WO2019242192A1 - 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法 - Google Patents

一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法 Download PDF

Info

Publication number
WO2019242192A1
WO2019242192A1 PCT/CN2018/112662 CN2018112662W WO2019242192A1 WO 2019242192 A1 WO2019242192 A1 WO 2019242192A1 CN 2018112662 W CN2018112662 W CN 2018112662W WO 2019242192 A1 WO2019242192 A1 WO 2019242192A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
solvent
compound represented
amino
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/112662
Other languages
English (en)
French (fr)
Inventor
杨汉荣
祁彥涛
李涛
王博
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Puyi Chemical Technology Co Ltd
Original Assignee
Shanghai Puyi Chemical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Puyi Chemical Technology Co Ltd filed Critical Shanghai Puyi Chemical Technology Co Ltd
Priority to US16/973,022 priority Critical patent/US11518741B2/en
Priority to EP18923290.3A priority patent/EP3812377A4/en
Priority to JP2020571459A priority patent/JP7097467B2/ja
Priority to CN201880090614.XA priority patent/CN112020498B/zh
Publication of WO2019242192A1 publication Critical patent/WO2019242192A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/20—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • 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
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with 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
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • 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

  • Brivaracetam is a new generation of antiepileptic drugs developed by UCB. In February 2016, the US FDA approved the market of bovaracetam. Bovaracetam can be used as an additional drug for other drugs to treat partial epilepsy.
  • CN107663185A reports the reaction of (R) -4-propyldihydrofuran-2 (3H) -one with L-aminobutyramide to give bovaracetam.
  • the synthesis route of chiral (R) -4-propyldihydrofuran-2 (3H) -one is very long, involving the reaction of metal reagents, and it also requires multiple steps to obtain the target with L-aminobutyramide. product. This makes the entire synthesis scheme long and cumbersome.
  • the present invention solves the above technical problems through the following technical solutions.
  • X may be a conventional organic acid in the art, preferably oxalic acid or maleic acid.
  • the solvent is preferably one or more of water, an alcohol solvent, and sulfoxide, more preferably a C 1-4 alcohol, and still more preferably one or more of methanol, ethanol, and isopropanol. Multiple.
  • the molar concentration of the compound represented by formula (II) -RX or (II) -R in the solvent may be a conventional molar concentration of the above-mentioned ring-forming reaction in the art, and preferably 0.2 to 1.0 mol / L is more preferably 0.4 to 0.8 mol / L, such as 0.48 mol / L and 0.72 mol / L.
  • the temperature of the ring-forming reaction may be a conventional temperature of the above-mentioned ring-forming reaction in the art, preferably 25 to 100 ° C, more preferably 25 to 80 ° C, and still more preferably 65 to 80 ° C.
  • the progress of the ring-forming reaction can be monitored by conventional detection methods (such as HPLC, TLC) in this type of reaction in the field, and generally the reaction is when the compound (II) -RX or (II) -R disappears
  • the reaction time is preferably 4 to 10 hours, such as 6 hours.
  • the extraction solvent may be a conventional extraction solvent for reactions of this type in the art, and preferably dichloromethane.
  • the drying conditions and operations may be conventional conditions and operations for reactions of this type in the art. .
  • the recrystallization conditions and operations may be conventional conditions and operations of such reactions in the art, and the recrystallization solvent may be conventional solvents of such reactions in the art, preferably ethyl acetate and n-heptane, or ethyl acetate.
  • the volume ratio of the ethyl acetate and (n-heptane or petroleum ether) is preferably 1: 5; the time for the recrystallization may be a conventional time for such reactions in the art, such as 1 h.
  • the conditions and operations of the suction filtration may be conventional conditions and operations of such reactions in the art.
  • the washing conditions and operations may be the conventional conditions and operations of such reactions in the art, and the washing solvent is preferably n-heptane or petroleum ether.
  • the drying conditions and operations may be conventional conditions and operations of such reactions in the art, such as drying.
  • the method for preparing bovaracetam as shown in formula (I) may further include the following steps: salting and crystallizing the compound represented by formula (II) with X to obtain the compound represented by formula (II) -RX Shown compounds; wherein X is an organic acid;
  • the mass ratio of the solvent in the crystallization step to the compound represented by the formula (II) is preferably (5-15): 1, more preferably (7-11): 1, such as 9: 1, 11: 1.
  • the crystallization time of the crystallization step can refer to the time required for crystallization in the art, preferably 0.5 to 5 hours, and more preferably 1 to 2 hours.
  • the compound represented by formula (II) is added to a mixed solvent of alcohols and water of C 1-4 , and then organic acids, ethers or alkane solvents are sequentially added to crystallize.
  • the compound represented by formula (II) is added to a mixed solvent of alcohols and water of C 1-4 , and then organic acids, ethers or alkane solvents are sequentially added to crystallize.
  • the product obtained by crystallization is added to a mixed solvent of alcohol and water of C 1-4 , and then ether or alkane solvents are added to crystallize.
  • a post-processing operation may be further included.
  • the conditions and operations of the post-treatment may be conventional conditions and operations of this type of reaction in the art, and preferably may include the following steps: suction filtration, washing, and drying.
  • the conditions and operations of the suction filtration may be conventional conditions and operations of such reactions in the art.
  • the washing conditions and operations may be the conventional conditions and operations of such reactions in the art.
  • the washing solvent is preferably an ether solvent and / or an alkane solvent, and more preferably isopropyl ether, petroleum ether, n-hexane or n-heptane.
  • the drying conditions and operations may be conventional conditions and operations of such reactions in the art, the drying temperature may be conventional temperatures of such reactions in the art, such as 65 ° C., and the drying time may be the same as in the art.
  • the general reaction time is like 12h.
  • the method for preparing bovaracetam as shown in formula (I) may further include the following steps: in a solvent, under the action of a catalyst, the compound represented by formula (III) and hydrogen are subjected to the following steps: Hydrogenation reaction to obtain a compound represented by formula (II);
