WO2019137358A1 - 一种parp抑制剂及其中间体的制备方法 - Google Patents

一种parp抑制剂及其中间体的制备方法 Download PDF

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WO2019137358A1
WO2019137358A1 PCT/CN2019/070797 CN2019070797W WO2019137358A1 WO 2019137358 A1 WO2019137358 A1 WO 2019137358A1 CN 2019070797 W CN2019070797 W CN 2019070797W WO 2019137358 A1 WO2019137358 A1 WO 2019137358A1
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group
compound
acid
formula
cycloalkyl
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PCT/CN2019/070797
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English (en)
French (fr)
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李文海
张英杰
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江苏恒瑞医药股份有限公司
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Priority to BR112020013449-0A priority Critical patent/BR112020013449A2/pt
Priority to CA3085660A priority patent/CA3085660A1/en
Priority to CN201980005431.8A priority patent/CN111278830B/zh
Priority to AU2019207072A priority patent/AU2019207072A1/en
Priority to RU2020122776A priority patent/RU2777597C2/ru
Priority to JP2020537491A priority patent/JP2021509906A/ja
Priority to EP19738775.6A priority patent/EP3738963A4/en
Priority to US16/960,117 priority patent/US11345709B2/en
Priority to KR1020207022785A priority patent/KR20200108021A/ko
Publication of WO2019137358A1 publication Critical patent/WO2019137358A1/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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine and relates to a preparation method of a PARP inhibitor and an intermediate thereof.
  • PARPs Poly(ADP-ribose) polymerases characterized by polyadenosine diphosphate-ribosylation activity constitute a superfamily of 18 kinds of nuclear enzymes and cytoplasmic enzymes. This polyadenosine diphosphate-ribosylation regulates the catalytic activity and protein interactions of the protein of interest and regulates many basic biological processes, including DNA repair, cell death, and genomic stability (see also D'Amours et al. Biochem. J, 1999, 342, 249). Since the DNA damage repair mechanism is the main mechanism for tumor cells to respond to chemotherapy drugs and ionizing radiation therapy, PARP is considered to be an effective target for exploring new cancer treatment methods.
  • CN102686591A discloses an effective PARP inhibitor and a process for its preparation, the structure of which is shown in Formula I. This compound has obvious pharmacodynamic advantages.
  • WO2004032836 reports a process for the preparation of the compound of the formula II, some of which are post-treated by column chromatography, the post-treatment efficiency is low, and the obtained compound of the formula II still contains some impurities which are difficult to remove, and the impurities are brought into the reaction of the final product. Medium seriously affects the purity of the final product.
  • Some methods use a method in which the imino group is purified by BOC protection and then deprotected. The method has a long reaction step and a low yield.
  • the invention provides a process for the preparation of a compound of formula II',
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a benzyl group, -C(O)OR 2 , -OC ( O) R 2 , -O(CH 2 ) n C(O)OR 2 , -(CH 2 ) n NR 3 R 4 , -C(O)R 2 , -NHC(O)R 2 , -NR 3 R 4 , -OC(O)NR 3 R 4 or -C(O)NR 3 R 4 , wherein alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently Optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy
  • R 2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters;
  • R 3 or R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group
  • the groups are each independently optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters.
  • R 3 or R 4 forms a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) m heteroatoms, and the heterocyclic group is Optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • X is an acid, which may be an inorganic acid or an organic acid, and the inorganic acid may be hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, trifluoroacetic acid, etc., and the organic acid may be formic acid, acetic acid, sulfonic acid, optionally substituted alkylsulfonic acid, Succinic acid, maleic acid, tartaric acid, citric acid, lactic acid, oxalic acid, gluconic acid, fumaric acid, malonic acid, malic acid, etc., preferably hydrochloric acid, phosphoric acid and maleic acid, more preferably hydrochloric acid.
  • the method comprises the step of reacting a compound of formula II with a corresponding acid.
  • the R 1 is —CF 3 .
  • the solvent used in the step of reacting the compound of the formula II with the corresponding acid may be a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetic acid B.
