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WO2019084740A1 - 一种Glecaprevir合成中间体及其胺盐的制备方法 - Google Patents

一种Glecaprevir合成中间体及其胺盐的制备方法 Download PDF

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Publication number
WO2019084740A1
WO2019084740A1 PCT/CN2017/108453 CN2017108453W WO2019084740A1 WO 2019084740 A1 WO2019084740 A1 WO 2019084740A1 CN 2017108453 W CN2017108453 W CN 2017108453W WO 2019084740 A1 WO2019084740 A1 WO 2019084740A1
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Prior art keywords
solvent
reaction
preparation
propenyloxycyclopentane
glecaprevir
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PCT/CN2017/108453
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English (en)
French (fr)
Inventor
叶方国
龙双喜
刘庆庆
Original Assignee
上海同昌生物医药科技有限公司
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Priority to PCT/CN2017/108453 priority Critical patent/WO2019084740A1/zh
Publication of WO2019084740A1 publication Critical patent/WO2019084740A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/07—Monoamines containing one, two or three alkyl groups, each having the same number of carbon atoms in excess of three
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/02—Preparation of ethers from oxiranes
    • C07C41/03—Preparation of ethers from oxiranes by reaction of oxirane rings with hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/196—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a preparation method of a Glecaprevir synthetic intermediate and an amine salt thereof.
  • Mavyret is a pan-genotype combination that treats all six subtypes of chronic hepatitis C patients. Mavyret consists of two major components, one of which is the NS3/4A protease inhibitor Glecaprevir (100 mg); the other is the NS5A protease inhibitor Pibrentasvir (40 mg). This new drug takes only once a day and does not require the additional use of ribavirin to provide a pan-genotype of hepatitis C treatment. Mavyret has a new treatment program for doctors and patients.
  • the structural formula of the NS3/4A protease inhibitor Glecaprevir is as shown in Formula I, and its structure is complex, and it is synthesized from a plurality of chiral fragments.
  • US9220748 reports a process for the synthesis of a compound of formula II: using racemic cyclopentanediol as a starting material, after acetylation, the hydrolase is resolved to give the hand intermediate, which is then subjected to allylation, hydrolysis and The condensation reaction gives the compound of formula II.
  • this method has many reaction steps, and the yield is low, and the total yield is about 10%.
  • the present invention provides a process for the preparation of a high yield of Glecaprevir synthetic intermediate.
  • the technical solution adopted by the present invention is:
  • a method for preparing a Glecaprevir synthetic intermediate comprises the following steps:
  • the catalyst is a boron trifluoride diethyl ether complex and/or a tris(pentafluorophenyl)borate diethyl ether complex;
  • the acetylating reagent is acetic anhydride and/or acetyl chloride
  • the base is one or more of sodium acetate, potassium acetate, triethylamine, diisopropylethylamine and pyridine;
  • the biological enzyme is one or more of Lipase PS, Novozym 435, Acalase 2.4L and Acalase 2.5L;
  • the buffer is a phosphate solution
  • the activating reagent is one or more of N,N'-carbonyldiimidazole, phosgene and triphosgene;
  • the active intermediate is mixed with L-tert-leucine, 2-hydroxypyridine oxynitride and a solvent to carry out an amino acid condensation reaction to obtain a Glecaprevir synthetic intermediate.
  • the temperature of the ring opening reaction is -10 to 30 ° C, and the time is 1 to 3 hours.
  • the solvent in the step (1) is one or more of dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile.
  • the mass ratio of the epoxycyclopentane, the propylene alcohol, the catalyst, the solvent and the triethylamine in the step (1) is 1: (1.2 to 10): (0.1 to 1): (5 to 10): (1.5 ⁇ 2.5).
  • the acetylation reaction has a temperature of 0 to 30 ° C and a time of 12 to 18 h.
  • the solvent in the step (2) is one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, acetonitrile and acetone.
  • the mass ratio of 2-hydroxy-1-propenyloxycyclopentane, acetylating agent, base and solvent in the step (2) is 1: (1 to 2): (1.2 to 5): (5) ⁇ 10).
  • the temperature of the hydrolysis and resolution is 0 to 40 ° C, and the time is 12 to 72 h.
  • the temperature of the activation reaction in the step (4) is -10 to 30 ° C, and the time is 1 to 3 hours.
  • the solvent in the step (4) is one or more of dimethyltetrahydrofuran, tetrahydrofuran, dimethylformamide and dichloromethane.
  • the mass ratio of (-)-2-hydroxy-1-propenyloxycyclopentane, activating reagent, solvent and ice water in the step (4) is 1: (1.5 to 2): (8-12) ): (1 to 5).
  • the temperature of the amino acid condensation reaction in the step (5) is 20 to 100 ° C, and the time is 12 to 16 hours.
  • the solvent in the step (5) is one or more of N-methylpyrrolidone, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide.
  • the mass ratio of the active intermediate to the solvent in the step (5) is 1: (5-15).
  • the invention also provides a preparation method of a Glecaprevir synthetic intermediate amine salt, comprising the following steps:
  • the Glecaprevir synthetic intermediate is prepared according to the steps (1) to (5) of the preparation method described in the above technical scheme;
  • the Glecaprevir synthesis intermediate and the amine are subjected to a salt formation reaction to obtain a Glecaprevir synthesis intermediate amine salt.
  • the amine is preferably one or more of t-butylamine, dicyclohexylamine, R-phenylethylamine and 2-butylamine.
