substituent substitution of a heteroaryl group substituted with an alkylthio group.
  • R is selected from C 1 -C 4 alkyl and benzyl, wherein said group is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 Substituted by an alkyl group, a C 3 -C 6 cycloalkyl group, a halogen-substituted C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, and a halogen-substituted C 1 -C 6 alkoxy group.
  • R is selected from methyl and ethyl, wherein said groups may be optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, halo-substituted C 1 - Substituent substitution of C 6 alkyl, C 3 -C 6 cycloalkyl, halogen substituted C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and halogen substituted C 1 -C 6 alkoxy .
  • R is selected from the group consisting of methyl and ethyl, wherein the above groups are optionally selected from one or more selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, and The substituent of the methoxy group is substituted.
  • R is selected from the group consisting of ethyl.
  • the present invention provides a compound of formula X or a salt or solvate thereof,
  • the application provides a compound of formula VI, a compound of formula VIII, a compound of formula VIIIa or a compound of formula X, or a salt thereof or a solvate thereof, in the preparation of N-(3-amino-4-chloro-2-fluorophenyl) Use in -3-fluoropropane-1-sulfonamide.
  • the application provides a compound of formula VI, a compound of formula VIII, a compound of formula VIIIa or a compound of formula X, or a salt thereof or a solvate thereof, in the preparation of N- ⁇ 3-[3-(9H- ⁇ -6-yl) Use in pyridin-2-ylamino]-4-chloro-2-fluorophenyl ⁇ -3-fluoropropane-1-sulfonamide.
  • 4-chloro-2-fluoroaniline is prepared as 1-(4-chloro-2-fluorophenyl)-2,5-dimethyl-1H-pyrrole, and then correspondingly
  • the acid halide reaction is linked to an ester group, and further reacted to obtain a 3-amino-6-chloro-2-fluorobenzoate compound of the formula II.
  • the raw materials and reagents used in the method are easily obtained, the reaction conditions are mild, the reaction period is short, the environment is friendly, the preparation steps are simple and easy to operate, and the yield is high.
  • N,N'-carbonyldiimidazole and NH 3 are used, and the reagents used are cheap and easy to obtain.
  • the preparation step is simple and easy to operate, not only significantly improves the yield, but also the product has high purity, so the preparation method described in the present application is particularly suitable for industrial production.
  • alkyl as used herein includes an optionally substituted alkyl group.
  • optionally substituted alkyl as defined below means “alkyl” or “substituted alkyl”.
  • the optionally substituted group may be unsubstituted (such as CH 2 CH 3 ), fully substituted (such as CF 2 CF 3 ), monosubstituted (such as CH 2 CH 2 F) or between fully substituted and monosubstituted The degree of substitution (such as CH 2 CHF 2 , CF 2 CH 3 , CFHCHF 2, etc.).
  • C 1 -C n as used herein includes C 1 -C 2 , C 1 -C 3 , ... C 1 -C n .
  • the "C 1 -C 4 " group means having from 1 to 4 carbon atoms in the moiety, ie the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbons The same is true for atoms, C 1 -C 2 and C 1 -C 3 .
  • C 1 -C 4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms, ie, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl and tert-butyl.
  • a numerical range, for example, "1-10” refers to each integer in a given range, for example "1-10 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 Carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • hetero refers to an atom other than carbon and hydrogen.
  • the heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • alkyl refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon.
  • Alkyl as used herein may have from 1 to about 18 carbon atoms, or from 1 to about 10 carbon atoms, preferably from 1 to 6 carbon atoms.
  • lower alkyl alone or in combination, refers to an alkyl group having a lower carbon number, for example, having from 1 to about 8 carbon atoms, preferably from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms.
  • alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1- Butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl -1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- Dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as h
  • C 1 -C 6 alkyl or “C 1 - 6 alkyl” means 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5
  • alkyl includes, but is not limited to, “alkyl” which is included in “alkoxy”, “alkylthio”, “mono-alkylamino” and “di-alkylamino” and the like.
  • alkenyl refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon having one or more carbon-carbon double bonds.
  • the alkenyl group has, for example, from 2 to about 18 carbon atoms, or from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms.
  • the double bond in these groups may be in the cis or trans configuration and should be understood to encompass both isomers.
  • “lower alkenyl”, alone or in combination refers to an alkenyl group having a lower carbon number, for example having from 2 to about 8 carbon atoms, preferably from 2 to about 6 carbon atoms, or from 2 to about 4 carbon atoms.
  • alkenyl group as defined herein appears in the numerical range, for example "C 2 -C 6 alkenyl” or "C 2 - 6 alkenyl” means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons
  • An alkenyl group consisting of an atom or 6 carbon atoms, and the alkenyl group herein also covers the case where the numerical range is not specified.
  • alkynyl refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon having one or more carbon-carbon triple bonds.
  • the alkynyl group has from 2 to about 18 carbon atoms or from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms.
  • lower alkynyl alone or in combination, refers to alkynyl groups having a lower carbon number, for example having from 2 to about 8 carbon atoms, preferably from 2 to about 6 carbon atoms or from 2 to about 4 carbon atoms.
  • alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like.
  • alkynyl groups as defined herein are in the numerical range, for example "C 2 -C 6 alkynyl” or "C 2 -6 alkynyl” means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons
  • An alkynyl group consisting of an atom or 6 carbon atoms, the alkynyl group herein also covers the unspecified range of numbers.
  • cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.
  • cycloalkyl as used herein, alone or in combination, means an optionally substituted monovalent saturated hydrocarbon ring containing from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms, which may also be included as Other non-cyclic carbon atoms of the substituent (e.g., methylcyclopropyl).
  • the cycloalkyl group may have 3 to about 10 or 3 to 8 or 3 to 6 or 3-5 ring atoms, and examples of the cycloalkyl group include, but are not limited to, cyclopropane, cyclobutane, cyclopentane. And cyclohexane.
  • lower cycloalkyl refers to a cycloalkyl group having a smaller number of ring atoms, for example containing from 5 to about 10 or from 5 to about 6 or from 5 to 6 ring atoms or from 3 to 3 6 ring-forming atoms, for example having 3, 4, 5 or 6 ring-forming atoms.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bicyclic or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • heterocycloalkyl examples include azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxalate Oxepanyl, thiepanyl, dioxanyl, 1,3-dioxolanyl, dithianyl, Dithiolanyl, pyrazolidinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl and 3-azabicyclo[4.1.0]heptyl and the like.
  • aryl refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system having from 6 to 14 carbon atoms, preferably from 6 to 12 carbon atoms, most It preferably has 6 carbon atoms.
  • Non-limiting examples of non-substituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to a monocyclic or fused ring of 5 to 12 ring atoms having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, which contains 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated ⁇ -electron system.
  • Heteroaryl groups can be unsubstituted or substituted, including but not limited to alkyl, alkoxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl, and hetero Alicyclic group.
  • Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • halogen means fluoro, chloro, bromo and iodo.
  • alkoxy as used herein, alone or in combination, means "-O-alkyl".
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • alkylthio as used herein, alone or in combination, means "-S-alkyl".
  • alkylthio groups include methylthio, ethylthio, propylthio, butylthio and the like.
  • lower alkyl means from 1 to about 8, or from 1 to 6 or 1-5 or 1 carbon atoms. - 4 or 1-3 or 1-2 of said alkyl, alkoxy and alkylthio groups.