  • the pressure of the hydrogen gas is preferably 1 to 30 bar, and more preferably 5 to 20 bar.
  • the mass ratio of the catalyst to the compound represented by formula (III) may be a conventional mass ratio of the above-mentioned hydrogenation reduction reaction in the art, preferably 0.05: 1 to 0.15: 1, and more preferably 0.1: 1.
  • the temperature of the reaction may be a conventional temperature of the above-mentioned hydrogenation reduction reaction in the art, preferably 10 to 50 ° C, more preferably 20 to 30 ° C, such as 25 ° C.
  • the hydrogenation reduction reaction may further include a post-treatment operation.
  • the conditions and operations of the post-treatment may be conventional conditions and operations of this type of reaction in the art, and preferably include the following steps: filtration, concentration.
  • the conditions and operations of the filtration may be the conditions and operations conventional for such reactions in the art.
  • the conditions and operations of concentration can be the conditions and operations conventional for such reactions in the art, and preferably concentrated under reduced pressure.
  • the method for preparing bovaracetam as shown in formula (I) may further include the following steps: in a solvent, the compound represented by formula (IV) is reacted with L-aminobutyramide as follows to obtain the formula ( III) the compound shown,
  • the solvent may be a conventional solvent in the art, preferably an alcohol solvent; the alcohol solvent is preferably a C 1-4 alcohol, such as isopropanol.
  • the reaction temperature may be a temperature conventional in the art, for example, 30 to 40 ° C.
  • the progress of the reaction can be monitored by conventional detection methods (such as HPLC, TLC) for the above reactions in the art.
  • the end point of the reaction is when the compound IV disappears, and the reaction time is, for example, 1 to 4 hours, and then, for example, 2 to 4 hours.
  • the L-aminobutyramide is preferably L-aminobutyramide hydrochloride.
  • the L-aminobutyramide hydrochloride is preferably freed into L-aminobutyramide under the condition of ammonia gas, and then reacted with the compound represented by formula (IV).
  • the reaction time is determined according to the pH value of the system, and the reaction is preferably performed until the pH is 9-10.
  • the method for adding the compound represented by the formula (IV) is not particularly limited, and it does not affect the reaction, and can be added all at once or in batches.
  • the conditions and operations of the post-treatment may be conventional conditions and operations of such reactions in the art, and preferably include the following steps: filtration, cooling and crystallization, filtration, and washing.
  • the conditions and operations of the filtration may be the conditions and operations conventional in the reaction in the art, and suction filtration is preferred.
  • the crystallization conditions and operations may be the conditions and operations conventional for this reaction in the art, and the crystallization temperature is preferably 0 to 5 ° C.
  • the washing conditions and operations may be the conditions and operations conventional for this reaction in the art, and the washing solvent may be the conventional washing solvents for this reaction in the art, preferably ethyl acetate.
  • the present invention provides a method for preparing a compound represented by formula (II) -RX, which includes the following steps: the compound represented by formula (II) is salted with X, and crystallized; the X is organic acid;
  • the invention provides a method for preparing a compound represented by formula (II) -S-X, which includes the following steps:
  • X is an organic acid, preferably oxalic acid or maleic acid.
  • step (1) the conditions and operations of the salt formation and crystallization are the same as those of the aforementioned reaction.
  • step (2) the molar ratio of X to the compound represented by formula (II) is preferably 1: (1 to 4), such as 1: 2.
  • the volume-to-mass ratio of the solvent to the compound represented by formula (II) is preferably (1 to 4) mL / g, for example, 2 mL / g.
  • step (2) it may further include a post-processing operation.
  • the conditions and operations of the post-treatment may be conventional conditions and operations of such reactions in the art, and preferably include the following steps: filtration, washing, and drying.
  • the conditions and operations of the filtration may be the conditions and operations conventional in the reaction in the art, and suction filtration is preferred.
  • the conditions and operations for washing may be the conditions and operations conventional for this reaction in the art, and the solvent for the washing is preferably an ether solvent, such as petroleum ether and / or isopropyl ether.
  • the drying conditions and operations may be conventional conditions and operations of the reaction in the art, the drying temperature may be conventional temperature in the art, such as 50 ° C, and the drying time may be conventional time in the art, such as 12h.
  • the present invention also provides a method for preparing a compound represented by formula (II), which includes the following steps: in a solvent, under the action of a catalyst, the compound represented by formula (III) and hydrogen are subjected to the following steps: Hydrogenation reaction to obtain a compound represented by formula (II);
  • the conditions and operations of the hydrogenation reduction reaction are the same as the conditions and operations of the aforementioned hydrogenation reduction reaction.
  • the temperature is not particularly emphasized, it usually means that the reaction is performed at room temperature, and the room temperature in the present invention means 20 to 30 ° C.
  • reagents and raw materials used in the present invention are all commercially available.
  • the invention uses n-valeraldehyde and glyoxylic acid as raw materials, which is cheap and easy to obtain, and the generated products need not be separated by column chromatography, and no metal reagent is required to participate in the reaction process.
  • the method of bovaracetam proposed by the invention has short steps, cheap raw materials, simple and efficient, does not require column chromatography to separate isomers or asymmetric synthesis, reduces production costs, and is suitable for industrialized large-scale production.
  • the crude product was dissolved in 6.0 mL of ethyl acetate, 30 mL of n-heptane was added dropwise, and the mixture was stirred and crystallized at room temperature for 1 hour. The solution was filtered with suction, n-heptane was rinsed, and dried to obtain 5.5 g of bovaracetam (I).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Analytical Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

