WO2021217579A1 - 布瓦西坦及其中间体的制备方法 - Google Patents

布瓦西坦及其中间体的制备方法 Download PDF

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WO2021217579A1
WO2021217579A1 PCT/CN2020/088275 CN2020088275W WO2021217579A1 WO 2021217579 A1 WO2021217579 A1 WO 2021217579A1 CN 2020088275 W CN2020088275 W CN 2020088275W WO 2021217579 A1 WO2021217579 A1 WO 2021217579A1
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formula
compound represented
preparation
buwaxitan
resolution
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PCT/CN2020/088275
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English (en)
French (fr)
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占轶鹏
樊海生
尹凯
季翔
刘博洋
郭效文
黄鲁宁
陶安平
安建国
顾虹
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上海科胜药物研发有限公司
浙江华海药业股份有限公司
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Application filed by 上海科胜药物研发有限公司, 浙江华海药业股份有限公司 filed Critical 上海科胜药物研发有限公司
Priority to PCT/CN2020/088275 priority Critical patent/WO2021217579A1/zh
Priority to US17/922,140 priority patent/US20230174478A1/en
Priority to EP20933084.4A priority patent/EP4144724A4/en
Publication of WO2021217579A1 publication Critical patent/WO2021217579A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention relates to a preparation method of Buwaxitan and its intermediates, and belongs to the technical field of medicine.
  • Brivaracetam whose chemical name is (S)-2-(R)-3-propylpyrrolidin-1-ylbutanamide, was developed by UCB Pharma in Belgium. It is an antiepileptic
  • the drug Levetiracetam (levetiracetam) is an analogue of n-propyl group connected to the 4-carbon atom of pyrrolidine.
  • Buwaxitan is also a selective and high-affinity ligand for synaptic vesicle protein 2a (SV2A) in the brain.
  • SV2A synaptic vesicle protein 2a
  • SV2A synaptic vesicle protein 2a
  • the drug is a derivative of Levetiracetam and belongs to the third generation of antiepileptic drugs.
  • Patent document CN106748950A reports a method for preparing Buwaxitan intermediate, the reaction route is as follows:
  • the R-phenethylamine/isopropanol system is used to resolve the compound mixture shown in B-IV to obtain the Buwaxitan intermediate shown in B-VI.
  • the use of the intermediate to prepare Buwaxitan does not require chiral chromatographic columns for resolution, thereby reducing production costs.
  • the inventor of the present application found that the Buwaxitan intermediate shown in B-VI can only be obtained with a very low yield, and the content of the SS isomer is not significantly reduced. Therefore, this method has no obvious separation and purification effect, and does not have industrial practicability.
  • the purpose of the present invention is to provide a method for preparing a Buwaracetam intermediate represented by formula B-R, and a method for preparing high-purity Buwaracetam from the intermediate.
  • the present invention provides a preparation method of the Buwaxitan intermediate represented by the following formula B-R, comprising:
  • the compound represented by formula B-Q is prepared by reacting the compound represented by formula B-P with the resolution reagent;
  • the resolution reagent is a (1S, 2S)-(+)-1,2-cyclohexanediamine compound having the following formula (I),
  • R 1 , R 2 and R 3 are independently H, CH 3 or Ts, and R 1 , R 2 and R 3 are not Ts at the same time.
  • the compound represented by formula B-P is a mixture of two diastereomers of (S)-2-3-propylpyrrolidin-1-yl butyric acid.
  • Ts is p-toluenesulfonyl.
  • the inventor of the present application has conducted in-depth research on the prior art and found that some resolution reagents that have been reported in the prior art, such as R-phenethylamine, etc., cannot achieve the resolution of the compound represented by BP; During further exploration, the inventor unexpectedly discovered that the above-mentioned specific resolution reagent can effectively resolve the Buwaxitan intermediate represented by the formula BR from the compound represented by the formula BP.
  • the resolution reagent can be selected from 1S,2S-cyclohexanediamine, 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine, (1S,2S)-N1, N1, N2, N2-tetramethylcyclohexane-1,2-diamine and N-((1S,2S)-2-(dimethylamino)cyclohexyl)-4-toluenesulfonamide or any combination thereof.
  • the inventors further found that as the molar ratio of the resolving reagent and the compound represented by formula B-P increases, the yield of the compound represented by B-Q first increases and then decreases; the chiral purity increases to a certain extent and basically no longer changes. Considering the yield, chiral purity and cost factors comprehensively, the molar ratio of the compound represented by formula B-P and the resolution reagent should be controlled. In some embodiments, the molar ratio of the compound represented by formula B-P to the resolution reagent is 1:(0.8-1.5), preferably 1:1.