  • salts examples include salts prepared by reacting a compound described herein with an inorganic or organic acid or an inorganic base. These salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, besylate, hydrogen sulfate, bisulfites, bromides, butyrates.
  • solvate refers to a combination of a compound of the invention and a solvent molecule formed by solvation.
  • a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of the compound of the invention and water forms a hydrate.
  • the compound of formula V (224 g, 1.00 mol) and dry tetrahydrofuran (1.3 L) were added to a 3 L three-neck reaction flask equipped with a constant pressure dropping funnel, and the mixture was stirred for 5 minutes until the system was uniformly mixed.
  • the reaction system was purged with nitrogen and cooled to -30.
  • a n-butyllithium solution (2.4 mol/L, 438 mL) was slowly added dropwise to maintain the system temperature below -30 °C. After the completion of the dropwise addition, stirring was continued at this temperature for 1 hour.
  • Ethyl chloroformate (217 g, 2.00 mol) was dissolved in dry tetrahydrofuran (220 mL), and was replaced with nitrogen and cooled to -30 °C. Then, an ethyl chloroformate solution was added dropwise to the above solution under a nitrogen atmosphere. This process keeps the system temperature below -30 °C. After the completion of the dropwise addition, stirring was continued for 30 minutes, and a saturated aqueous ammonium chloride solution (450 mL) was added and the mixture was allowed to warm to room temperature. Ethyl acetate (1.5 L) and water (3.0 L) were added and evaporated.
  • a compound of the formula VI-0 (286 g, 0.96 mol), ethanol (1.2 L) and water (400 mL) were added to a 3 L three-necked reaction flask, and stirred uniformly, and triethylamine (389 g, 3.84 mol) and hydroxylamine hydrochloride (997 g, 14.4) were added. Mol).
  • the reaction system was vigorously stirred at 80 ° C for 24 hours, concentrated to remove most of the ethanol, and water (3.0 L) and ethyl acetate (1.5 L) were added, stirred and separated, and the obtained aqueous phase was extracted with ethyl acetate (1 L) The organic phase was combined and washed with brine (2 mL).
  • a compound of the formula VIII-0 (309 g, 0.66 mol) and tetrahydrofuran (1.5 L) were added to a 5 L three-necked flask, and the mixture was stirred at room temperature for 10 minutes until the system was uniformly mixed, cooled in an ice water bath, and a 2 mol/L potassium hydroxide aqueous solution (1.65 L) was added dropwise. , 3.3mol), the temperature of the control system is lower than 10 °C during the dropwise addition. After the completion of the dropwise addition, the ice water bath is removed, and the mixture is stirred at room temperature for 3 days.
  • the reaction system was placed in an ice water bath, and concentrated hydrochloric acid was added dropwise to pH. After 5-6, the temperature of the control system is lower than 20 ° C, and the liquid phase is extracted twice with ethyl acetate (700 mL). The organic phase is combined and washed with water (1.0 L) and saturated brine (1.0 L). Add anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is added to 260 mL of ethanol, and filtered, and the filter cake is rinsed with about 50-60 mL of ethanol and dried to give a white solid (120 g, yield: 75%). The purity is greater than 99.5% (area normalization method).

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Abstract

本申请涉及用于调节激酶活性的化合物(N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺)的中间体式Ⅱ化合物和式Ⅲ化合物的制备方法。

Description

调节激酶活性的化合物的中间体的制备方法
相关申请的引用
本申请要求于2015年11月26日向中华人民共和国国家知识产权局提交的申请号为201510835557.1的中国发明专利申请的权益。
技术领域
本申请涉及调节激酶活性的化合物的中间体的制备方法。
背景技术
N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺(式Ⅰ)是调节激酶活性的化合物，其能用于治疗与激酶活性的调节相关的疾病和病症。WO2013071865的实施例9公开了式I化合物及其制备方法。
Figure PCTCN2016107274-appb-000001