  • the mass ratio of the amine to L-tert-leucine is (1 to 1.5):1.
  • the salt formation reaction is carried out in a methyl tert-butyl ether solvent, and the volume ratio of the mass of the amine to the methyl tert-butyl ether solvent is (1 to 1.5) g: (10 to 15) mL.
  • the salt formation reaction comprises a first-stage heat preservation stage and a second-stage heat preservation stage which are sequentially performed;
  • the temperature of the first-stage heat preservation stage is 40 to 50 ° C, and the time is 1 to 3 hours;
  • the temperature of the second-stage heat preservation stage is 20 to 30 ° C, and the time is 5 to 6 hours.
  • the invention provides a preparation method of a Glecaprevir synthetic intermediate, which comprises a cyclopentane as a starting material, a ring opening reaction to form 2-hydroxy-1-propenyloxycyclopentane, and acetylation to obtain a 2-acetoxy group.
  • 1-propenyloxycyclopentane after resolution, is sequentially activated and amino-condensed to obtain a Glecaprevir synthetic intermediate.
  • the method provided by the invention has fewer reaction steps, higher yield, and the total yield is higher than 30%, which is much higher than 10% in the prior art; at the same time, the cost is low, the environment is friendly, the reaction condition is mild, the operation is simple, and the suitable In industrial production.
  • the invention also provides a preparation method of the Glecaprevir synthetic intermediate amine salt, which has the characteristics of high yield, mild reaction and simple operation.
  • the invention provides a preparation method of a Glecaprevir synthetic intermediate, comprising the following steps:
  • the catalyst is a boron trifluoride diethyl ether complex and/or a tris(pentafluorophenyl)borate diethyl ether complex;
  • the acetylating reagent is acetic anhydride and/or acetyl chloride
  • the base is one or more of sodium acetate, potassium acetate, triethylamine, diisopropylethylamine and pyridine;
  • the biological enzyme is one or more of Lipase PS, Novozym 435, Acalase 2.4L and Acalase 2.5L;
  • the buffer is a phosphate solution having a pH of 5-8;
  • the activating reagent is one or more of N,N'-carbonyldiimidazole, phosgene and triphosgene;
  • the active intermediate is mixed with L-tert-leucine, 2-hydroxypyridine oxynitride and a solvent to carry out an amino acid condensation reaction to obtain a Glecaprevir synthetic intermediate.
  • the present invention mixes epoxycyclopentane, propylene alcohol, a catalyst and a solvent to carry out a ring opening reaction.
  • the catalyst is preferably a boron trifluoride diethyl ether complex and/or a tris(pentafluorophenyl)borate diethyl ether complex;
  • the solvent is preferably dichloromethane, chloroform, tetrahydrofuran, 2-methyl One or more of tetrahydrofuran and acetonitrile.
  • the present invention does not have any particular requirement for the source of the epoxycyclopentane, propylene alcohol, catalyst and solvent, and the above-mentioned commercially available materials well known to those skilled in the art may be used.
  • the present invention it is preferred to first mix the propylene alcohol, the catalyst and the solvent, and then add the epoxycyclopentane; in the present invention, it is preferred to add the epoxycyclopentane to the mixture of the above-mentioned propylene alcohol, the catalyst and the solvent at a temperature of 0 to 20 ° C. It is more preferably 5 to 15 ° C, and most preferably 8 to 13 ° C.
  • the temperature of the system changes during the dropping process, and the present invention does not have any special requirement for the rate of dropping the epoxycyclopentane to control the temperature of the reaction system to be maintained between 0 and 20 °C.
  • the temperature of the ring-opening reaction is preferably -10 to 30 ° C, more preferably 0 to 20 ° C, most preferably 10 to 15 ° C; and the time of the ring-opening reaction is preferably 1 to 3 h, It is preferably 2h.
  • the ring-opening reaction is started, and the ring opening reaction time of the present application is from all epoxycyclopentanes. Start timing when the alkane is added.
  • the present invention is added to triethylamine to quench the reaction to obtain 2-hydroxy-1- Propenyloxycyclopentane.
  • the temperature at which the reaction is quenched after the addition of triethylamine is preferably -10 to 10 ° C, more preferably -5 to 5 ° C; and the time is preferably 0.5 to 1 h, more preferably 0.6 to 0.8 h.
  • the mass ratio of the epoxycyclopentane, propylene alcohol, catalyst, solvent and triethylamine is preferably 1: (1.2 to 10): (0.1 to 1): (5 to 10): (1.5) ⁇ 2.5), more preferably 1: (3-8): (0.2-0.8): (6-9): (1.8-2.3), and most preferably 1: (4-6): (0.4-0.6): (7-8): (2 ⁇ 2.1).
  • the present invention preferably performs a vacuum distillation treatment on the obtained product system to obtain pure 2-hydroxy-1-propenyloxycyclopentane.
  • the vacuum degree of the vacuum distillation is preferably 20 mba, and the temperature is preferably 75 to 80 °C.
  • the present invention has no special requirement for the time of the vacuum distillation, and a pure target product can be obtained.
  • reaction of the present invention for preparing 2-hydroxy-1-propenyloxycyclopentane is:
  • the present invention combines the 2-hydroxy-1-propenyloxycyclopentane, an acetylating agent, a base and a solvent to carry out an acetylation reaction to obtain 2-acetyl.