  • step (1) may further include:
  • the resolution solvent may be selected from methyl tert-butyl ether (MTBE), isopropyl ether, tetrahydrofuran (THF), acetonitrile, ethyl acetate (EA), isopropyl acetate (IPAC), isopropyl ether Alcohol and dimethyl ether (DME) or any combination thereof, preferably selected from isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether or any combination thereof.
  • MTBE methyl tert-butyl ether
  • THF tetrahydrofuran
  • EA acetonitrile
  • EA ethyl acetate
  • IPAC isopropyl acetate
  • DME dimethyl ether
  • the ratio of the volume of the resolution solvent to the mass of the mixture of diastereomers may be (1-30) mL:1g , Preferably (1-10) mL:1g, more preferably (3-6) mL:1g. Within the above ratio range, the compound represented by formula B-Q with higher yield and chiral purity can be obtained.
  • the resolution temperature is 1-100°C, preferably 50-75°C.
  • the recrystallization solvent can be selected from MTBE, acetonitrile, ethyl acetate, IPAC and DME or any combination thereof, preferably selected from isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether or any combination thereof.
  • the compounds indicated by BQ obtained by using the above-mentioned recrystallization solvents have good chiral purity, especially when at least one of isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether is used as the recrystallization solvent.
  • the chiral purity of the compounds shown can reach more than 99%.
  • step b the ratio of the volume of the recrystallization solvent to the mass of the crude solid product of the compound represented by formula B-Q is (1-30) mL:1g, preferably (1-10) mL:1g, more preferably 3mL:1g.
  • the separation in the method of the present invention can be achieved by a filtration operation.
  • step (2) may include: in the reaction solvent, in the presence of an acid, converting the compound represented by the formula B-Q into the Buwaracetam intermediate represented by the formula B-R.
  • the reaction solvent in step (2) can be selected from isopropanol, ethyl acetate, isopropyl acetate and water.
  • the reaction solvent described in step (2) may be water, or a combination of water and an organic solvent selected from isopropanol, ethyl acetate, and isopropyl acetate.
  • the above-mentioned organic solvents can be used alone or in combination in any ratio.
  • the inventors found that by reacting the compound represented by BQ with an acid, the compound represented by BQ can be decomposed into the salt of the compound represented by BR and the resolving agent; the compound represented by BR is insoluble in water but soluble in organic solvents, but resolved The salt of the agent is soluble in water. Based on this difference in solubility, the compound represented by BR can be separated by the above-mentioned reaction solvent.
  • reaction solvent in step (2) only water can be used as the reaction solvent; when the compound shown in BQ reacts with acid in water, the salt of the resolving agent produced will dissolve in water, and the compound shown in BR produced will change from Precipitated in water.
  • the reaction solvent contains both water and organic solvent
  • the compound shown by BQ reacts with the acid in the reaction solvent, and the salt of the resolving agent produced will enter the water phase; and the compound shown by the produced BR will enter the organic In phase.
  • the organic phase can be extracted, concentrated and dried to obtain the Buwaxitan intermediate shown in B-R.
  • step (2) is performed in the presence of dilute hydrochloric acid, trifluoroacetic acid, or a combination of acids.
  • step (2) is performed under the condition of pH 1-2.
  • An acid can be used to adjust the pH of the reaction mixture within the above range, which can ensure that the compound represented by B-Q is fully reacted, so that the yield of the compound represented by B-R is higher.
  • the present invention also provides a preparation method of Buwaxitan, which includes:
  • the Buwaxitan intermediate represented by formula B-R is ammoniated to Buwaxitan.
  • This preparation method can avoid the use of chiral chromatography columns, shorten the preparation time, simplify the operation, and reduce the preparation cost.
  • the amination process of the Buwaxitan intermediate shown in B-R is not particularly limited, and Buwaxitan can be prepared by a known amination reaction.
  • Buwaxitan can be prepared by a known amination reaction.
  • the intermediate of Buwaxitan shown in BR, HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ), ammonium chloride and diisopropylethylamine are reacted in tetrahydrofuran to obtain Buwaxitan; among them, the Buwaxitan intermediate shown by BR, HATU, ammonium chloride and diisopropylethylamine
  • the molar ratio of is 1:(1.5-2.5):(2-3):(2.5-3.5), preferably 1:2:2.5:3; the volume-to-mass ratio of tetrahydrofuran to the Buwaxitan intermediate shown in BR It
  • the Buwaxitan intermediate shown in B-R can also be obtained by mixing the Buwaxitan intermediate shown in B-R with dichloromethane, adding an activator, and introducing ammonia gas for reaction.
