WO2018095320A1 - 吡咯并六元杂芳环类衍生物的制备方法及中间体 - Google Patents

吡咯并六元杂芳环类衍生物的制备方法及中间体 Download PDF

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Publication number
WO2018095320A1
WO2018095320A1 PCT/CN2017/112237 CN2017112237W WO2018095320A1 WO 2018095320 A1 WO2018095320 A1 WO 2018095320A1 CN 2017112237 W CN2017112237 W CN 2017112237W WO 2018095320 A1 WO2018095320 A1 WO 2018095320A1
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compound
formula
group
acid
protecting group
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PCT/CN2017/112237
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English (en)
French (fr)
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刘兵
边林
高晓晖
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江苏恒瑞医药股份有限公司
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Priority to BR112019008812A priority Critical patent/BR112019008812A2/pt
Priority to EP17873122.0A priority patent/EP3543241B8/en
Priority to US16/461,336 priority patent/US10851100B2/en
Priority to MX2019005319A priority patent/MX2019005319A/es
Priority to KR1020197017151A priority patent/KR20190084299A/ko
Priority to CN201780017873.5A priority patent/CN108884100B/zh
Priority to AU2017366400A priority patent/AU2017366400B2/en
Priority to CA3040981A priority patent/CA3040981A1/en
Priority to JP2019525997A priority patent/JP6937828B2/ja
Publication of WO2018095320A1 publication Critical patent/WO2018095320A1/zh
Priority to US17/071,687 priority patent/US20210024521A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 invention relates to a pyrrole hexa-heteroaryl ring derivative, a process for preparing the pharmaceutically acceptable salt thereof, an intermediate in the preparation process, and a preparation method thereof, and the pyrrole hexa-heteroaryl ring derivative can be used as JAK Use of an inhibitor for the preparation of a medicament for the treatment of myeloproliferative neoplasms and/or leukemia.
  • JAK protein kinase inhibitors block T cell activation and prevent transplant rejection after transplantation. These drugs can also be effective for other autoimmune diseases.
  • JAK3 As an important protein kinase, JAK3 also regulates the function of lymphocytes, macrophages and mast cells. JAK3 inhibitors are expected to be useful in the treatment or prevention of a variety of diseases involving lymphocyte, macrophage or mast cell function.
  • JAK2 activity is abnormally elevated in a variety of solid and hematological malignancies (glioblastoma, breast cancer, multiple myeloma, prostate cancer, AML, etc.).
  • JAK2 selective inhibitors has great medical value and market potential for the treatment of myeloproliferative neoplasms and leukemias (the JAK2 selective inhibitor Roxolitinib (INCB-018424) developed by INCYTE and NOVARTIS) has been approved by the FDA. Approved for successful listing).
  • JAK inhibitors of pyrrole hexa-heteroaryl derivatives are disclosed, for example, WO2001042246, WO2002000661, WO2009054941, WO2011013785, WO2013091539A1, WO2014194741A1, etc., wherein WO2013091539A1 discloses a pyrrole hexa-heteroaryl derivative.
  • the preparation method of (Compound 34) is as follows:
  • the starting material of the method has a naked imino group in the structure of the compound, which reacts with the chlorine atom on the self six-membered ring to form a by-product.
  • the yield of the intermediate 5 is only 5.0%, and the reaction time is as long as 48 hours.
  • the preparation method of the final product 34 is prepared by the hydrochloride of the compound of the formula (III) and the compound of the formula (C), and the post-treatment is carried out by column chromatography, and the yield is only 25.9%. Conducive to industrial expansion of production. Therefore, it is necessary to improve the existing preparation method.
  • the technical problem to be solved by the present invention is to provide a process and an intermediate for preparing a compound of the formula (IV), which are prepared by changing the starting material to improve the yield of the intermediate, and the final product is prepared by the free base of the formula (III).
  • the method is simple and easy to control, the reactants such as starting materials are simple and easy to purchase, the reaction conditions are simple and controllable, the post-reaction treatment method is simple, the reaction yield is remarkably improved, and the industry is expanded.
  • the present invention provides a compound of the formula (I) or a stereoisomer thereof:
  • R 1 is hydrogen or an amino protecting group
  • R 2 is an amino protecting group
  • R 3 is selected from a hydrogen atom, a C 1-6 alkyl group or an amino protecting group
  • the amino-protecting group is preferably an alkoxycarbonyl-based amino protecting group, an acyl-amino protecting group, a sulfonyl-based amino protecting group or an alkyl-based amino protecting group.
  • the alkoxycarbonylamino protecting group is selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl ( Teoc), methoxycarbonyl or ethoxycarbonyl,
  • the acylamino protecting group is selected from the group consisting of phthaloyl (Pht), trifluoroacetyl (Tfa), pivaloyl, benzoyl, formyl or acetyl;
  • the sulfonyl amino protecting group is selected from p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrophenylsulfonyl (p-Ns);
  • the alkyl-based amino protecting group is selected from the group consisting of trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB) or benzyl (Bn).
  • R 1 is selected from an alkoxycarbonyl-based amino protecting group, and the alkoxycarbonyl-based amino protecting group is preferably a benzyloxycarbonyl group (Cbz), a tert-butoxycarbonyl group (Boc), a fluorenylmethoxycarbonyl group (Fmoc) or an allyloxycarbonyl group ( Alloc), more preferably tert-butoxycarbonyl (Boc);
  • R 2 is selected from a sulfonyl amino protecting group, said sulfonyl amino protecting group p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrophenylsulfonyl (p- Ns), more preferably p-toluenesulfonyl (Ts);
  • R 3 is selected from a hydrogen atom or a methyl group.
  • the present invention provides a compound of the formula (Ia) or a stereoisomer thereof,
  • the present invention provides a compound of the formula (Ib) or a stereoisomer thereof,
  • the present invention provides a compound of the formula (Ic) or a stereoisomer thereof,
  • the present invention further relates to a process for the preparation of a compound of formula 1, characterized in that the process is a step of reacting a compound of formula (A) with a compound of formula (B),
  • X is selected from a halogen selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the method comprises reacting a compound represented by the formula (A) with a compound represented by the formula (B1) to obtain a compound of the formula (Ia).
  • the method comprises reacting a compound of the formula (A1) with a compound of the formula (B1) to obtain a compound of the formula (Ib),
  • the method comprises reacting a compound of the formula (A2) with a compound of the formula (B2) to obtain a compound of the formula (Ic),
  • reaction is carried out under the action of an organic solvent and a base. After the reaction is completed, water, crystallizing, and filtration are added, and the filter cake is dissolved in a halogenated hydrocarbon solvent, and the obtained crude product is obtained by recrystallization.
  • the reaction temperature is selected from the group consisting of 30 ° C - the boiling point of the solvent, preferably 100 ° C.
  • the organic solvent is selected from, but not limited to, one or more of an amide, an alcohol, an ether, a ketone or a nitrile, preferably N, N- Dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dimethyl sulfoxide, 1,4-dioxane, more preferably N,N-dimethyl Formamide (DMF), including but not limited to organic bases and inorganic bases, including but not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butyl Potassium alkoxide, sodium t-butoxide, 1,8-diazabicycloundec-7-ene, pyridine, 4-dimethylaminopyridine, said inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, Potassium carbonate
  • the recrystallization method may be carried out by a usual recrystallization operation method.
  • the raw material compound may be heated and dissolved in an organic solvent, and then slowly cooled and crystallized. After the crystallization is completed, the desired crystallization is obtained by filtration and drying. Or a positive or negative solvent (good solvent - anti-solvent method) recrystallization to obtain the target product.
  • the invention further relates to a compound of the formula (I) or a stereoisomer thereof:
  • R 2 and R 3 are as defined in the formula (I).
  • the present invention provides a compound of the formula (I ⁇ -1) or a stereoisomer thereof,
  • the present invention provides a process for the preparation of a compound of the formula (IV), which comprises obtaining a compound of the formula (IV) by a one-step or multi-step reaction of a compound of the formula (I).
  • the present invention provides a process for the preparation of a compound of the formula (IV), which is characterized in that the compound of the formula (I ⁇ -1) is obtained by one or more steps to give the formula (IV).
  • the compound of the formula (I ⁇ -1) is substituted with phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate to give a compound of the formula (IV).
  • the compound represented by the formula (I ⁇ -1) and the phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate are reacted in an organic solvent, then crystallized and filtered. After drying, the compound of the formula (IV) is obtained.
  • the present invention also relates to a process for the preparation of a compound of the formula (IV), which comprises the step of obtaining a compound of the formula (IV) from a compound of the formula (Ic) by one or more steps of a reaction,
  • the compound of the formula (Ic) is substituted with phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate to give a compound of the formula (IV).
  • the compound of the formula (Ic), phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate and a base are reacted in an organic solvent, then crystallized and filtered. After drying, the compound of the formula (IV) is obtained.
  • the organic solvent in the above scheme includes, but not limited to, one or more of an amide, an alcohol, an ether, an ester, a halogenated hydrocarbon, an aliphatic hydrocarbon, a ketone or a nitrile, preferably n-butane, N-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, methanol, ethanol, toluene, dimethyl sulfoxide , 1,4-dioxane, methyl ether, more preferably tetrahydrofuran;
  • the base includes but is not limited to an organic base and an inorganic base, including but not limited to triethylamine, N,N-diisopropyl Ethylethylamine, n-butyllithium, potassium t-but
  • the present invention also relates to a process for the preparation of a compound of the formula (IV), which comprises the step of reacting a compound of the formula (III) with a compound (C) to give a compound of the formula (IV),
  • the free base compound of formula (III) is substituted with phenyl (3-methoxy-1,2,4-thiadiazol-5-yl)carbamate to give a compound of formula (IV). .