式I化合物的制备涉及式Ⅱ所示的关键中间体3-氨基-6-氯-2-氟苯甲酸酯类化合物，该中间体用于制备式Ⅲ所示的中间体N-(3-氨基-4-氯-2-氟苯基)-3-氟丙烷-1-磺酰胺，其然后与6-(2-氟吡啶-3-基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤反应并脱去保护基得到式Ⅰ化合物。
Figure PCTCN2016107274-appb-000002
CN101808994A的方案4公开了3-氨基-6-氯-2-氟苯甲酸乙酯的制备方法,该方法中的多个步骤均需要将反应温度维持在-70℃以下，且步骤繁琐，与乙基氯甲酸酯反应长达64小时，并需要通过柱层析纯化产物，因此该方法不适应工业化生产。
CN102858754A公开了式Ⅲ化合物的制备方法。该方法的收率仅为46％，且所用的反应试剂DPPA价格高，也不适应工业化生产。
因此仍亟需制备式Ⅱ化合物和式Ⅲ化合物的方法，以适应工业化生产的需求。
发明内容
一方面，本申请提供式Ⅱ化合物的制备方法，其包括如下步骤：
(1)式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
(2)式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
(3)式Ⅵ化合物进行反应制备式Ⅱ化合物。
Figure PCTCN2016107274-appb-000003
其中R选自烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的芳基或杂芳基的取代基取代；
优选地，R选自C1-C6烷基、C3-C6环烷基、C3-C6杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的芳基或杂芳基的取代基取代；
更优选地，R选自C1-C4烷基和苄基，其中上述基团任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷硫基、卤素取代的C1-C6烷硫基和任选被一个或多个选自卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基和C1-C6烷硫基的基团取代的芳基或杂芳基的取代基取代；
最优选地，R选自C1-C4烷基和苄基，其中上述基团任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基和卤素取代的C1-C6烷氧基的取代基取代。
在本申请的一些具体实施方案中，R选自甲基、乙基和苄基，其中上述基团可以任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基和卤素取代的C1-C6烷氧基的取代基取代。
在本申请的一些具体实施方案中，R选自甲基、乙基和苄基，其中上述基团任选地被一个或多个选自氟、氯、溴、甲基、乙基、三氟甲基和甲氧基的取代基取代。
在本申请的一些具体实施方案中，R选自乙基或苄基；在本申请的一些更具体的实施方案中，式Ⅱ化合物为式Ⅱ-0化合物，式Ⅵ化合物为式Ⅵ-0化合物
Figure PCTCN2016107274-appb-000004
在本申请的一些具体实施方案中，在式Ⅶ化合物中，X选自卤素，优选为氯和溴，最优选为氯。
应当理解，在式Ⅶ化合物中，X也可以是其它基团，只要式Ⅴ化合物能够与式Ⅶ化合物进行反应制备式Ⅵ化合物即可。
任选地，在用于制备式Ⅴ化合物的步骤(1)中，可以根据需要选择合适的催化剂，所述催化剂的实例包括但不限于对甲苯磺酸、蒙脱石、β-环糊精、3,4-二羟基-3-环丁烯-1,2-二酮、氨基磺酸、三氯乙酸、α-淀粉酶及各种金属催化剂，例如硝酸铀酰、硝酸铋、四氯化锆、二氧化锆、氧氯化锆、碘化镁、二氧化钛、三氯化铋、氧化亚铅、三氟甲磺酸铟、三氯化钌和四氧化三铁等。在本申请的一些具体实施方案中，所述催化剂优选为对甲苯磺酸。
在本申请的一些具体实施方案中，在用于制备式Ⅴ化合物的步骤(1)中，可以根据需要选择合适的反应溶剂，所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为甲苯、四氢呋喃、二氯甲烷、甲醇、乙醇、乙腈或水中的一种或一种以上，最优选为甲苯。
在本申请的一些具体实施方案中，在用于制备式Ⅴ化合物的步骤(1)中，可以根据需 要选择合适的反应温度，反应温度优选为0℃到反应体系的沸点，更优选为反应体系的沸点。
在本申请的一些具体实施方案中，在用于制备式Ⅴ化合物的步骤(1)中，式Ⅳ化合物与2,5-己二酮可以根据需要选择合适的摩尔比，式Ⅳ化合物与2,5-己二酮的摩尔比可以为1：0.01-1：100，也可以为1:1-1：2。例如，在本申请的一些具体实施方案中，式Ⅳ化合物与2,5-己二酮的摩尔比为1：0.9。
在本申请的一些具体实施方案中，在步骤(2)中，式Ⅴ化合物与式Ⅶ化合物可以在碱的存在下反应。可以根据需要选择合适的碱，所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、吡啶、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基氨基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为正丁基锂。
在本申请的一些具体实施方案中，在用于制备式Ⅵ化合物的步骤(2)中，可以根据需要选择合适的反应溶剂，所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为四氢呋喃。
在本申请的一些具体实施方案中，在用于制备式Ⅵ化合物的步骤(2)中，加入碱时的温度为不大于25℃，优选为不大于0℃，最优选为不大于-30℃。
在本申请的一些具体实施方案中，在步骤(2)中可以先将式Ⅴ化合物与碱接触，然后所得混合物再与式Ⅶ化合物进行接触。在本申请的一些具体实施方案中，步骤(2)可以在氮气或者氩气的保护下进行。
在本申请的一些具体实施方案中，在用于制备式Ⅵ化合物的步骤(2)中，式Ⅴ化合物与式Ⅶ化合物可以根据需要选择合适的摩尔比。式Ⅴ化合物与式Ⅶ化合物的摩尔比可以为1：0.01-1：100，也可以为1:1-1：5。例如，在本申请的一些具体实施方案中，式Ⅴ化合物与式Ⅶ化合物的摩尔比为1：2。
在本申请的一些具体实施方案中，在用于制备式Ⅱ化合物的步骤(3)中，可以根据需要选择合适的反应溶剂。所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选 为乙醇和水的混合溶剂。
在本申请的一些具体实施方案中，在用于制备式Ⅱ化合物的步骤(3)中，可以根据需要添加合适的试剂。所述试剂包括但不限于盐酸羟胺、盐酸羟胺和碱、以及盐酸和碱，其中所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、吡啶、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上；其中当试剂为盐酸和碱时，先加入盐酸使反应进行一段时间，然后再加入碱；所述一段时间不特别限定，可以根据需要选择合适的时间段。在本申请的一些具体实施方案中，所述试剂优选为盐酸羟胺和三乙胺。
在本申请的一些具体实施方案中，在用于制备式Ⅱ化合物的步骤(3)中，反应温度为0℃到反应体系的沸点，优选为80℃。
另一方面，本申请提供式Ⅷ化合物的制备方法，其包括使式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷ化合物，
Figure PCTCN2016107274-appb-000005
其中R的定义如前文所述。
在本申请的一些具体实施方案中，3-氟-1-丙基磺酰氯可以通过现有技术中的常规方法制备，例如通过如下方法制备：
Figure PCTCN2016107274-appb-000006
在本申请的一些具体实施方案中，式Ⅷ化合物优选为式Ⅷ-0化合物，
Figure PCTCN2016107274-appb-000007
在本申请的一些具体实施方案中，在制备式Ⅷ化合物的反应中，式Ⅱ化合物与3-氟-1-丙基磺酰氯可以根据需要选择合适的摩尔比，例如式Ⅱ化合物与3-氟-1-丙基磺酰氯的摩尔 比可为1:2-1：5；式Ⅱ化合物与3-氟-1-丙基磺酰氯的摩尔比优选为1:2。
在本申请的一些具体实施方案中，在制备式Ⅷ化合物的反应中，可以根据需要选择合适的碱。所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、吡啶、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为三乙胺或吡啶。
在本申请的一些具体实施方案中，在制备式Ⅷ化合物的反应中，可以根据需要选择合适的溶剂。所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或几种，优选为二氯甲烷。
在本申请的一些具体实施方案中，在加入3-氟-1-丙基磺酰氯时，反应温度不大于40℃，优选为不大于30℃，最优选不大于20℃。
任选地，由式Ⅱ化合物制备式Ⅷ化合物的反应可以在氮气或者氩气的保护下进行。
另一方面，本申请提供式Ⅷa化合物的制备方法，其包括使式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷa化合物，