  • the molar ratio of the compound of the formula II to the corresponding acid may be from 1:1 to 1:10.
  • the compound of formula II' can be isolated.
  • the separation method may be a conventional method such as filtration, removal of a solvent, and the like.
  • Purification may optionally be carried out before or after isolation of the compound of formula II', such as recrystallization, beating, column chromatography and the like.
  • the method further comprises the step of hydrotreating a compound of formula III to form a compound of formula II;
  • the solvent used in the step of hydrotreating the compound of the formula III to form a compound of the formula II may be a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone or dimethyl sulfoxide. , tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethyl sulfoxide, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol, One or more of the waters, preferably one or more of methanol, ethanol, and isopropanol.
  • a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone or dimethyl sulfoxide.
  • tetrahydrofuran ethyl acetate, dioxane, toluene, dimethyl sul
  • the hydrogenation reduction reaction is preferably carried out in the presence of a catalyst which may be a palladium-containing catalyst such as palladium on carbon.
  • Another aspect of the invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula II' according to the invention;
  • the method further comprises the step of reacting a compound of Formula II' with a compound of Formula IV,
  • R a is selected from a hydroxyl group, a halogen or an alkoxy group.
  • Another aspect of the invention provides a method of purifying a compound of formula II, which comprises reacting a compound of formula II with a corresponding acid to form a compound of formula II', isolating the compound of formula II', and The compound of formula II' is converted to the compound of formula II.
  • the R 1 is —CF 3 .
  • the solvent used in the reaction may be a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethyl sulfoxide.
  • diethyl ether, diisopropyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, and isopropanol water, preferably tetrahydrofuran, ethyl acetate, dioxane
  • the molar ratio of the compound of the formula II to the corresponding acid may be from 1:1 to 1:10.
  • the separation method may be a conventional method such as filtration, removal of a solvent, and the like. Purification may optionally be carried out before or after isolation of the compound of formula II', such as recrystallization, beating, column chromatography and the like.
  • the conversion method may be a conventional method, for example, by reacting a compound of the formula II' with a base, which may be an inorganic base or an organic base such as sodium hydroxide, potassium hydroxide, aqueous ammonia or the like.
  • a base which may be an inorganic base or an organic base such as sodium hydroxide, potassium hydroxide, aqueous ammonia or the like.
  • the compound of Formula II is obtained by hydrogenation reduction of a compound of Formula III.
  • Another aspect of the invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the step of purifying a compound of formula II according to the invention.
  • the method further comprises the step of reacting a compound of Formula II with a compound of Formula IV, wherein Ra is selected from the group consisting of hydroxyl, halogen, or alkoxy.
  • the preparation method of the PARP inhibitor intermediate according to the present invention unexpectedly greatly improves the reaction yield and purity by using the salt-purifying method, shortens the product processing time in the production process, and greatly improves the production efficiency.
  • the intermediate after salt formation is solid and has suitable solubility. It can be purified by conventional methods such as recrystallization and beating to improve the purity of the intermediate, effectively preventing the reaction impurities from being brought into the final product, and is more conducive to the reaction of the final product. And purification.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpent
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains from 3 to 12 ring atoms, of which from 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably piperidinyl or pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle
  • An alkylthio group, a carboxyl group or a carboxylate group is preferably a phenyl group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 12 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine
  • the group or the like is preferably an imidazolyl group, a pyrazolyl group, a pyrimidinyl group or a thiazolyl group; more preferably a pyrazolyl group or a thiazolyl group.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • halogen means fluoro, chloro, bromo or iodo.
  • hydroxy refers to an -OH group.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • benzyl refers to -CH 2 - phenyl.
  • carboxylic acid refers to -C(O)OH.
  • carboxylate refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • the bond "/" does not specify a configuration, that is, if a configuration isomerized in the chemical structure, the bond "/" may be or Or both with Two configurations.