  • the organic solvent includes, but is not limited to, one or more of an amide, an alcohol, an ether, an ester, a halogenated hydrocarbon, an aliphatic hydrocarbon, a ketone or a nitrile, preferably n-butane, N-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile or methanol, Ethanol, toluene, dimethyl sulfoxide, 1,4-dioxane, methyl ether, more preferably tetrahydrofuran;
  • the base includes but is not limited to an organic base and an inorganic base, including but not limited to triethyl Amine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, sodium
  • R 1 and R 2 are as defined in the formula (I).
  • the deprotection reaction in the above scheme is carried out by a two-step deprotection reaction.
  • the deprotection reaction in the above scheme is carried out by a one-step deprotection reaction.
  • the two-step amino deprotection reaction includes,
  • Step 1 the intermediate compound of the formula (Ia) is obtained by removing the amino-protecting group to obtain the compound of the formula (II);
  • the compound of the formula (II) is obtained by deamination of a protecting group to give a compound of the formula (III).
  • the compound of the formula (III) is prepared by a compound represented by the formula (Ib) by a two-step deamination protecting group to obtain a compound of the formula (III).
  • the compound of the formula (III) is prepared by a compound represented by the formula (Ic) by a two-step deamination protecting group to obtain a compound of the formula (III).
  • the intermediate represented by the formula (Ia) in the first step is reacted with a base in an organic solvent under heating to remove an amino protecting group, and the obtained crude product is obtained by beating in a mixed solvent of an ester and an ether to obtain a target formula (II).
  • the heating temperature is selected from the group consisting of 50 ° C - the boiling point of the solvent, preferably 70 ° C
  • the organic solvent includes, but is not limited to, one or more of an amide, an alcohol, an ether, a ketone or a nitrile, preferably N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile or methanol, more preferably N,N-dimethylacetamide
  • the bases include, but are not limited to, organic bases and Inorganic base, including but not limited to lithium diisopropylamide (LDA), n-butyllithium, sodium ethoxide, sodium methoxide, sodium ethoxide, potassium ethoxide or sodium t-butoxide, said inorganic base
  • LDA lithium diisopropylamide
  • n-butyllithium sodium ethoxide, sodium methoxide, sodium
  • the intermediate represented by the formula (II) in the second step is reacted with an acid in an organic solvent to remove an amino protecting group.
  • the extracted aqueous phase is added with a base to adjust the pH, and the solid is precipitated, filtered, beaten, filtered, and dried to obtain
  • the intermediate represented by the formula (III) includes, but not limited to, an alcohol, a ketone, a nitrile, a mixed solvent of an alcohol and a halogenated hydrocarbon, a mixed solvent of an alcohol and an ether, an alcohol and Mixed solvent of ester, mixed solvent of ketone and halogenated hydrocarbon, mixed solvent of ketone and ether, mixed solvent of ketone and ester, mixed solvent of nitrile and halogenated hydrocarbon, nitrile and ether a mixed solvent or a mixed solvent of a nitrile and an ester, preferably methanol, ethanol, acetone, acetonitrile, methanol/dichloromethane, m
  • R 1 is selected from an alkoxycarbonyl-based amino protecting group, and the alkoxycarbonyl-based amino protecting group is preferably a benzyloxycarbonyl group (Cbz), a tert-butoxycarbonyl group (Boc), a fluorenylmethoxycarbonyl group (Fmoc) or an allyloxycarbonyl group ( Alloc), more preferably tert-butoxycarbonyl (Boc);
  • R 2 is selected from a sulfonyl amino protecting group, said sulfonyl amino protecting group p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrophenylsulfonyl (p- Ns) is more preferably p-toluenesulfonyl (Ts).
  • the one-step amino deprotection reaction comprises: obtaining a compound of the formula (III) by simultaneously removing two amino protecting groups from a compound represented by the formula (Ia) by a one-step reaction,
  • the compound represented by the formula (Ib) is obtained by simultaneously removing two amino protecting groups by a one-step reaction to obtain a compound of the formula (III).
  • a compound represented by the formula (Ic) is obtained by simultaneously removing two amino protecting groups by a one-step reaction to obtain a compound of the formula (III).
  • R 1 is selected from an alkoxycarbonyl-based amino protecting group, and the alkoxycarbonyl-based amino protecting group is preferably a benzyloxycarbonyl group (Cbz), a tert-butoxycarbonyl group (Boc), a fluorenylmethoxycarbonyl group (Fmoc) or an allyloxycarbonyl group ( Alloc), more preferably tert-butoxycarbonyl (Boc);
  • R 2 is selected from a sulfonyl amino protecting group, said sulfonyl amino protecting group p-toluenesulfonyl (Tos or Ts), o-nitrobenzenesulfonyl (o-Ns) or p-nitrophenylsulfonyl (p- Ns) is more preferably p-toluenesulfonyl (Ts).
  • One aspect of the invention relates to a process for the preparation of a compound of formula (IV), characterized in that it comprises the following steps,
  • the compounds A2 and B2 are dissolved in an organic solvent. After adding the alkali, the reaction is heated. After the reaction is completed, the mixture is cooled to room temperature, added with water, filtered, dissolved in a halogenated hydrocarbon solvent, extracted, dried, and concentrated under reduced pressure.
  • the intermediate Ic is obtained, which includes but is not limited to one or more of an amide, an alcohol, an ether, a ketone or a nitrile, preferably n-butane, n-hexane, N, N-dimethyl Acetamide, N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dimethyl sulfoxide, 1,4-dioxane, more preferably N,N-dimethylformamide
  • the base includes, but is not limited to, an organic base including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and tert-butyl.
  • Sodium alkoxide, 1,8-diazabicycloundec-7-ene, pyridine, 4-dimethylaminopyridine, and the inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, potassium carbonate, hydrogen carbonate.
  • the intermediate Ic is dissolved in an organic solvent, a base is added, water is added thereto with stirring, and the reaction is heated. After the reaction is completed, the mixture is cooled to room temperature, water and a halogenated hydrocarbon solvent are added, extracted, dried, and concentrated under reduced pressure to give Intermediate IIa.
  • the organic solvent includes, but is not limited to, one or more of an amide, an alcohol, an ether, a ketone or a nitrile, preferably N,N-dimethylacetamide, N,N-dimethylformamide , tetrahydrofuran, acetone, acetonitrile or methanol, more preferably N,N-dimethylacetamide, the base including but not limited to an organic base and an inorganic base, including but not limited to lithium diisopropylamide ( LDA), n-butyllithium, sodium ethoxide, sodium methoxide, sodium ethoxide, potassium ethoxide or sodium t-butoxide, said inorganic bases including but not limited to sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or hydroxide Potassium, the halogenated hydrocarbon solvent is preferably dichloromethane.
  • LDA lithium diisopropylamide
  • n-butyllithium sodium
  • intermediate IIa is dissolved in an organic solvent, and the acid is added dropwise at a low temperature.
  • the reaction is stirred at room temperature, and the reaction is completed.
  • the reaction solution is concentrated, dissolved in water, extracted with a halogenated hydrocarbon solvent, and the aqueous phase is adjusted to pH with an alkali to precipitate. Solid, filtered, dried to give intermediate III;
  • the organic solvent includes, but is not limited to, alcohols, ketones, nitriles, mixed solvents of alcohols and halogenated hydrocarbons, mixed solvents of alcohols and ethers, mixed solvents of alcohols and esters, ketones and halogens. a mixed solvent of hydrocarbons, a mixed solvent of a ketone and an ether, a mixed solvent of a ketone and an ester, a mixed solvent of a nitrile and a halogenated hydrocarbon, a mixed solvent of a nitrile and an ether, or a mixed solvent of a nitrile and an ester, preferably methanol.
  • the acid is selected from formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid , isethionylsulfonic acid, hydrochloric acid or trifluoroacetic acid, preferably hydrochloric acid
  • the base is preferably an inorganic base, and the inorganic base is preferably a metal hydroxide such as sodium
  • the intermediate III and the compound C are added to an organic solvent, and a base is added to heat the reaction. After the reaction is completed, the mixture is cooled, crystallized, filtered, and dried to obtain a product IV including, but not limited to, an amide, an alcohol, and an ether.
  • a class an ester, a halogenated hydrocarbon, an aliphatic hydrocarbon, a ketone or a nitrile, preferably n-butane, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, two Methyl chloride, chloroform, ethyl acetate, acetone, acetonitrile, methanol, ethanol, toluene, dimethyl sulfoxide, 1,4-dioxane, methyl ether, more preferably tetrahydrofuran, the base including but not limited to an organic base And an inorganic base, including but not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, sodium t-butoxide, 1,8-diaza Dicycloundec-7-ene, pyridine
  • Another aspect of the invention relates to a process for the preparation of a pharmaceutically acceptable salt of a compound of formula (IV), comprising the steps of the above scheme, and the preparation of a pharmaceutically acceptable compound thereof by reacting a compound of formula (IV) with an acid a step of an acceptable salt selected from the group consisting of organic or inorganic acids, preferably inorganic acids; the organic acid being selected from the group consisting of citric acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, P-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid; the inorganic acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid, preferably sulfuric acid.