Figure PCTCN2016107274-appb-000008
其中R的定义如前文所述。
在本申请的一些具体实施方案中，式Ⅷa化合物优选为式Ⅷa-0化合物，
Figure PCTCN2016107274-appb-000009
在本申请的一些具体实施方案中，在制备式Ⅷa化合物的反应中，式Ⅱ化合物与3-氟-1-丙基磺酰氯可以根据需要选择合适的摩尔比，例如式Ⅱ化合物与3-氟-1-丙基磺酰氯的摩尔比可为1:1-1：1.2；式Ⅱ化合物与3-氟-1-丙基磺酰氯的摩尔比优选为1:1.2。
在本申请的一些具体实施方案中，在制备式Ⅷa化合物的反应中，可以根据需要选择合 适的碱。所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、吡啶、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为三乙胺或吡啶。
在本申请的一些具体实施方案中，在制备式Ⅷa化合物的反应中，可以根据需要选择合适的溶剂。所述溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为二氯甲烷。
在本申请的一些具体实施方案中，在制备式Ⅷa化合物的反应中，加入3-氟-1-丙基磺酰氯时的反应温度不大于40℃，优选为不大于30℃，最优选为不大于25℃。
任选地，由式Ⅱ化合物制备式Ⅷa化合物的反应可以在氮气或者氩气的保护下进行。
再一方面，本申请提供式Ⅸ化合物的制备方法，其包括使式Ⅷ化合物进行反应制备式Ⅸ化合物，
Figure PCTCN2016107274-appb-000010
在本申请的一些具体实施方案中，在由式Ⅷ化合物制备式Ⅸ化合物的反应中，可以根据需要先加入合适的碱，然后再加入合适的酸。所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、吡啶、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为氢氧化钠或氢氧化钾；所述酸选自各种有机酸和无机酸，例如盐酸、硫酸、硝酸、磷酸、马来酸或柠檬酸等。
在本申请的一些具体实施方案中，在由式Ⅷ化合物制备式Ⅸ化合物的反应中，加入碱时的反应温度低于20℃，优选为低于0℃，最优选为低于10℃。
在本申请的一些具体实施方案中，在由式Ⅷ化合物制备式Ⅸ化合物的反应中，加入酸时的反应温度低于20℃，优选为低于0℃，最优选为低于10℃。
在本申请的一些具体实施方案中，在由式Ⅷ化合物制备式Ⅸ化合物的反应中，加入酸使得反应体系的pH值不大于7，优选为不大于5，最优选为不大于3。
在本申请的一些具体实施方案中，在由式Ⅷ化合物制备式Ⅸ化合物的反应中，可以根据需要选择合适的溶剂。所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为四氢呋喃。
再一方面，本申请提供式Ⅸ化合物的制备方法，其包括使式Ⅷa化合物进行反应制备式Ⅸ化合物，
Figure PCTCN2016107274-appb-000011
在本申请的一些具体实施方案中，在由式Ⅷa化合物制备式Ⅸ化合物的反应中，可以根据需要加入合适的碱，然后再加入合适的酸。所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、吡啶、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为氢氧化钠或氢氧化钾；所述酸选自各种有机酸和无机酸，例如盐酸、硫酸、硝酸、磷酸、马来酸或柠檬酸等。
在本申请的一些具体实施方案中，在由式Ⅷa化合物制备式Ⅸ化合物的反应中，加入碱时的反应温度低于20℃，优选为低于0℃，最优选为低于10℃。
在本申请的一些具体实施方案中，在由式Ⅷa化合物制备式Ⅸ化合物的反应中，加入酸时的反应温度低于20℃，优选为低于0℃，最优选为低于10℃。
在本申请的一些具体实施方案中，在由式Ⅷa化合物制备式Ⅸ化合物的反应中，加入酸使得反应体系的pH值不大于7，优选为不大于5，最优选为不大于3。
在本申请的一些具体实施方案中，在由式Ⅷa化合物制备式Ⅸ化合物的反应中，可以根据需要选择合适的溶剂。所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为四氢呋喃。
还一方面，本申请提供式Ⅹ化合物的制备方法，其包括使式Ⅸ化合物与N,N'-羰基二咪 唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
Figure PCTCN2016107274-appb-000012
在本申请的一些具体实施方案中，在制备式Ⅹ化合物的反应中，可以根据需要选择合适的溶剂。所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为四氢呋喃。
在本申请的一些具体实施方案中，在制备式Ⅹ化合物的反应中，NH3可以以氨气或氨水的形式加入。
在本申请的一些具体实施方案中，在制备式Ⅹ化合物的反应中，式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应的温度为0℃到反应体系的沸点，优选为反应体系的沸点。
在本申请的一些具体实施方案中，在制备式Ⅹ化合物的反应中，加入NH3时的反应温度为不大于25℃，优选为不大于5℃，最优选为不大于0℃。在本申请的一些具体实施方案中，加入NH3的温度为0℃。
在本申请的一些具体实施方案中，制备式Ⅹ化合物的方法还包括在加入NH3反应一段时间之后再加入酸的步骤，所述酸选自各种有机酸和无机酸，例如盐酸、硫酸、硝酸、磷酸、马来酸或柠檬酸等，优选为盐酸。在本申请的一些具体实施方案中，加入酸使得反应体系pH值不大于7，优选为不大于5，最优选为不大于3。
还一方面，本申请提供式Ⅲ化合物的制备方法，其包括使式Ⅹ化合物进行反应制备式Ⅲ化合物，
Figure PCTCN2016107274-appb-000013
在本申请的一些具体实施方案中，制备式Ⅲ化合物的方法优选包括如下步骤：
i.使式Ⅹ化合物在碱和次氯酸盐的存在下进行反应；
ii.向步骤i的反应体系中加入硫代硫酸盐；
iii.向步骤ii的反应体系中加入酸，得到式Ⅲ化合物。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法中，可以根据需要选择合适的溶剂。所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上，优选为四氢呋喃和水中的一种或两种，最优选为四氢呋喃和水的混合溶剂。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤i中，可以根据需要选择合适的碱。所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为氢氧化钠或氢氧化钾。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤i中，式Ⅹ化合物先与碱接触，再与次氯酸盐接触。
在本申请的一些具体实施方案中，与次氯酸盐接触时的反应温度不大于25℃，优选为不大于5℃。
在本申请的一些具体实施方案中，在与次氯酸盐接触之后升高反应温度；例如升高反应温度至25℃。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤ii中，加入硫代硫酸盐时的反应温度为25℃。
在本申请的一些具体实施方案中，次氯酸盐优选为次氯酸钠或次氯酸钾；硫代硫酸盐优选为硫代硫酸钠或硫代硫酸钾。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤iii中，所述酸选自各种有机酸和无机酸，例如盐酸、硫酸、硝酸、磷酸、马来酸或柠檬酸等，优选为盐酸。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤iii中，加入酸使得反应体系的pH值不大于7，优选为不大于6，更优选为5-6。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤iii中，维持反应体系的温度不大于40℃，优选为不大于30℃，最优选为不大于20℃。
在本申请的一些具体实施方案中，制备式Ⅲ化合物的方法还进一步包括在步骤iii之后，加入乙醇或异丙醇的步骤。
还一方面，本申请提供式Ⅲ化合物的制备方法，其包括如下步骤：
(a)使式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
(b)使式Ⅹ化合物进行反应制备式Ⅲ化合物，
Figure PCTCN2016107274-appb-000014