  • the activator can be selected from at least one of thionyl chloride, oxalyl chloride, phosphorus oxychloride, methanesulfonyl chloride, pivaloyl chloride and isobutyl chloroformate; the reaction temperature can be -20°C-30°C.
  • reagents and raw materials used in the present invention can be commercially available products or obtained by conventional methods in the art.
  • the raw materials used in the examples can be commercially available products or obtained by conventional methods in the art.
  • the preparation of (S)-2(4-propyl-1,5-dihydropyrrole-2-one)butyric acid can refer to the patent CN107513031;
  • (S)-2-3-propylpyrrolidine shown in formula BP- 1-Butyric acid can be prepared according to the palladium-carbon hydrogenation method, and can also be prepared by referring to the patent CN106748950A;
  • the preparation method of Buwaxitan (S)-2-3-propylpyrrolidin-1-ylbutanamide can refer to the patent CN106748950A;
  • the preparation method of 1S,2S-cyclohexanediamine can refer to patent US2009/30235;
  • the preparation method of 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine can refer to patent US4215114; (1S ,2S)-N1,N1,N2,N2-
  • RS represents the isomeric product of the RS configuration, that is, the compound represented by formula B-R
  • SS represents the isomeric product of the SS configuration, that is, the diastereomer of the compound represented by the formula B-R.
  • the abbreviation has the same meaning as in Example 1.
  • Example 1-(7) of patent CN10106748950A in a 250ml four-neck flask, add 80ml of tetrahydrofuran, the compound represented by formula BR (6.4g, 0.03mol), HATU (28.5g, 0.075mol), ammonium chloride (4.9 g, 0.09mol), diisopropylethylamine (11.7g, 0.09mol), stirred at room temperature for 2h, add 80ml of water and 160ml of ethyl acetate to the reaction solution and stir, separate the layers, and use 40ml of saturated sodium bicarbonate for the organic phase, saturated 40 ml of ammonium chloride solution and 40 ml of saturated saline were washed once, dried with anhydrous sodium sulfate, and concentrated to obtain 7 g of Buwaxitan as a white solid with a purity of 99.5% determined by HPLC and a chiral purity of 99.85%.