  • protecting group means that when a multifunctional organic compound is reacted, in order to cause the reaction to occur only at a desired group, and other groups are prevented from being affected, other groups are preceded by the reaction. Protected and restored when the reaction is complete.
  • An agent that protects a certain group is referred to as a protecting group for the group.
  • the basic principle of selecting a protecting group is as follows: the reaction conditions of the protecting group and the deprotecting group are required to be mild, convenient to operate, high in yield, low in side reactions, not involved in other reactions, and the product is easy to be separated and purified, and the price is low. Have to wait.
  • amino protecting group means a group capable of protecting an amino group from reaction
  • common amino protecting groups include, but are not limited to, formic acid esters (amino group and chloroformate, diazotate). Or various types of carbonates and other reaction preparations), imines (prepared by reaction of primary amines with aromatic aldehydes, aromatic ketones or aliphatic ketones), alkoxycarbonyls (benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), Preparation of methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyloxycarbonyl (Teoc), methoxycarbonyl or ethoxycarbonyl), acyl groups (amino groups and acid chlorides or anhydrides, etc.
  • the "beating" as used in the present invention refers to a method in which the solubility of a substance in a solvent is poor, but the solubility of the impurity in a solvent is good, and the beating and purifying can remove the color, change the crystal form or remove a small amount of impurities.
  • halogenated as used in the present invention means substituted by "halogen atom", and "halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • the "C 1-6 alkyl group” of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C 1-4 alkyl group", "C 1-3 alkyl group", and the like. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methyl Butyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl 2,2-Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl , 2-
  • cyano group as used in the present invention means a group such as -CN.
  • amide organic solvent refers to a liquid compound in which a hydroxyl group in a carboxyl group of a carboxylic acid molecule is substituted with an amino group or a hydrocarbon amino group (-NHR or -NR 2 ); it can also be regarded as an ammonia or an amine molecule.
  • a liquid compound in which a hydrogen in a nitrogen atom is substituted with an acyl group include, but are not limited to, N,N-dimethylformamide, N,N-dimethylacetamide.
  • ether solvent as used in the present invention means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran or , 4-dioxane.
  • ester solvent means a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to, acetic acid. Ethyl ester, isopropyl acetate or butyl acetate.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on the "C 1-6 alkyl group", said "hydroxyl group” and “C” 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, n-propanol or 2-propanol.
  • halogenated hydrocarbon solvent as used in the present invention means a group derived by substituting one or more "halogen atoms” for one or more hydrogen atoms on a "C 1-6 alkyl group", said "halogen atom” And “C 1-6 alkyl” are as defined above, and specific examples include, but are not limited to, methyl chloride, dichloromethane, chloroform or carbon tetrachloride.
  • the "ketone solvent” as used in the present invention means a compound in which a carbonyl group (-C(O)-) is bonded to two hydrocarbon groups, and the ketone can be classified into an aliphatic ketone, an alicyclic ketone, an aromatic ketone according to a hydrocarbon group in the molecule.
  • Saturated ketones and unsaturated ketones specific examples include, but are not limited to, acetone, methyl butanone or methyl isobutyl ketone.
  • nitrile solvent as used in the present invention means a group derived from one or more hydrogen atoms on one or more "cyano" substituted “C 1-6 alkyl", said “cyano” and “C 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • aliphatic hydrocarbon solvent refers to a carbon having a basic property of an aliphatic compound and having carbon atoms in the molecule which are connected to each other in a chain, and the carbon atoms are 1-10.
  • Hydrogen compounds such as saturated aliphatic hydrocarbons include alkane solvents, specific examples including, but not limited to, n-butane, n-pentane, n-hexane or n-heptane.
  • “Substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents.
  • substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort.
  • an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • the “mixed solvent” as used in the present invention means a solvent obtained by mixing one or more different kinds of organic solvents in a certain ratio, or a solvent obtained by mixing an organic solvent and water in a certain ratio, and the mixed solvent is preferably a mixed solvent of an alcohol and a halogenated hydrocarbon or a mixed solvent of an ester and an ether; a mixed solvent of the alcohol and a halogenated hydrocarbon is preferably a mixed solvent of methanol and dichloromethane, and the ratio may be a volume ratio Or a mass ratio, the mass ratio is selected from 10:1 to 1:10, preferably 1.6:1; the mixed solvent of the ester and the ether is preferably a mixed solvent of ethyl acetate and petroleum ether, and the certain ratio may be a volume.
  • the ratio or mass ratio is selected from the range of 1:1 to 1:10, preferably 1:4.
  • the “acid” as used in the present invention means an organic acid or an inorganic acid
  • the “organic acid” means a compound which can accept an electron pair according to the broad acid-base theory.
  • the organic acid includes a carboxylic acid, a halogenated acid, a hydroxy acid, a keto acid, an amino acid, a sulfonic acid, a sulfinic acid, a sulfuric acid, a phenolic acid, etc., preferably a sulfonic acid, and specific examples of the sulfonic acid include, but are not limited to, formic acid, acetic acid , methanesulfonic acid, ethanesulfonic acid, dodecylbenzenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, isethionic acid, etc.; "inorganic acid” means energy solution The
  • the “base” as used in the present invention refers to an organic base or an inorganic base, and the “organic base” refers to a compound which can give an electron pair according to the general theory of acid-base.
  • the organic base is classified into an amine, an amide or an alcohol.
  • An alkali metal salt, an alkyl metal lithium compound, a lithium amide compound, a nitrogen-containing heterocyclic compound, an organic base providing a hydroxide, an amino acid, etc. and specific examples include, but are not limited to, dimethylamine, triethylamine, and ethylene Amine, colchicine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, lithium t-butoxide, n-butyl lithium, N,N-diisopropylethylamine, lithium diisopropylamide (LDA) , pyrrolidine, pyridine, tetramethylammonium hydroxide, 1,8-diazabicycloundec-7-ene, 4-dimethylaminopyridine, lysine (Lys) and the like.
  • “Inorganic base” means an inorganic compound capable of dissociating a hydroxide ion. According to the composition, the inorganic base can be classified into a metal compound, a metal hydroxide, ammonia or ammonia monohydrate, a salt capable of dissociating the hydroxide ion, and the like. Specific examples include, but are not limited to, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate (soda), potassium carbonate, sodium hydrogencarbonate (sodium bicarbonate), potassium phosphate. , lithium carbonate, lithium hydrogen phosphate, potassium hydrogencarbonate or cesium carbonate.
  • the "pharmaceutically acceptable salt or pharmaceutically acceptable salt” as used herein means a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity.
  • Specific examples of the compound of the present invention and a mineral acid or an organic acid include, but are not limited to, citrate, hydrochloride, sulfate, hydrogen sulfate, phosphate, acetate, trifluoroacetate, Oxalate, tartrate, maleate, fumarate, sulfonate, p-toluenesulfonate, besylate, ethanesulfonate or methanesulfonate.
  • the present invention is different from the starting materials of the prior art, and the nitrogen atom on the pyrrolyl group of the compound of the formula (A) of the present invention is protected by a protecting group and then reacted with the compound of the formula (B). It can avoid that the exposed amino group on the five-membered ring of the compound represented by formula (A) reacts with the halogen on the self six-membered ring, affecting the incomplete reaction of the compound represented by formula (A) and the compound represented by formula (B), resulting in incomplete reaction. The yield of the product is reduced and the impurity is increased, that is, the occurrence of side reactions is reduced.
  • the method of the present invention is simple in operation, can improve the yield, and improve the purity of the product, and the method of preparing the compound of the formula (III) in the process by adding a base
  • the pH adjustment operation can also remove impurities, and the obtained compound of the formula (III) has a high purity.
  • the first step of the step of preparing the compound of the formula (IIa) of the present invention is 2 h,
  • the second step was 1 h, while the first step disclosed in the prior art was 48 h.
  • the yield is improved, the first step yield of the invention is 60-70%, the second step yield is 80-90%, and the two-step total yield is 48%-63%, and the yield of the prior art is It is 5.0%; the yield of the last step of the present invention is 80-90%, and the prior art is 25.9%.
  • the post-chemical treatment method is simple, and the post-treatment mode of the invention is cooling crystallization, simple washing to obtain impurities, and the target product is obtained, and the prior art is column chromatography separation and purification method, and the post-treatment method of the invention is easy to be industrially amplified. produce.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent high pressure liquid chromatograph and a Thermon UltiMate 3000 high performance liquid chromatograph (Kromasil C18 250 x 4.6 mm column).
  • Preparation Example 2 The starting material The compound of the formula (B2) was prepared according to the method of Example 5 in the known method WO2008089636A1 (Publication Day 2008.07.31) and the method of Example 5 in WO2013091539A1 (Publication Day 2013.06.27).
  • the mixture was stirred at room temperature for 1 hour, and filtered.
  • the filter cake was dissolved in dichloromethane (6 kg), and the organic layer was dried over anhydrous sodium sulfate.
  • the crude product was concentrated by pressure.