  • Oxy-1-propenyloxycyclopentane is
  • the acetylating agent is acetic anhydride and/or acetyl chloride
  • the base is one or more of sodium acetate, potassium acetate, triethylamine, diisopropylethylamine and pyridine
  • the solvent is preferably one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, acetonitrile and acetone.
  • the present invention does not have any particular requirement for the source of the acetylating agent, base and solvent, and it is also possible to use the above-mentioned commercially available materials well known to those skilled in the art.
  • the present invention it is preferred to first mix 2-hydroxy-1-propenyloxycyclopentane, a base and a solvent, and then add an acetylating agent; more preferably, the catalyst and 2-hydroxy-1-propenyloxycyclopentane are used in the present invention.
  • the alkane, the base and the solvent are mixed, and then the acetylating agent is added; in the present invention, the acetylating agent is preferably added dropwise to the mixture obtained by the above mixing at 0 to 10 ° C, more preferably 2 to 8 ° C, and most preferably 4 to 6 °C.
  • the present invention does not have any special requirement for the rate at which the acetylating agent is added dropwise, so as to control the temperature of the reaction system to be maintained between 0 and 10 °C.
  • the catalyst is preferably 4-dimethylaminopyridine (DMAP).
  • the temperature of the acetylation reaction is preferably 0 to 30 ° C, more preferably 10 to 20 ° C, most preferably 14 to 16 ° C; and the time is preferably 12 to 18 h, more preferably 14 to 16 h.
  • an acetylating agent is added to the above mixture of 2-hydroxy-1-propenyloxycyclopentane, a base and a solvent, the acetylation reaction starts, and the time of the acetylation reaction described in the present application It is timed from the time all the acetylation reagents are added.
  • the mass ratio of the 2-hydroxy-1-propenyloxycyclopentane, the acetylating agent, the base and the solvent is preferably 1: (0.1 to 2): (0.2 to 5): (5 to 10) More preferably, it is 1: (1.2 to 1.8): (2 to 4): (6 to 9), most preferably 1: (1.4 to 1.6): (2.5 to 3): (7 to 8);
  • the mass ratio of 2-hydroxy-1-propenyloxycyclopentane to the catalyst is preferably (10 to 11):1.
  • the present invention hydrolyzes the 2-acetoxy-1-propenyloxycyclopentane under the action of a biological enzyme and a buffer.
  • (-)-2-Hydroxy-1-propenyloxycyclopentane is obtained.
  • the hydrolysis and resolution process further comprises a solvent
  • the solvent is preferably acetone, dimethyl sulfoxide or tetrahydrofuran; the volume ratio of the solvent to the buffer is preferably 1: (3 to 7), It is preferably 1:5.
  • the temperature of the hydrolysis and resolution is preferably 0 to 40 ° C, more preferably 10 to 30 ° C, most preferably 15 to 25 ° C; time is preferably 12 to 72 h, more preferably 20 to 60 h, most It is preferably 40 to 50 hours.
  • a 1.0 N sodium hydroxide solution to the system during the hydrolysis and resolution to maintain the pH of the reaction system from 5 to 8, preferably from 6.8 to 7.1.
  • the 2-acetoxy-1-propenyloxycyclopentane in the step (3) a living being
  • the mass ratio of the enzyme to the buffer is preferably 1: (0.1 to 1): (5 to 20), more preferably 1: (0.2 to 0.8): (10 to 15), and most preferably 1: (0.4 to 0.6). :(12 ⁇ 13).
  • the present invention preferably filters the obtained product system, and extracts the filtrate obtained by filtration into ethyl acetate for extraction. After the extraction, the organic phase is concentrated under reduced pressure to give a crude material.
  • the present invention does not have any special requirements for the specific embodiment of the reduced pressure concentration, and may be carried out by means of a reduced pressure concentration means conventionally used by those skilled in the art.
  • reaction of the hydrolysis and resolution process of the present invention is:
  • the present invention combines the (-)-2-hydroxy-1-propenyloxycyclopentane with an activating reagent and a solvent under an inert atmosphere to cause an activation reaction.
  • the inert atmosphere is preferably a nitrogen atmosphere;
  • the activating reagent is preferably one or more of N,N'-carbonyldiimidazole (CDI), phosgene and triphosgene;
  • the solvent is preferably One or more of 2-methyltetrahydrofuran, tetrahydrofuran, dimethylformamide, and dichloromethane.
  • the present invention does not have any particular requirement for the source of the activating reagent and solvent, and commercially available materials as known to those skilled in the art may be employed.
  • the activating reagent and a portion of the solvent are first mixed, and then a mixture of the resolved product and the remaining solvent is added.
  • a mixture of the resolved product and the remaining solvent it is preferred to add a mixture of the resolved product and the remaining solvent at 0 to 5 ° C to avoid a sharp rise in temperature due to exothermic heat of the reaction, more preferably 1 to 4 ° C, and most preferably 2 to 3 ° C.
  • the temperature of the activation reaction in the step (4) is preferably -10 to 30 ° C, more preferably 0 to 20 ° C, most preferably 10 to 15 ° C; and the time is preferably 1 to 3 h, more preferably 2h.
  • the activation reaction is started, and the activation reaction time of the present application is from all the resolved products and The timing of the mixture of remaining solvents is started when the addition is completed.
  • the present invention is quenched by adding ice water to the reaction system to obtain an active intermediate.