  • Example 15 Using 1S,2S-N,N-dimethyl-1,2-cyclohexanediamine as a resolving reagent to resolve the compound represented by formula B-P

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

公开了一种式B-R所示布瓦西坦中间体的制备方法，包括使式B-P所示的化合物与拆分试剂反应制备得式B-Q所示化合物；和使式B-Q所示化合物转化为式B-R所示的布瓦西坦中间体，其中所述拆分试剂为(1S,2S)-(+)-1,2-环己二胺类化合物；还提供一种布瓦西坦的制备方法。上述方法能够便捷且有效地拆分(S)-2-3-丙基吡咯烷-1-基丁酸的两种非对映异构体的混合物，避免使用手性色谱柱，大大缩短工艺时间，简化操作及降低工艺成本，有利于工业化生产和环保。

Description

布瓦西坦及其中间体的制备方法 技术领域
本发明涉及布瓦西坦及其中间体的制备方法，属于医药技术领域。
背景技术
布瓦西坦(Brivaracetam)，化学名称为(S)-2-(R)-3-丙基吡咯烷-1-基丁酰胺，由比利时优时比制药公司(UCB Pharma)研制，是抗癫药左乙拉西坦(levetiracetam)吡咯烷烃的4位碳原子连接正丙基的类似物。布瓦西坦也是大脑突触囊泡蛋白2a(SV2A)选择性和高亲和力的配体，SV2A是抑制癫痫部分性发作的重要位点。欧洲医药管理局(EMA)和美国食品药品管理局(FDA)分别于2016年1月14日和2016年2月18日批准布瓦西坦用于治疗16岁及以上伴随或不伴随继发全身性发作的部分性发作型癫痫患者的辅助治疗药，商品名为
Figure PCTCN2020088275-appb-000001
该药是左乙拉西坦的衍生物，属于第3代抗癫痫药物。
目前，包括原研药在内，现有的布瓦西坦的制备工艺几乎都不可避免的要用手性色谱柱分离出其非对应异构体(S)-2-(S)-3-丙基吡咯烷-1-基丁酰胺。如原研药专利WO 2005028435就提到了在25±2℃温度下，采用手性固相、正己烷/乙醇(45/55，V/V)为洗脱剂，以色谱法分离得到的两个非对映异构体。WO 2007065634使用了另外一条合成路线，使用了价格昂贵的金属催化剂RuCl 3，该制备方法同样不可避免的通过柱色谱分离得到布瓦西坦(26％，e.e.＝94％)和其非对映异构体。布瓦西坦和其非对映异构体的结构如下图所示：
Figure PCTCN2020088275-appb-000002
专利文献CN106748950A报道了一种制备布瓦西坦中间体的方法，反应路线如下：
Figure PCTCN2020088275-appb-000003
其采用R-苯乙胺/异丙醇体系拆分B-IV所示的化合物混合物，得到B-VI所示的布瓦西坦中间体。采用该中间体制备布瓦西坦无需使用手性色谱柱进行拆分，从而可以降低生产成本。但是本申请的发明人重复该文献中的实施例后发现，仅能够以非常低的收率获得B-VI所示的布瓦西坦中间体，且其中SS异构体的含量无明显降低，因此该方法无明显的拆分纯化效果，不具有工业上的实用性。
鉴于现有的制备方法生产成本高，工业可行性差，因此迫切的需要提供一种更简单且能重复的工业化生产的制备高纯度布瓦西坦的方法。
发明内容
本发明的目的在于提供一种由式B-R所示的布瓦西坦中间体的制备方法，以及由该中间体制备高纯度布瓦西坦的方法。
一方面，本发明提供一种由以下式B-R所示的布瓦西坦中间体的制备方法，包括：
(1)使式B-P所示的化合物与拆分试剂反应制备得式B-Q所示化合物；和
(2)使式B-Q所示化合物转化为式B-R所示的布瓦西坦中间体；
Figure PCTCN2020088275-appb-000004
其中所述拆分试剂为具有下式(I)的(1S,2S)-(+)-1,2-环己二胺类化合物，
Figure PCTCN2020088275-appb-000005
式(I)中R 1、R 2和R 3彼此独立地为H、CH 3或Ts，且R 1、R 2和R 3不同时为Ts。
本发明中，式B-P所示的化合物为(S)-2-3-丙基吡咯烷-1-基丁酸的两种非对映异构体的混合物。Ts为对甲苯磺酰基。
