WO2017114461A1 - 一种芦可替尼的合成工艺 - Google Patents

一种芦可替尼的合成工艺 Download PDF

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WO2017114461A1
WO2017114461A1 PCT/CN2016/113000 CN2016113000W WO2017114461A1 WO 2017114461 A1 WO2017114461 A1 WO 2017114461A1 CN 2016113000 W CN2016113000 W CN 2016113000W WO 2017114461 A1 WO2017114461 A1 WO 2017114461A1
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compound
formula
acid
group
amino protecting
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PCT/CN2016/113000
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English (en)
French (fr)
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张喜全
张爱明
周舟
杨雷雷
姚华东
朱雪焱
王胡博
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正大天晴药业集团股份有限公司
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Priority to CN201680072360.XA priority Critical patent/CN108699063B/zh
Priority to JP2018534102A priority patent/JP6921087B2/ja
Priority to EP16881250.1A priority patent/EP3398952B1/en
Priority to US16/066,482 priority patent/US10562904B2/en
Priority to ES16881250T priority patent/ES2882118T3/es
Publication of WO2017114461A1 publication Critical patent/WO2017114461A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present application belongs to the field of pharmaceutical synthesis, and in particular, the present application relates to a preparation method of rucotinib, an intermediate used and a preparation method of related intermediates.
  • Ruxolitinib is a selective JAK1/JAK2 tyrosine kinase inhibitor developed by Incyte and Novartis. It was approved by the US FDA in November 2011 as the first drug to treat myelofibrosis.
  • the product name is Jakafi), indications for intermediate or high-risk myelofibrosis, including primary myelofibrosis, secondary erythrocytosis, myelofibrosis, and myeloproliferative myelofibrosis; December 2014, FDA Approved new indications for polycythemia vera that are inadequate or intolerant to semicarbazide. It was approved by the European Union in August 2012 (trade name is Jakavi); it was approved by Japan in July 2014.
  • the method disclosed above is reviewed.
  • the chiral split is close to the finished product step.
  • the atomic utilization rate is low and the cost is high; and the structure of the chiral catalyst is relatively complicated, and the amount of the catalyst is high.
  • the chiral separation product has a low ee value, and the chiral purity can only reach about 90%. It is still necessary to split the product or obtain a medicinal value through a multi-step refining process.
  • Angew. Chem. Int. Ed. 2015, 54, 7149 - 7153 discloses another preparation method of rucotinib, in which the ruthenium catalyst and its metal ligand are used in a high amount and the reaction conditions are harsh. From the perspective of cost and operation, it is not conducive to large-scale production.
  • the present application aims to provide a new preparation method for ricinibini suitable for industrial production.
  • the application provides a method of preparing a compound of formula I, rucotinib, comprising the steps of:
  • Step 4 Conversion of a compound of formula III to a compound of formula XI, followed by conversion of a compound of formula XI to a compound of formula XII in the presence of an amination reagent,
  • R is selected from H or an amino protecting group, and X is selected from Cl or Br;
  • Step 5-1 When R is H, the amide group of formula XII is converted to a cyano group in the presence of a dehydrating agent to give the compound of formula I, rotectinib, or
  • Step 5-2 When R is an amino protecting group, the amide group of formula XII is converted to a cyano group and the amino protecting group R is removed to provide a compound of formula I, rucotinib.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulf
  • the reagent used to convert the compound of Formula III to the compound of Formula XI in Step 4 is selected from one or more of the group consisting of phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and oxalyl chloride. A combination of oxalyl chloride is preferred.
  • the solvent used in the conversion of the compound of formula III to the compound of formula XI in step 4 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, ethyl acetate.
  • the amination reagent used to convert the compound of formula XI to the compound of formula XII in step 4 is selected from the group consisting of ammonia, liquid ammonia, and ammonia, preferably a combination of ammonia, preferably ammonia.
  • the solvent used in the conversion of the compound of formula XI to the compound of formula XII in step 4 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, ethyl acetate,
  • a mixed solvent of isopropyl acetate, toluene or xylene or one or more of the above solvents is preferably dichloromethane or tetrahydrofuran or a mixed solvent of the two.
  • the dehydrating agent used in step 5-1 is selected from the group consisting of phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, thionyl chloride, trifluoroacetic anhydride, trifluorosulfonate, and A combination of one or more of oxalyl chlorides, preferably phosphorus oxychloride or cyanuric chloride.
  • the solvent used in step 5-1 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, DMSO, ethyl acetate, isopropyl acetate, toluene Or a mixed solvent of xylene or one or more of the above solvents, preferably dichloromethane or NMP or a mixed solvent of the two.
  • the molar ratio of the compound of the formula XII to the dehydrating agent in the step 5-1 is 1:1 to 10, preferably It is selected from 1:3 to 8, more preferably from 1:4 to 7, and further preferably from 1:5 to 7.
  • the order in which the amide group of the formula XII in step 5-2 is converted to a cyano group and the amino group-protecting group R can be converted.
  • the reaction of converting the amide group into a cyano group may be carried out before the removal of the protecting group R, or the removal may be carried out first.
  • the reaction of the group R is followed by a reaction for converting an amide group into a cyano group, both of which are within the scope of protection of the present application.
  • the dehydrating agent used in the reaction of converting the amide group to the cyano group in the step 5-2 is selected from the group consisting of phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, and thionyl chloride.
  • a combination of one or more of trifluoroacetic anhydride, trifluorosulfonic anhydride and oxalyl chloride is preferably phosphorus oxychloride or cyanuric chloride.
  • the solvent used in the reaction of converting the amide group to the cyano group in the step 5-2 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, DMSO, Ethyl acetate, isopropyl acetate, toluene or xylene, preferably dichloromethane or NMP.
  • the removal of the protecting group R in step 5-2 can be carried out under acidic or basic conditions.
  • the reaction of removing the protecting group R can be carried out by selecting a suitable catalyst and solvent, respectively.
  • the catalyst used in the reaction for removing the protecting group R in the step 5-2 under acidic conditions is selected from the group consisting of trifluoroacetic acid, trifluoroacetic anhydride, lithium tetrafluoroborate or boron trifluoride.
  • Ethyl ether preferably trifluoroacetic acid or boron trifluoride-diethyl ether.
  • the solvent used in the reaction for removing the protecting group R in the step 5-2 under acidic conditions is selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, water, NMP, DMA or DMF, preferably acetonitrile. Or NMP.
  • the catalyst used in the reaction for removing the protecting group R in the step 5-2 under alkaline conditions is selected from the group consisting of sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, Lithium hydroxide, potassium t-butoxide, sodium t-butoxide, hydrazine hydrate or tetrabutylammonium fluoride, preferably lithium hydroxide or potassium carbonate.
  • the solvent used in the reaction for removing the protecting group R in the step 5-2 under basic conditions is selected from the group consisting of ethanol, water, methanol, tetrahydrofuran or isopropanol, preferably water or tetrahydrofuran.
  • the method for preparing the compound of the formula I of the present application, rucotinib optionally further comprises the step 3: reacting a compound of the formula II with a compound of the formula IV or a salt thereof to obtain a compound of the formula III,
  • R is selected from H or an amino protecting group.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulf
  • the compound of formula IV as described in step 3 of the present application may be the free base or a salt thereof.
  • the salt of the compound of Formula IV described in Step 3 may be selected from a chiral salt or an achiral salt.
  • the chiral acid used to form the chiral salt may be selected from the following acids or enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptan-1-yrene Methanesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative, preferably lactic acid, malic acid, camphor Acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoyltartari
  • the chiral acid used to form the chiral salt may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid, D-di-p-methylbenzoate.
  • Acid tartaric acid D-di-p-methoxybenzoyltartaric acid, D-di-p-chlorobenzoyltartaric acid, D-di-p-bromobenzoyltartaric acid, D-di-p-fluorobenzoyltartaric acid, D-di-p-nitro Benzoyl Acid tartaric acid, D-di-p-aminobenzoyltartaric acid or D-di-p-cyanobenzoyltartaric acid.
  • the achiral salt is selected from the group consisting of a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate, a formate, an acetate, a trifluoroacetate, and a rich Horse salt, oxalate, maleate, citrate, succinate, methanesulfonate, besylate or p-toluenesulfonate, preferably hydrochloride, hydrobromide, sulfuric acid Salt, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate or p-toluenesulfonate, more preferably hydrochloride or acetate.
  • the molar ratio of the compound of the formula II and the compound of the formula IV or a salt thereof in the step 3 is 1.0:1.0 to 5.0, preferably 1.0:1.0 to 3.0, more preferably 1.0:1.0 to 1.5, further Preferably, it is 1.0: 1.0 to 1.2.
  • Step 3 of the present application can be carried out under acidic conditions, under alkaline conditions or under neutral conditions.
  • reaction described in Step 3 is carried out under acidic conditions.
  • the acidic condition of Step 3 is provided by the addition of an acidic reagent selected from the group consisting of citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, ascorbic acid. Sulfuric acid, hydrochloric acid or hydrobromic acid, or a mixture thereof, preferably tartaric acid, acetic acid or hydrochloric acid.
  • reaction described in Step 3 is carried out under basic conditions.
  • the alkaline condition of step 3 is provided by the addition of an alkaline agent selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, carbonic acid.
  • an alkaline agent selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, carbonic acid.
  • the solvent used in the step 3 of the present application is selected from the group consisting of acetic acid, ethanol, methanol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, water, N-methylpyrrolidone, N,N-dimethylformamide and N,N.
  • the method of preparing the compound of the formula I of the present application, rucotinib optionally further comprises the step 2: converting the compound of the formula VI to a compound of the formula II by the action of DMF and a chlorinating reagent:
  • R is selected from H or an amino protecting group.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulf
  • the chlorinating agent is selected from one or a mixture of two or more of oxalyl chloride, phosphorus oxychloride and thionyl chloride, preferably phosphorus oxychloride.
  • the ratio of the amount of the compound of formula VI to the amount of the chlorinating agent is selected from the group consisting of 1.0:2.0 to 6.0, preferably 1.0:2.0 to 4.0, more preferably 1.0:2.5 to 3.5.
  • the solvent used is selected from the group consisting of 1,4-dioxane, dichloromethane, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylformamide.
  • One or more mixed solvents are preferably N,N-dimethylformamide, 1,4-dioxane or tetrahydrofuran or a mixed solvent of one or more of them.
  • the method of preparing the compound of the formula I of the present application, rucotinib optionally further comprises the step of reacting a compound of formula V in the presence of a catalyst and a methylating agent to provide a compound of formula VI:
  • the methylating agent in step 1 is selected from the group consisting of methyl magnesium bromide, methyl magnesium chloride or trimethyl aluminum, preferably methyl magnesium bromide.
  • the solvent used in step 1 is selected from the group consisting of toluene, dichloromethane, diethyl ether or tetrahydrofuran, preferably tetrahydrofuran or diethyl ether.
  • the catalyst used in step 1 is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(bppf)Cl 2 or Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , preferably Pd(bppf)Cl 2 .
  • the molar ratio of the compound of formula V in step 1 to the catalyst and methylating agent is from 1:0.005 to 0.05:1.5 to 4, preferably from 1:0.005 to 0.015:2 to 3.
  • the method of preparing the compound of Formula IV or a chiral salt thereof in Step 3 comprises the steps of:
  • Step C-1 a compound of formula X is reacted with a chiral acid in the presence of a solvent to form a chiral salt of a compound of formula IV,
  • Step C-2 isolating the chiral salt of the compound of formula IV;
  • Step C-3 Alternatively, the chiral salt of a compound of formula IV is treated with a base to provide a compound of formula IV.
  • the chiral acid described in Step C-1 may be selected from the following acids or their enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptan-1-yrene Methanesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative; preferably lactic acid, malic acid, camphor Acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoyltartaric acid
  • the chiral acid used to form the chiral salt of the compound of Formula IV in Step C-1 may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid.
  • the solvent used in the step C-1 is selected from one or more mixed solvents of acetone, 1,4-dioxane, tetrahydrofuran and ethyl acetate, preferably acetone. .
  • the molar ratio of the compound of the formula X to the chiral acid in the step C-1 is from 1.0:0.2 to 1.0, preferably from 1.0:0.3 to 0.7, more preferably from 1.0:0.4 to 0.6.
  • the method further includes the following steps:
  • Step A a compound of formula VII is reacted with malonic acid in the presence of a base to provide a compound of formula VIII,
  • Step B a compound of the formula VIII is reacted with hydrazine hydrate to give a compound of the formula X,
  • the base used in step A is selected from the group consisting of piperidine, triethylamine, valine, N,N-diisopropylethylamine, tetrahydropyrrolidine, pyridine or 4-di Methylaminopyridine, preferably piperidine.
  • the solvent used in step A is selected from the group consisting of pyridine, acetonitrile, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone or 1,4-di Oxy hexacyclo, preferably pyridine.
  • the solvent used in step B is selected from the group consisting of hydrazine hydrate, 1,4-dioxane, ethanol, methanol, isopropanol, tetrahydrofuran, N-methylpyrrolidone, and N,N- One or more mixed solvents of dimethylformamide, preferably hydrazine hydrate.
  • the present application provides a method of preparing a compound of formula I, rucotinib, the method comprising the steps of:
  • Step 2 The compound of formula VI is converted to a compound of formula II by the action of DMF and a chlorinating reagent,
  • Step 3 a compound of formula II is reacted with a compound of formula IV or a salt thereof to provide a compound of formula III,
  • Step 4 Conversion of a compound of formula III to a compound of formula XI, wherein the compound of formula XI is converted to a compound of formula XII in the presence of an amination reagent,
  • Step 5-1 When R is H, the amide group of formula XII is converted to a cyano group in the presence of a dehydrating agent to give the compound of formula I, rotectinib, or
  • Step 5-2 When R is an amino protecting group, the amide group of formula XII is converted to a cyano group and the amino protecting group R is deaminated to provide a compound of formula I, rucotinib.
  • R is selected from H or an amino protecting group
  • X is selected from Cl or Br.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulf
  • the chlorinating agent is selected from one or a mixture of two or more of oxalyl chloride, phosphorus oxychloride and thionyl chloride, preferably phosphorus oxychloride.
  • the ratio of the amount of the compound of formula VI to the amount of the chlorinating agent is selected from the group consisting of 1.0:2.0 to 6.0, preferably 1.0:2.0 to 4.0, more preferably 1.0:2.5 to 3.5.
  • the solvent used is selected from the group consisting of 1,4-dioxane, dichloromethane, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylformamide.