  • the crude product was dissolved in ethyl acetate (1.2 kg), and petroleum ether (3.6 kg) was slowly added at room temperature. The solid was gradually precipitated, stirred for 1 hour, filtered, and the filter cake was dried under reduced pressure to give the title product. (349 g, yield 70.0%).
  • reaction mixture was concentrated under reduced pressure to remove most of the organic solvent, and water (0.3 L) was added with dichloromethane (0.6 kg ⁇ 3) Extraction, discard the organic phase, adjust the pH to 9-10 with 30% sodium hydroxide solution, precipitate a large amount of solids, filter, fully beat with purified water (0.25kg ⁇ 2), filter, and dry under reduced pressure to obtain the title product (131 g, yield 97.3%).

Abstract

公开了一种用作JAK抑制剂的吡咯并六元杂芳环类衍生物的中间体及其制备方法、采用该中间体制备吡咯并六元杂芳环类衍生物的方法。该方法提高了反应产率、简单易操控、利于工业扩大生产。

Description

吡咯并六元杂芳环类衍生物的制备方法及中间体 技术领域
本发明涉及一种吡咯并六元杂芳环类衍生物、其可药用盐的制备方法和制备过程中的中间体及其制备方法，该吡咯并六元杂芳环类衍生物可作为JAK抑制剂用于制备治疗骨髓增生性肿瘤和/或白血病的药物中的用途。
背景技术
JAK蛋白激酶抑制剂，尤其是JAK3蛋白激酶抑制剂，能够阻止T细胞的活化，并防止移植手术后的移植排斥。这些药物对于其他自身免疫疾病亦能产生疗效。作为一个重要的蛋白激酶，JAK3也可调节淋巴细胞，巨噬细胞和肥大细胞的功能。JAK3抑制剂将有望用于治疗或预防涉及淋巴细胞，巨噬细胞或肥大细胞功能相关的多种疾病。研究发现，在患有骨髓纤维化类疾病病人人群中，大于50％的患者体内JAK2激酶产生突变，且疾病相关症状如贫血，脾肿大及向急性髓细胞型白血病(acute myeloid leukemia，AML)转化的风险的增加均与JAK2基因变异导致的活性增加和JAK-STAT信号通路的异常活跃有密切关系。同时，JAK2活性在多种实体和血液肿瘤疾病中(胶质母细胞瘤，乳腺癌，多发性骨髓瘤，前列腺癌，AML等)异常升高。因此，开发JAK2选择性的抑制剂对于骨髓增生性肿瘤和白血病的治疗有很大的医疗价值和市场潜力(INCYTE公司和NOVARTIS合作开发的JAK2选择性抑制剂Ruxolitinib(INCB-018424)-已被FDA批准成功上市)。
目前公开了一系列吡咯并六元杂芳环类衍生物的JAK抑制剂，例如WO2001042246、WO2002000661、WO2009054941、WO2011013785、WO2013091539A1、WO2014194741A1等，其中WO2013091539A1公开了一种吡咯并六元杂芳环类衍生物(化合物34)的制备方法，具体方法如下：
Figure PCTCN2017112237-appb-000001
该方法的起始原料1d化合物结构中存在裸露的亚氨基，会与自身六元环上的氯原子发生反应，生成副产物，中间体5的产率仅为5.0％，并且反应时间长达48h；终产物34制备方法通过式(III)所示化合物的盐酸盐与式(C)所示化合物来制备、后处理使用柱色谱分离提纯法，其产率仅为25.9％，这种方法不利于工业扩大生产。因此，有必要改进现有的制备方法。
发明内容
本发明要解决的技术问题是提供一种制备式(IV)所示化合物的方法和中间体，通过改变起始原料提高中间体产率，终产物通过式(III)所示游离碱来制备，该方法简单易控、起始原料等反应物简单易购买、反应条件简单可控、反应后处理方法简单，反应产率显著提高、利于工业扩大生产。
本发明的技术方案如下：
本发明提供一种式(I)所示的化合物或其立体异构体：
Figure PCTCN2017112237-appb-000002
其中，
R1为氢或氨基保护基；
R2为氨基保护基；
R3选自氢原子、C1-6烷基或氨基保护基；
所述氨基保护基优选烷氧羰基类氨基保护基、酰基类氨基保护基、磺酰基类氨基保护基或烷基类氨基保护基，
所述烷氧羰基类氨基保护基选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基或乙氧羰基，
所述酰基类氨基保护基选自邻苯二甲酰基(Pht)、三氟乙酰基(Tfa)、特戊酰基、苯甲酰基、甲酰基或乙酰基；
所述磺酰基类氨基保护基选自对甲苯磺酰基(Tos或Ts)、邻硝基苯磺酰基(o-Ns)或对硝基苯磺酰基(p-Ns)；
所述烷基类氨基保护基选自三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)或苄基(Bn)。
优选的，其中，
R1选自烷氧羰基类氨基保护基，所述烷氧羰基类氨基保护基优选苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)或烯丙氧羰基(Alloc)，更优选叔丁氧羰基(Boc)；
R2选自磺酰基类氨基保护基，所述磺酰基类氨基保护基对甲苯磺酰基(Tos或Ts)、邻硝基苯磺酰基(o-Ns)或对硝基苯磺酰基(p-Ns)，更优选对甲苯磺酰基(Ts)；
R3选自氢原子或甲基。
在本发明的一个优选实施例方案中，本发明提供一种式(Ia)所示化合物或其立体异构体，
Figure PCTCN2017112237-appb-000003
在本发明的一个优选实施例方案中，本发明提供一种式(Ib)所示化合物或其立体异构体，
Figure PCTCN2017112237-appb-000004
在本发明的一个优选实施例方案中，本发明提供一种式(Ic)所示化合物或其立体异构体，
Figure PCTCN2017112237-appb-000005
本发明进一步涉及一种式1化合物的制备方法，其特征在于，所述方法为式(A)所示化合物与式(B)所示化合物发生反应的步骤，
Figure PCTCN2017112237-appb-000006
其中，
X选自卤素，所述卤素选自氟原子、氯原子、溴原子或碘原子。
优选的，所述方法为由式(A)所示化合物与式(B1)所示化合物发生反应得到式(Ia)所示化合物，
Figure PCTCN2017112237-appb-000007
优选的，所述方法为式(A1)所示化合物与式(B1)所示化合物反应得到式(Ib)所示化合物，
Figure PCTCN2017112237-appb-000008
进一步优选的，所述方法为式(A2)所示化合物与式(B2)所示化合物反应得到式(Ic)所示化合物，
Figure PCTCN2017112237-appb-000009
上述方案中，所述反应是在有机溶剂和碱的作用下，反应结束后，加水、析晶、过滤，滤饼用卤代烃类溶剂溶解，分液，所得粗品通过重结晶法得到产物，反应温度选自30℃-溶剂沸点，优选100℃，所述有机溶剂选自但不限于酰胺类、醇类、醚类、酮类或腈类中的一种或多种，优选N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、丙酮、乙腈、甲醇、乙醇、二甲基亚砜、1,4-二氧六环，更优选N,N-二甲基甲酰胺(DMF)，所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾、叔丁醇钠、1,8-二氮杂二环十一碳-7-烯、吡啶、4-二甲氨基吡啶，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸钾、碳酸氢钠、磷酸钾、碳酸锂、磷酸氢锂、碳酸氢钾或碳酸铯，优选碳酸钾；所述卤代烃类溶剂优选二氯甲烷。所述重结晶方法包括可以用通常的重结晶操作方法进行，例如，可以用原料化合物在有机溶剂中加热溶解后慢慢冷却析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶；或者正反溶剂(良溶剂-反溶剂法)重结晶法得到目标产物。
本发明还涉及式(Iˊ)所示的化合物或其立体异构体：
Figure PCTCN2017112237-appb-000010
其中，R2、R3如式(I)中所定义。
优选的，本发明提供一种式(Iˊ-1)所示化合物或其立体异构体，
Figure PCTCN2017112237-appb-000011
进一步优选的，本发明提供一种制备式(IV)所示化合物的方法，其特征在于，所述方法包括由式(Iˊ)所示化合物通过一步或多步反应得到式(IV)所示化合物的步骤，
Figure PCTCN2017112237-appb-000012
更优选的，本发明提供一种制备式(IV)所示化合物的方法，其特征在于，所述方法为式(Iˊ-1)所示化合物通过一步或多步反应得到式(IV)所示化合物，
Figure PCTCN2017112237-appb-000013
优选式(Iˊ-1)所示化合物与(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯发生取代反应，得到式(IV)所示化合物。
进一步优选所述式(Iˊ-1)所示化合物、(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯在有机溶剂中反应后，析晶，过滤，干燥后即得目标式(IV)所示化合物。
本发明还涉及一种制备式(IV)所示化合物的方法，其特征在于，所述方法包括由式(Ic)所示化合物通过一步或多步反应得到式(IV)所示化合物的步骤，
Figure PCTCN2017112237-appb-000014
优选式(Ic)所示化合物与(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯发生取代反应，得到式(IV)所示化合物。
进一步优选所述式(Ic)所示化合物、(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯和碱在有机溶剂中反应后，析晶，过滤，干燥后即得目标式(IV)所示化合物。