  • the mass ratio of the (-)-2-hydroxy-1-propenyloxycyclopentane, the activating reagent, the solvent and the ice water is preferably 1: (1.5 to 2): (8 to 12): (1 to 5), more preferably 1: (1.6 to 1.9): (9 to 11): (2 to 4), most preferably 1: (1.7 to 1.8): 10:3.
  • the present invention preferably adds n-hexane to the quenching system to extract the active intermediate.
  • the mass ratio of the activating reagent to n-hexane is preferably (1.5 to 2): (5 to 10), more preferably (1.6 to 1.8): (6 to 8).
  • the present invention does not have any special requirements for the embodiment of the extraction, and may be carried out by an extraction method commonly used by those skilled in the art.
  • the present invention preferably evaporates the extracted organic phase.
  • the present invention does not have any special requirements for the embodiment of the evaporation drying treatment, and may be carried out by a steam drying method commonly used by those skilled in the art.
  • the mass ratio of the (-)-2-hydroxy-1-propoxycyclopentane, L-tert-leucine, and 2-hydroxypyridinium oxynitride is preferably 1: (0.8 to 2). : (0.8 to 2); more preferably 1: (1 to 1.8): (1 to 1.8), most preferably 1: (1.2 to 1.5): (1.2 to 1.5); quality of the active intermediate and solvent
  • the ratio is preferably 1: (5 to 15), more preferably 1: (8 to 13), and most preferably 1: (10 to 11).
  • the present invention preferably adds methyl tert-butyl ether (MTBE) to the product system, and the mass ratio of the methyl tert-butyl ether to the L-tert-leucine is preferably (5 to 10). (1 to 1.8), more preferably (6 to 9): (1.2 to 1.6), and most preferably (7 to 8): (1.3 to 1.4).
  • MTBE methyl tert-butyl ether
  • the Glecaprevir synthesis intermediate is specifically (S)-2-((((1R, 2R)-2-(allyloxy))cyclopentyloxy))carbonyl)amino)-3, 3-dimethylbutyric acid), the structural formula is as shown in formula II:
  • the invention also provides a preparation method of a Glecaprevir synthetic intermediate amine salt, comprising the following steps:
  • the Glecaprevir synthetic intermediate is prepared according to the steps (1) to (5) of the above preparation method;
  • the Glecaprevir synthesis intermediate and the amine are subjected to a salt formation reaction to obtain a Glecaprevir synthesis intermediate amine salt.
  • the amine is preferably one or more of t-butylamine, dicyclohexylamine, R-phenylethylamine and 2-butylamine.
  • the salt-forming reaction is preferably carried out in a methyl tert-butyl ether solvent
  • the mass ratio of the amine to L-tert-leucine is preferably (1 to 1.5): 1, more preferably (1.2). ⁇ 1.3): 1
  • the volume ratio of the mass of the amine to the methyl tert-butyl ether solvent is preferably (1 to 1.5) g: (10 to 15) mL, more preferably (1.2 to 1.3) g: (12) ⁇ 13) mL.
  • the present invention preferably filters the product system under an inert atmosphere to obtain a solid product; then the solid product is washed with methyl tert-butyl ether, and the washed solid product is dried.
  • the inert atmosphere is preferably nitrogen; the drying temperature is preferably from 30 to 40 ° C, more preferably from 34 to 36 ° C; and the drying time is preferably from 8 to 10 h.
  • the Glecaprevir synthesis intermediate obtained in Example 1 was used as a raw material, methyl tert-butyl ether was added to 10 V, and the organic phase was transferred to a 100 mL reaction flask. The temperature was raised to 45 ° C, and a solution of the prepared tert-butylamine (1.2 g) in methyl tert-butyl ether (12 mL) was added dropwise. After the completion of the dropwise addition, the reaction was kept at 45 ° C for 2 h. Slowly cool to 25 ° C and stir for 5 h.
  • the mixture was filtered under a nitrogen atmosphere, and the filter cake was washed with <RTIgt; The filter cake was dried under reduced pressure at 35 ° C for 9 h to give 4.5 g of the tert-butylamine salt of the Glecaprevir synthesis intermediate as a white solid.