本申请的发明人通过对现有技术进行深入的研究发现，现有技术中已报道过的一些拆分试剂，例如R-苯乙胺等并不能实现对B-P所示化合物的拆分；但在进一步地探索过程中，发明人意外地发现，如上所述的特定拆分试剂却可以有效地从式B-P所示化合物拆分出式B-R所示的布瓦西坦中间体。
在一些实施方式中，拆分试剂可以选自1S,2S-环己二胺、1S,2S-N,N-二甲基-1,2-环己二胺、(1S,2S)-N1,N1,N2,N2-四甲基环己烷-1,2-二胺和N-((1S,2S)-2-(二甲氨基)环己基)-4-甲苯磺酰胺或其任意组合。
发明人进一步发现，随着拆分试剂和式B-P所示化合物的摩尔比增大，B-Q所示化合物的收率先增大后减小；手性纯度增加到一定程度后基本不再变化。综合考虑收率、手性纯度及成本因素，应当控制式B-P所示化合物和拆分试剂的摩尔比。在一些实施方式中，式B-P所示化合物与拆分试剂的摩尔比为1:(0.8-1.5)，优选为1:1。
上述方法中，步骤(1)可以进一步包括：
a.将式B-P所示的化合物与拆分试剂溶于拆分溶剂中，在拆分温度下使固体溶解以获得澄清溶液，使溶液降温析晶，分离出晶体得到式B-Q所示化合物的固体粗品；
b.将上述固体粗品在重结晶溶剂中重结晶，分离出晶体得式B-Q所示化合物。
在一些实施方式中，拆分溶剂可以选自甲基叔丁基醚(MTBE)、异丙醚、四氢呋喃(THF)、乙腈、乙酸乙酯(EA)、乙酸异丙酯(IPAC)、异丙醇和二甲醚(DME)或其任意组合，优选选自乙酸异丙酯、乙腈、乙酸乙酯和二甲醚或其任意组合。
本申请的发明人进一步发现，随着拆分溶剂与B-P所示化合物的体积质量比增大，产物B-Q所示化合物的收率逐渐降低，但是手性纯度提高。综合考虑B-Q所示化合物的收率及手性纯度，在一些实施方式中，所述拆分溶剂的体积与非对映异构体的混合物的质量之比可以为(1-30)mL:1g，优选为(1-10)mL:1g，更优选为(3-6)mL:1g。在上述比例范围内，可以获得较高收率及手性纯度的式B-Q所示化合物。
在一些实施方式中，拆分温度为1-100℃，优选50-75℃。
步骤b中，重结晶溶剂可以选自MTBE、乙腈、乙酸乙酯、IPAC和DME或其任意组合，优选选自乙酸异丙酯、乙腈、乙酸乙酯和二甲醚或其任意组合。使用上述重结晶溶剂得到的B-Q所示化合物，均有较好的手性纯度，尤其是乙酸异丙酯、乙腈、乙酸乙酯和二甲醚中的至少一种作为重结晶溶剂时，B-Q所示化合物的手性纯度均能达到99％以上。
步骤b中，重结晶溶剂的体积与式B-Q所示化合物的固体粗品的质量之比为(1-30)mL:1g，优选为(1-10)mL:1g，更优选为3mL:1g。
在一些实施方式中，本发明方法中的分离可以通过过滤操作来实现。
上述方法中，步骤(2)可以包括：在反应溶剂中，在酸的存在下，将式B-Q所示化合物转化为式B-R所示的布瓦西坦中间体。
步骤(2)中所述的反应溶剂可以选自异丙醇、乙酸乙酯、乙酸异丙酯和水。特别地，步骤(2)中所述的反应溶剂可以为水，或者为水和选自异丙醇、乙酸 乙酯、乙酸异丙酯的有机溶剂的组合。上述有机溶剂可以单独使用，也可以按任意比例组合使用。
本发明人发现，通过将B-Q所示化合物与酸反应，可以使B-Q所示化合物分解为B-R所示化合物和拆分剂的盐；B-R所示化合物不溶于水而溶于有机溶剂，但拆分剂的盐溶于水中，基于这种溶解度上的差异，通过上述反应溶剂可以将B-R所示化合物分离出来。
关于步骤(2)的反应溶剂，可以只用水作为反应溶剂；当B-Q所示化合物与酸在水中进行反应时，生成的拆分剂的盐会溶于水中，而生成的B-R所示化合物会从水中析出。
在反应溶剂中既含有水又含有机溶剂时，B-Q所示化合物与酸在反应溶剂中进行反应，生成的拆分剂的盐会进入水相中；而生成的B-R所示化合物会进入到有机相中。当有机相与水相分层后，可以提取有机相，浓缩、干燥后即得到B-R所示布瓦西坦中间体。
在一些实施方式中，步骤(2)在稀盐酸、三氟乙酸或其组合的酸的存在下进行。
在一些实施方式中，步骤(2)在pH1-2的条件下进行。可以使用酸将反应混合物的pH值调节在上述范围，这可以保证B-Q所示化合物充分反应，从而使B-R所示化合物的收率更高。
另一方面，本发明还提供一种布瓦西坦的制备方法，其包括：
根据上述方法制备式B-R所示的布瓦西坦中间体；和
使式B-R所示的布瓦西坦中间体氨化为布瓦西坦。
此制备方法可以避免使用手性色谱柱，缩短了制备时间，简化了操作，及降低了制备成本。