  • One or more mixed solvents are preferably N,N-dimethylformamide, 1,4-dioxane or tetrahydrofuran or a mixed solvent of one or more of the above three solvents.
  • the salt of the compound of formula IV may be selected from a chiral salt or an achiral salt.
  • the chiral acid used to form the chiral salt may be selected from the following acids or their enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid , malic acid, 3-bromo camphor-8-sulfonic acid, 3-bromo camphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]g -1-methylenesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative, preferably from lactic acid , malic acid, camphoric acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoy
  • the chiral acid used to form the chiral salt may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid, and D-pair.
  • Methylbenzoyltartaric acid D-di-p-methoxybenzoyltartaric acid, D-di-p-chlorobenzoyltartaric acid, D-di-p-bromobenzoyltartaric acid, D-di-p-fluorobenzoyltartaric acid, D - Di-p-nitrobenzoyl tartaric acid, D-di-p-aminobenzoyltartaric acid or D-di-p-cyanobenzoyltartaric acid.
  • the achiral salt is selected from the group consisting of a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate, a formate, an acetate, and a trifluoroethane.
  • Acid salt fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, besylate or p-toluenesulfonate; preferably from hydrochloride, hydrogen Bromate, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate or p-toluenesulfonate, more preferably from hydrochloride Or acetate.
  • the molar ratio of the compound of formula II to the compound of formula IV is from 1.0: 1.0 to 5.0, preferably from 1.0: 1.0 to 3.0, more preferably from 1.0: 1.0 to 1.5, further preferably 1.0. : 1.0 to 1.2.
  • reaction of a compound of formula II as described herein with a compound of formula IV or a salt thereof to give a compound of formula III can be carried out under acidic conditions, under basic conditions or under neutral conditions.
  • step 3 the reaction is carried out under acidic conditions.
  • the acidic condition is provided by the addition of an acidic reagent selected from the group consisting of citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, Ascorbic acid, sulfuric acid, Hydrochloric acid or hydrobromic acid, or a mixture thereof, is preferably tartaric acid, acetic acid or hydrochloric acid.
  • an acidic reagent selected from the group consisting of citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, Ascorbic acid, sulfuric acid, Hydrochloric acid or hydrobromic acid, or a mixture thereof, is preferably tartaric acid, acetic acid or hydrochloric acid.
  • step 3 the reaction is carried out under basic conditions.
  • the basic condition is provided by the addition of an alkaline agent selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, Sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, triethylamine, diisopropylethylamine or DBU, or a mixture thereof; preferably triethylamine, sodium hydroxide or potassium hydroxide.
  • an alkaline agent selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, Sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, triethylamine, diisopropylethylamine or DBU, or a mixture thereof; preferably triethylamine, sodium hydroxide or potassium hydroxide.
  • the solvent used is selected from the group consisting of acetic acid, ethanol, methanol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, water, N-methylpyrrolidone, N, N-di
  • acetic acid ethanol, methanol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, water, N-methylpyrrolidone, N, N-di
  • One or a mixture of one or more of methyl formamide and N,N-dimethylacetamide is preferably water, acetic acid or ethanol or a mixed solvent of one or more of the above three solvents.
  • the reagent used to convert the compound of Formula III to the compound of Formula XI in Step 4 is selected from one or more of the group consisting of phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and oxalyl chloride. A combination of oxalyl chloride is preferred.
  • the solvent used in the conversion of the compound of formula III to the compound of formula XI in step 4 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, ethyl acetate. Isopropyl acetate, toluene or xylene or a mixed solvent of one or more, preferably NMP or dichloromethane or a mixed solvent thereof.
  • the amination reagent used in the conversion of the compound of formula XI to the compound of formula XII in step 4 is selected from the group consisting of ammonia, liquid ammonia or ammonia, preferably a combination of ammonia.
  • the solvent used in the conversion of the compound of formula XI to the compound of formula XII in step 4 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, ethyl acetate, Isopropyl acetate, toluene or xylene or a mixed solvent of one or more, preferably dichloromethane or tetrahydrofuran or a mixed solvent of the two.
  • the dehydrating agent used in step 5-1 is selected from the group consisting of phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, thionyl chloride, trifluoroacetic anhydride, trifluorosulfonate. Or a combination of one or more of oxalyl chlorides, preferably phosphorus oxychloride or cyanuric chloride.
  • the solvent used in the step 5-1 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, DMSO, ethyl acetate, isopropyl acetate, Toluene or xylene or a mixed solvent of one or more of the above solvents is preferably dichloromethane or NMP or a mixed solvent of the two.
  • step 5-2 in order to implement the method of the present application, those skilled in the art can change the order of the steps based on the existing embodiments.
  • the reaction of converting the amide group into a cyano group may be carried out before the deprotection group R may be carried out, or the deprotection may be carried out first.
  • the reaction of the protecting group R is followed by a reaction in which the amide group is converted into a cyano group, both of which are within the scope of protection of the present application.
  • the dehydrating agent used in the reaction of converting the amide group to the cyano group in the step 5-2 is selected from the group consisting of phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, and thionyl chloride.
  • a combination of one or more of trifluoroacetic anhydride, trifluorosulfonate or oxalyl chloride is preferably phosphorus oxychloride or cyanuric chloride.
  • the solvent used in the reaction of converting the amide group to the cyano group in the step 5-2 is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, DMSO, Ethyl acetate, isopropyl acetate, toluene or xylene, preferably dichloromethane or NMP.
  • the removal of the protecting group R in step 5-2 can be carried out under acidic or basic conditions.
  • the reaction of removing the protecting group R can be carried out by selecting a suitable catalyst and solvent, respectively.
  • the catalyst used in the reaction for removing the amino protecting group R in the step 5-2 is selected from the group consisting of trifluoroacetic acid, trifluoroacetic anhydride, lithium tetrafluoroborate or boron trifluoride-diethyl ether, preferably Trifluoroacetic acid or boron trifluoride-diethyl ether.
  • the solvent used in the reaction to remove the amino protecting group R in step 5-2 is selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, water, NMP, DMA or DMF, preferably acetonitrile or NMP.
  • the catalyst used in the removal of the amino protecting group R in the step 5-2 is selected from the group consisting of sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium t-butoxide.
  • the solvent used in the reaction to remove the protecting group R in step 5-2 is selected from the group consisting of ethanol, water, methanol, tetrahydrofuran or isopropanol, preferably water or tetrahydrofuran.
  • the method of preparing the compound of the formula I of the present application, rucotinib optionally comprises the following step 1: the compound of the formula V is reacted in the presence of a catalyst and a methylating agent to give a compound of the formula VI:
  • the methylating agent described in step 1 is selected from the group consisting of methyl magnesium bromide, methyl magnesium chloride. Or trimethylaluminum, preferably methylmagnesium bromide.
  • the solvent used in step 1 is selected from the group consisting of toluene, dichloromethane, diethyl ether or tetrahydrofuran, preferably tetrahydrofuran or diethyl ether.
  • the catalyst used in step 1 is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(bppf)Cl 2 or Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , preferably Pd(bppf)Cl 2 .
  • the molar ratio of the compound of formula V in step 1 to the catalyst and methylating agent is from 1:0.005 to 0.05:1.5 to 4, preferably from 1:0.005 to 0.015:2 to 3.
  • the application provides a compound of formula II-1, a compound of formula II-2, a compound of formula IV, a D-tartrate salt of a compound of formula IV, a compound of formula III-1, a compound of formula XI-1, a compound of formula XI-2 And a compound of formula XII-1.
  • the application provides a compound of formula II-1, a compound of formula II-2, a compound of formula IV, a D-tartrate salt of a compound of formula IV, a compound of formula III-1, a compound of formula XI-1, a compound of formula XI-2 And/or the use of a compound of formula XII-1 in the preparation of rucotinib.
  • the use of the compound of Formula IV or its D-tartrate salt in the preparation of rucotinib comprises the formation of a pyrazole ring in rucotinib using a compound of Formula IV or its D-tartrate salt. structure.
  • the use of the compound of Formula IV or its D-tartrate salt in the preparation of rucotinib comprises the introduction of a chiral carbon atom of rucotinib using a compound of Formula IV.
  • the application provides a process for the preparation of a compound of formula III, which comprises reacting a compound of formula II with a compound of formula IV Or a salt thereof to give a compound of formula III,
  • R is selected from H or an amino protecting group.
  • the amino protecting group is not removed from the compound in the corresponding reaction step.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethy
  • the salt of the compound of Formula IV may be selected from a chiral salt or an achiral salt.
  • the chiral acid used to form the chiral salt may be selected from the following acids or enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptan-1-yrene Methanesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative, preferably from lactic acid, malic acid, Camphoric acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoyl
  • the chiral acid used to form the chiral salt may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid, D-di-p-methylbenzoate.
  • Acid tartaric acid D-di-p-methoxybenzoyltartaric acid, D-di-p-chlorobenzoyltartaric acid, D-di-p-bromobenzoyltartaric acid, D-di-p-fluorobenzoyltartaric acid, D-di-p-nitrobenzoyltartaric acid, D-di-p-aminobenzoyltartaric acid Or D-di-p-cyanobenzoyltartaric acid.
  • the achiral salt is selected from the group consisting of a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate, a formate, an acetate, a trifluoroacetate, and a rich a horse salt, an oxalate, a maleate, a citrate, a succinate, a methanesulfonate, a besylate or a p-toluenesulfonate; preferably a hydrochloride, a hydrobromide, Sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate or p-toluenesulfonate, more preferably from hydrochloride or acetate .
  • the molar ratio of the compound of Formula II to the compound of Formula IV is from 1.0: 1.0 to 5.0, preferably from 1.0: 1.0 to 3.0, more preferably from 1.0: 1.0 to 1.5, still more preferably from 1.0: 1.0 to 1.2. .
  • reaction of a compound of formula II as described herein with a compound of formula IV or a salt thereof to give a compound of formula III can be carried out under acidic conditions, under basic conditions or under neutral conditions.
  • the reaction is carried out under acidic conditions.
  • the acidic condition is provided by the addition of an acidic reagent selected from the group consisting of citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, ascorbic acid, sulfuric acid, Hydrochloric acid or hydrobromic acid, or a mixture thereof, is preferably tartaric acid, acetic acid or hydrochloric acid.
  • an acidic reagent selected from the group consisting of citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, ascorbic acid, sulfuric acid, Hydrochloric acid or hydrobromic acid, or a mixture thereof, is preferably tartaric acid, acetic acid or hydrochloric acid.
  • the reaction is carried out under basic conditions.
  • the alkaline condition is provided by the addition of an alkaline agent selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, carbonic acid.
  • an alkaline agent selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, carbonic acid.
  • the solvent used is selected from the group consisting of acetic acid, ethanol, methanol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, water, N-methylpyrrolidone, N,N-dimethylformamide Or a mixed solvent of N,N-dimethylacetamide or one or more of the above solvents, preferably water, acetic acid or ethanol or a mixed solvent of one or more of the above three solvents.
  • the application provides a process for the preparation of a compound of formula XII, which comprises reacting a compound of formula II with a compound of formula IV or a salt thereof in the presence of NH 3 to provide a compound of formula XII,
  • R is selected from H or an amino protecting group.
  • the amino protecting group is not removed from the compound in the corresponding reaction step.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulf
  • the salt of the compound of Formula IV may be selected from a chiral salt or an achiral salt.
  • the chiral acid used to form the chiral salt may be selected from the following acids or enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptan-1-yrene Methanesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative, preferably lactic acid, malic acid, camphor Acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoyltartari
  • the chiral acid used to form the chiral salt may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid, D-di-p-methylbenzoate.
  • Acid tartaric acid D-di-p-methoxybenzoyltartaric acid, D-di-p-chlorobenzoyltartaric acid, D-di-p-bromobenzoyltartaric acid, D-di-p-fluorobenzoyltartaric acid, D-di-p-nitro Benzoyl tartaric acid, D-di-p-aminobenzoyltartaric acid or D-di-p-cyanobenzoyltartaric acid.
  • the achiral salt is selected from the group consisting of a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate, a formate, an acetate, a trifluoroacetate, and a rich Horse salt, oxalate, maleate, citrate, succinate, methanesulfonate, besylate or p-toluenesulfonate; preferably hydrochloride, hydrobromide, sulfuric acid Salt, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate or p-toluenesulfonate, more preferably hydrochloride or acetate.
  • a reagent selected from the group of NH 3 of ammonia, methanol and ammonia in a liquid ammonia and ammonia or more thereof, preferably aqueous ammonia.
  • a reaction of a compound of formula II with a compound of formula IV or a salt thereof to give a compound of formula XII wherein the solvent used is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, ethyl acetate, isopropyl acetate, toluene or xylene or a mixed solvent of one or more of the above solvents, preferably tetrahydrofuran.
  • the present application provides a process for the preparation of a compound of formula I, rucotinib, comprising the steps of:
  • Step (1) reacting a compound of the formula II with a compound of the formula IV or a salt thereof in the presence of NH 3 to give a compound of the formula XII,
  • R is selected from H or an amino protecting group
  • R is selected from H or an amino protecting group.
  • the amino protecting group described in step (1) is not removed from the compound in the corresponding reaction step.
  • the amino protecting group in step (1) and step (2-2) is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(Trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyl Oxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1 - dimethyl-2,2,2-trichloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p
  • the salt of the compound of formula IV described in step (1) may be selected from a chiral salt or an achiral salt.
  • the chiral acid used to form the chiral salt may be selected from the following acids or enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptan-1-yrene Methanesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative, preferably lactic acid, malic acid, camphor Acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoyltartari
  • the chiral acid used to form the chiral salt may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid, D-di-p-methylbenzoate.
  • Acid tartaric acid D-di-p-methoxybenzoyltartaric acid, D-di-p-chlorobenzoyltartaric acid, D-di-p-bromobenzoyltartaric acid, D-di-p-fluorobenzoyltartaric acid, D-di-p-nitro Benzoyl tartaric acid, D-di-p-aminobenzoyltartaric acid or D-di-p-cyanobenzoyltartaric acid.
  • the achiral salt is selected from the group consisting of a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate, a formate, an acetate, a trifluoroacetate, and a rich Horse salt, oxalate, maleate, citrate, succinate, methanesulfonate, besylate or p-toluenesulfonate; preferably hydrochloride, hydrobromide, sulfuric acid Salt, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate or p-toluenesulfonate, more preferably hydrochloride or acetate.
  • the reagent providing NH 3 in step (1) is selected from the group consisting of ammonia, ammonia, ammonia, and liquid ammonia, preferably a combination of ammonia, preferably ammonia.