本发明涉及一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法。本发明布瓦西坦的制备方法步骤短，原料便宜，简洁高效，不需要柱层析分离异构体或者不对称合成，适合工业化大规模生产。本发明公开了一种如式（II）所示化合物，可以用于布瓦西坦的合成。

Description

一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法
本申请要求申请日为2018年6月20日的中国专利申请CN201810634229.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法。
背景技术
布瓦西坦(Brivaracetam)是UCB公司开发的新一代抗癫痫药物，2016年2月，美国FDA批准布瓦西坦上市，布瓦西坦可以作为其他药物的附加药物治疗部分发作性癫痫。
布瓦西坦(S)-2-((R)-2-氧代-4-丙基吡咯啉-1-基)丁酰胺的结构如下所示。由于布瓦西坦分子中有两个手性中心，对应四个不同的异构体，这给布瓦西坦的合成带来了一定的难度。目前合成布瓦西坦的方法主要有以下报道：
Figure PCTCN2018112662-appb-000001
最早的方法是UCB开发的，以正戊醛为原料，先与乙醛酸环合，再与L-氨基丁酰胺反应，得到的产物氢化，生成一对非对映异构体，再通过柱层析分离纯化得到产物布瓦西坦，如专利CN1208319C、CN1882535B所述。该方法步骤虽短，但最后一步只能通过柱层析分离，成本高而且不适合大量生产，限制了其应用。
Figure PCTCN2018112662-appb-000002
CN107663185A报道了以(R)-4-丙基二氢呋喃-2(3H)-酮为中间体与L-氨基丁酰胺反 应得到布瓦西坦。但是手性的(R)-4-丙基二氢呋喃-2(3H)-酮的合成路线很长，涉及到金属试剂反应，而且它与L-氨基丁酰胺也需要多步转化才能得到目标产物。这使整个合成方案路线长，操作繁琐。
Figure PCTCN2018112662-appb-000003
CN106748950A报道了以差向异构体混合物酸为中间体，通过与R-苯乙胺的成盐纯化的方法得到单一异构体酸，再转化成布瓦西坦的方法。该方法相对比较简洁，但在实际操作过程中难以实施。
Figure PCTCN2018112662-appb-000004
发明内容
本发明所解决的技术问题在于克服现有的布瓦西坦制备方法中存在的成本高、步骤冗长、操作繁琐、不适合工业化生产的缺陷，而提供了一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法。该制备方法以价廉易得的正戊醛为原料，合成步骤短，简洁高效，不需要柱层析分离异构体或者不对称合成，适合工业化大规模生产。
本发明通过以下技术方案来解决上述技术问题。
本发明提供了一种3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)或其药学上可接受的盐，其结构如下所示：
Figure PCTCN2018112662-appb-000005
所述如式(II)所示化合物为(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(简称(II)-R)、(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(简称(II)-S)，或其任意比例如下结构的混合物；
Figure PCTCN2018112662-appb-000006
所述(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸、(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸的盐可为本领域常规的盐，优选与X所成的盐，其结构如下所示：
Figure PCTCN2018112662-appb-000007
其中，所述X可为本领域常规的有机酸，优选草酸或马来酸。
所述(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸、(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸的盐可为以下任一结构：
Figure PCTCN2018112662-appb-000008
本发明提供了一种如式(I)所示布瓦西坦的制备方法，其包括以下步骤：在溶剂中，将如式(II)-R-X或(II)-R所示化合物进行如下所示的成环反应，即可；其中，X为有机酸；
Figure PCTCN2018112662-appb-000009
成环反应中，所述X优选草酸或马来酸。
成环反应中，所述溶剂优选水、醇类溶剂和氯化亚砜中的一种或多种，更优选C 1-4的醇，进一步优选甲醇、乙醇和异丙醇中的一种或多种。
成环反应中，所述如式(II)-R-X或(II)-R所示化合物在所述溶剂中的摩尔浓度可为本领域上述成环反应常规的摩尔浓度，优选0.2～1.0mol/L，更优选0.4～0.8mol/L，例如0.48mol/L、0.72mol/L。
成环反应中，所述成环反应的温度可为本领域上述成环反应常规的温度，优选25～100℃，更优选25～80℃，进一步优选65～80℃。
成环反应中，所述成环反应的进程可以采用本领域该类反应常规的检测方法(例如HPLC、TLC)进行监控，一般以化合物(II)-R-X或(II)-R消失时为反应终点，反应时间优选4～10h，例如6h。
所述成环反应结束后，较佳地，还可进一步包括后处理步骤。所述后处理的条件和操作可为本领域该类反应常规的条件和操作，较佳地包括下列步骤：浓缩，调节pH至8～9，萃取，干燥，浓缩得粗品，将粗品重结晶，抽滤，洗涤，干燥。所述浓缩的条件和操作可为本领域该类反应常规的条件和操作，优选减压浓缩。所述调节pH的碱可为本领域该类反应常规的碱，优选碳酸钠，更优选10％的碳酸钠水溶液。所述萃取的条件和操作可为本领域该类反应常规的条件和操作。所述萃取溶剂可为本领域该类反应常规的萃取溶剂，优选二氯甲烷。所述干燥的条件和操作可为本领域该类反应常规的条件和操作。。所述重结晶的条件和操作可为本领域该类反应常规的条件和操作，所述重结晶的溶剂可 为本领域该类反应常规的溶剂，优选乙酸乙酯和正庚烷、或乙酸乙酯和石油醚，所述乙酸乙酯和(正庚烷或石油醚)的体积比优选1:5；所述重结晶的时间可为本领域该类反应常规的时间，例如1h。所述抽滤的条件和操作可为本领域该类反应常规的条件和操作。所述洗涤的条件和操作可为本领域该类反应常规的条件和操作，洗涤溶剂优选正庚烷或石油醚。所述干燥的条件和操作可为本领域该类反应常规的条件和操作，例如烘干。
所述如式(I)所示布瓦西坦的制备方法，其还可包括以下步骤：在碱的作用下，将如式(II)-R-X所示化合物进行游离，得如式(II)-R所示化合物；
Figure PCTCN2018112662-appb-000010
所述游离的条件和操作均与本领域该类反应常规的条件和操作相同。所述碱可为本领域游离常用的碱，例如氢氧化钠、氢氧化钾或氨水。
所述如式(I)所示布瓦西坦的制备方法，其还可包括以下步骤：将如式(II)所示化合物与X进行成盐，结晶，得如式(II)-R-X所示化合物；其中，X为有机酸；
Figure PCTCN2018112662-appb-000011
所述X优选草酸或马来酸。
所述成盐步骤的溶剂优选C 1-4的醇和/或水。所述C 1-4的醇优选异丙醇、正丁醇和异丁醇中的一种或多种。
当所述成盐步骤的溶剂为C 1-4的醇和水时，对所述C 1-4的醇和所述水的质量比不作特殊限制，不影响成盐即可。