上述方案中所述有机溶剂包括但不限于酰胺类、醇类、醚类、酯类、卤代烃类、脂肪烃类、酮类或腈类中的一种或多种，优选正丁烷、正己烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷、氯仿、乙酸乙酯、丙酮、乙腈、甲醇、乙醇、甲苯、二甲基亚砜、1,4-二氧六环、甲醚，更优选四氢呋喃；所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾、叔丁醇钠、1,8-二氮杂二环十一碳-7-烯、吡啶、4-二甲氨基吡啶，所述的无机碱包括但不限于氢化钠、碳酸钠、碳酸钾、碳酸氢钠、磷酸钾、碳酸锂、磷酸氢锂、碳酸氢钾或碳酸铯，优选三乙胺；所述反应温度选自15℃-溶剂沸点温度，优选50℃-溶剂沸点温度。
本发明还涉及一种制备式(IV)所示化合物的方法，其特征在于，所述方法包括由式(III)所示化合物与化合物(C)反应得到式(IV)所示化合物的步骤，
Figure PCTCN2017112237-appb-000015
优选的，式(III)所示游离碱化合物与(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯发生取代反应，得到式(IV)所示化合物。
进一步优选的，所述式(III)所示游离碱化合物、(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯和碱在有机溶剂中反应后，析晶，过滤，干燥后即得目标式(IV)所示化合物。
更优选的，所述有机溶剂包括但不限于酰胺类、醇类、醚类、酯类、卤代烃、脂肪烃类、酮类或腈类中的一种或多种，优选正丁烷、正己烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷、氯仿、乙酸乙酯、丙酮、乙腈或甲醇、 乙醇、甲苯、二甲基亚砜、1,4-二氧六环、甲醚，更优选四氢呋喃；所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾、叔丁醇钠、1,8-二氮杂二环十一碳-7-烯、吡啶、4-二甲氨基吡啶，所述的无机碱包括但不限于氢化钠、碳酸钠、碳酸钾、碳酸氢钠、磷酸钾、碳酸锂、磷酸氢锂、碳酸氢钾或碳酸铯，优选三乙胺；所述反应温度选自15℃-溶剂沸点温度，优选50℃-溶剂沸点温度。本发明进一步涉及一种式(III)所示化合物的制备方法，所述方法为由式(Ia)所示化合物通过脱氨基保护基得到式(III)所示化合物，其中，
Figure PCTCN2017112237-appb-000016
R1、R2如式(I)中所定义。
优选的，上述方案中的脱保护反应通过两步脱保护反应。
更优选的，上述方案中的脱保护反应通过一步脱保护反应。
上述方案中，两步氨基脱保护的反应包括，
Figure PCTCN2017112237-appb-000017
步骤一，中间体式(Ia)所示化合物通过脱去氨基保护基得到中间体式(II)所示化合物；
步骤二，中间体式(II)所示化合物通过脱去氨基保护基得到式(III)所示化合物。
优选的，所述式(III)所示化合物的制备方法是由式(Ib)所示化合物通过两步脱氨基保护基得到式(III)所示化合物，
Figure PCTCN2017112237-appb-000018
进一步优选的，所述式(III)所示化合物的制备方法是由式(Ic)所示化合物通过两步脱氨基保护基得到式(III)所示化合物，
Figure PCTCN2017112237-appb-000019
更优选的，
所述步骤一的式(Ia)所示中间体在有机溶剂中与碱在加热条件反应脱去氨基保护基，萃取，所得粗品通过在酯类与醚类混合溶剂中打浆得到目标式(II)所示中间体，加热温度选自50℃-溶剂沸点，优选70℃，所述有机溶剂包括但不限于酰胺类、醇类、醚类、酮类或腈类中的一种或多种，优选N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、丙酮、乙腈或甲醇，更优选N,N-二甲基乙酰胺；所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于二异丙基氨基锂(LDA)、正丁基锂、乙醇钠、甲醇钠、乙醇钠、乙醇钾或叔丁醇钠，所述的无机碱类包括但不限于氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、乙醇钠、乙醇钾、叔丁醇钠、氢氧化钠或氢氧化钾，优选氢氧化钠或氢氧化钾。
更优选的，
所述步骤二的式(II)所示中间体在有机溶剂中与酸反应，脱去氨基保护基，萃取的水相中加入碱调pH，析出固体，过滤，打浆，再过滤、干燥后得到目标式(III)所示中间体，所述有机溶剂包括但不限于醇类、酮类、腈类、醇类与卤代烃类的混合溶剂、醇类与醚类的混合溶剂、醇类与酯类的混合溶剂、酮类与卤代烃的混合溶剂、酮类与醚类的混合溶剂、酮类与酯类的混合溶剂、腈类与卤代烃类的混合溶剂、腈类与醚类的混合溶剂或腈类与酯类的混合溶剂，优选甲醇、乙醇、丙酮、乙腈、甲醇/二氯甲烷、甲醇/乙酸乙酯、甲醇/1,4-二氧六环、丙酮/二氯甲烷、丙酮/乙酸乙酯、丙酮/1,4-二氧六环、乙腈/二氯甲烷、乙腈/乙酸乙酯或乙腈/1,4-二氧六环，更优选甲醇/二氯甲烷，酸选自甲酸、乙酸、甲磺酸、对甲苯磺酸、羟乙基磺酸、盐酸或三氟乙酸，优选盐酸，碱选自金属氢氧化物，优选氢氧化钠或氢氧化钾。
最优选的，其中，
R1选自烷氧羰基类氨基保护基，所述烷氧羰基类氨基保护基优选苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)或烯丙氧羰基(Alloc)，更优选叔丁氧羰基(Boc)；
R2选自磺酰基类氨基保护基，所述磺酰基类氨基保护基对甲苯磺酰基(Tos或Ts)、邻硝基苯磺酰基(o-Ns)或对硝基苯磺酰基(p-Ns)，更优选对甲苯磺酰基(Ts)。
上述方案中，一步氨基脱保护的反应包括，由式(Ia)所示化合物通过一步反应同时脱去两个氨基保护基得到式(III)所示化合物，
Figure PCTCN2017112237-appb-000020
优选的，由式(Ib)所示化合物通过一步反应同时脱去两个氨基保护基得到式(III)所示化合物，
Figure PCTCN2017112237-appb-000021
优选的，由式(Ic)所示化合物通过一步反应同时脱去两个氨基保护基得到式(III)所示化合物，
Figure PCTCN2017112237-appb-000022
进一步优选的，其中，
R1选自烷氧羰基类氨基保护基，所述烷氧羰基类氨基保护基优选苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)或烯丙氧羰基(Alloc)，更优选叔丁氧羰基(Boc)；
R2选自磺酰基类氨基保护基，所述磺酰基类氨基保护基对甲苯磺酰基(Tos或Ts)、邻硝基苯磺酰基(o-Ns)或对硝基苯磺酰基(p-Ns)，更优选对甲苯磺酰基(Ts)。
本发明一方面涉及一种制备式(IV)所示化合物的方法，其特征在于，所述方法包括如下步骤，
Figure PCTCN2017112237-appb-000023
第一步，中间体Ic的制备
惰性气体保护下，化合物A2、B2溶解于有机溶剂中，加入碱后，加热反应，反应结束后冷却至室温，加入水、过滤、加入卤代烃类溶剂溶解，萃取，干燥后，减压浓缩后得到中间体Ic，所述有机溶剂包括但不限于酰胺类、醇类、醚类、酮类或腈类中的一种或多种，优选正丁烷、正己烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、丙酮、乙腈、甲醇、乙醇、二甲基亚砜、1,4-二氧六环，更优选N,N-二甲基甲酰胺；所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾、叔丁醇钠、1,8-二氮杂二环十一碳-7-烯、吡啶、4-二甲氨基吡啶，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸钾、碳酸氢钠、磷酸钾、碳酸锂、磷酸氢锂、碳酸氢钾或碳酸铯，优选碳酸钾；所述卤代烃类溶剂优选二氯甲烷。第二步，中间体IIa的制备
将中间体Ic溶解于有机溶剂中，加入碱，搅拌下加入水，加热反应，反应结束后冷却至室温，加入水和卤代烃类溶剂，萃取，干燥，减压浓缩后得到中间体IIa，所述有机溶剂包括但不限于酰胺类、醇类、醚类、酮类或腈类中的一种或多种，优选N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、丙酮、乙腈或甲醇，更优选N,N-二甲基乙酰胺，所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于二异丙基氨基锂(LDA)、正丁基锂、乙醇钠、甲醇钠，乙醇钠，乙醇钾或叔丁醇钠，所述的无机碱类包括但不限于氢氧化钠或氢氧化钾，优选氢氧化钠或氢氧化钾，所述卤代烃类溶剂优选二氯甲烷。
第三步，中间体III的制备
将中间体IIa溶解于有机溶剂中，低温滴加酸后，室温搅拌反应，反应结束，浓缩反应液，加入水溶解，加入卤代烃类溶剂萃取，水相用碱调pH至碱性，析出固体，过滤，干燥后得到中间体III；
所述有机溶剂包括但不限于醇类、酮类、腈类、醇类与卤代烃类的混合溶剂、醇类与醚类的混合溶剂、醇类与酯类的混合溶剂、酮类与卤代烃类的混合溶剂、 酮类与醚类的混合溶剂、酮类与酯类的混合溶剂、腈类与卤代烃类的混合溶剂、腈类与醚类的混合溶剂或腈类与酯类的混合溶剂，优选甲醇、乙醇、丙酮、乙腈、甲醇/二氯甲烷、甲醇/乙酸乙酯、甲醇/1,4-二氧六环、丙酮/二氯甲烷、丙酮/乙酸乙酯、丙酮/1,4-二氧六环、乙腈/二氯甲烷、乙腈/乙酸乙酯或乙腈/1,4-二氧六环，更优选甲醇/二氯甲烷，所述酸选自甲酸、乙酸、甲磺酸、对甲苯磺酸、羟乙基磺酸、盐酸或三氟乙酸，优选盐酸，所述碱优选无机碱，无机碱优选金属氢氧化物，如氢氧化钠或氢氧化钾，所述pH至碱性优选8-11，更优选9-10。
第四步，产物IV的制备
中间体III、化合物C加入到有机溶剂中，加入碱，加热反应，反应结束后，冷却，析晶，过滤，干燥后得到产物IV，所述有机溶剂包括但不限于酰胺类、醇类、醚类、酯类、卤代烃、脂肪烃类、酮类或腈类，优选正丁烷、正己烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷、氯仿、乙酸乙酯、丙酮、乙腈、甲醇、乙醇、甲苯、二甲基亚砜、1,4-二氧六环、甲醚，更优选四氢呋喃，所述碱包括但不限于有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾、叔丁醇钠、1,8-二氮杂二环十一碳-7-烯、吡啶、4-二甲氨基吡啶，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸钾、碳酸氢钠、磷酸钾、碳酸锂、磷酸氢锂、碳酸氢钾或碳酸铯；优选三乙胺。