  • the solvent used in step (1) is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, A mixed solvent of chlorobenzene, acetonitrile, DMA, NMP, ethyl acetate, isopropyl acetate, toluene or xylene or one or more of the above solvents, preferably tetrahydrofuran.
  • the dehydrating agent used in the step (2-1) is selected from the group consisting of phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, dichlorosulfoxide, trifluoroacetic anhydride, and trifluorocarbon.
  • a combination of one or more of sulphuric anhydride or oxalyl chloride is preferably phosphorus oxychloride or cyanuric chloride.
  • the solvent used in the step (2-1) is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, DMSO, ethyl acetate, and isopropyl acetate.
  • a mixed solvent of an ester, toluene or xylene or one or more of the above solvents is preferably dichloromethane or NMP or a mixed solvent of the two.
  • step (2-2) in order to implement the method of the present application, those skilled in the art can change the order of the steps based on the existing embodiments.
  • the reaction of converting the amide group into a cyano group may be carried out before the deprotection group R may be carried out, or the deprotecting group R may be first carried out.
  • the reaction is followed by a reaction in which an amide group is converted to a cyano group, both of which are within the scope of protection of the present application.
  • the dehydrating agent used in the reaction of converting the amide group into a cyano group in the step (2-2) is selected from the group consisting of phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, and dichloroa.
  • a combination of one or more of sulfone, trifluoroacetic anhydride, trifluorosulfonate or oxalyl chloride is preferably phosphorus oxychloride or cyanuric chloride.
  • the solvent used in the reaction of converting the amide group to the cyano group in the step (2-2) is selected from the group consisting of tetrahydrofuran, dichloromethane, chloroform, chlorobenzene, acetonitrile, DMA, NMP, DMSO, ethyl acetate, isopropyl acetate, toluene or xylene, preferably dichloromethane or NMP.
  • the reaction for removing the protecting group R in the step (2-2) can be carried out under acidic conditions or under basic conditions. Under acidic or basic conditions, the reaction of removing the protecting group R can be carried out by selecting a suitable catalyst and solvent, respectively.
  • the catalyst used in the reaction for removing the amino protecting group R in the step (2-2) is selected from the group consisting of trifluoroacetic acid, trifluoroacetic anhydride, lithium tetrafluoroborate or boron trifluoride-diethyl ether.
  • Preferred is trifluoroacetic acid or boron trifluoride-diethyl ether.
  • the solvent used in the reaction for removing the amino protecting group R in the step (2-2) is selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, water, NMP, DMA or DMF, preferably acetonitrile or NMP. .
  • the catalyst used in the step (2-2) to remove the amino protecting group R is selected from the group consisting of sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and tert-butyl. Potassium alkoxide, sodium t-butoxide, hydrazine hydrate or tetrabutylammonium fluoride, preferably lithium hydroxide or potassium carbonate.
  • the solvent used in the reaction for removing the protecting group R in the step (2-2) is selected from the group consisting of ethanol, water, methanol, tetrahydrofuran or isopropanol, preferably water or tetrahydrofuran.
  • the application provides a process for the preparation of a compound of formula II, which comprises the step of converting a compound of formula VI to a compound of formula II by the action of DMF and a chlorinating agent,
  • R is selected from H or an amino protecting group.
  • the amino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxylate Carbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl Carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-tri Chloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulf
  • the chlorinating agent is selected from one or a mixture of two or more of oxalyl chloride, phosphorus oxychloride, and thionyl chloride, preferably phosphorus oxychloride.
  • the ratio of the amount of the compound of formula VI to the amount of the chlorinating agent is selected from the group consisting of 1.0:2.0 to 6.0, preferably 1.0:2.0 to 4.0, more preferably 1.0:2.5 to 3.5.
  • the solvent used is selected from one of 1,4-dioxane, dichloromethane, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylformamide or
  • One or more mixed solvents are preferably N,N-dimethylformamide, 1,4-dioxane or tetrahydrofuran or a mixed solvent of one or more of them.
  • the method of preparing a compound of Formula II of the present application optionally further comprises reacting a compound of Formula V in the presence of a catalyst and a methylating agent to provide a compound of Formula VI,
  • the methylating agent is selected from the group consisting of methyl magnesium bromide, methyl magnesium chloride or trimethyl aluminum, preferably methyl magnesium bromide.
  • the solvent used is selected from the group consisting of toluene, dichloromethane, diethyl ether or tetrahydrofuran, preferably tetrahydrofuran or diethyl ether.
  • the catalyst used is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(bppf)Cl 2 or Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 , preferably Pd(bppf)Cl 2 .
  • the molar ratio of the compound of formula V to the catalyst and methylating agent is from 1:0.005 to 0.05:1.5 to 4, preferably from 1:0.005 to 0.015:2 to 3.
  • the present application provides a process for the preparation of a compound of formula IV or a chiral salt thereof, which comprises the steps of:
  • Step C-1 a compound of formula X is reacted with a chiral acid in the presence of a solvent to form a chiral salt of a compound of formula IV,
  • Step C-2 isolating the chiral salt of the compound of formula IV;
  • Step C-3 Alternatively, the chiral salt of a compound of formula IV is treated with a base to provide a compound of formula IV.
  • the chiral acid described in Step C-1 may be selected from the following acids or their enantiomeric excess forms: mandelic acid, 2-chloromandelic acid, camphoric acid, lactic acid, malic acid, 3-bromocamphor-8-sulfonic acid, 3-bromocamphor-10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,1]heptan-1-yrene Methanesulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonic acid or tartaric acid and its acyl derivative; preferably lactic acid, malic acid, camphor Acid, 10-camphorsulfonic acid, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid, di-p-methoxybenzoyltartaric acid
  • the chiral acid used to form the chiral salt of the compound of Formula IV in Step C-1 may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-dibenzoyltartaric acid.
  • the solvent used in the step C-1 is selected from one or more mixed solvents of acetone, 1,4-dioxane, tetrahydrofuran and ethyl acetate, preferably acetone. .
  • the molar ratio of the compound of the formula X to the chiral acid in the step C-1 is from 1.0:0.2 to 1.0, preferably from 1.0:0.3 to 0.7, more preferably from 1.0:0.4 to 0.6.
  • the method of preparing a compound of Formula IV or a chiral salt thereof optionally further comprises the steps of:
  • Step A a compound of formula VII is reacted with malonic acid in the presence of a base to provide a compound of formula VIII,
  • Step B a compound of the formula VIII is reacted with hydrazine hydrate to give a compound of the formula X,
  • the base used in step A is selected from the group consisting of piperidine, triethylamine, valine, N,N-diisopropylethylamine, tetrahydropyrrolidine, pyridine or 4-di Methylaminopyridine, preferably piperidine.
  • the solvent used in step A is selected from the group consisting of pyridine, acetonitrile, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone or 1,4-di Oxy hexacyclo, preferably pyridine.
  • the solvent used in step B is selected from the group consisting of hydrazine hydrate, 1,4-dioxane, ethanol, methanol, isopropanol, tetrahydrofuran, N-methylpyrrolidone, and N,N- One or more mixed solvents of dimethylformamide, preferably hydrazine hydrate.
  • Amino protecting groups as described herein include, but are not limited to, the amino protecting groups described in "Protective Groups in Organic Synthesis” (4th edition, John Wiley & Sons: New Jersey), which is incorporated herein by reference. . In the present application, those skilled in the art can attach or remove from the reaction compound by a known method depending on the characteristics of the amino-protecting group.
  • the amino protecting group described herein may be selected from the group consisting of benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-Trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc) , 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl ( TcBoc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrophenylsulfonyl, p-methylbenzenesulfonyl
  • keto-enol tautomerism Basic Organic Chemistry, Third Edition, Higher Education Publishing
  • the keto-enol tautomer of the compound of formula II is also within the scope of the present application, ISBN 7-04-016637-2, pages 654-656.
  • the keto-enol tautomers of the compounds of formula II described herein include the following structures:
  • the amino protecting group means a functional group which, in the course of the reaction, is desired to reversibly convert an amino group into an inert group in addition to a specific functional group.
  • an amino protecting group is not essential, and those skilled in the art can optionally introduce an amino protecting group into the reaction substrate according to the reaction conditions of each step and the need for the reaction result. Or no amino protecting group is introduced.
  • reaction steps in the following reaction steps,
  • reaction conditions are mild, the reaction can be carried out under acidic conditions, alkaline conditions or neutral conditions, and there is no strong oxidation, strong reduction or active catalytic environment in the reaction system, and R is selected from H or an amino protecting group.
  • R is selected from H or an amino protecting group.
  • the compounds of formula IV described herein may be in the form of their free bases or in the form of their salts.
  • the salt form can be selected from a chiral salt or an achiral salt.
  • the chiral salt refers to a salt of an acidic compound having an asymmetric atom (for example, a carbon atom) and an enantiomeric excess of a corresponding chiral base compound.
  • the chiral acid refers to an acid having an asymmetric atom, including its enantiomeric excess form or enantiomeric non-excess form.
  • the chiral salt may be selected from the group consisting of mandelate, 2-chloromandelate, camphorate, lactate, malate, 3-bromo camphor-8-sulfonate, 3-bromo camphor-10-sulfonate Acid salt, 10-camphorsulfonate, 2-amino-7,7-dimethylbicyclo[2,2,1]hept-1-methanesulfonate, 2-acrylamide-7,7-di Methylbicyclo[2,2,1]hept-1-methanesulfonate or tartaric acid and its acyl derivative salt; preferably from lactate, malate, camphorate, 10-camphorsulfonate , tartrate, diacetyl-tartrate, dibenzoyl tartrate, di-p-methylbenzoyl tartrate, di-p-methoxybenzoyl tartrate, di-p-chlorobenzoyl tartrate, di-p-bromo Benzoyl tartrate, di-
  • the chiral salt described herein may be selected from its enantiomeric excess form, for example, the enantiomeric excess of the tartaric acid and its acyl derivative salt may be selected from the group consisting of D-tartaric acid, D-diacetyltartaric acid, D-di Benzoyl tartaric acid, D-di-p-methylbenzoyltartaric acid, D-di-p-methoxybenzoyltartaric acid, D-di-p-chlorobenzoyltartaric acid, D-di-p-bromobenzoyltartaric acid, D- Di-p-fluorobenzoyltartaric acid, D-di-p-nitrobenzoyltartaric acid, D-di-p-aminobenzoyltartaric acid or D-di-p-cyanobenzoyltartaric acid.
  • tartaric acid and its acyl derivative described herein also include hydrated forms thereof.
  • tartaric acid includes tartaric acid and tartaric acid monohydrate
  • D-dibenzoyltartaric acid includes D-dibenzoyltartaric acid and D-dibenzoyltartaric acid monohydrate.
  • the achiral salt described herein may be selected from the group consisting of hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, grass.
  • the ratio of the molar ratio to the amount of the substance described in the present application is equivalent to each other.
  • R when R is H in the compound of the formula V, it can be derived from a commercially available compound; the compound of the formula V (R is an amino-protecting group) can be obtained by using the compound of the formula V (R is H). According to the characteristics of different amino protecting groups, it is prepared by a known method. For example, when the compound of the formula V is a structure of the following formula V-2,
  • the compound of the formula V-2 can be obtained by reacting 4-chloropyrrolo[2,3-d]pyrimidine with 2-(trimethylsilyl)ethoxymethyl chloride under basic conditions.
  • DMF means N,N-dimethylformamide
  • NMP refers to N-methylpyrrolidone
  • SEM- means 2-(trimethylsilyl)ethoxymethyl.
  • DMA means N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • the methylating agent refers to an agent that can introduce a methyl group to a carbon, silicon, nitrogen, phosphorus, oxygen or sulfur atom in a substrate molecule.
  • the chlorinating agent means an agent capable of providing a chlorine atom to introduce a chlorine atom into a carbon, silicon, nitrogen, phosphorus or sulfur atom in a substrate molecule.
  • the dehydrating agent refers to an agent capable of removing water molecules in a compound structure under the action of heating or a catalyst.
  • the amination reagent is an agent that introduces an amino group or a substituted amino group to a carbon, silicon, nitrogen, phosphorus, oxygen or sulfur atom in a substrate molecule.
  • the chiral compound is in enantiomeric excess
  • the enantiomeric excess means that the content of chiral isomer (the amount of substance) is equal to or greater than about 10 %, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, About 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.
  • the achiral salt of the compound of formula IV can be prepared by contacting a compound of formula IV in a solvent with a corresponding achiral acid compound.
  • the hydrochloride salt of a compound of formula IV can be prepared from a compound of formula IV and HCl.
  • the compounds may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomeric or diastereomeric excess mixtures, all of which belong to the present Within the scope of the application.
  • Additional asymmetric carbonogen may be present in the substituent such as an alkyl group child. All such isomers, as well as mixtures thereof, are included within the scope of this application.
  • reaction is optionally carried out in a solvent. All solvents used in the present application are commercially available and can be used without further purification.
  • the reaction is generally carried out under inert nitrogen in an anhydrous solvent. .
  • proton nuclear magnetic resonance data was recorded on a BRUKER AV-500 (500 MHz) spectrometer with chemical shifts expressed in ppm at the low field of tetramethylsilane; mass spectra were determined on a Waters XEVO G2 QTOF.
  • the mass spectrometer is equipped with an electrospray ionization source (ESI) operating in either positive or negative mode.
  • ESI electrospray ionization source
  • the preparation method of the present application has the characteristics of short steps, high stereoselectivity, high atomic utilization rate, mild reaction conditions and simple post-treatment, and avoids the use of expensive asymmetric reaction catalysts, and is suitable for industrial production.
  • the organic layer was stirred by adding 4 L of 9% sodium hydroxide (1.3 L ⁇ 3), and the combined aqueous layer was cooled to 0-5 ° C, and concentrated hydrochloric acid was added dropwise to adjust the pH to 2 to 5, and then extracted with 2.6 L of ethyl acetate. Ethyl acetate (1.3 L ⁇ 2) was washed, and the organic layer was washed with EtOAc. ).
  • the aqueous phase was adjusted to pH 6 NaHCO 3, filtered off with suction, the filter cake was washed with 455 mL of purified water, the filtrate was collected and extracted 3 times with 1.05 L of ethyl acetate, the organic phase was concentrated to give 4-methyl -7H- pyrrolo [2,3- -d]pyrimidine (109.5 g, 84.2%).