所述成盐步骤的溶剂与如式(II)所示化合物的质量比优选(2～10):1，更优选(3～5):1，进一步优选4:1。
所述如式(II)所示化合物与所述X的摩尔比可为本领域上述成盐常规的摩尔比，优选 (0.8～2):1，更优选(1～1.5):1，进一步优选(1～1.3):1，例如1.1:1。
所述结晶步骤的溶剂优选C 1-4的醇、水和醚类溶剂的混合溶剂，或C 1-4的醇、水和烷烃类溶剂的混合溶剂。所述C 1-4的醇优选异丙醇、正丁醇和异丁醇中的一种或多种。所述醚类溶剂优选石油醚和/或异丙醚。所述烷烃类溶剂优选正己烷和/或正庚烷。
所述结晶步骤的溶剂优选正丁醇，水和异丙醚的混合溶剂、异丁醇，水和异丙醚的混合溶剂、异丁醇，水和石油醚的混合溶剂、正丁醇，水和正庚烷的混合溶剂、异丙醇，水和异丙醚的混合溶剂、或异丙醇，水和正己烷的混合溶剂，更优选异丁醇，水和异丙醚的混合溶剂、或异丙醇，水和异丙醚的混合溶剂。
所述结晶步骤中，所述C 1-4的醇、水和(醚类溶剂或烷烃类溶剂)的质量比优选(2～10):1:(2～10)，更优选(3～5):1:(4～6)，进一步优选4:1:(4～6)，例如4:1:4、4:1:6。
所述结晶步骤的溶剂与所述如式(II)所示化合物的质量比优选(5～15):1，更优选(7～11):1，例如9:1、11:1。
所述结晶的温度优选5～50℃，更优选10～40℃，进一步优选25～30℃。
所述结晶步骤的结晶时间可参考本领域结晶常规需要的时间，优选0.5～5h，更优选1～2h。
对所述结晶步骤的次数不作特殊限制，能够实现SR:SS≥99.0:1.0即可，例如2次，3次。
本发明一优选实施方案中，将如式(II)所示化合物加入到C 1-4的醇和水的混合溶剂中，再依次加入有机酸，醚类或烷烃类溶剂，结晶。
本发明一优选实施方案中，将如式(II)所示化合物加入到C 1-4的醇和水的混合溶剂中，再依次加入有机酸，醚类或烷烃类溶剂，结晶。将结晶得到的产品加入到C 1-4的醇和水的混合溶剂中，再加入醚类或烷烃类溶剂，结晶。
所述结晶结束后，较佳地，还可进一步包括后处理的操作。所述后处理的条件和操作可为本领域该类反应常规的条件和操作，较佳地可包括下列步骤：抽滤，洗涤，干燥。所述抽滤的条件和操作可为本领域该类反应常规的条件和操作。所述洗涤的条件和操作可为本领域该类反应常规的条件和操作，所述洗涤溶剂优选醚类溶剂和/或烷烃类溶剂， 更优选异丙醚、石油醚、正己烷或正庚烷。所述干燥的条件和操作可为本领域该类反应常规的条件和操作，所述干燥的温度可为本领域该类反应常规的温度，例如65℃；所述干燥的时间可为本领域该类反应常规的时间，例如12h。
所述如式(I)所示布瓦西坦的制备方法，其还可包括以下步骤：在溶剂中，在催化剂的作用下，将如式(III)所示化合物与氢气进行如下所示的氢化还原反应，得如式(II)所示化合物；
Figure PCTCN2018112662-appb-000012
氢化还原反应中，所述溶剂优选水和/或C 1-4的醇。所述C 1-4的醇优选乙醇、异丙醇、正丁醇和异丁醇中的一种或多种。
氢化还原反应中，所述催化剂可为本领域上述氢化还原反应常规的催化剂，优选Pd/C。
氢化还原反应中，所述氢气的压力优选1～30bar，更优选5～20bar。
氢化还原反应中，所述催化剂与所述如式(III)所示化合物的质量比可为本领域上述氢化还原反应常规的质量比，优选0.05:1～0.15:1，更优选0.1:1。
氢化还原反应中，所述如式(III)所示化合物在所述溶剂中的摩尔浓度可为本领域上述氢化还原反应常规的摩尔浓度，优选0.1～0.8mol/L，更优选0.3～0.5mol/L，例如0.44mol/L。
氢化还原反应中，所述反应的温度可为本领域上述氢化还原反应常规的温度，优选10～50℃，更优选20～30℃，例如25℃。
氢化还原反应中，所述反应的进程可以采用本领域上述氢化还原反应常规的检测方法(例如HPLC、TLC)进行监控，一般以化合物III消失时为反应终点，反应时间优选8～24h，更优选16～20h，例如18h。
所述氢化还原反应优选在有机酸参与条件下进行，所述有机酸优选柠檬酸、草酸和马来酸中的一种或多种，更优选柠檬酸。所述有机酸与所述如式(III)所示化合物的摩尔比优选(7～10):1，例如8.4:1。
所述氢化还原反应结束后，较佳地，还可进一步包括后处理的操作。所述的后处理的条件和操作可为本领域该类反应常规的条件和操作，较佳地包括下列步骤：过滤，浓缩。所述过滤的条件和操作可为本领域该类反应常规的条件和操作。所述浓缩的条件和操作可为本领域该类反应常规的条件和操作，优选减压浓缩。
所述如式(I)所示布瓦西坦的制备方法，其还可包括以下步骤：溶剂中，将如式(IV)所示化合物与L-氨基丁酰胺进行如下反应，得如式(III)所示化合物，
Figure PCTCN2018112662-appb-000013
所述溶剂可为本领域常规的溶剂，优选醇类溶剂；所述醇类溶剂优选C 1-4的醇，例如异丙醇。
所述L-氨基丁酰胺在所述溶剂中的浓度可为本领域常规的浓度，例如1～2mol/L。
所述反应的温度可为本领域常规的温度，例如30～40℃。
所述反应的进程可以采用本领域上述反应常规的检测方法(例如HPLC、TLC)进行监控，一般以化合物IV消失时为反应终点，反应时间例如1～4h，再例如2～4h。
所述L-氨基丁酰胺优选L-氨基丁酰胺盐酸盐。所述L-氨基丁酰胺盐酸盐优选在氨气条件下游离成L-氨基丁酰胺后，再与式(IV)所示化合物反应。所述反应的时间根据体系pH值来判断，优选反应至pH为9～10。
对所述如式(IV)所示化合物的加入方式不作特殊限定，不影响反应即可，可一次性加入或分批加入。
所述反应结束后，较佳地，还可进一步包括后处理的操作。所述后处理的条件和操作可为本领域该类反应常规的条件和操作，较佳地包括下列步骤：过滤、降温析晶、过滤、洗涤即可。所述过滤的条件和操作可为本领域该反应常规的条件和操作，优选抽滤。所述析晶的条件和操作可为本领域该反应常规的条件和操作，析晶温度优选0～5℃。所述洗涤的条件和操作可为本领域该反应常规的条件和操作，所述洗涤溶剂可为本领域该反 应常规的洗涤溶剂，优选乙酸乙酯。
本发明提供了一种如式(II)-R-X所示化合物的制备方法，其包括以下步骤：将如式(II)所示化合物与X进行成盐，结晶，即可；所述X为有机酸；
Figure PCTCN2018112662-appb-000014
所述成盐、结晶的条件和操作均与前述该反应的条件和操作相同。
本发明提供了一种如式(II)-S-X所示化合物的制备方法，其包括以下步骤：
(1)将如式(II)所示化合物与X进行成盐，结晶，得如式(II)-R-X所示化合物；
(2)向步骤(1)中结晶后的母液中加入X和溶剂，析晶，即可；
Figure PCTCN2018112662-appb-000015
其中，所述X为有机酸，优选草酸或马来酸。
步骤(1)中，所述成盐、结晶的条件和操作均与前述该反应的条件和操作相同。
步骤(2)中，所述溶剂优选醚类溶剂，更优选石油醚和/或异丙醚。
步骤(2)中，所述X与所述如式(II)所示化合物的摩尔比优选1:(1～4)，例如1:2。
步骤(2)中，所述溶剂与所述如式(II)所示化合物的体积质量比优选(1～4)mL/g，例如2mL/g。
步骤(2)中，所述析晶的温度优选-20～0℃，例如-10℃。
步骤(2)中，所述析晶步骤的析晶时间可参考本领域析晶常规需要的时间，例如0.5～5h，再例如2～4h。
步骤(2)结束后，较佳地，还可进一步包括后处理的操作。所述的后处理的条件和操作可为本领域该类反应常规的条件和操作，较佳地包括下列步骤：过滤，洗涤，干燥。所述过滤的条件和操作可为本领域该反应常规的条件和操作，优选抽滤。所述洗涤的条件和操作可为本领域该反应常规的条件和操作，所述洗涤的溶剂优选醚类溶剂，例如石 油醚和/或异丙醚。所述干燥的条件和操作可为本领域该反应常规的条件和操作，所述干燥的温度可为本领域常规的温度，例如50℃，所述干燥的时间可为本领域常规的时间，例如12h。