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法中，可以根据需要选择合适的溶剂。所述溶剂选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO中的一种或一种以上。在步骤(a)中溶剂优选为四氢呋喃。在步骤(b)中溶剂优选为四氢呋喃和水中的一种或两种，最优选为四氢呋喃和水的混合溶剂。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤(a)中，NH3可以以氨气或氨水的形式加入。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤(a)中，式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应的温度为0℃到反应体系的沸点，优选为反应体系的沸点。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法的步骤(a)中，加入NH3时的反应温度为不大于25℃，优选为不大于5℃，更优选为不大于0℃，最优选为0℃。
在本申请的一些具体实施方案中，制备式Ⅲ化合物的方法的步骤(a)还进一步包括加入酸的步骤，所述酸选自各种有机酸和无机酸，例如盐酸、硫酸、硝酸、磷酸、马来酸或柠檬酸等，优选盐酸。
在本申请的一些具体实施方案中，在制备式Ⅲ化合物的方法中，加入酸使得反应体系的pH值不大于7，优选为不大于5，最优选为不大于3。
在本申请的一些具体实施方案中，制备式Ⅲ化合物的方法的步骤(b)包括如下步骤：
i.式Ⅹ化合物在碱和次氯酸盐的存在下进行反应；
ii.步骤i的体系中加入硫代硫酸盐；
iii.步骤ii的体系中加入酸。
在本申请的一些具体实施方案中，在步骤i中，可以根据需要选择合适的碱。所述碱选自氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、N,N-二异丙基乙胺、三乙胺、二乙胺、乙二胺、碳酸铯、碳酸锂、氢化钠、氨基钠、正丁基锂、叔丁醇锂、二异丙基胺基锂、碳酸钠、碳酸钾、醋酸钠、醋酸钾、碳酸氢钠或碳酸氢钾中的一种或一种以上，优选为氢氧化钠或氢氧化钾。
在本申请的一些具体实施方案中，在步骤i中使式Ⅹ化合物先与碱接触，然后再与次氯酸盐接触。
在本申请的一些具体实施方案中，在步骤i中，与次氯酸盐接触时的反应温度不大于25℃，优选为不大于5℃。
在本申请的一些具体实施方案中，在步骤i中，与次氯酸盐接触后升高反应温度；例如升高反应温度至25℃。
在本申请的一些具体实施方案中，在步骤ii中加入硫代硫酸盐时的反应温度为25℃。
在本申请的一些具体实施方案中，次氯酸盐为次氯酸钠或次氯酸钾。
在本申请的一些具体实施方案中，硫代硫酸盐为硫代硫酸钠或硫代硫酸钾。
在本申请的一些具体实施方案中，在步骤iii中，所述酸选自各种有机酸和无机酸，例如盐酸、硫酸、硝酸、磷酸、马来酸或柠檬酸等，优选为盐酸。
在本申请的一些具体实施方案中，在步骤iii中，加入酸使得反应体系的pH值不大于7，优选为不大于6，更优选为5-6。
在本申请的一些具体实施方案中，在步骤iii中，维持反应体系的温度不大于40℃，优选为不大于30℃，最优选为不大于20℃。
在本申请的一些具体实施方案中，式Ⅲ化合物的制备还进一步包括在步骤iii之后，加入乙醇或异丙醇的步骤。
还一方面，本申请提供式Ⅲ化合物的制备方法，其包括如下步骤：
(1)式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
(2)式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
(3)式Ⅵ化合物进行反应制备式Ⅱ化合物，
(4)式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷ化合物，
(5)式Ⅷ化合物进行反应制备式Ⅸ化合物，
(6)式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
(7)式Ⅹ化合物进行反应制备式Ⅲ化合物。
Figure PCTCN2016107274-appb-000015
反应方案I
还一方面，本申请提供式Ⅲ化合物的制备方法，包括如下步骤：
(1)式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
(2)式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
(3)式Ⅵ化合物进行反应制备式Ⅱ化合物，
(4)式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷa化合物，
(5)式Ⅷa化合物进行反应制备式Ⅸ化合物，
(6)式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
(7)式Ⅹ化合物进行反应制备式Ⅲ化合物。
Figure PCTCN2016107274-appb-000016
反应方案II
再一方面，本发明提供了式Ⅵ化合物或其盐或溶剂化物，
Figure PCTCN2016107274-appb-000017
其中R选自烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的芳基或杂芳基的取代基取代；
优选地，R选自C1-C6烷基、C3-C6环烷基、C3-C6杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的芳基或杂芳基的取代基取代；
更优选地，R选自C1-C4烷基和苄基，其中上述基团任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷硫基、卤素取代的C1-C6烷硫基和任选被一个或多个选自卤素、 羟基、氨基、C1-C6烷基、C1-C6烷氧基和C1-C6烷硫基的基团取代的芳基或杂芳基的取代基取代；
最优选地，R选自C1-C4烷基和苄基，其中上述基团任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基和卤素取代的C1-C6烷氧基的取代基取代；
在本申请的一些具体实施方案中，R选自甲基、乙基和苄基，其中上述基团可以任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基和卤素取代的C1-C6烷氧基的取代基取代。
在本申请的一些具体实施方案中，R选自甲基、乙基和苄基，其中上述基团任选地被一个或多个选自氟、氯、溴、甲基、乙基、三氟甲基、甲氧基的取代基取代。
在本申请的一些具体实施方案中，R选自乙基和苄基。
还一方面，本申请提供了式Ⅷ、式Ⅷa化合物或其盐或溶剂化物，
Figure PCTCN2016107274-appb-000018
其中R选自烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的杂芳基的取代基取代。
优选地，R选自C1-C6烷基、C3-C6环烷基、C3-C6杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的杂芳基的取代基取代。
更优选地，R选自C1-C4烷基，其中上述基团任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷硫基、卤素取代的C1-C6烷硫基和任选被一个或多个选自卤素、羟基、氨基、C1-C6烷基、C1-C6烷氧基和C1-C6烷硫基的基团取代的杂芳基的取代基取代。
最优选地，R选自C1-C4烷基和苄基，其中上述基团任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基和卤素取代的C1-C6烷氧基的取代基取代。
在本申请的一些具体实施方案中，R选自甲基和乙基，其中上述基团可以任选地被一个或多个选自卤素、C1-C6烷基、卤素取代的C1-C6烷基、C3-C6环烷基、卤素取代的C3-C6环烷基、C1-C6烷氧基和卤素取代的C1-C6烷氧基的取代基取代。
在本申请的一些具体实施方案中，R选自甲基和乙基，其中上述基团任选地被一个或多个选自氟、氯、溴、甲基、乙基、三氟甲基和甲氧基的取代基取代。
在本申请的一些具体实施方案中，R选自乙基。
还一方面，本发明提供了式Ⅹ化合物或其盐或溶剂化物，
Figure PCTCN2016107274-appb-000019
还一方面，本申请提供了式Ⅵ化合物、式Ⅷ化合物、式Ⅷa化合物或式Ⅹ化合物，或其盐或其溶剂化物在制备N-(3-氨基-4-氯-2-氟苯基)-3-氟丙烷-1-磺酰胺中的用途。
还一方面，本申请提供了式Ⅵ化合物、式Ⅷ化合物、式Ⅷa化合物或式Ⅹ化合物，或其盐或其溶剂化物在制备N-{3-[3-(9H-嘌呤-6-基)吡啶-2-基氨基]-4-氯-2-氟苯基}-3-氟丙烷-1-磺酰胺中的用途。
在本申请的制备方法中，通过将4-氯-2-氟苯胺制备成1-(4-氯-2-氟苯基)-2,5-二甲基-1H-吡咯，然后再与相应的酰卤反应连接酯基，进一步反应得到式Ⅱ所示的3-氨基-6-氯-2-氟苯甲酸酯类化合物。该方法所用的原料和试剂容易获得，反应条件温和，反应周期短，对环境友好，制备步骤简单易操作，收率高。在制备N-(3-氨基-4-氯-2-氟苯基)-3-氟丙烷-1-磺酰胺时，采用N,N'-羰基二咪唑和NH3，所用试剂廉价易得，制备步骤简单易操作，不仅明显提高了收率，而且产品具有高纯度，因此本申请所述的制备方法特别适合工业化生产。
术语及定义