  • Step 3 (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanoic acid
  • Method 1 54 g of 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrolein was added to a mixed solvent of 648 mL of acetic acid and 324 mL of purified water, and then 87 g of (R)- 5-cyclopentylpyrazol-3-one D-tartrate, warmed to reflux for 8 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (500 mL) was added to the residue to adjust to pH 6.5-7, and then washed twice with 300 mL of ethyl acetate.
  • the aqueous phase was adjusted to pH 5 to 5.5 with 3M HCl, and (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 was obtained by suction filtration.
  • -yl)-3-cyclopentylpropionic acid 55.8 g, 60.0%).
  • Method 2 Add 5 g of 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrolein to 100 mL of water, then add 1.3 g of sodium hydroxide, 4.1 g (R)-5 -cyclopentylpyrazol-3-one, warmed to reflux for 8 hours. After the completion of the reaction, the pH was adjusted to 1-2 with hydrochloric acid, concentrated under reduced pressure, and dissolved in methanol (100 mL), and then evaporated. Sodium 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionate (6.7 g, 73.0%).
  • Step 4 (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide
  • Step 5 (R)-3-Cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile
  • Step 1 4-Methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
  • Step 3 (R)-3-Cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid
  • Step 4 (R)-3-Cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanamide
  • Step 5 (R)-3-Cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile
  • Step 6 (R)-3-Cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile

Abstract

本申请属于药物合成领域，具体而言，本申请涉及芦可替尼的制备方法、所用中间体及相关中间体的制备方法。该方法包括式II化合物与式IV化合物或其盐反应得到式III化合物，之后式III化合物经酰卤化反应、酰胺化反应、酰胺脱水生成氰基或脱除保护基的反应制备得到芦可替尼。该方法具有步骤简短、高立体选择性、原子利用率高、反应条件温和、后处理简便的特点，避免使用价格昂贵的不对称反应催化剂，适合工业化生产。

Description

一种芦可替尼的合成工艺
相关申请的交叉引用
本申请要求于2015年12月31日向中国国家知识产权局提交的第201511028724.8号中国专利申请的优先权和权益，所述专利申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物合成领域，具体而言，本申请涉及一种芦可替尼的制备方法、所用中间体及相关中间体的制备方法。
背景技术
芦可替尼(Ruxolitinib)是由Incyte公司和Novartis公司合作开发的一种选择性JAK1/JAK2酪氨酸激酶抑制剂，2011年11月被美国FDA批准为首个用于治疗骨髓纤维化的药物(商品名为Jakafi)，适应症为中间或高危骨髓纤维化，包括原发性骨髓纤维化、继发性红细胞增多症骨髓纤维化、原发性血小板增多症骨髓纤维化；2014年12月，FDA批准新增适应症为对氨基脲应答不足或不能耐受的真性红细胞增多症。2012年8月获欧盟批准上市(商品名为Jakavi)；2014年7月获日本批准上市。
芦可替尼的化学名称为(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈，其结构式如式I所示：
Figure PCTCN2016113000-appb-000001
WO2007070514、WO2010039939、WO2010116282、US20090181959和Org Lett,2009,10(9):1999-2002分别公开了芦可替尼及相关中间体的制备方法，Drugs of the Future(2010),35(6),457-465对上述公开的方法进行了综述，在该综述所公开的路线中，手性拆分接近成品步骤， 原子利用率较低，成本较高；且手性催化剂的结构较为复杂，催化剂用量较高。手性拆分产品的ee值不高，手性纯度只能达到约90％，仍需要对其拆分或通过多步精制工艺才能得到药用价值的产品。
Angew.Chem.Int.Ed.2015,54,7149–7153公开了另一种芦可替尼的制备方法，该方法中所使用的铑催化剂及其金属配体的用量较高，反应条件苛刻，从成本和操作方面考虑不利于规模化生产。
为了解决上述合成工艺的缺点，本申请旨在提供一种芦可替尼新的适于工业化生产的制备方法。
发明内容
一方面，本申请提供一种式I化合物芦可替尼的制备方法，其包括以下步骤：
步骤4：将式III化合物转化为式XI化合物，然后将式XI化合物在氨基化试剂的存在下转化为式XII化合物，
Figure PCTCN2016113000-appb-000002
其中，R选自H或氨基保护基，X选自Cl或Br；以及
步骤5-1：当R为H时，式XII的酰胺基团在脱水剂的存在下转化为氰基，得到式I化合物芦可替尼，或者
步骤5-2：当R为氨基保护基时，式XII的酰胺基团转化为氰基并且脱除氨基保护基R，得到式I化合物芦可替尼，
Figure PCTCN2016113000-appb-000003
在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，步骤4中将式III化合物转化为式XI化合物所使用的试剂选自三氯化磷、五氯化磷、亚硫酰氯和草酰氯中的一种或多种的组合，优选草酰氯。
在本申请的部分实施方案中，步骤4中将式III化合物转化为式XI化合物所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、乙酸乙酯，乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选NMP或二氯甲烷或者两者的混合溶剂。
在本申请的部分实施方案中，步骤4中将式XI化合物转化为式XII化合物所使用的氨基化试剂选自氨水、液氨和氨气中的一种或多种的组合，优选氨水。
在本申请的部分实施方案中，步骤4中将式XI化合物转化为式XII化合物所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选二氯甲烷或四氢呋喃或者两者的混合溶剂。
在本申请的部分实施方案中，步骤5-1中使用的脱水剂选自三氯氧磷、三聚氯氰、五氧化二磷、二氯亚砜、三氟乙酸酐、三氟磺酐和草酰氯中的一种或多种的组合，优选三氯氧磷或三聚氯氰。
在本申请的部分实施方案中，步骤5-1中使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、DMSO、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选二氯甲烷或NMP或者两者的混合溶剂。
在本申请的部分实施方案中，步骤5-1中式XII化合物与脱水剂的摩尔比为1：1～10，优 选1：3～8，更优选1：4～7，进一步优选1：5～7。
在本申请中，步骤5-2中式XII的酰胺基团转化为氰基和脱除氨基保护基R的顺序可以进行变换。例如，由式XII化合物(R＝氨基保护基)制备芦可替尼时，可以先进行将酰胺基团转化为氰基的反应再进行脱除保护基R的反应，也可以先进行脱除保护基R的反应再进行将酰胺基团转化为氰基的反应，两者均在本申请的保护范围内。
在本申请的部分实施方案中，步骤5-2中酰胺基团转化为氰基的反应所使用的脱水剂选自三氯氧磷、三聚氯氰、五氧化二磷、二氯亚砜、三氟乙酸酐、三氟磺酐和草酰氯中的一种或多种的组合，优选三氯氧磷或三聚氯氰。
在本申请的部分实施方案中，步骤5-2中酰胺基团转化为氰基的反应所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、DMSO、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯，优选二氯甲烷或NMP。
在本申请的部分实施方案中，步骤5-2中酰胺基团在脱水剂的存在下转化为氰基，其中式XII化合物(R＝氨基保护基)与脱水剂的摩尔比为1：1～10，优选1：3～8，更优选1：4～7，进一步优选1：5～7。
在本申请的部分实施方案中，步骤5-2中脱除保护基R的反应可以在酸性条件或碱性条件下进行。在酸性条件或碱性条件下，可以各自选择合适的催化剂和溶剂进行脱除保护基R的反应。
在本申请的部分实施方案中，在酸性条件下，步骤5-2中脱除保护基R的反应所使用的催化剂选自三氟乙酸、三氟乙酸酐、四氟硼酸锂或三氟化硼-乙醚，优选三氟乙酸或三氟化硼-乙醚。
在本申请的部分实施方案中，在酸性条件下，步骤5-2中脱除保护基R的反应所使用的溶剂选自二氯甲烷、四氢呋喃、乙腈、水、NMP、DMA或DMF，优选乙腈或NMP。
在本申请的部分实施方案中，在碱性条件下，步骤5-2中脱除保护基R的反应所使用的催化剂选自碳酸钠、碳酸铯、碳酸钾、氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钾、叔丁醇钠、水合肼或四丁基氟化铵，优选氢氧化锂或碳酸钾。
在本申请的部分实施方案中，在碱性条件下，步骤5-2中脱除保护基R的反应所使用的溶剂选自乙醇、水、甲醇、四氢呋喃或异丙醇，优选水或四氢呋喃。
在本申请的部分实施方案中，本申请的式I化合物芦可替尼的制备方法可选地还包括步骤3：式II化合物与式IV化合物或其盐反应得到式III化合物，
Figure PCTCN2016113000-appb-000004
其中，R选自H或氨基保护基。
在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
本申请步骤3中所述的式IV化合物可以为游离碱或其盐。
在本申请的部分实施方案中，步骤3中所述式IV化合物的盐可以选自手性盐或者非手性盐。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物，优选乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸，更优选酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲 酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，所述非手性盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐，优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐或对甲基苯磺酸盐，更优选盐酸盐或乙酸盐。
在本申请的部分实施方案中，步骤3中所述式II化合物和式IV化合物或其盐的摩尔比为1.0:1.0～5.0，优选1.0:1.0～3.0，更优选1.0:1.0～1.5，进一步优选1.0:1.0～1.2。
本申请步骤3可以在酸性条件下、碱性条件下或者中性条件下进行。
在本申请的部分实施方案中，步骤3所述的反应在酸性条件下进行。
在本申请的部分实施方案中，步骤3的所述酸性条件通过加入酸性试剂提供，所述酸性试剂选自柠檬酸、富马酸、酒石酸、马来酸、苹果酸、琥珀酸、乙酸、抗坏血酸、硫酸、盐酸或氢溴酸，或者它们的混合物，优选酒石酸、乙酸或盐酸。
在本申请的部分实施方案中，步骤3所述的反应在碱性条件下进行。
在本申请的部分实施方案中，步骤3的所述碱性条件通过加入碱性试剂提供，所述碱性试剂选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸铯、碳酸钠、三乙胺、二异丙基乙基胺或DBU，或者它们的混合物，优选三乙胺、氢氧化钠或氢氧化钾。
本申请步骤3中所用溶剂选自乙酸、乙醇、甲醇、乙二醇单甲醚、乙二醇二甲醚、水、N-甲基吡咯烷酮、N,N-二甲基甲酰胺和N,N-二甲基乙酰胺中的一种或一种以上的混合溶剂，优选水、乙酸或乙醇或者上述三种溶剂中一种以上的混合溶剂。
在本申请的部分实施方案中，本申请的式I化合物芦可替尼的制备方法可选地还包括步骤2：式VI化合物在DMF和氯化试剂的作用下转化为式II化合物：
Figure PCTCN2016113000-appb-000005
其中，R选自H或氨基保护基。
在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3- 基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，步骤2中，所述氯化试剂选自草酰氯、三氯氧磷和氯化亚砜中的一种或任意两种以上的混合物，优选三氯氧磷。
在本申请的部分实施方案中，步骤2中，式VI化合物与氯化试剂的物质的量之比选自1.0:2.0～6.0，优选1.0:2.0～4.0，更优选1.0:2.5～3.5。
在本申请的部分实施方案中，步骤2中，所使用的溶剂选自1,4-二氧六环、二氯甲烷、四氢呋喃、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或一种以上的混合溶剂，优选N,N-二甲基甲酰胺、1,4-二氧六环或四氢呋喃或者它们中的一种以上的混合溶剂。
在本申请的部分实施方案中，本申请的式I化合物芦可替尼的制备方法可选地还包括步骤1：式V化合物在催化剂和甲基化试剂的存在下反应得到式VI化合物：
Figure PCTCN2016113000-appb-000006
其中，R如上所定义。
在本申请的部分实施方案中，步骤1中的甲基化试剂选自甲基溴化镁、甲基氯化镁或三甲基铝，优选甲基溴化镁。
在本申请的部分实施方案中，步骤1中所使用的溶剂选自甲苯、二氯甲烷、乙醚或四氢呋喃，优选四氢呋喃或乙醚。
在本申请的部分实施方案中，步骤1中所使用的催化剂选自Pd(PPh3)4、Pd(bppf)Cl2或Pd(dppf)Cl2·CH2Cl2，优选Pd(bppf)Cl2。
在本申请的部分实施方案中，步骤1中的式V化合物与催化剂和甲基化试剂的摩尔比为1:0.005～0.05:1.5～4，优选1:0.005～0.015:2～3。
在本申请的部分实施方案中，步骤3中式IV化合物或其手性盐的制备方法包括以下步骤：
Figure PCTCN2016113000-appb-000007
步骤C-1：式X化合物与手性酸在溶剂存在下反应，以形成式IV化合物的手性盐，
Figure PCTCN2016113000-appb-000008
步骤C-2：分离式IV化合物的手性盐；以及
步骤C-3：可选地，用碱处理式IV化合物的手性盐，得到式IV化合物。
在本申请的部分实施方案中，步骤C-1中所述的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物；优选乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸；更优选酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，步骤C-1中形成所述式IV化合物的手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，步骤C-1中所使用的溶剂选自丙酮、1,4-二氧六环、四氢呋喃和乙酸乙酯中的一种或一种以上的混合溶剂，优选丙酮。