本发明还提供了一种如式(II)所示化合物的制备方法，其包括以下步骤：在溶剂中，在催化剂的作用下，将如式(III)所示化合物与氢气进行如下所示的氢化还原反应，得如式(II)所示化合物；
Figure PCTCN2018112662-appb-000016
所述氢化还原反应的条件和操作均与前述氢化还原反应的条件和操作相同。
所述如式(II)所示化合物的制备方法，其还可包括以下步骤：溶剂中，将如式(IV)所示化合物与L-氨基丁酰胺进行如下反应，得如式(III)所示化合物，
Figure PCTCN2018112662-appb-000017
所述反应的条件和操作均与前述该反应的条件和操作相同。
如没有特别强调温度，通常指在室温下进行反应，本发明中的室温是指20～30℃。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
若无特殊说明，本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明以正戊醛和乙醛酸作为原料，价廉易得，且生成的产物不用通过柱层析分离进行分离，同时反应过程中无需金属试剂的参与。本发明提出的布瓦西坦合成路线步骤短，原料便宜，简洁高效，不需要柱层析分离异构体或者不对称合成，降低了生产成本， 适合工业化大规模生产。
具体实施方式
为更好地理解本发明的内容，下面结合具体实施例作进一步说明。应理解，下列具体实施例仅仅用于说明本发明，而不是对本发明的限制。以下实施例中提到的异构体比例均通过HPLC测得。
实施例1：5-羟基-4-丙基呋喃-2(5H)-酮(IV)的制备
Figure PCTCN2018112662-appb-000018
将正庚烷125mL和吗啡啉30mL加入到三口瓶中，常温下搅拌10min混合均匀，降温至4℃以下滴加50％乙醛酸水溶液25.0g。滴完后升温至25～30℃搅拌反应2h，然后在40℃以下缓慢加入正戊醛30.5g，继续搅拌反应18h。反应完成后降温至20℃，缓慢滴加浓盐酸21.3g搅拌。
降至室温，静置分去正庚烷相。水相中加入乙酸乙酯100mL，缓慢加入碳酸钠固体调至pH＝4，分层取有机相，再用乙酸乙酯萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥、抽滤、减压浓缩，得棕色油状物5-羟基-4-丙基呋喃-2(5H)-酮(IV)43.9g，收率91.5％。 1H NMR(400MHz,Chloroform-d)δ0.93-1.00(t,3H),1.56-1.67(q,2H),2.31-2.43(q,2H),5.81(s,1H),6.02(s,1H).MS(ESI)m/z＝143(M+H) +.
实施例2：(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(III)的制备
Figure PCTCN2018112662-appb-000019
将氨基丁酰胺盐酸盐96.2g混溶于异丙醇1000mL中，通氨气进行游离，直至体系pH值为9～10，且pH值不变化为止。过滤除去盐，滤液浓缩至500mL待用。
将5-羟基-4-丙基呋喃-2(5H)-酮(IV)98.4g分批加入上述500mL氨基丁酰胺溶液中， 控温30～40℃反应2h以上。反应完成后过滤去除盐，滤液缓慢降温至0～5℃析晶，抽滤，用少量乙酸乙酯漂洗，得白色固体(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(III)139.2g，收率88.8％。 1H NMR(500MHz,Chloroform-d)δ6.45(s,1H),5.89(s,1H),5.85(s,1H),5.57(s,1H),3.42(s,1H),2.39(s,3H),1.82(dq,J＝14.4,7.4,6.9Hz,1H),1.74(dt,J＝14.2,7.2Hz,1H),1.67(dd,J＝14.6,7.2Hz,2H),1.02(dt,J＝11.3,7.4Hz,6H).MS(ESI)m/z＝227(M+H) +.
实施例3：3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)的制备
Figure PCTCN2018112662-appb-000020
将(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(III)15.0g加入到150mL水中，再加入1.5g柠檬酸和5％的Pd/C 1.5g,搅拌均匀，氮气置换。通氢气至20bar，常温搅拌反应过夜。反应完后，过滤去钯碳，滤液在低于50℃下旋干得到淡黄色油状物3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)16.3g，收率93.7％。 1H NMR(400MHz,DMSO-d 6)δ7.34(s,1H),7.01(s,1H),2.96–2.79(m,1H),2.56(dd,J＝11.6,4.9Hz,1H),2.40(d,J＝4.8Hz,1H),2.29(ddt,J＝28.6,20.1,10.3Hz,1H),2.13(ddd,J＝21.1,11.9,5.2Hz,1H),1.93–1.74(m,1H),1.49(tt,J＝13.6,6.5Hz,2H),1.41–1.07(m,4H),0.82(dt,J＝29.2,6.6Hz,6H).MS(ESI)m/z＝231(M+H) +.
重复上述还原反应操作，采用不同的溶剂、有机酸和氢气压力，常温(25℃)反应18小时后，分离计算收率，实验结果如表1所示：
表1
序号 溶剂 有机酸 氢气压力 收率
1 水 无 20bar 78.2％
2 水 柠檬酸 20bar 93.7％
3 水 草酸 20bar 71.5％
4 水 柠檬酸 5bar 83.3％
5 乙醇 柠檬酸 20bar 67.5％
6 异丙醇 柠檬酸 20bar 74.0％
7 正丁醇 柠檬酸 20bar 73.1％
8 异丁醇 马来酸 20bar 66.4％
9 异丙醇:水＝1:1 柠檬酸 20bar 84.2％
10 正丁醇:水＝2:1 柠檬酸 20bar 81.8％
实施例4：(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸草酸盐(II)-R-1的制备
Figure PCTCN2018112662-appb-000021
将3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)100g溶于含有异丁醇400g和水100g的混合溶剂中，再加入35.2g草酸成盐，滴加入435g异丙醚，搅拌25～30℃结晶1-2小时，抽滤，固体用异丙醚淋洗，65℃干燥12小时，得100g白色固体，异构体比例SR:SS＝80:20。
将上述100g白色固体用4倍重量异丁醇和1倍重量水溶解，滴加4倍重量的异丙醚结晶，重复两次，得28.5g白色固体(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸草酸盐(II)-R-1，异构体比例SR:SS＝99.8:0.2。收率20.5％。 1H NMR(400MHz,DMSO-d 6)δ8.05(s,1H),7.65(s,1H),3.63(t,J＝6.3Hz,1H),2.85(t,J＝9.6Hz,1H),2.78–2.61(m,1H),2.43(dd,J＝16.5,5.8Hz,1H),2.25(dd,J＝16.5,6.6Hz,1H),2.10(s,1H),1.78(ddt,J＝30.3,15.3,7.9Hz,2H),1.57–1.11(m,4H),0.87(dd,J＝13.7,7.1Hz,6H).MS(ESI)m/z＝231(M+H) +.