除非另有定义，否则本文所有科技术语具有的涵义与所声称的主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。如果引用的是URL 或其它这种标识符或地址，应理解这种标识符会改变，因特网上的特定信息来去自由，但是通过搜索因特网或其它合适的参考资源可以找到相应的信息。这里引用表明这些信息的可获得和公开传播。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对所声称主题作任何限制。在本申请中，除非另有特别说明，否则使用单数时也包括复数。应注意的是，除非上下文明确指示，否则在说明书和所附权利要求书中使用的单数形式“a”、“an”和“the”包括复数形式。还应注意，除非另有说明，否则所用“或”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
除非另有说明，否则所用的通用化学术语，例如但不限于，“烷基”、“芳基”等同于其任选取代的形式。例如，本文所用的“烷基”包括任选取代的烷基。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，下文定义的“任选取代的烷基”是指“烷基”或“取代的烷基”。此外，任选取代的基团可以是未被取代(如CH2CH3)、完全取代(如CF2CF3)、单取代(如CH2CH2F)或介于完全取代和单取代之间的取代程度(如CH2CHF2、CF2CH3、CFHCHF2等)。
本文所用C1-Cn包括C1-C2、C1-C3、……C1-Cn。举例而言，所述“C1-C4”基团是指该部分中具有1-4个碳原子，即基团包含1个碳原子，2个碳原子、3个碳原子或4个碳原子，C1-C2和C1-C3也一样。因此，举例而言“C1-C4烷基”是指有1-4个碳原子的烷基，即所述烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。本文中的数字范围，例如“1-10”是指给定范围中的各个整数，例如“1-10个碳原子”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
本文单独或组合使用的术语“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。
本文单独或组合使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃。本文的“烷基”可具有1-约18个碳原子，或具有1-约10个碳原子，优选1-6个碳原子。本文单独或组合使用的“低级烷基”是指碳数较少的烷基，例如其具有1-约8个碳原子，优选1-约6个碳原子，或1-约4个碳原子。本文的烷基实例包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-l-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-l-丁基、 2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-l-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-l-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基和己基，以及更长的烷基基团，如庚基和辛基等。本文中出现数字范围时，例如“C1-C6烷基”或“C1-6烷基”是指可由1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烷基，本文的烷基也包含未指定数字范围的情况。
本文组合使用的“烷基”包括但不限于包含在“烷氧基”、“烷硫基”、“单-烷基氨基”和“二-烷基氨基”等中的“烷基”。
本文单独或组合使用的术语“烯基”是指任选取代的直链或任选取代的支链的一价烃，其具有一个或多个碳-碳双键。所述烯基例如具有2-约18个碳原子，或具有2-约10个碳原子，更优选2-约6个碳原子。这些基团中的双键可以为顺式或反式构型，并应被理解为包含所述两种异构体。本文单独或组合使用的“低级烯基”是指碳数较少的烯基，例如其具有2-约8个碳原子，优选2-约6个碳原子，或2-约4个碳原子。实例包括但不限于乙烯基(-CH＝CH2)、1-丙烯基(-CH2CH＝CH2)、异丙烯基(-C(CH3)＝CH2)、丁烯基和1,3-丁二烯基等。本文定义的烯基出现数字范围时，例如“C2-C6烯基”或“C2-6烯基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烯基，本文的烯基也涵盖未指定数字范围的情况。
本文单独或组合使用的术语“炔基”是指任选取代的直链或任选取代的支链的一价烃，其具有一个或多个碳-碳三键。例如所述炔基具有2-约18个碳原子或2-约10个碳原子，更优选2-约6个碳原子。本文单独或组合使用的“低级炔基”是指碳数较少的炔基，例如其具有2-约8个碳原子，优选2-约6个碳原子或2-约4个碳原子。本文的炔基实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。本文定义的炔基出现数字范围时，例如“C2-C6炔基”或“C2-6炔基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的炔基基团，本文的炔基也涵盖未指定数字范围的情况。
术语“元”是指组成环的骨架原子的数目。因此，举例而言，环己烷、吡啶、吡喃和嘧啶为六元环，而环戊烷、吡咯、四氢呋喃和噻吩为五元环。
本文单独或组合使用的术语“环烷基”是指任选取代的一价饱和烃环，其包含3-约15个成环碳原子或3-约10个成环碳原子，也可包括作为取代基的其它非成环碳原子(例如甲基环丙基)。环烷基可具有3至约10个或3-约8个或3-约6个或3-5个成环原子，环烷基的实例包括但不限于环丙烷、环丁烷、环戊烷和环己烷。
本文单独或组合使用的术语“低级环烷基”是指成环原子数较少的环烷基，例如含有5到约10个或5到约6个或5到6个成环原子或者3至6个成环原子，例如具有3、4、5或6个成环原子。
术语“杂环烷基”是指完全饱和的并且可以以单环、双环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至7元环。“杂环烷基”的非限制性实例包括氮杂环丁烷基(azetidinyl)、氧杂环丁基(oxetanyl)、硫杂环丁基(thietanyl)、高哌啶基(homopiperidinyl)、氧杂环庚基(oxepanyl)、硫杂环庚基(thiepanyl)、二氧杂环己基(dioxanyl)、1,3-二氧戊环基(1,3-dioxolanyl)、二硫环己基(dithianyl)、二硫环戊基(dithiolanyl)、吡唑烷基、咪唑烷基(imidazolidinyl)、3-氮杂双环[3.1.0]己基和3-氮杂双环[4.1.0]庚基等。
本文单独或组合使用的术语“芳基”是指具有完全共轭的π电子体系的全碳单环或稠合环，其具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。非取代的芳基的非限制性实例包括但不限于苯基、萘基和蒽基。
本文单独或组合使用的术语“杂芳基”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。杂芳基可以是未取代的或取代的，所述的取代基包括但不限于烷基、烷氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。未取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。
本文单独或组合使用的术语“卤素”、“卤代”或“卤化物”是指氟、氯、溴和碘。
本文单独或组合使用的术语“烷氧基”是指“-O-烷基”。烷氧基的非限定性实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。
本文单独或组合使用的术语“烷硫基”是指“-S-烷基”。烷硫基的非限定性实例包括甲硫基、乙硫基、丙硫基和丁硫基等。
本文单独或组合使用的术语“低级烷基”、“低级烷氧基”、“低级烷硫基”是指碳原子数为1-约8个，或1-6个或1-5个或1-4个或1-3个或1-2个的所述烷基、烷氧基和烷硫基。