在本申请的部分实施方案中，步骤C-1中式X化合物与手性酸的摩尔比为1.0:0.2～1.0，优选1.0:0.3～0.7，更优选1.0:0.4～0.6。
在本申请的部分实施方案中，可选地还包括如下步骤：
步骤A：式VII化合物在碱存在下与丙二酸反应，得到式VIII化合物，
Figure PCTCN2016113000-appb-000009
以及
步骤B：式VIII化合物与水合肼反应得到式X化合物，
Figure PCTCN2016113000-appb-000010
在本申请的部分实施方案中，步骤A中所使用的碱选自哌啶、三乙胺、脯氨酸、N,N-二异丙基乙胺、四氢比咯、吡啶或4-二甲氨基吡啶，优选哌啶。
在本申请的部分实施方案中，步骤A中所使用的溶剂选自吡啶、乙腈、乙醇、N,N-二甲基甲酰胺、二甲亚砜、乙酸乙酯、丙酮或1,4-二氧六环，优选吡啶。
在本申请的部分实施方案中，步骤B中所使用的溶剂选自水合肼、1,4-二氧六环、乙醇、甲醇、异丙醇、四氢呋喃、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或一种以上的混合溶剂，优选水合肼。
另一方面，本申请提供一种式I化合物芦可替尼的制备方法，该方法包括以下步骤：
步骤2：式VI化合物在DMF和氯化试剂的作用下转化为式II化合物，
Figure PCTCN2016113000-appb-000011
步骤3：式II化合物与式IV化合物或其盐反应得到式III化合物，
Figure PCTCN2016113000-appb-000012
步骤4：将式III化合物转化为式XI化合物，然后式XI化合物在氨基化试剂的存在下转化为式XII化合物，
Figure PCTCN2016113000-appb-000013
以及
步骤5-1：当R为H时，式XII的酰胺基团在脱水剂的存在下转化为氰基，得到式I化合物芦可替尼，或者
步骤5-2：当R为氨基保护基时，式XII的酰胺基团转化为氰基并且脱氨基保护基R，得到式I化合物芦可替尼，
Figure PCTCN2016113000-appb-000014
其中，R选自H或氨基保护基，X选自Cl或Br。
在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，步骤2中，所述氯化试剂选自草酰氯、三氯氧磷和氯化亚砜中的一种或任意两种以上的混合物，优选三氯氧磷。
在本申请的部分实施方案中，步骤2中，式VI化合物与氯化试剂的物质的量之比选自1.0:2.0～6.0，优选1.0:2.0～4.0，更优选1.0:2.5～3.5。
在本申请的部分实施方案中，步骤2中，所使用的溶剂选自1,4-二氧六环、二氯甲烷、四氢呋喃、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或一种以上的混合溶剂，优选N,N-二甲基甲酰胺、1,4-二氧六环或四氢呋喃或者上述三种溶剂中一种以上的混合溶剂。
在本申请的部分实施方案中，步骤3中，所述式IV化合物的盐可以选自手性盐或者非手性盐。
在本申请的部分实施方案中，步骤3中，形成所述手性盐所用的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物，优选自乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸，更优选自酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，步骤3中，形成所述手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，步骤3中，所述非手性盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐；优选自盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐或对甲基苯磺酸盐，更优选自盐酸盐或乙酸盐。
在本申请的部分实施方案中，步骤3中，所述式II化合物和式IV化合物的摩尔比为1.0:1.0～5.0，优选1.0:1.0～3.0，更优选1.0:1.0～1.5，进一步优选1.0:1.0～1.2。
本申请所述的式II化合物与式IV化合物或其盐反应得到式III化合物反应(即，步骤3中的反应)可以在酸性条件下、碱性条件下或者中性条件下进行。
在本申请的部分实施方案中，步骤3中，所述反应在酸性条件下进行。
在本申请的部分实施方案中，步骤3中，所述酸性条件通过加入酸性试剂提供，所述酸性试剂选自柠檬酸、富马酸、酒石酸、马来酸、苹果酸、琥珀酸、乙酸、抗坏血酸、硫酸、 盐酸或氢溴酸，或者它们的混合物，优选酒石酸、乙酸或盐酸。
在本申请的部分实施方案中，步骤3中，所述反应在碱性条件下进行。
在本申请的部分实施方案中，步骤3中，所述碱性条件通过加入碱性试剂提供，所述碱性试剂选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸铯、碳酸钠、碳酸氢钾、碳酸氢钠、三乙胺、二异丙基乙基胺或DBU，或者它们的混合物；优选三乙胺、氢氧化钠或氢氧化钾。
在本申请的部分实施方案中，步骤3中，所用溶剂选自乙酸、乙醇、甲醇、乙二醇单甲醚、乙二醇二甲醚、水、N-甲基吡咯烷酮、N,N-二甲基甲酰胺和N,N-二甲基乙酰胺中的一种或者一种以上的混合溶剂，优选水、乙酸或乙醇或者上述三种溶剂中一种以上的混合溶剂。
在本申请的部分实施方案中，步骤4中将式III化合物转化为式XI化合物所使用的试剂选自三氯化磷、五氯化磷、亚硫酰氯和草酰氯中的一种或多种的组合，优选草酰氯。
在本申请的部分实施方案中，步骤4中将式III化合物转化为式XI化合物所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、乙酸乙酯，乙酸异丙酯、甲苯或二甲苯或者一种以上的混合溶剂，优选NMP或二氯甲烷或者它们的混合溶剂。
在本申请的部分实施方案中，步骤4中将式XI化合物转化为式XII化合物所使用的氨基化试剂选自氨水、液氨或氨气中的一种或多种的组合，优选氨水。
在本申请的部分实施方案中，步骤4中将式XI化合物转化为式XII化合物所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上的混合溶剂，优选二氯甲烷或四氢呋喃或者两者的混合溶剂。
在本申请的部分实施方案中，步骤5-1中所使用的脱水剂选自三氯氧磷、三聚氯氰、五氧化二磷、二氯亚砜、三氟乙酸酐、三氟磺酐或草酰氯中的一种或多种的组合，优选三氯氧磷或三聚氯氰。
在本申请的部分实施方案中，步骤5-1中所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、DMSO、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选二氯甲烷或NMP或者两者的混合溶剂。
在本申请的部分实施方案中，步骤5-1中式XII化合物(R＝H)与脱水剂的摩尔比为1：1～10，优选1：3～8，更优选1：4～7，进一步优选1：5～7。
在本申请中，步骤5-2中，为了实现本申请的方法，本领域的技术人员在已有实施方案的基础上可以对步骤的顺序进行变换。例如，由式XII化合物(R＝氨基保护基)制备芦可替尼时，可以先进行酰胺基团转化为氰基的反应再进行脱保护基R的反应，也可以先进行脱保 护基R的反应再进行酰胺基团转化为氰基的反应，两者均属于本申请的保护范围内。
在本申请的部分实施方案中，步骤5-2中酰胺基团转化为氰基的反应所使用的脱水剂选自三氯氧磷、三聚氯氰、五氧化二磷、二氯亚砜、三氟乙酸酐、三氟磺酐或草酰氯中的一种或多种的组合，优选三氯氧磷或三聚氯氰。
在本申请的部分实施方案中，步骤5-2中酰胺基团转化为氰基的反应所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、DMSO、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯，优选二氯甲烷或NMP。
在本申请的部分实施方案中，步骤5-2中酰胺基团转化为氰基的反应中式XII化合物(R＝氨基保护基)与脱水剂的摩尔比为1：1～10，优选1：3～8，更优选1：4～7，进一步优选1：5～7。
在本申请的部分实施方案中，步骤5-2中脱除保护基R的反应可以在酸性条件或碱性条件下进行。在酸性条件或碱性条件下，可以各自选择合适的催化剂和溶剂进行脱除保护基R的反应。
在本申请的部分实施方案中，步骤5-2中脱除氨基保护基R的反应所使用的催化剂选自三氟乙酸、三氟乙酸酐、四氟硼酸锂或三氟化硼-乙醚，优选三氟乙酸或三氟化硼-乙醚。
在本申请的部分实施方案中，步骤5-2中脱除氨基保护基R的反应所使用的溶剂选自二氯甲烷、四氢呋喃、乙腈、水、NMP、DMA或DMF，优选乙腈或NMP。
在本申请的部分实施方案中，步骤5-2中脱除氨基保护基R使用的催化剂选自碳酸钠、碳酸铯、碳酸钾、氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钾、叔丁醇钠、水合肼或四丁基氟化铵，优选氢氧化锂或碳酸钾。
在本申请的部分实施方案中，步骤5-2中脱除保护基R的反应所使用的溶剂选自乙醇、水、甲醇、四氢呋喃或异丙醇，优选水或四氢呋喃。
在本申请的部分实施方案中，本申请的式I化合物芦可替尼的制备方法可选地包括如下步骤1：式V化合物在催化剂和甲基化试剂的存在下反应得到式VI化合物：
Figure PCTCN2016113000-appb-000015
其中，R如上所定义。
在本申请的部分实施方案中，步骤1中所述的甲基化试剂选自甲基溴化镁、甲基氯化镁 或三甲基铝，优选甲基溴化镁。
在本申请的部分实施方案中，步骤1中所使用的溶剂选自甲苯、二氯甲烷、乙醚或四氢呋喃，优选四氢呋喃或乙醚。
在本申请的部分实施方案中，步骤1中所使用的催化剂选自Pd(PPh3)4、Pd(bppf)Cl2或Pd(dppf)Cl2·CH2Cl2，优选Pd(bppf)Cl2。
在本申请的部分实施方案中，步骤1中式V化合物与催化剂和甲基化试剂的摩尔比为1:0.005～0.05:1.5～4，优选1:0.005～0.015:2～3。
再一方面，本申请提供了式II-1化合物、式II-2化合物、式IV化合物、式IV化合物的D-酒石酸盐、式III-1化合物、式XI-1化合物、式XI-2化合物和式XII-1化合物。
Figure PCTCN2016113000-appb-000016
又一方面，本申请提供了式II-1化合物、式II-2化合物、式IV化合物、式IV化合物的D-酒石酸盐、式III-1化合物、式XI-1化合物、式XI-2化合物和/或式XII-1化合物在制备芦可替尼中的用途。
在本申请的部分实施方案中，所述式IV化合物或其D-酒石酸盐在制备芦可替尼中的用途包括利用式IV化合物或其D-酒石酸盐形成芦可替尼中的吡唑环结构。
在本申请的部分实施方案中，所述式IV化合物或其D-酒石酸盐在制备芦可替尼中的用途包括利用式IV化合物引入芦可替尼的手性碳原子。
另一方面，本申请提供了式III化合物的制备方法，其包括使式II化合物与式IV化合物 或其盐反应得到式III化合物，
Figure PCTCN2016113000-appb-000017
其中，R选自H或氨基保护基。
在本申请的部分实施方案中，所述氨基保护基在相应的反应步骤中不会从化合物中脱除。在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，所述式IV化合物的盐可以选自手性盐或者非手性盐。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物，优选自乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸，更优选自酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、 D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，所述非手性盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐；优选自盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐或对甲基苯磺酸盐，更优选自盐酸盐或乙酸盐。
在本申请的部分实施方案中，所述式II化合物和式IV化合物的摩尔比为1.0:1.0～5.0，优选1.0:1.0～3.0，更优选1.0:1.0～1.5，进一步优选1.0:1.0～1.2。
本申请所述的式II化合物与式IV化合物或其盐反应得到式III化合物的反应可以在酸性条件下、碱性条件下或者中性条件下进行。
在本申请的部分实施方案中，所述反应在酸性条件下进行。
在本申请的部分实施方案中，所述酸性条件通过加入酸性试剂提供，所述酸性试剂选自柠檬酸、富马酸、酒石酸、马来酸、苹果酸、琥珀酸、乙酸、抗坏血酸、硫酸、盐酸或氢溴酸，或者它们的混合物，优选酒石酸、乙酸或盐酸。
在本申请的部分实施方案中，所述反应在碱性条件下进行。
在本申请的部分实施方案中，所述碱性条件通过加入碱性试剂提供，所述碱性试剂选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸铯、碳酸钠、碳酸氢钾、碳酸氢钠、三乙胺、二异丙基乙基胺或DBU，或者它们的混合物，优选三乙胺、氢氧化钠或氢氧化钾。
在本申请的部分实施方案中，所用溶剂选自乙酸、乙醇、甲醇、乙二醇单甲醚、乙二醇二甲醚、水、N-甲基吡咯烷酮、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或者一种以上上述溶剂的混合溶剂，优选水、乙酸或乙醇或者上述三种溶剂中一种以上的混合溶剂。
另一方面，本申请提供了式XII化合物的制备方法，其包括使式II化合物与式IV化合物或其盐在NH3存在的条件下反应得到式XII化合物，
Figure PCTCN2016113000-appb-000018
其中，R选自H或氨基保护基。
在本申请的部分实施方案中，所述氨基保护基在相应的反应步骤中不会从化合物中脱除。
在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，所述式IV化合物的盐可以选自手性盐或者非手性盐。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物，优选乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸，更优选酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，所述非手性盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐；优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐或对甲基苯磺酸盐，更优选盐酸盐或乙酸盐。
在本申请的部分实施方案中，提供NH3的试剂选自氨水、氨甲醇、氨气和液氨中的一种或多种的组合，优选氨水。
在本申请的部分实施方案中，由式II化合物与式IV化合物或其盐反应得到式XII化合物的反应中，所用溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选四氢呋喃。
另一方面，本申请提供了式I化合物芦可替尼的制备方法，其包括以下步骤：
步骤(1)：使式II化合物与式IV化合物或其盐在NH3存在的条件下反应得到式XII化合物，
Figure PCTCN2016113000-appb-000019
其中，R选自H或氨基保护基；以及
步骤(2-1)：当R为H时，式XII的酰胺基团在脱水剂的存在下转化为氰基，得到式I化合物芦可替尼，或者
步骤(2-2)：当R为氨基保护基时，式XII的酰胺基团转化为氰基并且脱氨基保护基R，得到式I化合物芦可替尼，
Figure PCTCN2016113000-appb-000020
其中，R选自H或氨基保护基。
在本申请的部分实施方案中，步骤(1)中所述氨基保护基在相应的反应步骤中不会从化合物中脱除。
在本申请的部分实施方案中，步骤(1)和步骤(2-2)中所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基 苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，步骤(1)中所述式IV化合物的盐可以选自手性盐或者非手性盐。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物，优选乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸，更优选酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，形成所述手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，所述非手性盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐；优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐或对甲基苯磺酸盐，更优选盐酸盐或乙酸盐。