本发明的另一方面涉及一种制备式(IV)所示化合物的药学上可接受的盐的方法，包括上述方案中的步骤，以及通过式(IV)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选无机酸；所述有机酸选自柠檬酸、乙酸、三氟乙酸、草酸、酒石酸、马来酸、富马酸、对甲苯磺酸、苯磺酸或甲磺酸；所述无机酸选自盐酸、硫酸或磷酸，优选硫酸。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“保护基”是指当多功能基有机化合物进行反应时，为使反应只发生在所希望的基团处，而避免其他基团遭受影响，此反应前将其他基团先加以保护，当反应完成后再恢复。能保护某种基团的试剂称为该基团的保护基。选择保护基的基本原则为：要求上保护基和脱保护基的反应条件都要温和、操作方便、产率高、副反应少、不会一起参与其他反应、且产物易于分离纯化、价廉易得等。
本发明所述的“氨基保护基”是指能够保护氨基、避免发生反应的基团，常 见的氨基保护基包括但不限于：甲酸酯类(氨基与氯代甲酸酯、重氮甲酸酯或各类碳酸酯等反应制备)、亚胺类(伯胺与芳香醛、芳香酮或脂肪酮等反应制备)、烷氧羰基类(苄氧羰基(Cbz)、叔丁氧羰基(Boc)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基或乙氧羰基)、酰基类(氨基与酰氯或酸酐等反应制备，如邻苯二甲酰基(Pht)、三氟乙酰基(Tfa)、特戊酰基、苯甲酰基、甲酰基或乙酰基)、磺酰基类(芳香磺酰胺类如对甲苯磺酰基(Tos或Ts)、邻硝基苯磺酰基(o-Ns)或对硝基苯磺酰基(p-Ns))或烷基类(三苯甲基(Trt)、2,4-二甲氧基苄基(Dmb)、对甲氧基苄基(PMB)或苄基(Bn))等，其中“烷氧羰基类、酰基类、磺酰基类”分别是指R-O-C(O)-、R-C(O)-、R-S(O)2-，其中R可以是氢原子、烷基或芳基等基团。
本发明所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本发明所述“卤代”是指被“卤素原子”取代，“卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本发明所述“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C1-4烷基”、“C1-3烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述“氰基”是指-CN等基团。
本发明所述的“酰胺类有机溶剂”是指羧酸分子中羧基中的羟基被氨基或烃氨基(-NHR或-NR2)取代而成的液体化合物；也可看作是氨或胺分子中氮原子上的氢被酰基取代而成的液体化合物；具体实例包括但不限于：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：丙二醇甲醚、四氢呋喃或1,4-二氧六环。
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、正丙醇或2-丙醇。
本发明所述的“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C1-6烷基”如前文所定义，具体实例包括但不限于：氯甲烷、二氯甲烷、氯仿或四氯化碳。
本发明所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、甲基丁酮或甲基异丁酮。
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
本发明所述的“脂肪烃类溶剂”是指具有脂肪族化合物基本属性、分子中碳原子间连结成链状碳架两端张开不成环的且碳原子个数为1-10个的碳氢化合物如饱和脂肪烃类，包括烷烃类溶剂，具体实例包括但不限于：正丁烷、正戊烷、正己烷或正庚烷。“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本发明所述的“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂，所述混合溶剂优选为醇类与卤代烃类的混合溶剂或酯类与醚类混合溶剂；所述醇类与卤代烃类的混合溶剂优选为甲醇与二氯甲烷的混合溶剂，所述一定比例可以是体积比或者质量比，质量比例选自10:1-1:10，优选1.6:1；所述酯类与醚类的混合溶剂优选为乙酸乙酯与石油醚的混合溶剂，所述一定比例可以是体积比或质量比，体积比选自1:1～1:10，优选为1:4。
本发明所述的“酸”是指有机酸或无机酸，“有机酸”指按照广义的酸碱理论，能接受电子对的化合物。有机酸包括羧酸、卤代酸、羟基酸、酮酸、氨基酸、磺酸、亚磺酸、硫羧酸、酚酸等，优选磺酸，磺酸的具体实例包括但不限于：甲酸、乙酸、甲磺酸、乙磺酸、十二烷基苯磺酸、苯磺酸、对甲苯磺酸、三氟甲磺酸、三氟乙酸、羟乙基磺酸等；“无机酸”指能解离出氢离子的无机化合物，按照组成成分，无机酸可分成含氧酸、无氧酸、络合酸、混酸、超酸等，优选含氧酸或无氧酸，含氧酸的具体实例包括但不限于：碳酸、硝酸、亚硝酸、次氯酸、硫酸或磷酸等；无氧酸的具体实例包括但不限于：氢氟酸、盐酸、溴酸或硫化氢等。
本发明所述的“碱”是指有机碱或无机碱，“有机碱”指按照广义的酸碱理论，碱就是能给出电子对的化合物，有机碱分为胺类、酰胺类、醇的碱金属盐类、烷基金属锂化合物、氨基锂化合物、含氮的杂环化合物、提供氢氧根的有机碱、氨基酸等，具体实例包括但不限于：二甲胺、三乙胺、乙二胺、秋水仙碱、甲醇钠、乙醇钠、乙醇钾、叔丁醇钠、叔丁醇锂、正丁基锂、N,N-二异丙基乙胺、二异丙基氨基锂(LDA)、吡咯烷、吡啶、四甲基氢氧化铵、1,8-二氮杂二环十一碳-7-烯、 4-二甲氨基吡啶、赖氨酸(Lys)等。“无机碱”指能解离出氢氧根离子的无机化合物，按照组成成分，无机碱可分成金属化物、金属氢氧化物、氨水或一水合氨、能够解离出氢氧根离子的盐等，具体实例包括但不限于：氢化钠、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、碳酸钠(纯碱)、碳酸钾、碳酸氢钠(小苏打)、磷酸钾、碳酸锂、磷酸氢锂、碳酸氢钾或碳酸铯等。三乙胺、N,N-二异丙基乙胺、正丁基锂或、叔丁醇钾、叔丁醇钠，所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸钾或、碳酸氢钠、碳酸氢钾或碳酸铯。
本发明所述的“药学上可接受的盐或可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性，具体为本发明化合物与无机酸或有机酸形成的化合物，具体实例包括但不限于：柠檬酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、三氟乙酸盐、草酸盐、酒石酸盐、马来酸盐、富马酸盐、磺酸盐、对甲苯磺酸盐、苯磺酸盐、乙磺酸盐或甲磺酸盐等。
发明的有益效果
与现有技术(WO2013091539A1，公开日2013.06.27)相比，本发明制备式(IV)所示化合物的技术方案具有以下优点：
(1)本发明与现有技术的起始原料不同，本发明的起始原料式(A)所示化合物的吡咯基上的氮原子通过保护基保护后再与式(B)所示化合物反应，可以避免式(A)所示化合物五元环上裸露的氨基会与自身六元环上的卤素发生反应，影响式(A)所示化合物和式(B)所示化合物反应不完全，导致产物的产率降低和杂质的增加，即降低副反应的发生。
(2)现有技术中公开的通过式(III)所示化合物之盐制备目标产物，该方法中的三乙胺先与式(III)所示化合物的盐酸盐
Figure PCTCN2017112237-appb-000024
反应，将式(III)所示化合物游离出来，再与式(C)所示化合物反应得到目标产物，但此方法可能会剩余过多的式(III)所示化合物，反应不完全；本发明将式(I)所示化合物通过脱去保护基，得到游离的式(III)所示化合物
Figure PCTCN2017112237-appb-000025
与式(C)所示化合物发生反应后得到目标终产物，本发明的方法操作简单、可以提高产率、提高产物纯度，并且此方法中制备式(III)所示化合物的过程中通过加入碱调pH的操作还可以除去杂质，得到的式(III)所示化合物的纯度较高。
(3)缩短反应时间，本发明制备式(IIa)所示化合物的步骤中第一步反应为2h， 第二步反应1h，而现有技术公开的第一步反应时间为48h。
(4)产率提高，本发明第一步产率为60-70％、第二步产率为80-90％，两步总收率为48％-63％，而现有技术的产率为5.0％；本发明最后一步产率为80-90％，现有技术为25.9％。
(5)化学反应后处理方法简单，本发明后处理方式为冷却析晶、简单的洗涤除杂质后即得目标产物，而现有技术为柱色谱分离提纯法，本发明后处理方法易于工业放大生产。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦高压液相色谱仪和Thermon UltiMate3000高效液相色谱仪(Kromasil C18 250×4.6mm色谱柱)。
制备例1、起始原料式(A2)所示化合物的制备方法如下：
Figure PCTCN2017112237-appb-000026
4-氯-7-对甲苯磺酸-7H-吡咯并[2,3-d]嘧啶的制备
室温下，将4-氯-7H-吡咯并[2,3-d]嘧啶(2kg，12.96mol)和二氯甲烷(40L)加入反应瓶中，搅拌溶解后，依次加入三乙胺(3.88kg，38.4mol)和4-二甲氨基吡啶(157.6g，1.28mol)，搅拌溶解后，0℃滴加对甲苯磺酰氯(2.6kg，13.6mol)的二氯甲烷(30L)溶液，滴毕，室温搅拌反应30min，TLC跟踪反应结束后，向反应液依次用水(16L×3)洗涤，合并有机层，无水硫酸钠干燥，过滤，滤液减压浓缩，减压干燥后得到标题产物(3.9kg，产率97.7％)。
MS m/z(ESI):309.0[M+1]
1H-NMR(400MHz,CDCl3)δ8.77(s,1H),8.10-8.08(d,2H),7.79-7.78(d,1H), 7.34-7.32(d,2H),6.72-6.71(d,1H),2.41(s,3H)。
制备例2、起始原料式(B2)所示化合物按照公知方法WO2008089636A1(公开日2008.07.31)中的实施例1和WO2013091539A1(公开日2013.06.27)中的实施例5的方法制备。
MS m/z(ESI):241.5[M+1]
1H-NMR(400MHz,CDCl3)δ3.21(m,2H),2.90-2.83(m,3H),2.47-2.45(m,2H),2.08(s,3H),1.42-1.33(m,4H),1.15(s,9H),0.94(s,1H)。.