对于B-R所示的布瓦西坦中间体的氨化过程没有特别限定，可以采用已知的氨化反应制备布瓦西坦。例如：可以通过将B-R所示的布瓦西坦中间体、HATU(2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、氯化铵和二异丙基乙基胺于四氢呋喃中反应，得到布瓦西坦；其中，B-R所示的布瓦西坦中间体、HATU、氯化铵和二异丙基乙基胺的摩尔比为 1:(1.5-2.5):(2-3):(2.5-3.5)，优选为1:2:2.5:3；四氢呋喃与B-R所示的布瓦西坦中间体的体积质量比为(10-50)mL:1g。
还可以通过将B-R所示的布瓦西坦中间体与二氯甲烷混合，加入活化剂，通入氨气反应，得到布瓦西坦。其中，活化剂可以选自二氯亚砜、草酰氯、三氯氧磷、甲磺酰氯、特戊酰氯和氯甲酸异丁酯中的至少一种；反应温度可以为-20℃-30℃。
在不违背本领域常识的基础上，上述各实施方式和优选条件可任意组合。本发明所用试剂和原料均可为市售产品或由本领域常规方法得到。
与现有技术相比，本发明方法的优点体现在：
(1)能够避免在合成过程中使用手性色谱柱分离非对映异构体，大大缩短工艺时间，简化操作及降低工艺成本，有利于工业化生产；
(2)与现有的R-苯乙胺拆分方法对比具有明显更好的拆分和纯化效果；
(3)所使用的拆分试剂价格便宜，回收率高，可重复使用。
具体实施方式
下面通过实施例进一步说明本发明，它们仅用于说明目的，不在任何方面限制本发明的范围。
实施例中使用的原料可为市售产品或由本领域常规方法得到。例如(S)-2(4-丙基-1,5-二氢吡咯-2-酮)丁酸的制备可参考专利CN107513031；式B-P所示(S)-2-3-丙基吡咯烷-1-基丁酸可按钯碳加氢方法制备得到，也可参考专利CN106748950A制备；布瓦西坦(S)-2-3-丙基吡咯烷-1-基丁酰胺的制备方法可参考专利CN106748950A；1S,2S-环己二胺的制备方法可参考专利US2009/30235；1S,2S-N,N-二甲基-1,2-环己二胺的制备方法可参考专利US4215114；(1S,2S)-N1,N1,N2,N2-四甲基环己烷-1,2-二胺的制备方法可参考文献Kizirian,Jean-Claude；Caille,Jean-Claude；Alexakis,Alexandre[TetrahedronLetters,2003,vol.44,#49,p.8893-8895]；N-((1S,2S)-2-(二甲氨基)环己基)-4-甲苯磺酰胺的制备方法可参考文献Chai,Zhuo；Yang,Pei-Jun[Angew.Chem.,2017,vol.129,#2,p.665-669,5]。
实施例1：式B-P所示化合物的制备
将150g的(S)-2(4-丙基-1,5-二氢吡咯-2-酮)丁酸(0.71mol，1eq)，加入到2L氢气高压釜中，加入1.5L甲醇，加入1.5g的Pd(OH) 2/C(1％)，20MPa下反应20h，将反应混合物过滤，浓缩滤液至干，得式B-P所示化合物的固体140g。
经计算式B-P所示化合物中两种异构体的比例为RS构型：SS构型＝85:15，手性纯度85％。其中RS表示RS构型的异构产物，即式B-R所示化合物；SS表示SS构型的异构产物，即式B-R所示化合物的非对映异构体。以下实施例中该缩写具有与实施例1中相同的含义。
实施例2：式B-P所示化合物的制备
150g的(S)-2(4-丙基-1,5-二氢吡咯-2-酮)丁酸(0.71mol，1eq)，加入到2L氢气高压釜中，加入1.5L异丙醇，加入45g Pd(OH) 2/C(30％)，20MPa下反应20h，将反应混合物过滤，浓缩滤液至干，得式B-P所示化合物固体145g。
经计算式B-P所示化合物中两种异构体的比例为RS构型：SS构型＝54:45，手性纯度54％。
实施例3：式B-Q所示化合物的制备
500ml三口瓶中加入180ml乙酸乙酯、6g实施例1制备的式B-P所示化合物(0.028mol，1eq，含SS 15％)和3.2g 1S,2S-N,N-二甲基-1,2-环己二胺(0.8eq，0.0224mol)，1℃左右搅拌1h后抽滤，得10g式B-Q所示化合物的固体粗品(下称“湿品”)，再将湿品直接加入10ml的乙酸乙酯中，升温使固体溶解以获得澄清溶液，经1.5h缓慢降温至20℃析晶，抽滤，得式B-Q所示化合物8.0g，收率：94.6％，纯度：99.8％，非对映异构体0.2％。
实施例4：式B-Q所示化合物的制备
500ml三口瓶中加入360ml乙腈、60g实施例1制备的式B-P所示化合物(0.28mol，1eq，含SS 15％)和47.7g(1S,2S)-N1,N1,N2,N2-四甲基环己烷-1,2-二胺(1eq，0.28mol)，50℃左右搅拌1h后抽滤，得108g湿品，再将湿品直接加入300ml的异丙醇中，升温溶解，经1.5h缓慢降温至20℃，抽滤，得式B-Q所示化合物89.6g，收率：98.1％，纯度：99.8％，含SS 0.2％。
实施例5：式B-Q所示化合物的制备