在本申请的部分实施方案中，步骤(1)中提供NH3的试剂选自氨水、氨甲醇、氨气和液氨中的一种或多种的组合，优选氨水。
在本申请的部分实施方案中，步骤(1)中所用溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、 氯苯、乙腈、DMA、NMP、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选四氢呋喃。
在本申请的部分实施方案中，步骤(2-1)中所使用的脱水剂选自三氯氧磷、三聚氯氰、五氧化二磷、二氯亚砜、三氟乙酸酐、三氟磺酐或草酰氯中的一种或多种的组合，优选三氯氧磷或三聚氯氰。
在本申请的部分实施方案中，步骤(2-1)中所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、DMSO、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯或者一种以上上述溶剂的混合溶剂，优选二氯甲烷或NMP或者两者的混合溶剂。
在本申请的部分实施方案中，步骤(2-1)中式XII化合物(R＝H)与脱水剂的摩尔比为1：1～10，优选1：3～8，更优选1：4～7，进一步优选1：5～7。
在本申请中，步骤(2-2)中，为了实现本申请的方法，本领域的技术人员在已有实施方案的基础上可以对步骤的顺序进行变换。例如，由式XII化合物(R＝氨基保护基)制备芦可替尼时，可以先进行酰胺基团转化为氰基的反应再进行脱保护基R的反应，也可以先进行脱保护基R的反应再进行酰胺基团转化为氰基的反应，两者均属于本申请的保护范围内。
在本申请的部分实施方案中，步骤(2-2)中酰胺基团转化为氰基的反应所使用的脱水剂选自三氯氧磷、三聚氯氰、五氧化二磷、二氯亚砜、三氟乙酸酐、三氟磺酐或草酰氯中的一种或多种的组合，优选三氯氧磷或三聚氯氰。
在本申请的部分实施方案中，步骤(2-2)中酰胺基团转化为氰基的反应所使用的溶剂选自四氢呋喃、二氯甲烷、三氯甲烷、氯苯、乙腈、DMA、NMP、DMSO、乙酸乙酯、乙酸异丙酯、甲苯或二甲苯，优选二氯甲烷或NMP。
在本申请的部分实施方案中，步骤(2-2)中酰胺基团转化为氰基的反应中式XII化合物(R＝氨基保护基)与脱水剂的摩尔比为1：1～10，优选1：3～8，更优选1：4～7，进一步优选1：5～7。
在本申请的部分实施方案中，步骤(2-2)中脱除保护基R的反应可以在酸性条件或碱性条件下进行。在酸性条件或碱性条件下，可以各自选择合适的催化剂和溶剂进行脱除保护基R的反应。
在本申请的部分实施方案中，步骤(2-2)中脱除氨基保护基R的反应所使用的催化剂选自三氟乙酸、三氟乙酸酐、四氟硼酸锂或三氟化硼-乙醚，优选三氟乙酸或三氟化硼-乙醚。
在本申请的部分实施方案中，步骤(2-2)中脱除氨基保护基R的反应所使用的溶剂选自二氯甲烷、四氢呋喃、乙腈、水、NMP、DMA或DMF，优选乙腈或NMP。
在本申请的部分实施方案中，步骤(2-2)中脱除氨基保护基R使用的催化剂选自碳酸钠、碳酸铯、碳酸钾、氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钾、叔丁醇钠、水合肼或四丁基氟化铵，优选氢氧化锂或碳酸钾。
在本申请的部分实施方案中，步骤(2-2)中脱除保护基R的反应所使用的溶剂选自乙醇、水、甲醇、四氢呋喃或异丙醇，优选水或四氢呋喃。
另一方面，本申请提供了式II化合物的制备方法，其包括以下步骤：式VI化合物在DMF和氯化试剂的作用下转化为式II化合物，
Figure PCTCN2016113000-appb-000021
其中，R选自H或氨基保护基。
在本申请的部分实施方案中，所述氨基保护基选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)或N-特戊酰氧基甲基(POM)，优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基或苄基，更优选2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
在本申请的部分实施方案中，所述氯化试剂选自草酰氯、三氯氧磷和氯化亚砜中的一种或任意两种以上的混合物，优选三氯氧磷。
在本申请的部分实施方案中，式VI化合物与氯化试剂的物质的量之比选自1.0:2.0～6.0，优选1.0:2.0～4.0，更优选1.0:2.5～3.5。
在本申请的部分实施方案中，所使用的溶剂选自1,4-二氧六环、二氯甲烷、四氢呋喃、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或一种以上的混合溶剂，优选N,N-二甲基甲酰胺、1,4-二氧六环或四氢呋喃或者它们中的一种以上的混合溶剂。
在本申请的部分实施方案中，本申请的式II化合物的制备方法可选地还包括：式V化合物在催化剂和甲基化试剂的存在下反应得到式VI化合物，
Figure PCTCN2016113000-appb-000022
其中，R如上所定义。
在本申请的部分实施方案中，所述甲基化试剂选自甲基溴化镁、甲基氯化镁或三甲基铝，优选甲基溴化镁。
在本申请的部分实施方案中，所使用的溶剂选自甲苯、二氯甲烷、乙醚或四氢呋喃，优选四氢呋喃或乙醚。
在本申请的部分实施方案中，所使用的催化剂选自Pd(PPh3)4、Pd(bppf)Cl2或Pd(dppf)Cl2·CH2Cl2，优选Pd(bppf)Cl2。
在本申请的部分实施方案中，式V化合物与催化剂和甲基化试剂的摩尔比为1:0.005～0.05:1.5～4，优选1:0.005～0.015:2～3。
再一方面，本申请提供了式IV化合物或其手性盐的制备方法，其包括以下步骤：
步骤C-1：式X化合物与手性酸在溶剂存在下反应，以形成式IV化合物的手性盐，
Figure PCTCN2016113000-appb-000023
步骤C-2：分离式IV化合物的手性盐；以及
步骤C-3：可选地，用碱处理式IV化合物的手性盐，得到式IV化合物。
在本申请的部分实施方案中，步骤C-1中所述的手性酸可以选自以下酸或其对映体过量形式：扁桃酸、2-氯扁桃酸、樟脑酸、乳酸、苹果酸、3-溴樟脑-8-磺酸、3-溴樟脑-10-磺酸、10-樟脑磺酸、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸或酒石酸及其酰基衍生物；优选乳酸、苹果酸、樟脑酸、10-樟脑磺酸、酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二对甲基苯甲酰酒石酸、二对甲氧基苯甲酰酒石酸、二对氯苯甲酰酒石酸、二对溴苯甲酰酒石酸、二对氟苯甲酰酒石酸、二对硝基苯甲酰酒石酸、二对氨基苯甲酰酒石酸或二对氰基苯甲酰酒石酸；更优选酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸或二对甲基苯甲酰酒石酸。
在本申请的部分实施方案中，步骤C-1中形成所述式IV化合物的手性盐所用的手性酸可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
在本申请的部分实施方案中，步骤C-1中所使用的溶剂选自丙酮、1,4-二氧六环、四氢呋喃和乙酸乙酯中的一种或一种以上的混合溶剂，优选丙酮。
在本申请的部分实施方案中，步骤C-1中式X化合物与手性酸的摩尔比为1.0:0.2～1.0，优选1.0:0.3～0.7，更优选1.0:0.4～0.6。
在本申请的部分实施方案中，式IV化合物或其手性盐的制备方法可选地还包括以下步骤：
步骤A：式VII化合物在碱存在下与丙二酸反应，得到式VIII化合物，
Figure PCTCN2016113000-appb-000024
以及
步骤B：式VIII化合物与水合肼反应得到式X化合物，
Figure PCTCN2016113000-appb-000025
在本申请的部分实施方案中，步骤A中所使用的碱选自哌啶、三乙胺、脯氨酸、N,N-二异丙基乙胺、四氢比咯、吡啶或4-二甲氨基吡啶，优选哌啶。
在本申请的部分实施方案中，步骤A中所使用的溶剂选自吡啶、乙腈、乙醇、N,N-二甲基甲酰胺、二甲亚砜、乙酸乙酯、丙酮或1,4-二氧六环，优选吡啶。
在本申请的部分实施方案中，步骤B中所使用的溶剂选自水合肼、1,4-二氧六环、乙醇、甲醇、异丙醇、四氢呋喃、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或一种以上的混合溶剂，优选水合肼。
定义部分
本申请所述的氨基保护基包括但不限于《Protective Groups in Organic Synthesis》(第4版，John Wiley & Sons:New Jersey)中描述的氨基保护基，该文献以引用的方式并入本申请中。在本申请中，本领域的技术人员可以根据氨基保护基的特点采用已知的方法，与反应化合物 连接或者从反应化合物上脱除。本申请所述的氨基保护基可以选自苄氧羰基(Cbz)、2,2,2-三氯乙氧羰基(Troc)、2-(三甲基甲硅烷基)乙氧羰基(Teoc)、2-(4-三氟甲基苯磺酰基)乙氧羰基(Tsc)、叔丁氧羰基(Boc)、1-金刚烷基氧基羰基(Adoc)、2-金刚烷基羰基(2-Adoc)、2,4-二甲基戊-3-基氧基羰基(Doc)、环己基氧基羰基(Hoc)、1,1-二甲基-2,2,2-三氯乙氧羰基(TcBoc)、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基(Bum)、苄氧基甲基(Bom)、2-四氢吡喃基(THP)、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-特戊酰氧基甲基(POM)。
在本申请中，根据所述的式II化合物结构特点，本领域的技术人员可以遇见到其具有酮式-烯醇互变异构的性质(《基础有机化学》，第三版，高等教育出版社，ISBN 7-04-016637-2，第654-656页)，式II化合物的酮式-烯醇互变异构体也在本申请的保护范围内。本申请所述的式II化合物的酮式-烯醇互变异构体包括如下结构：
Figure PCTCN2016113000-appb-000026
在本申请中，所述氨基保护基是指在反应过程中，希望除了特定官能团发生以外，使得氨基可逆地转化成惰性基团的官能团。本申请所述的各个步骤的反应中，氨基保护基并不是必须的，本领域的技术人员根据每一步骤的反应条件和针对反应结果的需要，可选地在反应底物中引入氨基保护基或者不引入氨基保护基。例如，在下述反应步骤中，
Figure PCTCN2016113000-appb-000027
实验人员发现，该反应条件温和，反应可以在酸性条件、碱性条件或者中性条件下反应，反应体系中不存在强氧化、强还原或者活性催化环境，R选自H或氨基保护基都可以实现本申请所述的合成方案。
本申请所述的式IV化合物可以采用其自由碱形式，也可以采用其盐形式。所述盐形式可以选自手性盐或者非手性盐。所述手性盐是指具有不对称原子(例如碳原子)的酸性化合物与对映体过量的对应手性碱化合物形成的盐。所述手性酸指具有不对称原子的酸，包括其对映体过量形式或者对映体非过量形式。所述手性盐可以选自扁桃酸盐、2-氯扁桃酸盐、樟脑酸盐、乳酸盐、苹果酸盐、3-溴樟脑-8-磺酸盐、3-溴樟脑-10-磺酸盐、10-樟脑磺酸盐、2-氨基-7,7-二甲基双环[2,2,1]庚-1-亚甲基磺酸盐、2-丙烯酰胺-7,7-二甲基双环并[2,2,1]庚-1-亚甲基磺酸盐或酒石酸及其酰基衍生物盐；优选自乳酸盐、苹果酸盐、樟脑酸盐、10-樟脑磺酸盐、酒石酸盐、二乙酰基酒石酸盐、二苯甲酰基酒石酸盐、二对甲基苯甲酰酒石酸盐、二对甲氧基苯甲酰酒石酸盐、二对氯苯甲酰酒石酸盐、二对溴苯甲酰酒石酸盐、二对氟苯甲酰酒石酸盐、二对硝基苯甲酰酒石酸盐、二对氨基苯甲酰酒石酸盐或二对氰基苯甲酰酒石酸盐。
本申请所述的手性盐可以选自其对映体过量形式，例如，酒石酸及其酰基衍生物盐的对映体过量形式可以选自D-酒石酸、D-二乙酰基酒石酸、D-二苯甲酰基酒石酸、D-二对甲基苯甲酰酒石酸、D-二对甲氧基苯甲酰酒石酸、D-二对氯苯甲酰酒石酸、D-二对溴苯甲酰酒石酸、D-二对氟苯甲酰酒石酸、D-二对硝基苯甲酰酒石酸、D-二对氨基苯甲酰酒石酸或D-二对氰基苯甲酰酒石酸。
本申请所述的酒石酸及其酰基衍生物也包括其水合物形式。例如，酒石酸包括酒石酸和酒石酸一水合物，D-二苯甲酰基酒石酸包括D-二苯甲酰基酒石酸和D-二苯甲酰基酒石酸一水合物。
本申请所述的非手性盐可以选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐。
本申请所述的摩尔比与物质的量之比相互等同。
在本申请中，所述式V所示化合物中R为H时，可来源于市售；式V所示化合物(R为氨基保护基)可以使用式V所示化合物(R为H)为原料，根据不同氨基保护基的特性，采用已知的方法制备得到。例如，式V所示化合物为如下式V-2结构时，
Figure PCTCN2016113000-appb-000028
用4-氯吡咯并[2,3-d]嘧啶为原料，在碱性条件下与2-(三甲基甲硅烷基)乙氧甲基氯反应可以得到式V-2化合物。
在本申请中，式VII化合物可来源于市售。
在本申请中，术语“DMF”是指N,N-二甲基甲酰胺。
在本申请中，术语“NMP”是指N-甲基吡咯烷酮。
在本申请中，术语“SEM-”是指2-(三甲基硅)乙氧基甲基。
在本申请中，术语“DMA”是指N,N-二甲基乙酰胺。
在本申请中，术语“DMSO”是指二甲基亚砜。
在本申请中，所述甲基化试剂是指可向底物分子中的碳、硅、氮、磷、氧或硫原子上引入甲基的试剂。
在本申请中，所述氯化试剂是指能提供氯原子向底物分子中的碳、硅、氮、磷或硫原子上引入氯原子的试剂。
在本申请中，所述脱水剂是指在加热或催化剂作用下能够去除化合物结构中水分子的试剂。
在本申请中，所述氨基化试剂是指向底物分子中的碳、硅、氮、磷、氧或硫原子上引入氨基或取代氨基的试剂。
在本申请中，在一些实施方案中，所述手性化合物是对映体过量的，所述对映体过量是指其中的手性异构体的含量(物质的量)等于或大于约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％、约95％、约96％、约97％、约98％、约99％、约99.1％、约99.2％、约99.3％、约99.4％、约99.5％、约99.6％、约99.7％、约99.8％、约99.9％或约99.99％。
在本申请中，所述式IV化合物的非手性盐可以通过将式IV化合物在溶剂中与对应的非手性酸化合物接触制备得到。例如，式IV化合物的盐酸盐可以通过式IV化合物与HCl制备得到。
在本申请中，消旋体、ambiscalemic和scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本申请的范围之内。
在本申请中，化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体过量的混合物，所有这些混合物都属于本申请的范围之内。烷基等取代基中可存在另外的不对称碳原 子。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。
在本申请中，所述反应可选地在溶剂中进行，本申请中所使用的所有溶剂是市售的，无需进一步纯化即可使用，反应一般是在惰性氮气下、无水溶剂中进行的。
化合物经手工或者
Figure PCTCN2016113000-appb-000029
软件命名，市售化合物采用供应商目录名称。
在本申请中，质子核磁共振数据记录在BRUKER AV-500(500MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示；质谱是在Waters XEVO G2 QTOF上测定。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本申请的制备方法具有步骤简短、高立体选择性、原子利用率高、反应条件温和、后处理简便的特点，避免使用价格昂贵的不对称反应催化剂，适合工业化生产。
具体实施方式
以下实施例对本申请技术方案作进一步非限制性的详细说明。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。本申请中使用的溶剂、试剂和原料等均为市售化学纯或分析纯产品。
实施例1：(R)-5-环戊基吡唑烷-3-酮D-酒石酸盐
Figure PCTCN2016113000-appb-000030
步骤1：3-环戊基丙烯酸