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Abstract

公开了一种Glecaprevir合成中间体的制备方法，以环氧环戊烷为原始材料，进行开环反应生成2-羟基-1-丙烯氧基环戊烷，乙酰化得到2-乙酰氧基-1-丙烯氧基环戊烷，拆分后再顺次进行活化和氨基缩合，得到Glecaprevir合成中间体。公开的方法反应步骤少，收率较高，总收率均高于30％，远远高于现有技术中的10％；同时成本低、环境友好、反应条件温和、操作简便、适于工业化生产。还公开了一种Glecaprevir合成中间体胺盐的制备方法，同样具有收率高、反应温和、操作简便的特点。

Description

一种Glecaprevir合成中间体及其胺盐的制备方法 技术领域
本发明涉及有机合成技术领域，尤其涉及一种Glecaprevir合成中间体及其胺盐的制备方法。
背景技术
2017年8月美国食品药品管理局(FDA)批准了艾伯维研发的抗丙肝新药Mavyret的上市申请。Mavyret是一种泛基因型的复方药物，可以治疗所有6种亚型的慢性丙肝患者。Mavyret由两种主要成分组成，其中一种是NS3/4A蛋白酶抑制剂Glecaprevir(100mg)；另一种是NS5A蛋白酶抑制剂Pibrentasvir(40mg)。这款新药每日只需服用一次，且不需要额外使用利巴韦林(ribavirin)，就能起到泛基因型的丙肝治疗效果。Mavyret让医生与患者有了全新的治疗方案，它高度有效，有潜力在短短8周之内治愈大部分丙肝患者，而不用考虑病毒的基因型，极大的简化了丙肝的治疗方案。该复方药物一直受到广泛关注，曾获得美国FDA颁发的突破性疗法认定，以及优先审评资格，具有广阔的市场预期值。
其中，NS3/4A蛋白酶抑制剂Glecaprevir的结构式如式Ⅰ所示，其结构复杂，由多个手性片断合成得到。
Figure PCTCN2017108453-appb-000001
式Ⅰ
而式Ⅱ所示化合物((S)-2-(((((1R,2R)-2-(烯丙氧基)环戊氧基)羰基)氨基)-3,3-二甲基丁酸))是合成Glecaprevir的重要中间体，该中间体具有 三个手性中心，合成难度大。
Figure PCTCN2017108453-appb-000002
式Ⅱ
US9220748报道了一种合成式Ⅱ所示化合物的方法：以消旋的环戊二醇为原料，经过乙酰化后，水解酶拆分得到手型中间体，再通过烯丙基化反应、水解和缩合反应得到式Ⅱ所示化合物。然而，这一方法反应步骤多，收率较低，总收率约为10％。
发明内容
为了克服现有技术的上述缺点，本发明提供一种高收率的Glecaprevir合成中间体的制备方法。
为了解决上述技术问题，本发明采用的技术方案是：
一种Glecaprevir合成中间体的制备方法，包含如下步骤：
(1)将环氧环戊烷、丙烯醇、催化剂和溶剂混合，进行开环反应，加入三乙胺淬灭后得到2-羟基-1-丙烯氧基环戊烷；
所述催化剂为三氟化硼乙醚络合物和/或三(五氟苯基)硼乙醚络合物；
(2)所述2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂混合进行乙酰化反应，得到2-乙酰氧基-1-丙烯氧基环戊烷；
所述乙酰化试剂为乙酸酐和/或乙酰氯；
所述碱为乙酸钠、乙酸钾、三乙胺、二异丙基乙胺和吡啶中的一种或几种；
(3)将所述2-乙酰氧基-1-丙烯氧基环戊烷在生物酶和缓冲液的作用下进行水解拆分，分别得到(-)-2-羟基-1-丙烯氧基环戊烷；
所述生物酶为Lipase PS、Novozym 435、Acalase 2.4L和Acalase 2.5L中的一种或几种；
所述缓冲液为磷酸盐溶液；
(4)惰性气氛下，将所述(-)-2-羟基-1-丙烯氧基环戊烷与活化试剂和溶剂混合，发生活化反应，加入冰水淬灭后得到活性中间体；
所述活化试剂为N,N'-羰基二咪唑、光气和三光气中的一种或几种；
(5)将所述活性中间体与L-叔亮氨酸、2-羟基吡啶氮氧化合物和溶剂混合，进行氨基酸缩合反应，得到Glecaprevir合成中间体。
优选的，所述开环反应的温度为-10～30℃，时间为1～3h。
优选的，所述步骤(1)中溶剂为二氯甲烷、氯仿、四氢呋喃、2-甲基四氢呋喃和乙腈中的一种或几种。
优选的，所述步骤(1)中环氧环戊烷、丙烯醇、催化剂、溶剂和三乙胺的质量比为1:(1.2～10):(0.1～1):(5～10):(1.5～2.5)。
优选的，所述乙酰化反应的温度为0～30℃，时间为12～18h。
优选的，所述步骤(2)中的溶剂为二氯甲烷、氯仿、四氢呋喃、甲基叔丁基醚、乙腈和丙酮中的一种或几种。
优选的，所述步骤(2)中2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂的质量比为1:(1～2):(1.2～5):(5～10)。
优选的，所述水解拆分的温度为0～40℃，时间为12～72h。
优选的，所述步骤(3)中2-乙酰氧基-1-丙烯氧基环戊烷、生物酶和缓冲液的质量比为1:(0.1～1):(5～20)。
优选的，所述步骤(4)中活化反应的温度为-10～30℃，时间为1～3h。
优选的，所述步骤(4)中溶剂为二甲基四氢呋喃、四氢呋喃、二甲基甲酰胺和二氯甲烷中的一种或几种。
优选的，所述步骤(4)中(-)-2-羟基-1-丙烯氧基环戊烷、活化试剂、溶剂和冰水的质量比为1:(1.5～2):(8～12):(1～5)。
优选的，所述步骤(5)中氨基酸缩合反应的温度为20～100℃，时间为12～16h。
优选的，所述步骤(5)中溶剂为N-甲基吡咯烷酮、四氢呋喃、二甲基甲酰胺和二甲亚砜中的一种或几种。
优选的，所述步骤(5)中(-)-2-羟基-1-丙烯氧基环戊烷、L-叔亮氨酸、2-羟基吡啶氮氧化合物的质量比为1:(0.8～2):(0.8～2)。
优选的，所述步骤(5)中活性中间体和溶剂的质量比为1:(5～15)。
本发明还提供了一种Glecaprevir合成中间体胺盐的制备方法，包含如下步骤：