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Abstract

本申请公开了一种PARP抑制剂及其中间体的制备方法，该方法收率高、产物纯度好，更有利于工业化生产。

Description

一种PARP抑制剂及其中间体的制备方法
本申请要求申请日为2018年1月9日的中国专利申请CN201810019736.1的优先权。本申请要求申请日为2018年12月18日的中国专利申请CN201811547590.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，涉及一种PARP抑制剂及其中间体的制备方法。
背景技术
近年来我国的肿瘤死亡率呈明显上升趋势，癌症严重威胁着人们的生命和生活质量。对于恶性肿瘤增殖，利用传统化疗药物化疗或放疗毒性大、并且特异性差，因此寻找高效、低毒的抗肿瘤药物是当今生命科学中极富挑战性且意义重大的课题。科学研究表明，肿瘤细胞中存在特定的DNA修复机制，可以快速响应并修复与增殖调节相关的染色体损伤，从而使其自身幸免于一些治疗药物的细胞毒性作用并保持继续存活。而通过对DNA损伤信号修复机制的调节，能够以肿瘤细胞特异性的方式实现对DNA损伤药剂的细胞毒性的提高。其中，以聚腺苷二磷酸-核糖基化活性为特征的PARPs(Poly(ADP-ribose)polymerases)，构成了18种细胞核酶和细胞质酶的超家族。这种聚腺苷二磷酸-核糖基化作用可以调节目的蛋白的催化活性和蛋白质间相互作用，并且对许多基本生物过程进行调控，包括DNA修复,细胞死亡,基因组稳定性也与之相关(参见D'Amours et al.Biochem.J,1999,342,249)。由于DNA损伤修复机制是肿瘤细胞应对化疗药物和电离辐射治疗产生耐受作用的主要机制，因此PARP被认为是探索新的癌症治疗方法的一个有效靶点。
目前已公开了一系列PARP抑制剂，其中，CN102686591A公开了一种 有效的PARP抑制剂及其制备方法，其结构如式I所示。该化合物具有明显的药效优势。
Figure PCTCN2019070797-appb-000001
在式I所示化合物的制备过程中，使用了式II所示化合物这一关键中间体，该中间体的收率和纯度直接影响了终产品的收率和纯化难度。
Figure PCTCN2019070797-appb-000002
现有的制备该中间体的方法存在着一些问题。WO2004032836报道了制备式II所示化合物的方法，有些方法采用柱层析进行后处理，后处理效率低，且得到的式II化合物仍然含有部分杂质较难除去，这些杂质被带入终产品的反应中严重影响终产品的纯度。有些方法采用将亚氨基通过BOC保护再脱保护的方式进行纯化，该方法反应步骤长且收率不高。另外，将上述方法用于工业化生产时反应收率低，后处理时间长，成本高，并且氢化反应使用的钯催化剂无法完全除净，进一步影响了产物的纯度。因此，目前急需一种收率高、产物纯度好、后处理简便的工业化制备式II所示化合物的方法。
发明内容
为了克服现有技术的不足，本发明的目的在于提供一种新的PARP抑制剂及其中间体的制备方法。
本发明一方面提供了一种式II’所示化合物的制备方法，
Figure PCTCN2019070797-appb-000003
其中：
R 1选自氢原子、烷基、卤素、羟基、氰基、烷氧基、环烷基、杂环基、芳基、杂芳基、苄基、-C(O)OR 2、-OC(O)R 2、-O(CH 2) nC(O)OR 2、-(CH 2) nNR 3R 4、-C(O)R 2、-NHC(O)R 2、-NR 3R 4、-OC(O)NR 3R 4或-C(O)NR 3R 4，其中烷基、烷氧基、环烷基、杂环基、芳基、杂芳基或苄基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、氧代、-C(O)OR 2、-OC(O)R 2、-O(CH 2) nC(O)OR 2、-C(O)R 2、-NHC(O)R 2、-N 3R 4,-OC(O)NR 3R 4或-C(O)NR 3R 4的取代基所取代；
R 2选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
R 3或R 4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
或者，R 3或R 4与相连接的氮原子形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O) m杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
m选自0，1或2；
n选自0，1或2；