将660mL环戊基甲醛和500g丙二酸加入到1L吡啶中，滴加13.4mL哌啶，室温下搅拌反应1小时，升温至80℃继续搅拌反应5小时。反应结束后，减压浓缩，蒸除吡啶，加入纯化水2.6L，浓盐酸调pH至2～5，乙酸乙酯(1.7L×3)萃取，合并有机层，依次用1L水洗涤、1L饱和食盐水洗涤。有机层加入4L 9％氢氧化钠(1.3L×3)搅拌，合并水层降温至0～5℃，滴加浓盐酸调pH至2～5，加入2.6L乙酸乙酯萃取，水层用乙酸乙酯(1.3L×2)洗涤，合并有机层，2.6L纯化水洗涤，2.6L饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到3-环戊基丙烯酸(650g，96.6％)。
1H-NMR(500MHz,CDCl3)：δ＝11.24(bs,1H),7.08(dd,J＝15.6,8.0Hz,1H),5.81(dd,J＝ 15.5,1.2Hz,1H),2.64(dd,J＝8.1,7.6Hz,1H),1.92～1.81(m,2H),1.71(ddq,J＝12.5,6.5,2.9Hz,2H),1.68～1.58(m,2H),1.48～1.37(m,2H)；
MS(ES):141.09(M+H+)。
步骤2：5-环戊基吡唑烷-3-酮
将586g水合肼降温至0～5℃，搅拌下加入3-环戊基丙烯酸600g，加毕升温至70～75℃反应0.5小时。反应结束后，将反应液减压浓缩至油状物，加入纯化水1.2L，搅拌溶解，降温至0～5℃，搅拌析晶过夜。抽滤，滤饼用1.5L异丙醚淋洗，45℃干燥，得到5-环戊基吡唑烷-3-酮(508g，77.0％)。
1H-NMR(500MHz,DMSO-d6)：δ＝8.92(bs,1H),5.17(bs,1H),3.13(q,J＝8.3Hz,1H),2.32(dd,J＝15.8,7.3Hz,1H),2.03(dd,J＝15.9,8.4Hz,1H),1.89(d,J＝8.2Hz,1H),1.75～1.62(m,2H),1.60～1.42(m,4H),1.26(dq,J＝12.4,7.6Hz,1H),1.20～1.06(m,1H)；
MS(ES):155.21(M+H+)。
步骤3：(R)-5-环戊基吡唑烷-3-酮D-酒石酸盐
将消旋的5-环戊基吡唑烷-3-酮406g加入4.1L丙酮中，搅拌溶清，加入D-酒石酸198g，搅拌30分钟后，降温至0～5℃析晶，过滤，滤饼用1.5L丙酮淋洗。滤饼于45℃干燥得到(R)-5-环戊基吡唑烷-3-酮D-酒石酸盐(326g，40.7％)，ee值为99.4％。
步骤4：(R)-5-环戊基吡唑烷-3-酮
将220mL氢氧化钠(3M)溶液缓慢滴入(R)-5-环戊基吡唑烷-3-酮D-酒石酸盐(64g)中，冰浴降温至0～5℃，搅拌下缓慢滴加浓盐酸至料液浑浊，再以30mL盐酸3M调溶液pH至中性，加入二氯甲烷500mL分三次萃取，合并有机层，无水硫酸镁干燥，过滤，收集滤液，减压浓缩得产物(24.71g，76.2％)。
1H-NMR(500MHz,DMSO-d6)：δ＝8.93(bs,1H),5.15(bs,1H),3.17(q,J＝7.9Hz,1H),2.30(dd,J＝16.0,7.3Hz,1H),2.01(dd,J＝16.0,8.4Hz,1H),1.89(m,1H),1.74～1.60(m,2H),1.55(m，2H),1.47(m,2H),1.26(m,1H),1.14(m,1H)；
MS(ES):155.12(M+H+)。
实施例2：(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈
Figure PCTCN2016113000-appb-000031
步骤1：4-甲基-7H-吡咯并[2,3-d]嘧啶
将4-氯-7H-吡咯并[2,3-d]嘧啶150g和5.72g Pd(bppf)Cl2，加入1.5L四氢呋喃中，室温下搅拌0.5小时，然后降温至0℃以下，缓慢滴加850mL甲基溴化镁(3M溶于乙醚)，滴毕升温至60～65℃回流反应2小时，降温至0℃以下，缓慢滴加浓盐酸淬灭反应，加毕再加入纯化水650mL，搅拌15分钟，分液，弃去有机相。水相用NaHCO3调节pH至6，抽滤，455mL纯化水洗涤滤饼，收集滤液，用乙酸乙酯1.05L萃取3次，有机相浓缩得到4-甲基-7H-吡咯并[2,3-d]嘧啶(109.5g，84.2％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.00(bs,1H),8.61(s,1H),7.47(d,J＝3.6Hz,1H),6.62(d,J＝3.5Hz,1H),2.64(d,J＝1.6Hz,3H)；
MS(ES):134.07(M+H+)。
步骤2：3-羟基-2-(7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛
将91.6g 4-甲基-7H-吡咯并[2,3-d]嘧啶加入230mL DMF和460mL二氧六环的混合溶剂中，降温至0℃以下，搅拌下滴加190mL三氯氧磷，控制料液温度低于20℃，加毕升温至80℃搅拌反应3小时。减压浓缩除去二氧六环及DMF，残余物中加入920mL四氢呋喃，用25％NaOH水溶液调pH至10～12，加毕升温至60℃搅拌反应2小时。然后用浓盐酸调节pH至6-7，降温搅拌析晶2小时，抽滤得滤饼，60℃干燥得到3-羟基-2-(7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛(78.3g，60.2％)。
1H-NMR(500MHz,DMSO-d6)：δ＝13.51(bs,1H),12.04(bs,1H),9.49(s,2H),8.72(s,1H),7.47(dd,J＝46.2,3.7Hz,2H)；
MS(ES):190.06(M+H+)。
步骤3：(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酸
方法一：将54g 3-羟基-2-(7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛加入648mL乙酸和324mL纯化水的混合溶剂中，再加入87g(R)-5-环戊基吡唑烷-3-酮D-酒石酸盐，升温至回流反应8小时。反应结束后，将反应液减压浓缩，余物中加入500mL水，调pH至6.5～7，然后用300mL乙酸乙酯洗涤2次。水相用3M HCl继续调pH至5～5.5，抽滤得到(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酸(55.8g，60.0％)。
方法二：将5g 3-羟基-2-(7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛加入100mL水中，再加入氢氧化钠1.3g，4.1g(R)-5-环戊基吡唑烷-3-酮，升温至回流反应8小时。反应结束后，盐酸调pH至1～2，减压浓缩，100mL甲醇溶解，加入甲醇钠1.4g，加热回流0.5h，浓缩至干，残余物乙酸乙酯打浆2h，抽滤得到(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酸钠(6.7g，73.0％)。
方法三：取3-羟基-2-(7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛10.1g加入200mL无水乙醇中，然后加入(R)-5-环戊基吡唑烷-3-酮8.23g，升温至回流反应36h。反应结束后，减压浓缩蒸去溶剂，余物中加入2M NaOH溶液120g，室温下搅拌5h，3M HCl调pH至6～7，加入乙酸乙酯200mL洗涤三次，水相用3M HCl继续调pH至5～5.5，然后用400mL乙酸乙酯萃取3次，合并有机层，浓缩至干燥得(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酸(11.3g，65.7％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.12(bs,1H),8.66(s,2H),8.28(s,1H),7.56(s,1H),6.98(s,1H),4.68～4.39(m,1H),2.99(t,J＝13.0Hz,1H),2.84(d,J＝16.6Hz,1H),2.43～0.89(m,10H)；
MS(ES):326.16(M+H+)。
步骤4：(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺
48g(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酸加入48mL二氯甲烷和80mL NMP的混合溶剂中，滴入48mL草酰氯，过程中控制温度不超过5℃，加毕后，保持20～25℃反应2.5小时。然后将上述反应液滴入适量氨水中，反应1小时。反应结束后，减压浓缩除去二氯甲烷，水相用乙酸乙酯(800mL×3)萃取，减压浓缩除去乙酸乙酯，得到(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺(29.8g，62％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.06(bs,1H),8.67(s,1H),8.58(s,1H),8.28(s,1H),7.56(d,J＝3.6Hz,1H),7.35(d,J＝3.1Hz,1H),6.98(d,J＝3.6Hz,1H),6.79(d,J＝3.1Hz,1H), 4.59(td,J＝9.7,3.9Hz,1H),2.90(dd,J＝15.3,10.0Hz,1H),2.73～2.62(m,2H),1.84(dddd,J＝40.6,13.1,8.0,4.6Hz,2H),1.56～1.24(m,6H)；
MS(ES):325.18(M+H+)。
步骤5：(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈
将14.6g(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺加入480mL二氯甲烷和40mL NMP的混合溶剂中，滴加28mL三氯氧磷，室温条件下反应，过程中控制温度不超过30℃，反应3小时。反应结束后，反应液中加入纯化水600mL，滴加饱和碳酸氢钠溶液至混合液pH为7，混合液分层，有机相减压浓缩得到(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈(10.6g，77.3％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.13(bs,1H),8.84(d,J＝0.4Hz,1H),8.69(s,1H),8.37(s,1H),7.63(dd,J＝2.3,3.5Hz,1H),7.01(dd,J＝1.4,3.4Hz,1H),4.56(td,J＝19.5,4.6Hz,1H),3.26(dd,J＝17.3,9.9Hz,1H),3.17(dd,J＝17.4,4.3Hz,1H),2.43(m,1H),1.83(m,1H),1.64～1.09(m,7H)；
MS(ES):307.17(M+H+)。
实施例3：4-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
Figure PCTCN2016113000-appb-000032
将450g 4-氯吡咯并[2,3-d]嘧啶加入3.6L DMF中，降温至-10℃～-20℃，分批加入144g氢化钠(60％)。缓慢滴加586.0g 2-(三甲基硅烷基)乙氧甲基氯，搅拌反应2小时。反应结束后，搅拌下滴加36g冰醋酸淬灭反应，将反应液倾入纯化水14.4L中，用乙酸乙酯萃取，饱和食盐水洗涤。有机层减压浓缩蒸除溶剂，残余物用200～300目硅胶柱层析纯化，得到4-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(808.2g，97.2％)。
1H-NMR(500MHz,DMSO-d6)：δ＝8.69(s,1H),7.85(d,J＝3.8Hz,1H),6.70(d,J＝3.6Hz,1H),5.62(s,2H),3.53(t,J＝7.9Hz,2H),0.81(t,J＝8.1Hz,2H),0.23(s,9H)；
MS(ES):284.10(M+H+)。
实施例4：(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈
Figure PCTCN2016113000-appb-000033
步骤1：4-甲基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶
将4-氯-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶103.6g、[1,1’-双(二苯基膦)二茂铁]二氯化钯2.96g，加入1.13L四氢呋喃中，降温至-15～-5℃，缓慢滴加200mL甲基溴化镁(3M溶于乙醚)，滴毕升温至60～65℃回流反应2小时。反应结束后，降温至-15～-5℃，缓慢滴加455mL饱和氯化铵溶液淬灭反应，过滤，滤饼用455mL四氢呋喃淋洗，弃去滤饼，滤液减压浓缩，余物中加入455mL纯化水，加入1.13L乙酸乙酯萃取2次，合并有机相，150g饱和食盐水洗涤，有机相减压浓缩蒸去溶剂得到4-甲基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶103.2g。
1H-NMR(500MHz,DMSO-d6)：δ＝8.67(s,1H),7.63(d,J＝3.7Hz,1H),6.70(d,J＝3.6Hz,1H),5.60(s,2H),3.54～3.45(m,2H),2.64(s,3H),0.81(t,J＝8.0Hz,2H),0.12(s,9H)；
MS(ES):264.15(M+H+)。
步骤2：3-羟基-2-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4- 基)丙烯醛
取4-甲基-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶103.2g加入453mL DMF中，降温至-15～-5℃，搅拌下滴加184.2g三氯氧磷，控制温度-5～5℃，加毕升温至80℃搅拌反应3小时。反应结束后，减压浓缩蒸去DMF，余物中加入1.13L四氢呋喃，降温至0～5℃，缓慢滴加NaOH溶液，控制料液温度低于20℃，加毕升温至60℃，搅拌反应2小时。将反应液减压浓缩，3M盐酸调pH至4，加入乙酸乙酯1.13L萃取两次，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，活性炭脱色。过滤，滤液减压浓缩得黑色黏稠残余物，加入无水乙醚453mL，升温至物料溶清，缓慢降温至0～5℃搅拌析晶4小时，过滤，乙醚113mL分两次淋洗滤饼，滤饼减压干燥，得到3-羟基-2-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛(53.2g，41.9％)。
1H-NMR(500MHz,DMSO-d6)：δ＝15.77(s,1H),9.51(s,2H),8.80(s,1H),7.70(d,J＝3.7Hz,1H),7.58(d,J＝3.7Hz,1H),5.63(s,2H),3.55～3.48(m,2H),0.83(t,J＝8.0Hz,2H),0.10(s,9H)；
MS(ES):320.14(M+H+)。
步骤3：(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酸
取3-羟基-2-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛51.2g加入2.05L无水乙醇中，待料液溶清，加入53.7g(R)-5-环戊基吡唑烷-3-酮D-酒石酸盐，升温至80～85℃回流反应9小时。反应结束后，减压浓缩蒸去溶剂，残余物中加入2M NaOH溶液640g，室温下搅拌1.0小时，3M HCl调pH至3～4，加入乙酸乙酯256mL萃取两次，合并有机层，饱和食盐水洗涤。过滤，滤液减压浓缩，残余物用200-300目硅胶柱层析纯化，得到(R)-3-环戊基-3-(4-(7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酸(58.4g，79.6％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.22(s,1H),8.74(s,1H),8.70(s,1H),8.31(s,1H),7.74(d,J＝3.7Hz,1H),7.09(d,J＝3.7Hz,1H),5.63(s,2H),4.55(td,J＝9.9,3.7Hz,1H),3.52(t,J＝8.0Hz,2H),3.04(dd,J＝16.5,10.3Hz,1H),2.89(dd,J＝16.4,3.7Hz,1H),2.35(d,J＝8.5Hz,1H),1.81(dtd,J＝11.0,6.9,3.7Hz,1H),1.62～1.47(m,3H),1.31～1.21(m,3H),0.83(t,J＝8.0Hz,2H),0.10(s,9H)；