按照上述技术方案所述制备方法的步骤(1)～(5)制备得到Glecaprevir合成中间体；
将所述Glecaprevir合成中间体和胺进行成盐反应，得到Glecaprevir合成中间体胺盐。
优选的，所述胺优选为叔丁胺、二环已基胺、R-苯乙胺和2-丁胺中的一种或几种。
优选的，所述胺和L-叔亮氨酸的质量比为(1～1.5):1。
优选的，所述成盐反应在甲基叔丁基醚溶剂中进行，所述胺的质量和甲基叔丁基醚溶剂的体积比为(1～1.5)g:(10～15)mL。
优选的，所述成盐反应包含顺次进行的一级保温阶段和二级保温阶段；
所述一级保温阶段的温度为40～50℃，时间为1～3h；
所述二级保温阶段的温度为20～30℃，时间为5～6h。
本发明提供了一种Glecaprevir合成中间体的制备方法，以环氧环戊烷为原始材料，进行开环反应生成2-羟基-1-丙烯氧基环戊烷，乙酰化得到2-乙酰氧基-1-丙烯氧基环戊烷，拆分后再顺次进行活化和氨基缩合，得到Glecaprevir合成中间体。本发明提供的方法反应步骤少，收率较高，总收率均高于30％，远远高于现有技术中的10％；同时成本低、环境友好、反应条件温和、操作简便、适于工业化生产。本发明还提供了一种Glecaprevir合成中间体胺盐的制备方法，同样具有收率高、反应温和、操作简便的特点。
具体实施方式
本发明提供了一种Glecaprevir合成中间体的制备方法，包含如下步骤：
(1)将环氧环戊烷、丙烯醇、催化剂和溶剂混合，进行开环反应，加入三乙胺淬灭后得到2-羟基-1-丙烯氧基环戊烷；
所述催化剂为三氟化硼乙醚络合物和/或三(五氟苯基)硼乙醚络合物；
(2)所述2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂混合进行乙酰化反应，得到2-乙酰氧基-1-丙烯氧基环戊烷；
所述乙酰化试剂为乙酸酐和/或乙酰氯；
所述碱为乙酸钠、乙酸钾、三乙胺、二异丙基乙胺和吡啶中的一种或几种；
(3)将所述2-乙酰氧基-1-丙烯氧基环戊烷在生物酶和缓冲液的作用下进行水解拆分，得到(-)-2-羟基-1-丙烯氧基环戊烷；
所述生物酶为Lipase PS、Novozym 435、Acalase 2.4L和Acalase 2.5L中的一种或几种；
所述缓冲液为pH值为5～8的磷酸盐溶液；
(4)惰性气氛下，将所述(-)-2-羟基-1-丙烯氧基环戊烷与活化试剂和溶剂混合，发生活化反应，加入冰水淬灭后得到活性中间体；
所述活化试剂为N,N'-羰基二咪唑、光气和三光气中的一种或几种；
(5)将所述活性中间体与L-叔亮氨酸、2-羟基吡啶氮氧化合物和溶剂混合，进行氨基酸缩合反应，得到Glecaprevir合成中间体。
本发明将环氧环戊烷、丙烯醇、催化剂和溶剂混合，进行开环反应。在本发明中，所述催化剂优选为三氟化硼乙醚络合物和/或三(五氟苯基)硼乙醚络合物；所述溶剂优选为二氯甲烷、氯仿、四氢呋喃、2-甲基四氢呋喃和乙腈中的一种或几种。本发明对所述环氧环戊烷、丙烯醇、催化剂和溶剂的来源没有任何的特殊要求，采用本领域技术人员所熟知的市售的上述物质即可。
本发明优选先将丙烯醇、催化剂和溶剂混合，然后再加入环氧环戊烷；本发明优选在0～20℃温度下向上述丙烯醇、催化剂和溶剂的混合物中滴加环氧环戊烷，更优选为5～15℃，最优选为8～13℃。所述滴加过程中体系温度会发生变化，本发明对滴加所述环氧环戊烷的速率没有任何的特殊要求，以控制反应体系的温度保持在0～20℃之间即可。
在本发明中，所述开环反应的温度优选为-10～30℃，更优选为0～20℃，最优选为10～15℃；所述开环反应的时间优选为1～3h，更优选为2h。在本发明中，只要有环氧环戊烷加入到上述丙烯醇、催化剂和溶剂的混合物中，所述开环反应就开始进行，本申请所述开环反应的时间是从所有环氧环戊烷添加完毕时开始计时。
开环反应时间达到后，本发明加入三乙胺淬灭反应后得到2-羟基-1- 丙烯氧基环戊烷。在本发明中，加入三乙胺后淬灭反应的温度优选为-10～10℃，更优选为-5～5℃；时间优选为0.5～1h，更优选为0.6～0.8h。
在本发明中，所述环氧环戊烷、丙烯醇、催化剂、溶剂和三乙胺的质量比优选为1:(1.2～10):(0.1～1):(5～10):(1.5～2.5)，更优选为1:(3～8):(0.2～0.8):(6～9):(1.8～2.3)，最优选为1:(4～6):(0.4～0.6):(7～8):(2～2.1)。
所述淬灭结束后，本发明优选对得到的产物体系进行减压蒸馏处理，得到纯净的2-羟基-1-丙烯氧基环戊烷。在本发明中，所述减压蒸馏的真空度优选为20mba，温度优选为75～80℃。本发明对所述减压蒸馏的时间没有特殊要求，能够得到纯净的目标产物即可。
本发明制备2-羟基-1-丙烯氧基环戊烷的反应实质为：
Figure PCTCN2017108453-appb-000003
得到2-羟基-1-丙烯氧基环戊烷后，本发明将所述2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂混合进行乙酰化反应，得到2-乙酰氧基-1-丙烯氧基环戊烷。在本发明中，所述乙酰化试剂为乙酸酐和/或乙酰氯；所述碱为乙酸钠、乙酸钾、三乙胺、二异丙基乙胺和吡啶中的一种或几种；所述溶剂优选为二氯甲烷、氯仿、四氢呋喃、甲基叔丁基醚、乙腈和丙酮中的一种或几种。本发明对所述乙酰化试剂、碱和溶剂的来源没有任何的特殊要求，采用本领域技术人员所熟知的市售的上述物质即可。
本发明优选先将2-羟基-1-丙烯氧基环戊烷、碱和溶剂混合，然后再加入乙酰化试剂；本发明更优选的先将催化剂和2-羟基-1-丙烯氧基环戊烷、碱、溶剂混合，然后再加入乙酰化试剂；本发明优选在0～10℃下向上述混合得到的混合物中滴加乙酰化试剂，更优选为2～8℃，最优选为4～6℃。本发明对滴加所述乙酰化试剂的速率没有任何的特殊要求，以控制反应体系的温度保持在0～10℃之间即可。在本发明明中，所述催化剂优选为4-二甲氨基吡啶(DMAP).