本文所用术语“盐”的实例包括通过本文所述化合物与无机酸或有机酸或无机碱反应而制备的盐。这些盐包括乙酸盐、丙烯酸盐、己二酸盐、海藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、重亚硫酸盐、溴化物、丁酸盐、丁炔-1,4-二酸盐、樟脑酸盐、樟脑 磺酸盐、辛酸盐、氯代苯甲酸盐、氯化物、柠檬酸盐、环戊烷丙酸盐、癸酸盐、葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、己炔-1,6-二酸盐(hexyne-1,6-dioate)、羟基苯甲酸盐、y-羟基丁酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟乙磺酸盐、碘化物、异丁酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、扁桃酸盐、偏磷酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、磷酸一氢盐、1-萘磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、双羟萘酸盐、果冻酸盐(pectinate)、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、焦硫酸盐、焦磷酸盐、丙炔酸(propiolate)、邻苯二甲酸盐、苯乙酸盐、苯丁酸盐、丙磺酸盐、水杨酸盐、琥珀酸盐、硫酸盐、亚硫酸盐、辛二酸盐、癸二酸盐、磺酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐(undeconate)和二甲苯磺酸盐。
本文所用术语“溶剂化物”是指通过溶剂化作用形成的本发明化合物与溶剂分子的组合。在某些情况下，溶剂化物指水合物，即溶剂分子为水分子，本发明化合物与水的组合形成水合物。
具体实施方式
实施例1 1-(4-氯-2-氟苯基)-2,5-二甲基-1H-吡咯(式Ⅴ)的制备
Figure PCTCN2016107274-appb-000020
向装配有分水器的5L三口反应瓶中加入4-氯-2-氟苯胺(598g，4.11mol)、2,5-己二酮(518g，4.54mol)和甲苯(3.0L)，搅拌10分钟至体系混合均匀。加入催化量的对甲苯磺酸(1.4g)，加热回流2小时。待体系冷却后，分别用水(1L)和饱和食盐水(1L)洗，并加入无水硫酸钠干燥。滤除干燥剂后，真空浓缩去除溶剂，所得残余物减压浓缩得到无色透明液体(850g，收率92％)，该液体产物遇冷会迅速固化。
1H NMR(CDCl3):δ7.28-7.18(3H,m),5.93(2H,s),2.00(6H,s)。
实施例2 6-氯-3-(2,5-二甲基-1H-吡咯-1-基)-2-氟苯甲酸乙酯(式Ⅵ-0)的制备
Figure PCTCN2016107274-appb-000021
向装配有恒压滴液漏斗的3L三口反应瓶中加入式Ⅴ化合物(224g，1.00mol)和干燥的四氢呋喃(1.3L)，搅拌5分钟至体系混合均匀，反应体系氮气置换并冷却至-30℃，缓慢滴加正丁基锂溶液(2.4mol/L，438mL)，保持体系温度低于-30℃。滴加完成后，在此温度下继续搅拌1小时。将氯甲酸乙酯(217g，2.00mol)溶于干燥的四氢呋喃溶液中(220mL)，氮气置换并冷却到-30℃。然后，在氮气保护下，将氯甲酸乙酯溶液滴加到上述溶液中。此过程保持体系温度低于-30℃。滴加完成后继续搅拌30分钟，加入饱和氯化铵水溶液(450mL)并自然升至室温。加入乙酸乙酯(1.5L)和水(3.0L)，分液，水相用乙酸乙酯(1.5L)萃取。合并有机相，用饱和食盐水(2.0L)洗涤，加入无水硫酸钠干燥。滤除干燥剂后，真空浓缩去除溶剂，所得残余物减压浓缩得到无色透明液体(266g，收率：90％)，该液体产物遇冷会迅速固化。
1H NMR(CDCl3):δ7.33-7.23(2H,m),5.93(2H,s),4.47(2H,q)，2.00(6H,s)，1.43-1.39(3H,m)。
实施例3 3-氨基-6-氯-2-氟苯甲酸乙酯(式Ⅱ-0)化合物的制备
Figure PCTCN2016107274-appb-000022
向3L三口反应瓶中加入式Ⅵ-0化合物(286g，0.96mol)、乙醇(1.2L)和水(400mL)，搅拌均匀，加入三乙胺(389g，3.84mol)和盐酸羟胺(997g，14.4mol)。反应体系在80℃下剧烈搅拌24小时，减压浓缩去除大部分乙醇，加入水(3.0L)和乙酸乙酯(1.5L)，搅拌并分液，所得水相用乙酸乙酯(1L)萃取两次，合并有机相并用饱和食盐水(2L)洗涤，加入无水硫酸钠干燥，过滤，减压浓缩，得到无色液体(140g，收率：90％)。
1H NMR(CDCl3):δ6.97(1H,dd,J＝8.8Hz,J＝0.8Hz),6.73(1H,t,J＝9.2Hz),4.44(2H,q,J＝6.8Hz),3.84(2H,s),1.41-1.38(3H,m)。
实施例4 6-氯-2-氟-3-[3-氟-N-(3-氟-丙基磺酰基)丙基磺酰氨基]苯甲酸乙酯(式Ⅷ-0)的制备
Figure PCTCN2016107274-appb-000023
向3L三口反应瓶中加入式Ⅱ-0化合物(162g，0.74mol)、三乙胺(244g，2.22mol)和二氯甲烷(970mL)，搅拌10分钟至体系混合均匀，然后缓慢滴加3-氟-1-丙基磺酰氯(244g，1.52mol)，控制体系温度低于20℃，滴加完成后，常温搅拌3小时，反应液依次用1mol/L盐酸(2.5L)、水(2.0L)和饱和食盐水(1.0L)洗涤，加入无水硫酸钠干燥，过滤，减压浓缩，得到浅褐色液体(329g，95％)。
1H NMR(CDCl3):δ7.40-7.39(1H,m),7.35-7.28(1H,m),4.65-4.63(2H,m),4.53-4.44(4H,m),3.80-3.68(4H,m),2.37-2.27(4H,m)，1.43-1.38(3H,m)。
实施例5 6-氯-2-氟-3-(3-氟-丙基磺酰氨基)苯甲酸(式Ⅸ)的制备
Figure PCTCN2016107274-appb-000024
向5L三口瓶中加入式Ⅷ-0化合物(309g，0.66mol)和四氢呋喃(1.5L)，常温下搅拌10分钟至体系混合均匀，冰水浴冷却，滴加2mol/L氢氧化钾水溶液(1.65L，3.3mol)，滴加期间控制体系温度低于10℃，滴加完成后撤去冰水浴，常温搅拌3天，体系再置于冰水浴中，滴加浓盐酸至pH值小于3，期间控制体系温度低于10℃，过滤，所得固体置于2L水中打浆，再次过滤并用2-3L水洗涤，干燥后得到产物(309g，95％)。
1H NMR(CDCl3):δ10.04(1H,s),7.50(1H,t,J＝8.8Hz),7.39(1H,dd,J＝8.8Hz,J＝1.2Hz),4.60(1H,t,J＝5.6Hz),4.48(1H,t,J＝5.6Hz),3.28-3.24(2H,m),2.16-2.03(2H,m)。
实施例6 6-氯-2-氟-3-(3-氟-丙基磺酰氨基)苯甲酸乙酯(式Ⅷa-0)的制备
Figure PCTCN2016107274-appb-000025
向3L三口反应瓶中加入式Ⅱ-0化合物(190g，0.87mol)、吡啶(345g，4.36mol)和二氯甲烷(1.9L)，搅拌10分钟至体系混合均匀，然后缓慢滴加3-氟-1-丙基磺酰氯(168g，1.05mol)的二氯甲烷(0.34L)溶液。滴加过程中控制体系温度为20-25℃。滴加完成后，体系升温至30℃并在此温度下反应24h，反应液依次用4mol/L盐酸(1.9L)、饱和食盐水洗(1L)，有机相真空浓缩，得到红棕色液体(298g)。
1H NMR(CDCl3):δ7.48(1H,t),7.36(1H,dd),4.64-4.62(2H,m),4.58(1H,t),4.47(1H,t),3.28-3.24(2H,m),2.16-2.03(2H,m)，1.41-1.38(3H,m)。
实施例7 6-氯-2-氟-3-(3-氟-丙基磺酰氨基)苯甲酸(式Ⅸ)的制备
Figure PCTCN2016107274-appb-000026
向5L三口瓶中加入式Ⅷa-0化合物(298g，0.87mol)和四氢呋喃(1.5L)，常温下搅拌10分钟至体系混合均匀，降温至低于0℃，滴加2mol/L氢氧化钾水溶液(1.7L)，滴加期间控制体系温度低于10℃，滴加完成后在35℃下搅拌3天，降温，滴加浓盐酸至pH值小于3，期间控制体系温度低于10℃，分层，水相用乙酸乙酯反萃(0.6L)两次，有机相集中经饱和食盐水洗(0.9L)，有机相真空浓缩，干燥后得到产物(259g，95％)
实施例8 6-氯-2-氟-3-(3-氟-丙基磺酰氨基)苯甲酰胺(式Ⅹ)的制备
Figure PCTCN2016107274-appb-000027
向3L三口反应瓶中加入式Ⅸ化合物(239g，0.76mol)、N,N'-羰基二咪唑(184g， 1.14mol)和干燥四氢呋喃(1.2L)，加热回流1小时，反应完成后，体系冷却至0℃，加入水(500mL)，在0℃下搅拌，并通入氨气至反应完成，加入500mL冰水，滴加浓盐酸调节pH值到3-4，期间冰水浴冷却控制体系温度低于15℃，分液，水相用乙酸乙酯(1L)萃取两次，合并有机相，加入无水硫酸钠干燥，过滤，减压浓缩，所得残余物加入240mL乙醇搅拌2小时，过滤，干燥得到产物(208g，收率：87％)，HPLC检测纯度大于99％(面积归一化法)。
1H NMR(CDCl3):δ9.98(1H,s),8.14(1H,s),7.87(1H,s),7.44-7.42(1H,m),7.35-7.32(1H,m),4.60(1H,t,J＝5.6Hz),4.48(1H,t,J＝5.6Hz),3.26-3.22(2H,m),2.14-2.06(2H,m)。
实施例9 N-(3-氨基-4-氯-2-氟苯基)-3-氟丙烷-1-磺酰胺(式Ⅲ)的制备
Figure PCTCN2016107274-appb-000028