X为酸，可以是无机酸和有机酸，无机酸可以是盐酸、硫酸、磷酸、氢溴酸、三氟乙酸等，有机酸可以是甲酸、乙酸、磺酸、任意取代的烷基磺酸、琥珀酸、马来酸、酒石酸、柠檬酸、乳酸、草酸、葡萄糖酸、富马酸、丙二酸、苹果酸等，优选盐酸、磷酸和马来酸，更优选盐酸。
所述方法包括式II所示化合物与对应的酸反应的步骤。
在某些实施方式中，所述R 1为-CF 3。
所述的式II所示化合物与对应的酸反应的步骤中使用的溶剂可以是常规溶剂，例如二甲基甲酰胺、1-甲基-2-吡咯烷酮、二甲基亚砜、四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇、水中的一种或多种，优选四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇中的一种或多种。
所述的式II所示化合物与对应的酸的摩尔比可以为1:1～1:10。
在某些实施方式中，可以对式II’所示化合物进行分离。所述的分离方法可以是常规的方法，例如过滤、除去溶剂等。在式II’所示化合物分离前或分离后，可任选地进行纯化，例如重结晶、打浆、柱层析等。
在某些实施方式中，所述方法还包括式III所示化合物加氢还原反应生成式II所示化合物的步骤；
Figure PCTCN2019070797-appb-000004
所述的式III所示化合物加氢还原反应生成式II所示化合物的步骤中使用的溶剂可以是常规溶剂，例如二甲基甲酰胺、1-甲基-2-吡咯烷酮、二甲基亚砜、四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇、水中的一种或多种，优选甲醇、乙醇、异丙醇中的一种或多种。
所述的加氢还原反应优选在催化剂存在的条件下进行，所述催化剂可以是含钯催化剂，例如钯碳。
本发明另一方面还提供了一种式I所示化合物或其药学上可接受的盐的制备方法，包括本发明所述的制备式II’所示化合物的步骤；
Figure PCTCN2019070797-appb-000005
在某些实施方式中，所述方法还包括式II’所示化合物与式IV所示化合物反应的步骤，
Figure PCTCN2019070797-appb-000006
其中，R a选自羟基、卤素或烷氧基。
本发明另一方面还提供了一种如式II所示化合物的纯化方法，包括将式II所示化合物与对应的酸反应生成式II’所示化合物，分离式II’所示化合物，以及将式II’所示化合物转化为式II所示化合物。
在某些实施方式中，所述R 1为-CF 3。
所述反应使用的溶剂可以是常规溶剂，例如二甲基甲酰胺、1-甲基-2-吡咯烷酮、二甲基亚砜、四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇、水中的一种或多种，优选四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇中的一种或多种。
所述的式II所示化合物与对应的酸的摩尔比可以为1:1～1:10。
所述的分离方法可以是常规的方法，例如过滤、除去溶剂等。在式II’所示化合物分离前或分离后，可任选地进行纯化，例如重结晶、打浆、柱层析等。
所述的转化方法可以是常规方法，例如将式II’所示化合物与碱反应，所 述的碱可以是无机碱或有机碱，例如氢氧化钠、氢氧化钾、氨水等等。
在某些实施方式中，所述的式II所示化合物是由式III所示化合物加氢还原反应得到的。
本发明另一方面还提供了一种式I所示化合物或其药学上可接受的盐的制备方法，包括本发明所述的纯化式II所示化合物的步骤。
在某些实施方式中，所述方法还包括式II所示化合物与式IV所示化合物反应的步骤，其中，R a选自羟基、卤素或烷氧基。
本发明所述的PARP抑制剂中间体的制备方法，通过采用成盐纯化的方法，出人意料地大幅提高了反应收率和纯度，缩短了生产工艺中的产物处理时间，大大提高了生产效率。成盐后的中间体呈固体，溶解性适宜，可以采用重结晶、打浆等常规方法进行纯化，提高了中间体的纯度，有效阻止了反应杂质带入终产品中，更有利于终产品的反应和纯化。
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。 更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至6个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。 所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2019070797-appb-000007