在本发明中，所述乙酰化反应的温度优选为0～30℃，更优选为10～20℃，最优选为14～16℃；时间优选为12～18h，更优选为14～16h。在 本发明中，只要有乙酰化试剂加入到上述2-羟基-1-丙烯氧基环戊烷、碱和溶剂的混合物中，所述乙酰化反应就开始进行，本申请所述乙酰化反应的时间是从所有乙酰化试剂添加完毕时开始计时。
在本发明中，所述2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂的质量比优选为1:(0.1～2):(0.2～5):(5～10)，更优选为1:(1.2～1.8):(2～4):(6～9)，最优选为1:(1.4～1.6):(2.5～3):(7～8)；所述2-羟基-1-丙烯氧基环戊烷和催化剂的质量比优选为(10～11):1。
本发明制备2-乙酰氧基-1-丙烯氧基环戊烷的反应实质为：
Figure PCTCN2017108453-appb-000004
得到2-乙酰氧基-1-丙烯氧基环戊烷后，本发明将所述2-乙酰氧基-1-丙烯氧基环戊烷在生物酶和缓冲液的作用下进行水解拆分，得到(-)-2-羟基-1-丙烯氧基环戊烷。
在本发明中，所述水解拆分过程还包含溶剂，所述溶剂优选为丙酮、二甲基亚砜或四氢呋喃；所述溶剂和缓冲液的体积比优选为1:(3～7)，更优选为1:5。
在本发明中，所述生物酶为Lipase PS、Novozym 435、Acalase 2.4L和Acalase 2.5L中的一种或几种；所述缓冲液为磷酸盐溶液，所述磷酸盐优选为磷酸钾和/或磷酸钠；所述缓冲液的浓度优选为0.5～1.5M。更优选为1M。本发明对所述生物酶和缓冲液的来源没有任何的特殊要求，采用本领域技术人员所熟知的市售的上述物质即可。
在本发明中，所述水解拆分的温度优选为0～40℃，更优选为10～30℃，最优选为15～25℃；时间优选为12～72h，更优选为20～60h，最优选为40～50h。
本发明优选在所述水解拆分的过程中向体系中补加1.0N的氢氧化钠溶液，以维持反应体系的pH值为5～8，优选为6.8～7.1。
在本发明中，所述步骤(3)中2-乙酰氧基-1-丙烯氧基环戊烷、生物 酶和缓冲液的质量比优选为1:(0.1～1):(5～20)，更优选为1:(0.2～0.8):(10～15)，最优选为1:(0.4～0.6):(12～13)。
所述水解拆分结束后，本发明优选对得到的产物体系进行过滤，对过滤得到的滤液加入乙酸乙酯进行萃取。萃取后，有机相减压浓缩得到粗品即可进行下序步骤。本发明对所述减压浓缩的具体实施方式没有任何的特殊要求，采用本领域技术人员所常规使用的减压浓缩手段进行即可。
本发明所述水解拆分过程的反应实质为：
水解拆分后，本发明在惰性气氛下，将所述(-)-2-羟基-1-丙烯氧基环戊烷与活化试剂和溶剂混合，发生活化反应。在本发明中，所述惰性气氛优选为氮气气氛；所述活化试剂优选为N,N'-羰基二咪唑(CDI)、光气和三光气中的一种或几种；所述溶剂优选为2-甲基四氢呋喃、四氢呋喃、二甲基甲酰胺和二氯甲烷中的一种或几种。本发明对所述活化试剂和溶剂的来源没有任何的特殊要求，采用本领域技术人员所熟知的市售的上述物质即可。
本发明优选先将活化试剂和部分溶剂混合，然后再加入拆分产物与剩余溶剂的混合物。本发明优选在0～5℃下添加拆分产物与剩余溶剂的混合物，以避免反应放热导致的温度急剧升高，更优选为1～4℃，最优选为2～3℃。
在本发明中，所述步骤(4)中活化反应的温度优选为-10～30℃，更优选为0～20℃，最优选为10～15℃；时间优选为1～3h，更优选为2h。在本发明中，只要有拆分产物与剩余溶剂的混合物加入到上述活化试剂和部分溶剂的混合物中，所述活化反应就开始进行，本申请所述活化反应的时间是从所有拆分产物与剩余溶剂的混合物添加完毕时开始计时。
所述活化反应时间达到后，本发明向反应体系中加入冰水淬灭后得到活性中间体。在本发明中，所述(-)-2-羟基-1-丙烯氧基环戊烷、活化试剂、溶剂和冰水的质量比优选为1:(1.5～2):(8～12):(1～5)，更优选为 1:(1.6～1.9):(9～11):(2～4)，最优选为1:(1.7～1.8):10:3。