制备例3、起始原料式(C)所示化合物的制备方法如下：
(1)1-(甲基异硫氰酰酸)-4-甲氧基苯甲醚的制备
Figure PCTCN2017112237-appb-000027
将甲氧基苄胺(14kg)、四氢呋喃(50L)和三乙胺(26.8kg)加入反应釜中，搅拌溶解，10-15℃条件下滴加二硫化碳(7.8kg)溶解在四氢呋喃(5L)中的溶液，滴毕反应液中析出固体，10-20℃搅拌反应30min，10-20℃滴加对甲苯磺酰氯(20.5kg)溶解在四氢呋喃(50L)中的溶液，滴毕搅拌反应30min，TLC跟踪反应结束后，在反应液中加入石油醚(30L)、纯化水(100L)，萃取分层，有机相用稀盐酸(40L)洗涤至pH＝4-5，再依次用水(40L)洗，盐水(25L)洗，分层，有机相用无水硫酸钠干燥，过滤，减压浓缩后得标题产物(21.2kg，产率116％)。
(2)3-甲氧基-N-(4-甲氧基苄基)-1,2,4-噻二唑-5-胺的制备
Figure PCTCN2017112237-appb-000028
将DMF(40L)、O-甲基异脲硫酸盐(7.5kg)、碳酸氢钠(6kg)加入反应釜中，30-40℃搅拌反应0.5h，加入1-(甲基异硫氰酰酸)-4-甲氧基苯甲醚(21.2kg)溶解于N,N-二甲基甲酰胺(5L)的溶液，30-40℃搅拌反应6-8h，TLC跟踪反应结束，在30-40℃下滴加偶氮二甲酸二异丙酯(12.9kg)，滴完后35-45℃搅拌反应2h，TLC跟踪反应结束，加入纯化水(180L)，析出大量淡黄色固体，搅拌析晶2-3h，离心过滤，甩干，依次用水、石油醚洗涤滤饼，过滤、干燥后得标题产物(278.7g，产率110％)。
(3)3-甲氧基-1,2,4-噻二唑-5-胺的制备
Figure PCTCN2017112237-appb-000029
将3-甲氧基-N-(4-甲氧基苄基)-1,2,4-噻二唑-5-胺(12.4kg)和三氟乙酸(25L)加入 反应瓶中，氩气保护，73-75℃搅拌反应7-9h，TLC跟踪反应结束，将反应液减压浓缩，得到棕褐色液体，冷却到室温，搅拌加入盐酸(1N，5L)和石油醚:乙酸乙酯(5L，V/V＝1:1)，搅拌溶解后，过滤，用1N盐酸洗涤滤饼(3L×3)，滤液分层，有机相用1N盐酸反萃(25L×3)，合并水层，用滤布加滤纸过滤，除去不溶的固体，滤液用石油醚(25L)再萃取，水层加入乙酸乙酯(50L)，搅拌下用固体碳酸钾调节水层pH＝8-9，分层，水层用乙酸乙酯再提取三次(30L×3)，合并有机相，减压浓缩后析出大量白色固体，稍冷却，过滤，干燥后得标题产物(45.8g，产率50％)。
1H-NMR(400MHz,DMSO-d6)δ7.92(s,2H),3.80(s,3H)。
(4)(3-甲氧基-1,2,4-噻二唑-5-基)甲酸苯酯的制备
Figure PCTCN2017112237-appb-000030
将3-甲氧基-1,2,4-噻二唑-5-胺(500mg，3.82mmol)和氯甲酸苯酯(600mg，3.82mmol)溶解于二氯甲烷(20mL)中，滴加三乙胺(0.8mL，5.73mmol)，滴毕反应16h，向反应液中加入水(30mL)稀释，分液，水相用二氯甲烷萃取(20mL×2)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩反应液，用硅胶柱色谱法以洗脱剂(二氯甲烷和甲醇)纯化所得残余物，得到标题产物3-甲氧基-1,2,4-噻二唑-5-基氨基甲酸苯酯(200mg，产率20.8％)。
MS m/z(ESI):252.2[M+1]
1H-NMR(400MHz,CDCl3)δ12.33(s,1H),7.46-7.42(m,2H),7.33-7.26(m,3H),4.01(s,3H)。
实施例1、(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺(化合物IV)的制备
Figure PCTCN2017112237-appb-000031
Figure PCTCN2017112237-appb-000032
第一步
(3aR,5s,6aS)-5-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(Ic)的制备
氮气保护下，将4-氯-7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶(300g，0.98mol)、N-BOC-双环辛烷酮(234g，0.98mol)和N,N-二甲基甲酰胺(2.3kg)加入反应瓶中，搅拌溶解，加入碳酸钾(336g，2.44mol)，搅拌下将反应液升温至100℃反应2h，TLC跟踪反应结束后，将反应液冷却至室温，加入冰水(15kg)，析出大量土黄色固体，常温搅拌1h，过滤，滤饼用二氯甲烷(6kg)溶解，萃取，有机层用无水硫酸钠干燥，过滤，减压浓缩得产物粗品，将粗品加热溶于乙酸乙酯(1.2kg)中，室温下缓慢加入石油醚(3.6kg)，逐渐有固体析出，搅拌1h，过滤，滤饼减压干燥后得标题产物(349g，产率70.0％)。
第二步
(3aR,5s,6aS)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(IIa)的制备
将(3aR,5s,6aS)-5-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(315g，0.62mol)和N,N-二甲基乙酰胺(1.5kg)加入反应瓶中，搅拌溶解，加入氢氧化钾(176g，3.15mol)，搅拌下加入水(300g)，反应液析出固体，升温至70℃，搅拌反应1h。TLC跟踪反应结束后，将反应液冷却至室温，加入二氯甲烷(3.9kg)和水(3.0kg)，萃取、分液，无水硫酸钠干燥，过滤，滤液减压浓缩，得到淡黄色固体，加入乙酸乙酯/石油醚混合溶剂(1.0kg，v/v＝1/4)，50℃热打浆0.5h，过滤，减压干燥后得标题产物(192g，产率87.2％)。
第三步
N-甲基-N-((3aR,5s,6aS)-八氢环戊二烯并[c]吡咯-5-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(III)的制备
将(3aR,5s,6aS)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡 咯-2(1H)-甲酸叔丁酯(187g，0.52mol)、无水甲醇和二氯甲烷(0.8kg,w/w＝1.6)加入反应瓶中，搅拌溶解，冰水浴冷却下，滴加盐酸(0.55kg，15mol)，滴毕于室温搅拌反应10h，TLC跟踪反应结束，减压浓缩反应液至去除大部分有机溶剂，加入水(0.3L)，用二氯甲烷(0.6kg×3)萃取，弃去有机相，水相用30％氢氧化钠溶液调pH至9-10，有大量固体析出，过滤，用纯化水(0.25kg×2)充分打浆，过滤，减压干燥得标题产物(131g，产率97.3％)。
第四步
(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺(化合物IV)的制备
氮气保护下，将N-甲基-N-((3aR,5s,6aS)-八氢环戊二烯并[c]吡咯-5-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(101g，0.39mol)、(3-甲氧基-1,2,4-噻二唑-5-基)氨基甲酸苯酯(106g，0.42mol)和四氢呋喃(1.8kg)加入反应瓶中，搅拌均匀，加入三乙胺(170g，1.68mol)，加毕，加热回流，搅拌反应5h，TLC跟踪反应结束后，将反应液冷却至室温，过滤，滤饼用四氢呋喃(400g)洗涤、无水乙醇(200g)洗涤，减压干燥后得标题产物(157g，产率96.5％)。
HPLC纯度：99％
MS m/z(ESI):415.2[M+1]
1H-NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.59(s,1H),8.10(s,1H),7.07(m,1H),6.54-6.53(m,1H),5.50-5.46(m,1H),3.91-3.87(s,3H),3.73-3.60(m,2H),3.37-3.33(m,2H),3.19-3.16(s,3H),2.89(m,2H),2.05-1.97(m,2H),1.81-1.76(m,2H)。
实施例2、(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的制备
Figure PCTCN2017112237-appb-000033
(1)粗品的制备