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基，优选苯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至12元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基、嘧啶基或噻唑基；更优选为吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2019070797-appb-000008
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环 丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH基团。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“苄基”指-CH 2-苯基。
术语“氧代”指＝O。
术语“羧酸”指-C(O)OH。
术语“羧酸酯”指-C(O)O(烷基)或-C(O)O(环烷基)。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
本发明所述化合物的化学结构中，键“/”并未指定构型，即如果化学结构中存在构型异构，键“/”可以为
Figure PCTCN2019070797-appb-000009
或
Figure PCTCN2019070797-appb-000010
或者同时包含
Figure PCTCN2019070797-appb-000011
和
Figure PCTCN2019070797-appb-000012
两种构型。
具体实施方式
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。
实施例1
Figure PCTCN2019070797-appb-000013
将5.0kg化合物1和10％钯碳250g，甲醇80L加入到反应釜中，在0.4MPa，25℃下加氢反应24h。过滤除去钯碳，滤饼用甲醇洗涤，收集滤液，减压蒸干，向浓缩物中加入乙酸乙酯20L，搅拌溶清后冰水浴冷却至0℃，用4M盐酸乙酸乙酯调pH＝2～3，搅拌，过滤，滤饼再加入20L乙酸乙酯，室温打浆3～4h，过滤，真空干燥45℃6～8h得5.5kg化合物3固体，收率91.7％，HPLC纯度99.69％。
实施例2
Figure PCTCN2019070797-appb-000014
根据CN102686591A实施例19的方法，投入2g化合物3和2.79g化合物4，得到式I所示化合物3.6g，收率87.8％。
实施例3
室温下，将2.0g化合物2(根据WO2009025784公开的方法制备)溶于30mL异丙醇，搅拌下滴加浓硫酸调节pH至3，室温搅拌，无固体析出；将反应液倒入150mL正己烷中，继续室温搅拌，仍无固体析出，无法得到化合物2的硫酸盐固体。
实施例4
室温下，将1.11g化合物2溶于10mL异丙醇，搅拌下滴加15％的磷酸/异丙醇溶液调节pH至3，室温搅拌，过滤，滤饼用异丙醇洗涤，真空干燥， 得化合物2磷酸盐固体1.46g，收率87.1％，HPLC纯度99.72％。
实施例5
室温下，将1.28g化合物2溶于10mL异丙醇，搅拌下滴加20％的乙酸/异丙醇溶液调节pH至3，室温搅拌，无固体析出；反应液倒入100mL正己烷中，继续室温搅拌，仍无固体析出，无法得到化合物2的乙酸盐固体。
实施例6
室温下，将1.05g化合物2溶于10mL异丙醇，搅拌下，滴加15％的柠檬酸/异丙醇溶液调节pH至3，室温搅拌，无固体析出；反应液倒入100mL正己烷中，继续室温搅拌，仍无固体析出，无法得到化合物2的柠檬酸盐固体。
实施例7
室温下，将1.12g化合物2溶于10mL异丙醇，搅拌下，加入0.74g马来酸，室温搅拌，过滤，滤饼用异丙醇洗涤，真空干燥，得化合物2的马来酸盐固体1.51g，收率84.6％。
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于精通此领域的技术人员是显而易见的且包括在本发明的范围内。

Claims (15)

  1. 一种如式II’所示化合物的制备方法，
    Figure PCTCN2019070797-appb-100001
    其中：
    R 1选自氢原子、烷基、卤素、羟基、氰基、烷氧基、环烷基、杂环基、芳基、杂芳基、苄基、-C(O)OR 2、-OC(O)R 2、-O(CH 2) nC(O)OR 2、-(CH 2) nNR 3R 4、-C(O)R 2、-NHC(O)R 2、-NR 3R 4、-OC(O)NR 3R 4或-C(O)NR 3R 4，其中烷基、烷氧基、环烷基、杂环基、芳基、杂芳基或苄基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、氧代、-C(O)OR 2、-OC(O)R 2、-O(CH 2) nC(O)OR 2、-C(O)R 2、-NHC(O)R 2、-N 3R 4,-OC(O)NR 3R 4或-C(O)NR 3R 4的取代基所取代；