重复上述操作，采用不同的溶剂体系结晶(结晶3次)，实验结果如表2所示：
表2
序号 溶剂体系 SR:SS 收率
1 异丁醇:水:异丙醚＝4:1:4 99.8:0.2 20.5％
2 正丁醇:水:异丙醚＝4:1:4 99.5:0.5 18.8％
3 异丁醇:水:正庚烷＝4:1:4 99.0:1.0 22.3％
4 异丁醇:水:石油醚＝4:1:4 99.1:0.9 16.3％
5 正丁醇:水:异丙醚＝4:1:4 99.8:0.2 12.5％
6 异丙醇:水:异丙醚＝4:1:6 99.9:0.1 10.5％
7 异丙醇:水:正己烷＝4:1:6 99.4:0.6 13.5％
实施例5：布瓦西坦(I)的制备
Figure PCTCN2018112662-appb-000022
将9.3g异构体比例为SR:SS＝99.8:0.2的(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸草酸盐(II)-R-1溶于含有60mL异丙醇中，加热至回流反应6小时后降温，减压浓缩；得到的浓缩液用10％的碳酸钠水溶液调节体系pH至8～9，再用二氯甲烷萃取，干燥，浓缩，得粗品6.1g。
将粗品溶于6.0mL乙酸乙酯，滴加正庚烷30mL，室温搅拌结晶1小时，抽滤，正庚烷淋洗，烘干得布瓦西坦(I)5.5g，异构体比例SR:SS＝99.8:0.2，收率：89.3％。 1H NMR(400MHz,CDCl 3)δ6.53(s,1H),5.89(s,1H),4.43(dd,J＝9.0,6.8Hz,1H),3.44(dd,J＝9.8,7.9Hz,1H),3.01(dd,J＝9.8,7.1Hz,1H),2.52(dd,J＝16.7,8.6Hz,1H),2.35–2.18(m,1H),2.04(dd,J＝16.7,8.1Hz,1H),1.87(dd,J＝14.2,7.1Hz,1H),1.74–1.47(m,1H),1.43–1.33(m,2H),1.27(ddd,J＝11.4,8.2,5.8Hz,2H),0.85(dd,J＝13.6,7.3Hz,6H).MS(ESI)m/z＝213(M+H) +.
重复上述操作，采用不同关环条件，实验结果如表3所示：
表3
序号 溶剂 温度 收率
1 异丙醇 80℃ 89.3％
2 甲醇 65℃ 82.8％
3 乙醇 80℃ 93.3％
4 氯化亚砜 25℃ 77.6％
实施例6：(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸马来盐(II)-R-2的制备
Figure PCTCN2018112662-appb-000023
将3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)100g溶于含有正丁醇400g和水100g的混合溶剂中，再加入45.4g马来酸成盐，滴加入290g异丙醚，搅拌25～30℃结晶1-2小时，抽滤，固体用异丙醚淋洗，65℃干燥12小时，得88g白色固体，异构体比例SR:SS＝76:24。
将上述88g白色固体用4倍重量正丁醇和1倍重量水溶解，滴加4倍重量的异丙醚结晶，重复两次，得21.8g白色固体(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸马来酸盐(II)-R-2，异构体比例SR:SS＝99.6:0.4。收率14.5％。 1H NMR(400MHz,DMSO-d 6)δ7.98(s,1H),7.73(s,1H),6.04(s,2H),3.83–3.58(m,1H),3.02–2.66(m,2H),2.27(dd,J＝16.6,6.5Hz,1H),2.11(s,1H),1.80(ddt,J＝29.9,15.0,7.5Hz,2H),1.32(d,J＝42.8Hz,4H),0.90(dd,J＝17.2,8.5Hz,6H).MS(ESI)m/z＝231(M+H) +.
重复上述操作，采用不同的溶剂体系结晶(结晶3次)，实验结果如表4所示：
表4
序号 溶剂体系 SR:SS 收率
1 正丁醇:水:异丙醚＝4:1:4 99.6:0.4 14.5％
2 异丁醇:水:异丙醚＝4:1:4 99.7:0.3 17.8％
3 异丁醇:水:石油醚＝4:1:4 99.5:0.5 11.1％
4 正丁醇:水:正庚烷＝4:1:6 99.1:0.9 20.3％
5 异丙醇:水:异丙醚＝4:1:6 99.8:0.2 9.6％
6 异丙醇:水:正己烷＝4:1:6 99.5:0.5 11.7％
实施例7：布瓦西坦(I)的制备
Figure PCTCN2018112662-appb-000024
将10.0g异构体比例为SR:SS＝99.7:0.3的(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸马来酸盐(II)-R-2溶于含有60mL乙醇中，加热至回流反应6小时后降温，减压浓缩；浓缩液用10％的碳酸钠水溶液调节体系pH至8～9，再用二氯甲烷萃取，萃取液干燥，浓缩，得粗品5.5g。
将粗品溶于6.0mL乙酸乙酯，滴加石油醚30mL，室温搅拌结晶1小时，抽滤，石油醚淋洗，烘干得布瓦西坦(I)5.0g，异构体比例SR:SS＝99.7:0.3，收率：81.6％。结构鉴定数据见实施例5。
实施例8：(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸马来盐(II)-S-2的制备
Figure PCTCN2018112662-appb-000025
将实施例6中拆分所得的母液加入反应瓶中，加入25.3g马来酸，滴加入200mL异丙醚，搅拌下降温-10℃析晶3小时，低温抽滤，异丙醚淋洗，50℃干燥12小时，得16.2g白色固体(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸马来酸盐(II)-S-2，异构体比例SR:SS＝3.1:96.9，收率22％。 1H NMR(400MHz,DMSO-d 6)δ8.00(s,1H),7.74(s,1H),6.06(s,2H),3.71–3.62(m,2H),2.89(dd,J＝12.3,4.9Hz,1H),2.75(dd,J＝12.0,7.9Hz,1H),2.49–2.39(m,1H),2.37–2.18(m,1H),2.11(s,1H),1.83(dd,J＝12.4,7.1Hz,2H),1.27(s,4H),0.97–0.66(m,6H).
实施例9：布瓦西坦(I)的制备
Figure PCTCN2018112662-appb-000026
将实施例4中所得的(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸草酸盐(II)-R-1溶于水中，氢氢化钠调至pH＝10，再用二氯甲烷萃取，干燥，浓缩，可得(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)-R。
将5.0g异构体比例为SR:SS＝99.8:0.2的(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)-R溶于30mL异丙醇中，加热至回流反应4小时，减压浓缩；得到的粗品溶于5.0mL乙酸乙酯，滴加正庚烷25mL，室温搅拌结晶1小时，抽滤，正庚烷淋洗，烘干得布瓦西坦(I)4.3g，异构体比例SR:SS＝99.8:0.2，收率：93.2％。结构鉴定数据见实施例5。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (21)