500ml三口瓶中加入60ml醋酸异丙酯、60g实施例1制备的式B-P所示化合物(0.28mol，1eq，含SS 15％)和47.88g 1S,2S-环己二胺(1.5eq，0.42mol)，升温至100℃左右，溶清，自然降温至20℃±5℃，搅拌1h后抽滤，得100g湿品，再将湿品直接加入180ml的乙腈，升温至72℃下溶解，经1.5h缓慢降温至20℃，抽滤，得式B-Q所示化合物73.3g，收率：94％，纯度：99.8％，含SS 0.2％。
实施例6：式B-Q所示化合物的制备
500ml三口瓶中加入180ml乙二醇二甲醚、60g实施例1制备的式B-P所示化合物(0.28mol，1eq，含SS 15％)和83g N-((1S,2S)-2-(二甲氨基)环己基)-4-甲苯磺酰胺(1eq，0.28mol)，升温至75℃左右，溶清，自然降温，搅拌1h后抽滤，得145g湿品，再将湿品直接加入700ml的IPAC，升温溶解，经1.5h缓慢降温，抽滤，得式B-Q所示化合物118g，收率：97.3％，纯度：99.8％，含SS 0.2％。
实施例7：式B-Q所示化合物的制备
500ml三口瓶中加入300ml甲叔醚、60g实施例2制备的式B-P所示化合物(0.28mol，1eq，含SS 45％)和39.8g 1S,2S-N,N-二甲基-1,2-环己二胺(1eq，0.28mol)，50℃左右搅拌1h后抽滤，得65g湿品，再将湿品直接加入60ml的乙酸乙酯中，升温溶解，经1.5h缓慢降温至20℃，抽滤，得式B-Q所示化合物52g，收率：95％，纯度：99.5％，含SS 0.5％。
实施例8：式B-Q所示化合物的制备
100ml三口瓶中加入60ml异丙醚、6g实施例2制备的式B-P所示化合物(0.028mol，1eq，含SS 45％)和3.98g 1S,2S-N,N-二甲基-1,2-环己二胺(1eq，0.028mol)，40℃左右搅拌1h后抽滤，得6.5g湿品，再将湿品直接加入60ml的甲叔醚中，升温溶解，降温，抽滤，得式B-Q所示化合物4.9g，收率：90％，纯度：99.5％，含SS 0.5％。
实施例9：式B-Q所示化合物的制备
100ml三口瓶中加入18ml四氢呋喃、6g实施例2制备的式B-P所示化 合物(0.028mol，1eq，含SS 45％)和3.98g 1S,2S-N,N-二甲基-1,2-环己二胺(1eq，0.028mol)，75℃左右搅拌1h后抽滤，得5g湿品，再将湿品直接加入120ml的甲叔醚中，升温溶解，降温，抽滤，得式B-Q所示化合物4.5g，收率：82％，纯度：99.5％，含SS 0.5％。
实施例10：式B-Q所示化合物的制备
50ml三口瓶中加入180ml醋酸异丙酯(3v)，6g实施例2制备的式B-P所示化合物(0.028mol，1eq，含SS 45％)，3.18g 1S,2S-环己二胺(1eq，0.028mol)，升温至72℃左右，溶清，自然降温至20℃±5℃，搅拌1h后抽滤，得7g湿品，再将湿品直接加入18ml醋酸异丙酯，升温溶解，缓慢降温，抽滤，得式B-Q所示化合物4.8g，收率：95％，纯度：99.8％，含SS 0.2％。
实施例11：式B-Q所示化合物的制备
50ml三口瓶中加入240ml醋酸异丙酯，6g实施例2制备的式B-P所示化合物(0.028mol，1eq，含SS 45％)，3.98g 1S,2S-N,N-二甲基-1,2-环己二胺(1eq，0.028mol)，升温至72℃左右，溶清，自然降温至20℃±5℃，搅拌1h后抽滤，得7.5g湿品，再将湿品直接加入18ml乙酸乙酯，升温溶解，降温，抽滤，得式B-Q所示化合物5.25g，收率：96％，纯度：99.8％，含SS 0.2％。
实施例12：式B-R所示化合物的制备
在500ml三口瓶中加入上述任意实施例中制备的式B-Q所示化合物30g，加入120ml水，240ml乙酸乙酯，用6N盐酸调至pH 1-2，搅拌0.5h后分层，水相用30mlEA萃取后，合并有机相，减压浓缩，得到式B-R所示化合物的白色固体19.5g，收率100％，纯度99.8％。
实施例13：式B-R所示化合物的制备
在500ml三口瓶中加入上述任意实施例中制备的式B-Q所示化合物30g，加入120ml水，用6N三氟乙酸调至pH 1-2，搅拌0.5h后过滤，得到式B-R所示化合物的白色固体19.5g，收率100％，纯度99.8％。
实施例14：布瓦西坦的制备
参考专利CN10106748950A实施例1-(7)，在250ml的四口瓶中，加入四氢呋喃80ml、式B-R所示化合物(6.4g，0.03mol)，HATU(28.5g，0.075mol)、 氯化铵(4.9g，0.09mol)、二异丙基乙胺(11.7g，0.09mol)，室温搅拌2h，向反应液加入水80ml和乙酸乙酯160ml搅拌，分层，有机相用饱和碳酸氢钠40ml、饱和氯化铵溶液40ml、饱和食盐水40ml各洗涤一次，无水硫酸钠干燥，浓缩，得布瓦西坦白色固体7g，HPLC测定的纯度99.5％，手性纯度99.85％。