向3L三口反应瓶中加入式Ⅹ化合物(176g，0.56mol)和四氢呋喃(880mL)，搅拌10分钟至体系混合均匀，体系置于冰水浴中，并加入4mol/L的氢氧化钠水溶液(1400mL，5.60mol)，搅拌10分钟，在5分钟内，向体系内分批加入冷却至5℃以下的次氯酸钠水溶液(1.05L，含氯量10％)，继续搅拌1小时，撤去冰水浴，体系自然升至室温，继续搅拌4-5小时，加入硫代硫酸钠(1.12kg，4.51mol)，搅拌20分钟至硫代硫酸钠完全溶解，将反应体系置于冰水浴中，滴加浓盐酸至pH值到5-6，期间控制体系温度低于20℃，分液，水相用乙酸乙酯(700mL)萃取两次，合并有机相，依次用水(1.0L)和饱和食盐水(1.0L)洗，加入无水硫酸钠干燥，过滤，减压浓缩，所得残余物加入260mL乙醇打浆，过滤，并用约50-60mL乙醇冲洗滤饼，干燥，得到白色固体(120g，收率：75％)，HPLC检测纯度大于99.5％(面积归一化法)。
1H NMR(CDCl3):δ9.66(1H,s),7.04(1H,dd,J＝8.4Hz，J＝1.6Hz),6.57(1H,t,J＝8.4Hz),4.60(1H,t,J＝6.0Hz),4.48(1H,t,J＝6.0Hz),3.19-3.16(2H,m),2.15-2.02(2H,m)。

Claims (19)

  1. 制备式Ⅲ化合物的方法，其包括使式Ⅹ化合物进行反应制备式Ⅲ化合物，
    Figure PCTCN2016107274-appb-100001
  2. 如权利要求1所述的制备方法，其还包括使式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
    Figure PCTCN2016107274-appb-100002
  3. 如权利要求2所述的制备方法，其还包括使式Ⅷ化合物进行反应制备式Ⅸ化合物，
    Figure PCTCN2016107274-appb-100003
    或者
    使式Ⅷa化合物进行反应制备式Ⅸ化合物，
    Figure PCTCN2016107274-appb-100004
    其中各个R独立地选自烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、-OH、-NH2、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的芳基或杂芳基的取代基取代。
  4. 如权利要求3所述的制备方法，其还包括使式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷa化合物，
    Figure PCTCN2016107274-appb-100005
    其中R如同权利要求3中所定义，
    或者
    使式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷ化合物，
    Figure PCTCN2016107274-appb-100006
    其中R如同权利要求3中所定义。
  5. 如权利要求4所述的制备方法，其还包括使式Ⅵ化合物进行反应制备式Ⅱ化合物：
    Figure PCTCN2016107274-appb-100007
    其中R如同权利要求3中所定义。
  6. 如权利要求5所述的制备方法，其还包括
    (1)使式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
    (2)使式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
    Figure PCTCN2016107274-appb-100008
    其中R如同权利要求3中所定义以及X选自卤素。
  7. 式Ⅱ化合物的制备方法，其包括如下步骤：
    (1)式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
    (2)式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
    (3)式Ⅵ化合物进行反应制备式Ⅱ化合物
    Figure PCTCN2016107274-appb-100009
    其中R如同权利要求3中所定义以及X选自卤素。
  8. 如权利要求7所述的制备方法，其中在步骤(1)中，在催化剂的存在下，使式Ⅳ化合物与2,5-己二酮进行反应。
  9. 如权利要求7所述的制备方法，其中在步骤(3)中在选自盐酸羟胺；盐酸羟胺和碱；或者盐酸和碱的试剂的存在下，使式Ⅵ化合物进行反应，其中当所述试剂为盐酸和碱时，先加入盐酸反应一段时间后再加入碱。
  10. 制备式Ⅷ化合物的方法，其包括使式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷ化合物，
    Figure PCTCN2016107274-appb-100010
    其中R如同权利要求3中所定义。
  11. 制备式Ⅷa化合物的方法，其包括使式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷa化合物，
    Figure PCTCN2016107274-appb-100011
    其中R如同权利要求3中所定义。
  12. 制备式Ⅸ化合物方法，其包括使式Ⅷ化合物进行反应制备式Ⅸ化合物，
    Figure PCTCN2016107274-appb-100012
    其中R如同权利要求3中所定义，或者
    使式Ⅷa化合物进行反应制备式Ⅸ化合物，
    Figure PCTCN2016107274-appb-100013
    其中R如同权利要求3中所定义。
  13. 制备式Ⅹ化合物的方法，其包括使式Ⅸ化合物与N,N'-羰基二咪唑进行反应，然后加入NH3制备式Ⅹ化合物，
    Figure PCTCN2016107274-appb-100014
  14. 制备式Ⅲ化合物的方法，其包括如下步骤：
    (1)使式Ⅸ化合物与N,N'-羰基二咪唑进行反应，然后加入NH3制备式Ⅹ化合物，
    (2)使式Ⅹ化合物进行反应制备式Ⅲ化合物，
    Figure PCTCN2016107274-appb-100015
  15. 制备式Ⅲ化合物的方法，其包括如下步骤：
    (1)式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
    (2)式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
    (3)式Ⅵ化合物进行反应制备式Ⅱ化合物，
    (4)式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷ化合物，
    (5)式Ⅷ化合物进行反应制备式Ⅸ化合物，
    (6)式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
    (7)式Ⅹ化合物进行反应制备式Ⅲ化合物，
    Figure PCTCN2016107274-appb-100016
  16. 制备式Ⅲ化合物的方法，其包括如下步骤：
    (1)式Ⅳ化合物与2,5-己二酮进行反应制备式Ⅴ化合物，
    (2)式Ⅴ化合物与式Ⅶ化合物进行反应制备式Ⅵ化合物，
    (3)式Ⅵ化合物进行反应制备式Ⅱ化合物，
    (4)式Ⅱ化合物与3-氟-1-丙基磺酰氯进行反应制备式Ⅷa化合物，
    (5)式Ⅷa化合物进行反应制备式Ⅸ化合物，
    (6)式Ⅸ化合物与N,N'-羰基二咪唑(CDI)进行反应，然后加入NH3制备式Ⅹ化合物，
    (7)式Ⅹ化合物进行反应制备式Ⅲ化合物，
    Figure PCTCN2016107274-appb-100017
  17. 式Ⅵ化合物或其盐或溶剂化物，
    Figure PCTCN2016107274-appb-100018
    其中R选自烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的芳基或杂芳基的取代基取代。
  18. 式Ⅷ、式Ⅷa化合物或其盐或溶剂化物，
    Figure PCTCN2016107274-appb-100019
    其中R选自烷基、烯基、炔基、环烷基、杂环烷基、芳基和杂芳基，其中上述基团任选地被一个或多个选自卤素、低级烷基、卤素取代的低级烷基、环烷基、卤素取代的环烷基、低级烷氧基、卤素取代的低级烷氧基、低级烷硫基、卤素取代的低级烷硫基、单-烷基氨基、二-烷基氨基、环烷基氨基和任选被一个或多个选自卤素、羟基、氨基、低级烷基、低级烷氧基和低级烷硫基的基团取代的杂芳基的取代基取代。
  19. 式Ⅹ化合物或其盐或溶剂化物，
    Figure PCTCN2016107274-appb-100020
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