  1. 一种3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)或其药学上可接受的盐，其特征在于，
    Figure PCTCN2018112662-appb-100001
  2. 如权利要求1所述的3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)或其药学上可接受的盐，其特征在于，所述3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)为(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸、(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸，或其任意比例如下结构的混合物；
    Figure PCTCN2018112662-appb-100002
  3. 如权利要求2所述的3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)或其药学上可接受的盐，其特征在于，其为以下结构：
    Figure PCTCN2018112662-appb-100003
    其中，X为有机酸，优选草酸或马来酸。
  4. 如权利要求2或3所述的3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(II)或其药学上可接受的盐，其特征在于，其为以下任一结构：
    Figure PCTCN2018112662-appb-100004
    Figure PCTCN2018112662-appb-100005
  5. 一种如式(I)所示布瓦西坦的制备方法，其特征在于，其包括以下步骤：在溶剂中，将如式(II)-R-X或(II)-R所示化合物进行如下所示的成环反应，即可；其中，X为有机酸；
    Figure PCTCN2018112662-appb-100006
  6. 如权利要求5所述的如式(I)所示布瓦西坦的制备方法，其特征在于，
    所述X为草酸或马来酸；
    和/或，所述溶剂为水、醇类溶剂和氯化亚砜中的一种或多种，优选C 1-4的醇，更优选甲醇、乙醇和异丙醇中的一种或多种；
    和/或，所述如式(II)-R-X或(II)-R所示化合物在所述溶剂中的摩尔浓度为0.2～1.0mol/L，优选0.4～0.6mol/L；
    和/或，所述成环反应的温度为25～100℃，优选25～80℃，更优选65～80℃；
    和/或，所述成环反应的时间为4～10h。
  7. 如权利要求5或6所述的如式(I)所示布瓦西坦的制备方法，其特征在于，其还包括以下步骤：在碱的作用下，将如式(II)-R-X所示化合物进行游离，得如式(II)-R所示化合物；
    Figure PCTCN2018112662-appb-100007
  8. 如权利要求5所述的如式(I)所示布瓦西坦的制备方法，其特征在于，其还包括以下步骤：在溶剂中，将如式(II)所示化合物与X进行成盐、结晶，得如式(II)-R-X所示化合物；其中，X为有机酸；
    Figure PCTCN2018112662-appb-100008
  9. 如权利要求8所述的如式(I)所示布瓦西坦的制备方法，其特征在于，
    所述X为草酸或马来酸；
    和/或，所述成盐步骤的溶剂为C 1-4的醇和/或水；
    和/或，所述成盐步骤的溶剂与如式(II)所示化合物的质量比为(2～10):1，优选(3～5):1，更优选4:1；
    和/或，所述如式(II)所示化合物与所述X的摩尔比为(0.8～2):1，优选(1～1.5):1，更优选(1～1.3):1；
    和/或，所述结晶步骤的溶剂为C 1-4的醇、水和醚类溶剂的混合溶剂，或C 1-4的醇、水和烷烃类溶剂的混合溶剂；
    和/或，所述结晶步骤的溶剂与所述如式(II)所示化合物的质量比为(5～15):1，更优选(7～11):1；
    和/或，所述结晶的温度为5～50℃，优选10～40℃，更优选25～30℃；
    和/或，所述结晶步骤的结晶时间为0.5～5h，优选1～2h。
  10. 如权利要求9所述的如式(I)所示布瓦西坦的制备方法，其特征在于，
    所述C 1-4的醇为丙醇、正丁醇和异丁醇中的一种或多种；
    和/或，所述醚类溶剂为石油醚和/或异丙醚；
    和/或，所述烷烃类溶剂为正己烷和/或正庚烷；
    和/或，所述结晶步骤中，所述C 1-4的醇、水和(醚类溶剂或烷烃类溶剂)的质量比为(2～10):1:(2～10)，优选(3～5):1:(4～6)，更优选4:1:(4～6)。
  11. 如权利要求8～10中任一项所述的如式(I)所示布瓦西坦的制备方法，其特征在于，所述结晶步骤的溶剂为正丁醇，水和异丙醚的混合溶剂、异丁醇，水和异丙醚的混合溶剂、异丁醇，水和石油醚的混合溶剂、正丁醇，水和正庚烷的混合溶剂、异丙醇，水和异丙醚的混合溶剂、或异丙醇，水和正己烷的混合溶剂，优选异丁醇，水和异丙醚的混合溶剂、或异丙醇，水和异丙醚的混合溶剂。
  12. 如权利要求9～10中任一项所述的如式(I)所示布瓦西坦的制备方法，其特征在于，其还包括以下步骤：将如式(II)所示化合物加入到C 1-4的醇和水的混合溶剂中，再依次加入有机酸，醚类或烷烃类溶剂，结晶。
  13. 如权利要求9～10中任一项所述的如式(I)所示布瓦西坦的制备方法，其特征在于，其还包括以下步骤：将如式(II)所示化合物加入到C 1-4的醇和水的混合溶剂中，再依次加入有机酸，醚类或烷烃类溶剂，结晶；将结晶得到的产品加入到C 1-4的醇和水的混合溶剂中，再加入醚类或烷烃类溶剂，结晶。
  14. 如权利要求8所述的如式(I)所示布瓦西坦的制备方法，其特征在于，其还包括以下步骤：在溶剂中，在催化剂的作用下，将如式(III)所示化合物与氢气进行如下所示的氢化还原反应，得如式(II)所示化合物；
    Figure PCTCN2018112662-appb-100009
  15. 如权利要求14所述的如式(I)所示布瓦西坦的制备方法，其特征在于，
    所述氢化还原反应在有机酸参与条件下进行；所述有机酸为柠檬酸、草酸和马来酸中的一种或多种，优选柠檬酸；
    和/或，所述有机酸与所述如式(III)所示化合物的摩尔比为(7～10):1。
  16. 如权利要求14或15所述的如式(I)所示布瓦西坦的制备方法，其特征在于，其还包括以下步骤：溶剂中，将如式(IV)所示化合物与L-氨基丁酰胺进行如下反应，得如式(III)所示化合物，
    Figure PCTCN2018112662-appb-100010
  17. 一种如式(II)-R-X所示化合物的制备方法，其包括以下步骤：将如式(II)所示化合物与X进行成盐，结晶，即可；其中，X为有机酸；
    Figure PCTCN2018112662-appb-100011
  18. 一种如式(II)-S-X所示化合物的制备方法，其特征在于，其包括以下步骤：
    (1)将如式(II)所示化合物与X进行成盐，结晶，得如式(II)-R-X所示化合物；
    (2)向步骤(1)中结晶后的母液中加入X和溶剂，析晶，即可；
    Figure PCTCN2018112662-appb-100012
    其中，X为有机酸。
  19. 如权利要求18所述的如式(II)-S-X所示化合物的制备方法，其特征在于，
    所述X为草酸或马来酸；
    和/或，步骤(2)中，所述溶剂为醚类溶剂，优选石油醚和/或异丙醚；
    和/或，步骤(2)中，所述X与所述如式(II)所示化合物的摩尔比为1:(1～4)；
    和/或，步骤(2)中，所述溶剂与所述如式(II)所示化合物的体积质量比为(1～4)mL/g；
    和/或，步骤(2)中，所述析晶的温度为-20～0℃。
  20. 一种如式(II)所示化合物的制备方法，其特征在于，其包括以下步骤：在溶剂中， 在催化剂的作用下，将如式(III)所示化合物与氢气进行如下所示的氢化还原反应，得如式(II)所示化合物，
    Figure PCTCN2018112662-appb-100013
  21. 如权利要求20所述的如式(II)所示化合物的制备方法，其特征在于，其还包括以下步骤：溶剂中，将如式(IV)所示化合物与L-氨基丁酰胺进行如下反应，得如式(III)所示化合物，
    Figure PCTCN2018112662-appb-100014
PCT/CN2018/112662 2018-06-20 2018-10-30 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法 Ceased WO2019242192A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/973,022 US11518741B2 (en) 2018-06-20 2018-10-30 Brivaracetam intermediate, preparation method therefor, and preparation method for brivaracetam
EP18923290.3A EP3812377A4 (en) 2018-06-20 2018-10-30 BRIVARACETAM INTERMEDIATE, METHOD FOR PREPARING IT, AND METHOD FOR PREPARING BRIVARACETAM
JP2020571459A JP7097467B2 (ja) 2018-06-20 2018-10-30 ブリバラセタム中間体、その製造方法及びブリバラセタムの製造方法
CN201880090614.XA CN112020498B (zh) 2018-06-20 2018-10-30 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810634229.9 2018-06-20
CN201810634229.9A CN110615744B (zh) 2018-06-20 2018-06-20 一种布瓦西坦中间体及其制备方法