将(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺(140g，0.34mol)、无水甲醇(350g)和二氯甲烷(2.0kg)加入反应瓶中，搅拌，室温下缓慢滴加硫酸(34.8g，0.36mol)，反应液溶清，搅拌反应30min，过滤除去不溶物，滤液减压浓缩得固体，加入无水乙醇(700mL)，室温搅拌4h，过滤，减压干燥得到(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯 -2(1H)-甲酰胺硫酸氢盐粗品(160g，产率92.4％)。
HPLC纯度：99％
(2)产品的纯化
将(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺硫酸氢盐粗品(145g，0.28mol)和无水甲醇(11kg)加入反应瓶中，回流溶清，热过滤，减压浓缩反应液，将该浓缩液冷却至室温搅拌、析晶，过滤，滤饼用无水乙醇(200g)洗涤，减压干燥后得到纯化后的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊二烯并[c]吡咯-2(1H)-甲酰胺硫酸氢盐(138g，产率95.2％)。
HPLC纯度：99.4％
MS m/z(ESI):415.2[M+1]
1H-NMR(400MHz,DMSO-d6)δ12.75(s,1H),11.04(s,1H),8.37(s,1H),7.42-7.41(t,1H),6.89(s,1H),5.19-5.15(m,1H),3.89(s,3H),3.70-3.68(m,2H),3.40-3.38(m,2H),3.29(s,3H),2.95(s,2H),2.16-2.09(m,2H),1.97-1.92(m,2H)。

Claims (26)

  1. 式(I)所示的化合物或其立体异构体：
    Figure PCTCN2017112237-appb-100001
    其中，
    R1为氢或氨基保护基；
    R2为氨基保护基；
    R3选自氢原子、C1-6烷基或氨基保护基；
    所述氨基保护基优选烷氧羰基类氨基保护基、酰基类氨基保护基、磺酰基类氨基保护基或烷基类氨基保护基；
    所述烷氧羰基类氨基保护基选自苄氧羰基、叔丁氧羰基、笏甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基或乙氧羰基；
    所述酰基类氨基保护基选自邻苯二甲酰基、三氟乙酰基、特戊酰基、苯甲酰基、甲酰基或乙酰基；
    所述磺酰基类氨基保护基选自对甲苯磺酰基、邻硝基苯磺酰基或对硝基苯磺酰基；
    所述烷基类氨基保护基选自三苯甲基、2,4-二甲氧基苄基、对甲氧基苄基或苄基。
  2. 如权利要求1所述的式(I)所示的化合物或其立体异构体，
    其中，
    R1选自烷氧羰基类氨基保护基，所述烷氧羰基类氨基保护基优选苄氧羰基、叔丁氧羰基、笏甲氧羰基或烯丙氧羰基，更优选叔丁氧羰基；
    R2选自磺酰基类氨基保护基，所述磺酰基类氨基保护基优选对甲苯磺酰基、邻硝基苯磺酰基或对硝基苯磺酰基，更优选对甲苯磺酰基；
    R3选自氢原子或甲基。
  3. 如权利要求1所述的式(I)所示的化合物或其立体异构体，其中所述化合物具有下述式(Ia)所示的结构，
    Figure PCTCN2017112237-appb-100002
  4. 如权利要求1所述的式(I)所示的化合物或其立体异构体，其中所述化合物具有下述式(Ib)所示的结构，
    Figure PCTCN2017112237-appb-100003
  5. 如权利要求1所述的式(I)所示的化合物或其立体异构体，其中所述化合物具有下述式(Ic)所示的结构，
    Figure PCTCN2017112237-appb-100004
  6. 一种制备如权利要求1所述式(I)化合物的方法，其特征在于，所述方法包括由式(A)所示化合物与式(B)所示化合物反应的步骤，
    Figure PCTCN2017112237-appb-100005
    其中，X选自卤素。
  7. 一种如权利要求6所述的方法，其特征在于，所述方法为式(A)所示化合物与式(B1)所示化合物反应得到式(Ia)所示化合物，
    Figure PCTCN2017112237-appb-100006
  8. 一种如权利要求7所述的方法，其特征在于，所述方法为式(A1)所示化合物与式(B1)所示化合物反应得到式(Ib)所示化合物，
    Figure PCTCN2017112237-appb-100007
  9. 一种如权利要求8所述的方法，其特征在于，所述方法为式(A2)所示化合物与式(B2)所示化合物反应得到式(Ic)所示化合物，
    Figure PCTCN2017112237-appb-100008
  10. 式(Iˊ)所示的化合物或其立体异构体：
    Figure PCTCN2017112237-appb-100009
    其中，R2、R3如权利要求1中所定义。
  11. 如权利要求10所述的式(Iˊ)所示的化合物或其立体异构体，其中所述化合物具有下述式(Iˊ-1)所示的结构，
    Figure PCTCN2017112237-appb-100010
  12. 一种制备式(IV)所示化合物或其药学上可接受盐的方法，其特征在于，所述方法包括由式(Iˊ)所示化合物通过一步或多步反应得到式(IV)所示化合物的步骤，
    Figure PCTCN2017112237-appb-100011
  13. 如权利要求12所述的方法，其特征在于，所述方法为由式(Iˊ-1)所示化合物通过一步或多步反应得到式(IV)所示化合物，
    Figure PCTCN2017112237-appb-100012
  14. 一种制备式(IV)所示化合物或其药学上可接受盐的方法，其特征在于，所述方法包括由式(Ic)所示化合物通过一步或多步反应得到式(IV)所示化合物的步骤，
    Figure PCTCN2017112237-appb-100013
  15. 一种制备式(IV)所示化合物或其药学上可接受盐的方法，其特征在于，所述方法包括由式(III)所示化合物与化合物(C)反应得到式(IV)所示化合物的步骤，
    Figure PCTCN2017112237-appb-100014
  16. 如权利要求15所述的方法，其特征在于，由式(Ia)所示化合物通过氨基脱保护得到式(III)所示化合物，其中，
    Figure PCTCN2017112237-appb-100015
    R1、R2如权利要求1中所定义。
  17. 如权利要求16所述的方法，其特征在于，所述氨基脱保护的反应包括，
    Figure PCTCN2017112237-appb-100016
    步骤一，中间体式(Ia)所示化合物通过脱去氨基保护基得到中间体式(II)所示化合物；
    步骤二，中间体式(II)所示化合物通过脱去氨基保护基得到式(III)所示化合物。
  18. 如权利要求17所述的方法，其特征在于，所述脱保护的反应包括，
    Figure PCTCN2017112237-appb-100017
  19. 如权利要求16-18中任一项所述的方法，其中，R1、R2如权利要求2中所定义。
  20. 如权利要求18所述的方法，其特征在于，所述脱保护的反应包括如下步骤，
    Figure PCTCN2017112237-appb-100018
  21. 如权利要求16所述的方法，其特征在于，由式(Ia)所示化合物通过一步反应同时脱去氨基保护基得到式(III)所示化合物，
    Figure PCTCN2017112237-appb-100019
  22. 如权利要求21所述的方法，其特征在于，由式(Ib)所示化合物通过一步反应同时脱去氨基保护基得到式(III)所示化合物，
    Figure PCTCN2017112237-appb-100020
  23. 如权利要求21-22中任一项所述的方法，其中，R1、R2如权利要求2中所定义。
  24. 如权利要求22所述的方法，其特征在于，所述式(III)所示化合物的制备方法是由式(Ic)所示化合物通过一步反应脱去氨基保护基得到式(III)所示化合物，
    Figure PCTCN2017112237-appb-100021
  25. 一种制备式(IV)所示化合物的方法，其特征在于，所述方法包括如下步骤，
    Figure PCTCN2017112237-appb-100022
  26. 一种制备式(IV)所示化合物的药学上可接受的盐的方法，包括权利要求12至15任意一项或权利要求25中所述的步骤，以及通过式(IV)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸选自有机酸或无机酸，优选无机酸；所述有机酸选自柠檬酸、乙酸、三氟乙酸、草酸、酒石酸、马来酸、富马酸、对甲苯磺酸、苯磺酸或甲磺酸；所述无机酸选自盐酸、硫酸或磷酸，优选硫酸。
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