实施例15：采用1S,2S-N,N-二甲基-1,2-环己二胺作为拆分试剂来拆分式B-P所示化合物
50ml三口瓶中加入18ml异丙醇，9g实施例2制备的式B-P所示化合物(0.042mol，1eq，含异构体45％)，升温至55℃左右，编号为a；在另一50ml三口瓶中加入异丙醇18ml，1S,2S-N,N-二甲基-1,2-环己二胺5g(0.83eq，0.035mol)，搅拌溶解，编号为b；再将a所得溶液滴加加入b中，搅拌后升温至70℃，随后冷却析晶，抽滤，析出7g固体，收率86％，纯度：99.5％，非对映异构体0.5％。
对比实施例：采用R-(+)-a-苯乙胺作为拆分试剂来拆分式B-P所示化合物
50ml三口瓶中加入18ml异丙醇，9g式B-P所示化合物(0.042mol，1eq，含异构体45％)，升温至55℃左右，编号为a；在另一50ml三口瓶中加入异丙醇18ml，R-(+)-a-苯乙胺4.2g(0.83eq，0.035mol)，搅拌溶解，编号为b；再将a所得溶液滴加加入b中，搅拌后冷却析晶，无固体析出，浓缩部分异丙醇，析出1g固体，收率13％，RS：SS异构体比例为55：45，无明显的拆分纯化效果。

Claims (12)

  1. 一种由以下式B-R所示的布瓦西坦中间体的制备方法，其包括：
    (1)使式B-P所示的化合物与拆分试剂反应制备得式B-Q所示化合物；和
    (2)使式B-Q所示化合物转化为式B-R所示的布瓦西坦中间体；
    Figure PCTCN2020088275-appb-100001
    其中所述拆分试剂为具有下式(I)的(1S,2S)-(+)-1,2-环己二胺类化合物，
    Figure PCTCN2020088275-appb-100002
    式(I)中R 1、R 2和R 3彼此独立地为H、CH 3或Ts，且R 1、R 2和R 3不同时为Ts。
  2. 根据权利要求1所述的制备方法，其中所述拆分试剂选自1S,2S-环己二胺、1S,2S-N,N-二甲基-1,2-环己二胺、(1S,2S)-N1,N1,N2,N2-四甲基环己烷-1,2-二胺和N-((1S,2S)-2-(二甲氨基)环己基)-4-甲苯磺酰胺或其任意组合。
  3. 根据权利要求1或2所述的制备方法，其中所述式B-P所示的化合物与拆分试剂的摩尔比为1:(0.8～1.5)，优选为1:1。
  4. 根据权利要求1至3中任一项所述的制备方法，其中步骤(1)包括：
    a.将式B-P所示的化合物与拆分试剂溶于拆分溶剂中，在拆分温度下使固体溶解以获得澄清溶液，使溶液降温析晶，分离出晶体得到式B-Q所示化合 物的固体粗品；
    b.将所述固体粗品在重结晶溶剂中重结晶，分离出晶体得式B-Q所示化合物。
  5. 根据权利要求4所述的制备方法，其中所述拆分溶剂选自甲基叔丁基醚(MTBE)、异丙醚、四氢呋喃(THF)、乙腈、乙酸乙酯(EA)、乙酸异丙酯(IPAC)、异丙醇和二甲醚(DME)或其任意组合。
  6. 根据权利要求4或5所述的制备方法，其中所述拆分溶剂的体积与式B-P所示化合物的质量之比为(1-30)mL:1g，优选为(1-10)mL:1g，更优选体积质量比为(3-6)mL:1g。
  7. 根据权利要求4至6中任一项所述的制备方法，其中所述重结晶溶剂选自甲基叔丁基醚、乙腈、乙酸乙酯、乙酸异丙酯和二甲醚或其任意组合，优选选自乙酸异丙酯、乙腈、乙酸乙酯和二甲醚或其任意组合。
  8. 根据权利要求4至7中任一项所述的制备方法，其中所述重结晶溶剂的体积与式B-Q所示化合物的质量之比为(1-30)mL:1g，优选为(1-10)mL:1g，更优选体积质量比为3mL:1g。
  9. 根据权利要求1至8中任一项所述的制备方法，其中步骤(2)包括：在反应溶剂中，在酸的存在下，将式B-Q所示化合物转化为式B-R所示的布瓦西坦中间体。
  10. 根据权利要求9所述的制备方法，步骤(2)中所述的酸为稀盐酸、三氟乙酸或其组合。
  11. 根据权利要求9或10所述的制备方法，其特征在于，步骤(2)中所述的反应溶剂选自异丙醇、乙酸乙酯、乙酸异丙酯和水。
  12. 一种布瓦西坦的制备方法，其包括：
    根据权利要求1至11中任一项所述的方法制备式B-R所示的布瓦西坦中间体；和
    使式B-R所示的布瓦西坦中间体氨化为布瓦西坦。
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