Publications (1)

Publication Number Publication Date
WO2019242192A1 true WO2019242192A1 (zh) 2019-12-26

Family

ID=68920349

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/112662 Ceased WO2019242192A1 (zh) 2018-06-20 2018-10-30 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法

Country Status (5)

Country Link
US (1) US11518741B2 (zh)
EP (1) EP3812377A4 (zh)
JP (1) JP7097467B2 (zh)
CN (2) CN110615744B (zh)
WO (1) WO2019242192A1 (zh)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110615744B (zh) 2018-06-20 2023-01-06 上海朴颐化学科技有限公司 一种布瓦西坦中间体及其制备方法
CN112341413A (zh) * 2019-12-18 2021-02-09 上海朴颐化学科技有限公司 一种用于合成布瓦西坦的中间体及其制备方法
CN111187175A (zh) * 2020-01-08 2020-05-22 上海朴颐化学科技有限公司 一种利用微通道反应器氢化制备布瓦西坦的中间体的方法
CN113651745B (zh) * 2021-09-09 2023-06-02 上海医药工业研究院 布瓦西坦中间体及其制备方法和纯化方法
CN114634437B (zh) * 2022-03-29 2023-05-30 武汉氟本氘合新材料科技有限公司 一种布瓦西坦的简易制备方法
CN116891879A (zh) * 2023-09-08 2023-10-17 山东静远药业有限公司 一种布瓦西坦关键中间体的合成方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1208319C (zh) 2000-02-23 2005-06-29 Ucb公司 2－氧代－1－吡咯烷衍生物、其制备方法和用途
CN1882535B (zh) 2003-09-24 2011-05-11 Ucb药物股份有限公司 2-氧代-1-吡咯烷衍生物的制备方法
CN106279074A (zh) * 2015-05-25 2017-01-04 苏州鹏旭医药科技有限公司 一种化合物及其制备方法和在合成布瓦西坦中的用途
CN106748950A (zh) 2017-01-13 2017-05-31 成都美域高制药有限公司 一种布瓦西坦及其中间体的制备方法
CN107513032A (zh) * 2017-07-25 2017-12-26 峨眉山宏昇药业股份有限公司 一种用于治疗癫痫的药物及其中间体的合成方法
CN107663185A (zh) 2017-11-14 2018-02-06 安徽华胜医药科技有限公司 一种丁内酯衍生物的合成方法
WO2018220646A1 (en) * 2017-05-29 2018-12-06 Msn Laboratories Private Limited, R&D Center An improved process for the preparation of (2s)-2-[(4r)-2-oxo-4-propyltetrahydro-1h-pyrrol-1-yl] butanamide and its intermediates thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1206699B (it) * 1984-02-27 1989-04-27 Isf Spa Procedimento per preparare derivati di pirrolidone.
AU2002224847A1 (en) * 2000-11-21 2002-06-03 U C B, S.A. N-alkylated gaba compounds, processes for their preparation and their use as medicaments
WO2008132142A2 (en) 2007-04-27 2008-11-06 Ucb Pharma S.A. New heterocyclic derivatives useful for the treatment of cns disorders
WO2011086565A1 (en) * 2010-01-15 2011-07-21 Lupin Limited Method for preparation of enantiomerically enriched and/or racemic gamma-amino acids
WO2016191435A1 (en) * 2015-05-25 2016-12-01 Peng Wang Processes to produce brivaracetam
TWI629261B (zh) * 2016-02-24 2018-07-11 蘇州鵬旭醫藥科技有限公司 Preparation method of bovasacetam
RU2629117C1 (ru) * 2016-06-14 2017-08-24 Сизов Владимир Владимирович Способ получения 4-замещенного 2-[2-оксо-1-пирролидинил] ацетамида
CN109593055B (zh) * 2017-09-30 2022-04-26 上海医药工业研究院 一种布瓦西坦异构体(2s，4s)的制备方法
CN110615744B (zh) * 2018-06-20 2023-01-06 上海朴颐化学科技有限公司 一种布瓦西坦中间体及其制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1208319C (zh) 2000-02-23 2005-06-29 Ucb公司 2－氧代－1－吡咯烷衍生物、其制备方法和用途
CN1882535B (zh) 2003-09-24 2011-05-11 Ucb药物股份有限公司 2-氧代-1-吡咯烷衍生物的制备方法
CN106279074A (zh) * 2015-05-25 2017-01-04 苏州鹏旭医药科技有限公司 一种化合物及其制备方法和在合成布瓦西坦中的用途
CN106748950A (zh) 2017-01-13 2017-05-31 成都美域高制药有限公司 一种布瓦西坦及其中间体的制备方法
WO2018220646A1 (en) * 2017-05-29 2018-12-06 Msn Laboratories Private Limited, R&D Center An improved process for the preparation of (2s)-2-[(4r)-2-oxo-4-propyltetrahydro-1h-pyrrol-1-yl] butanamide and its intermediates thereof
CN107513032A (zh) * 2017-07-25 2017-12-26 峨眉山宏昇药业股份有限公司 一种用于治疗癫痫的药物及其中间体的合成方法
CN107663185A (zh) 2017-11-14 2018-02-06 安徽华胜医药科技有限公司 一种丁内酯衍生物的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3812377A4

Also Published As

Publication number Publication date
EP3812377A1 (en) 2021-04-28
CN112020498B (zh) 2024-04-02
US20210253523A1 (en) 2021-08-19
EP3812377A4 (en) 2022-03-16
CN110615744A (zh) 2019-12-27
CN112020498A (zh) 2020-12-01
JP2021527703A (ja) 2021-10-14
CN110615744B (zh) 2023-01-06
JP7097467B2 (ja) 2022-07-07
US11518741B2 (en) 2022-12-06

Similar Documents

Publication Publication Date Title
WO2019242192A1 (zh) 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法
TWI799435B (zh) 製備化合物之製程
CN112739683B (zh) 布瓦西坦的制备方法及其中间体
WO2008062460A2 (en) Crystalline forms of pregabalin
JP5901534B2 (ja) タペンタドールおよびその中間体を調製するための新しい方法
CN111606826A (zh) 一种依度沙班中间体的制备方法
HU229188B1 (hu) Új eljárás N-[(S)-1-karboxibutil]-(S)-alanin-észterek elõállítására, és a perindopril szintézisnél történõ alkalmazása
CN116514666A (zh) 一种盐酸溴己新的制备方法
CN1451660A (zh) 一种制备格拉司琼及其盐的方法
CN116836069B (zh) 一种盐酸左沙丁胺醇的制备方法
CN101973909B (zh) 一种米屈肼的制备方法
CN101481335B (zh) 卡巴拉汀中间体的制备方法
CN112341413A (zh) 一种用于合成布瓦西坦的中间体及其制备方法
CN110845305B (zh) 一种采用改性均相催化剂制备l-薄荷醇的方法
CN110577476A (zh) 一种苯丙胺类化合物、其制备方法、分离方法和用途
CN109734653B (zh) 一种阿加曲班起始原料异构体杂质的拆分方法
CN109761886B (zh) 一种阿加曲班起始原料异构体杂质的拆分方法
EP3068746B1 (en) Process for the preparation of enantiomerically pure 1-aminoindan
CN111333552B (zh) β-苯并氨基酸类化合物的合成方法
CN104628600B (zh) 一种(s)-甲基多巴中间体化合物的制备方法
KR100900573B1 (ko) (ｓ)-아테놀롤의 제조방법
WO2005118524A1 (en) Process for preparing [(s)-(-)alpha-methylamino phenylacetone]2 (2r, 3r)-tartaric acid derivates
JP4208174B2 (ja) アミノ化合物類ならびにその立体選択的製造方法
CN118878427A (zh) 一种制备瑞波替尼中间体的方法
CN118530145A (zh) 一种达芦那韦关键中间体的合成方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18923290

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020571459

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018923290

Country of ref document: EP

Effective date: 20210120