    R 2选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R 3或R 4各自独立选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    或者，R 3或R 4与相连接的氮原子形成杂环基，其中所述的杂环基内含有一个或多个N、O或S(O) m杂原子，并且所述杂环基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    m选自0，1或2；
    n选自0，1或2；
    X为酸，选自无机酸和有机酸，优选盐酸、硫酸、磷酸、氢溴酸、三氟乙酸、甲酸、乙酸、磺酸、任意取代的烷基磺酸、琥珀酸、马来酸、酒石酸、柠檬酸、乳酸、草酸、葡萄糖酸、富马酸、丙二酸、苹果酸，更优选盐酸、磷酸和马来酸，最优选盐酸；
    所述方法包括式II所示化合物与对应的酸反应的步骤。
  2. 根据权利要求1所述的制备方法，其特征在于，R 1选自-CF 3。
  3. 根据权利要求1所述的制备方法，其特征在于，所述的式II所示化合物与对应的酸反应的步骤中使用的溶剂选自二甲基甲酰胺、1-甲基-2-吡咯烷酮、二甲基亚砜、四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇、水中的一种或多种，优选四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇中的一种或多种。
  4. 根据权利要求1所述的制备方法，其特征在于，所述的式II所示化合物与对应的酸的摩尔比为1:1～1:10。
  5. 根据权利要求1所述的制备方法，其特征在于，所述方法还包括分离式II’所示化合物的步骤。
  6. 根据权利要求1所述的制备方法，其特征在于，所述方法还包括式III所示化合物加氢还原反应生成式II所示化合物的步骤；
    Figure PCTCN2019070797-appb-100002
  7. 一种式I所示化合物或其药学上可接受的盐的制备方法，包括根据权利要求1～6任意一项所述的方法制备式II’所示化合物的步骤；
    Figure PCTCN2019070797-appb-100003
  8. 根据权利要求7所述的制备方法，其特征在于，所述方法还包括式II’所示化合物与式IV所示化合物反应的步骤，
    Figure PCTCN2019070797-appb-100004
    其中，R a选自羟基、卤素或烷氧基。
  9. 一种如式II所示化合物的纯化方法，包括将式II所示化合物与对应的酸反应生成式II’所示化合物，分离式II’所示化合物，以及将式II’所示化合物转化为式II所示化合物，其中R 1、X如权利要求1所述；
    Figure PCTCN2019070797-appb-100005
  10. 根据权利要求9所述的纯化方法，其特征在于，R 1选自-CF 3。
  11. 根据权利要求9所述的纯化方法，其特征在于，所述反应中使用的溶剂选自二甲基甲酰胺、1-甲基-2-吡咯烷酮、二甲基亚砜、四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、甲基叔丁基醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇、水中的一种或多种，优选四氢呋喃、乙酸乙酯、二氧六环、甲苯、二甲亚砜、乙醚、异丙醚、二氯甲烷、氯仿、丙酮、乙腈、甲醇、乙醇、异丙醇中的一种或多种。
  12. 根据权利要求9所述的纯化方法，其特征在于，所述的式II所示化合物与对应的酸的摩尔比为1:1～1:10。
  13. 根据权利要求9所述的纯化方法，其特征在于，所述方法还包括式 III所示化合物加氢还原反应生成式II所示化合物的步骤；
    Figure PCTCN2019070797-appb-100006
  14. 一种式I所示化合物或其药学上可接受的盐的制备方法，包括根据权利要求9～13任意一项所述的方法纯化式II所示化合物的步骤；
    Figure PCTCN2019070797-appb-100007
  15. 根据权利要求14所述的制备方法，其特征在于，所述方法还包括式II所示化合物与式IV所示化合物反应的步骤，其中，R a选自羟基、卤素或烷氧基；
    Figure PCTCN2019070797-appb-100008
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