MS(ES):456.24(M+H+)。
步骤4：(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酰胺
取(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酸49.2g加入480mL二氯甲烷中，滴入16.59mL草酰氯，加毕后，加入0.1mL DMF，20～25℃反应3小时。然后将反应液滴入480mL氨水中反应1小时。反应结束后，减压浓缩除去二氯甲烷，水相用乙酸乙酯(450mL×3)萃取三次，减压浓缩除去乙酸乙酯，得到(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酰胺(48g，97.5％)。
1H-NMR(500MHz,DMSO-d6)：δ＝8.73(s,1H),8.61(s,1H),8.29(s,1H),7.74(d,J＝3.7Hz,1H),7.34(d,J＝2.6Hz,1H),7.08(d,J＝3.6Hz,1H),6.76(d,J＝2.5Hz,1H),5.63(s,2H),4.59(td,J＝9.7,3.9Hz,1H),3.53(t,J＝8.0Hz,2H),2.89(dd,J＝15.3,10.0Hz,1H),2.66(dd,J＝15.3,3.9Hz,1H),2.36(q,J＝8.4Hz,1H),1.81(dtd,J＝11.6,7.1,3.7Hz,1H),1.62～1.48(m,3H),1.46～1.37(m,1H),1.26(td,J＝14.9,13.6,7.9Hz,3H),0.83(t,J＝8.0Hz,2H),0.10(d,J＝1.7Hz,9H)；
MS(ES):455.26(M+H+)。
步骤5：(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈
向(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酰胺42.6g中加入200mL二氯甲烷中，滴加57mL三氯氧磷，室温反应24小时。反应结束后，加入纯化水300mL，滴加饱和碳酸氢钠溶液至混合液pH为7，混合液分层，有机相减压浓缩得到(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈(38.4g，93.8％)。
1H-NMR(500MHz,DMSO-d6)：δ＝8.83(s,1H),8.75(s,1H),8.39(s,1H),7.77(d,J＝3.7Hz,1H),7.09(d,J＝3.7Hz,1H),5.63(s,2H),4.53(td,J＝9.4,4.0Hz,1H),3.51(t,J＝8.1Hz,2H),3.23(dq,J＝9.3,4.3Hz,2H),2.41(m,1H),1.79(m,1H),1.66～1.13(m,7H),0.81(t,J＝8.2Hz,2H),0.124(s,9H)；
MS(ES):437.25(M+H+)。
步骤6：(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈
取(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙腈35g加入700mL乙腈中，滴加31.5mL三氟化硼·乙醚，加毕后升温60～70℃反应5小时。然后加入270mL氨水和540mL纯化水，室温搅拌12小时。反应结束后，向反应液中加入乙酸乙酯200mL和饱和氯化铵200mL，水相用乙酸乙酯(300mL×3)萃取三次，有机相减压浓缩得到(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡 唑-1-基)丙腈(22.61g，92.1％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.10(bs,1H),8.80(d,J＝0.4Hz,1H),8.68(s,1H),8.37(s,1H),7.60(dd,J＝2.3,3.5Hz,1H),6.99(dd,J＝1.4,3.4Hz,1H),4.53(td,J＝9.5,4.3Hz,1H),3.26(dd,J＝17.3,9.9Hz,1H),3.19(dd,J＝17.4,4.3Hz,1H),2.39(m,1H),1.82(m,1H),1.60～1.08(m,7H)；
MS(ES):307.17(M+H+)。
实施例5：(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺
Figure PCTCN2016113000-appb-000034
取(R)-3-环戊基-3-(4-(7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)丙酰胺6.0g加入120mL乙腈中，滴加6mL三氟化硼·乙醚，加毕后升温60～70℃反应7小时。然后加入60mL氨水和54mL纯化水，室温搅拌6小时。反应结束后，向反应液中加入乙酸乙酯60mL和饱和氯化钠50mL，水相用乙酸乙酯(60mL×3)萃取三次，有机相减压浓缩得到(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺(4.08g，95.3％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.06(bs,1H),8.66(s,1H),8.58(s,1H),8.29(s,1H),7.56(d,J＝3.6Hz,1H),7.33(d,J＝3.1Hz,1H),6.97(d,J＝3.6Hz,1H),6.79(d,J＝3.1Hz,1H),4.55(td,J＝9.7,3.9Hz,1H),2.90(dd,J＝15.3,10.0Hz,1H),2.72～2.62(m,2H),1.84(dddd,J＝40.6,13.1,8.0,4.6Hz,2H),1.55～1.24(m,6H)；
MS(ES):325.11(M+H+)。
实施例6(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺
Figure PCTCN2016113000-appb-000035
将3-羟基-2-(7H-吡咯并[2,3-d]嘧啶-4-基)丙烯醛(30.1g)加入至180mL四氢呋喃和180mL氨水的混合溶剂中溶清，加入29.4g(R)-5-环戊基吡唑烷-3-酮，加毕后，保持60～70℃反应10h。加入水(1.2L)，乙酸乙酯(1.8L×3)萃取，减压浓缩除去乙酸乙酯，得浓缩物(50.4g)。该浓缩物于乙腈中加热回流打浆1h，缓慢降温，0～5℃搅拌1h，抽滤得红棕色固体，收料得粗品(33.2g)，收率：64.4％。粗品于300ml异丙醇中加热，溶清后，冷却搅拌析晶，抽滤得(R)-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙酰胺(15.3g，46.1％，纯度≥99.4％)。
1H-NMR(500MHz,DMSO-d6)：δ＝12.04(bs,1H),8.67(s,1H),8.56(s,1H),8.26(s,1H),7.54(d,J＝3.6Hz,1H),7.33(d,J＝3.1Hz,1H),6.96(d,J＝3.6Hz,1H),6.77(d,J＝3.1Hz,1H),4.57(td,J＝9.7,3.9Hz,1H),2.90(dd,J＝15.3,10.0Hz,1H),2.71～2.63(m,2H),1.82(dddd,J＝40.6,13.1,8.0,4.6Hz,2H),1.54～1.22(m,6H)；
MS(ES):325.18(M+H+)。

Claims (26)

  1. 一种式I化合物芦可替尼的制备方法，其包括以下步骤：
    步骤4：将式III化合物转化为式XI化合物，然后将式XI化合物在氨基化试剂的存在下转化为式XII化合物，
    Figure PCTCN2016113000-appb-100001
    其中，R选自H或氨基保护基，X选自Cl或Br；以及
    步骤5-1：当R为H时，式XII的酰胺基团在脱水剂的存在下转化为氰基，得到式I化合物芦可替尼，或者
    步骤5-2：当R为氨基保护基时，式XII的酰胺基团转化为氰基并且脱氨基保护基R，得到式I化合物芦可替尼，
    Figure PCTCN2016113000-appb-100002
    其中，R选自H或氨基保护基。
  2. 根据权利要求1所述的制备方法，其还包括步骤3：式II化合物与式IV化合物或其盐反应得到式III化合物，
    Figure PCTCN2016113000-appb-100003
    其中，R选自H或氨基保护基。
  3. 根据权利要求2所述的制备方法，其还包括步骤2：式VI化合物在DMF和氯化试剂的作用下转化为式II化合物，
    Figure PCTCN2016113000-appb-100004
    其中，R选自H或氨基保护基。
  4. 根据权利要求3所述的制备方法，其还包括步骤1：式V化合物在催化剂和甲基化试剂的存在下反应得到式VI化合物，
    Figure PCTCN2016113000-appb-100005
    其中，R选自H或氨基保护基。
  5. 根据权利要求2或4所述的制备方法，其中步骤3中式IV化合物或其手性盐的制备方法包括以下步骤：
    Figure PCTCN2016113000-appb-100006
    步骤C-1：式X化合物与手性酸在溶剂存在下反应，以形成式IV化合物的手性盐，
    Figure PCTCN2016113000-appb-100007
    步骤C-2：分离式IV化合物的手性盐；以及
    步骤C-3：可选地，用碱处理式IV化合物的手性盐，得到式IV化合物。
  6. 根据权利要求5所述的制备方法，其中步骤3中式IV化合物或其手性盐的制备方法还包括以下步骤：
    步骤A：式VII化合物在碱存在下，与丙二酸反应得式VIII化合物，
    Figure PCTCN2016113000-appb-100008
    以及
    步骤B：式VIII化合物与水合肼反应得式X化合物，
    Figure PCTCN2016113000-appb-100009
  7. 一种式I化合物芦可替尼的制备方法，其包括以下步骤：
    步骤2：式VI化合物在DMF和氯化试剂的作用下转化为式II化合物，
    Figure PCTCN2016113000-appb-100010
    步骤3：式II化合物与式IV化合物或其盐反应得到式III化合物，
    Figure PCTCN2016113000-appb-100011
    步骤4：将式III化合物转化为式XI化合物，然后式XI化合物在氨基化试剂的存在下转化为式XII化合物，
    Figure PCTCN2016113000-appb-100012
    以及
    步骤5-1：当R为H时，式XII的酰胺基团在脱水剂的存在下转化为氰基，得到式I化合物芦可替尼，或者
    步骤5-2：当R为氨基保护基时，式XII的酰胺基团转化为氰基并且脱氨基保护基R，得到式I化合物芦可替尼，
    Figure PCTCN2016113000-appb-100013
    其中，R选自H或氨基保护基，X选自Cl或Br。
  8. 根据权利要求7所述的制备方法，其还包括步骤1：式V化合物在催化剂和甲基化试剂的存在下反应得到式VI化合物，
    Figure PCTCN2016113000-appb-100014
    其中，R选自H或氨基保护基。
  9. 化合物，其选自以下化合物：
    Figure PCTCN2016113000-appb-100015
  10. 如下所示式IV化合物或其D-酒石酸盐：
    Figure PCTCN2016113000-appb-100016
  11. 权利要求9所述化合物在制备芦可替尼中的用途。
  12. 权利要求10所述化合物在制备芦可替尼中的用途。
  13. 根据权利要求12所述的用途，其中所述用途包括利用式IV化合物或其D-酒石酸盐形成芦可替尼中的吡唑环结构。
  14. 根据权利要求12所述的用途，其中所述用途包括利用式IV化合物或其D-酒石酸盐引入芦可替尼的手性碳原子。
  15. 一种式III化合物的制备方法，其包括使式II化合物与式IV化合物或其盐反应得到式III化合物，
    Figure PCTCN2016113000-appb-100017
    其中，R选自H或氨基保护基。
  16. 根据权利要求15所述的式III化合物的制备方法，其中所述氨基保护基选自苄氧羰基、 2,2,2-三氯乙氧羰基、2-(三甲基甲硅烷基)乙氧羰基、2-(4-三氟甲基苯磺酰基)乙氧羰基、叔丁氧羰基、1-金刚烷基氧基羰基、2-金刚烷基羰基、2,4-二甲基戊-3-基氧基羰基、环己基氧基羰基、1,1-二甲基-2,2,2-三氯乙氧羰基、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基、苄氧基甲基、2-四氢吡喃基、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基或N-特戊酰氧基甲基。
  17. 根据权利要求15所述的式III化合物的制备方法，其中所述式IV化合物的盐选自手性盐或者非手性盐。
  18. 根据权利要求15所述的式III化合物的制备方法，其中所述式II化合物和式IV化合物的摩尔比为1.0:1.0～5.0。
  19. 一种式I化合物芦可替尼的制备方法，其包括以下步骤：
    步骤(1)：使式II化合物与式IV化合物或其盐在NH3存在的条件下反应得到式XII化合物，
    Figure PCTCN2016113000-appb-100018
    其中，R选自H或氨基保护基；以及
    步骤(2-1)：当R为H时，式XII的酰胺基团在脱水剂的存在下转化为氰基，得到式I化合物芦可替尼，或者
    步骤(2-2)：当R为氨基保护基时，式XII的酰胺基团转化为氰基并且脱氨基保护基R，得到式I化合物芦可替尼，
    Figure PCTCN2016113000-appb-100019
    其中，R选自H或氨基保护基。
  20. 一种式XII化合物的制备方法，其包括使式II化合物与式IV化合物或其盐在NH3存在的条件下反应得到式XII化合物，
    Figure PCTCN2016113000-appb-100020
    其中，R选自H或氨基保护基。
  21. 根据权利要求20所述的式XII化合物的制备方法，其中所述氨基保护基选自苄氧羰基、2,2,2-三氯乙氧羰基、2-(三甲基甲硅烷基)乙氧羰基、2-(4-三氟甲基苯磺酰基)乙氧羰基、叔丁氧羰基、1-金刚烷基氧基羰基、2-金刚烷基羰基、2,4-二甲基戊-3-基氧基羰基、环己基氧基羰基、1,1-二甲基-2,2,2-三氯乙氧羰基、乙烯基、2-氯乙基、2-苯磺酰乙基、对硝基苯磺酰基、对甲基苯磺酰基、苯基磺酰基、甲磺酰基、烯丙基、苄基、2-硝基苄基、4-硝基苄基、二苯基-4-吡啶基甲基、N’,N’-二甲基肼基、甲氧基甲基、叔丁氧甲基、苄氧基甲基、2-四氢吡喃基、三(C1-4烷基)甲硅烷基、1,1-二乙氧基甲基、2-(三甲基甲硅烷基)乙氧基甲基或N-特戊酰氧基甲基。
  22. 根据权利要求20所述的式XII化合物的制备方法，其中提供NH3的试剂选自氨水、氨甲醇、氨气和液氨中的一种或多种的组合，优选氨水。
  23. 一种式II化合物的制备方法，其包括以下步骤：式VI化合物在DMF和氯化试剂的作用下转化为式II化合物，
    Figure PCTCN2016113000-appb-100021
    其中，R选自H或氨基保护基。
  24. 根据权利要求23所述的式II化合物的制备方法，其还包括：式V化合物在催化剂和甲基化试剂的存在下反应得到式VI化合物，
    Figure PCTCN2016113000-appb-100022
    其中，R选自H或氨基保护基。
  25. 一种式IV化合物或其手性盐的制备方法：
    Figure PCTCN2016113000-appb-100023
    其包括以下步骤：
    步骤C-1：式X化合物与手性酸在溶剂存在下反应，以形成式IV化合物的手性盐，
    Figure PCTCN2016113000-appb-100024
    步骤C-2：分离式IV化合物的手性盐；以及
    步骤C-3：任选地，用碱处理式IV化合物的手性盐，得到式IV化合物。
  26. 根据权利要求25所述的式IV化合物或其手性盐的制备方法，其还包括以下步骤：
    步骤A：式VII化合物在碱存在下，与丙二酸反应得式VIII化合物，
    Figure PCTCN2016113000-appb-100025
    以及
    步骤B：式VIII化合物与水合肼反应得式X化合物，
    Figure PCTCN2016113000-appb-100026
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