所述淬灭结束后，本发明优选向淬灭体系中添加正己烷来萃取活性中间体。在本发明中，所述活化试剂和正己烷的质量比优选为(1.5～2):(5～10)，更优选为(1.6～1.8):(6～8)。本发明对所述萃取的实施方式没有任何的特殊要求，采用本领域技术人员所常用的萃取方法进行即可。
所述萃取结束后，本发明优选对萃取得到的有机相进行蒸干处理。本发明对所述蒸干处理的实施方式没有任何的特殊要求，采用本领域技术人员所常用的蒸干方法进行即可。
得到活性中间体后，本发明将所述活性中间体与L-叔亮氨酸、2-羟基吡啶氮氧化合物和溶剂混合，进行氨基酸缩合反应，得到Glecaprevir合成中间体。在本发明中，所述溶剂优选为N-甲基吡咯烷酮、四氢呋喃、二甲基甲酰胺和二甲亚砜中的一种或几种。本发明对所述L-叔亮氨酸、2-羟基吡啶氮氧化合物和溶剂的来源没有任何的特殊要求，采用本领域技术人员所熟知的市售来源的上述物质即可。
在本发明中，所述(-)-2-羟基-1-丙烯氧基环戊烷、L-叔亮氨酸、2-羟基吡啶氮氧化合物的质量比优选为1:(0.8～2):(0.8～2)；更优选为1:(1～1.8):(1～1.8)，最优选为1:(1.2～1.5):(1.2～1.5)；所述活性中间体和溶剂的质量比优选为1:(5～15)，更优选为1:(8～13)，最优选为1:(10～11)。
在本发明中，所述步骤(5)中氨基酸缩合反应的温度优选为20～100℃，更优选为40～80℃，最优选为50～60℃；时间优选为12～16h，更优选为13～15h。
所述氨基酸缩合反应结束后，本发明优选向产物体系中加入甲基叔丁基醚(MTBE)，所述甲基叔丁基醚和L-叔亮氨酸的质量比优选为(5～10):(1～1.8)，更优选为(6～9):(1.2～1.6)，最优选为(7～8):(1.3～1.4)。
加入甲基叔丁基醚后，本发明优选顺次对得到的体系进行水洗萃取、甲基叔丁基醚萃取和饱和食盐水萃取，以得到纯净的Glecaprevir合成中间体。
在本发明中，所述Glecaprevir合成中间体具体的为(S)-2-(((((1R,2R)-2-(烯丙氧基)环戊氧基)羰基)氨基)-3,3-二甲基丁酸)，其结构式如式Ⅱ所示：
Figure PCTCN2017108453-appb-000006
式Ⅱ。
本发明还提供了一种Glecaprevir合成中间体胺盐的制备方法，包含如下步骤：
按照上述制备方法的步骤(1)～(5)制备得到Glecaprevir合成中间体；
将所述Glecaprevir合成中间体和胺进行成盐反应，得到Glecaprevir合成中间体胺盐。
在本发明中，所述胺优选为叔丁胺、二环已基胺、R-苯乙胺和2-丁胺中的一种或几种。
在本发明中，所述成盐反应优选在甲基叔丁基醚溶剂中进行，所述胺和L-叔亮氨酸的质量比优选为(1～1.5):1，更优选为(1.2～1.3):1；所述胺的质量和甲基叔丁基醚溶剂的体积比优选为(1～1.5)g:(10～15)mL，更优选为(1.2～1.3)g:(12～13)mL。
在本发明中，所述成盐反应包含顺次进行的一级保温阶段和二级保温阶段，所述一级保温阶段的温度优选为40～50℃，更优选为42～48℃，最优选为45～46℃；所述一级保温阶段的时间优选为1～3h，更优选为2h；所述二级保温阶段的温度优选为20～30℃，更优选为22～28℃，最优选为24～26℃；所述二级保温阶段的时间优选为5～6h，更优选为5.5h。
所述成盐反应结束后，本发明优选在惰性气氛下对产物体系进行过滤处理，得到固体产物；然后使用甲基叔丁基醚对所述固体产物进行洗涤，对洗涤后的固体产物进行干燥，得到纯净的Glecaprevir合成中间体胺盐。在本发明中，所述惰性气氛优选为氮气；所述干燥的温度优选为30～40℃，更优选为34～36℃；所述干燥的时间优选为8～10h。
下面结合实施例对本发明提供的Glecaprevir合成中间体及其胺盐进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
向反应瓶中依次加入1.4L丙烯醇，82mL三氟化硼乙醚溶液，15L二氯甲烷，搅拌均匀。降温至10℃，滴加0.52L的环氧环戊烷，维持温度在10℃。滴加完成，维持该温度搅拌3h。GC跟踪反应完全后，滴加1.4L三乙胺淬灭反应，加压浓缩溶剂后蒸馏得到无色油状物(6.17g，75.8％)。
对得到的无色油状物进行核磁检测检测结果为：1H NMR(400MHz,CDCl3)δ6.06(m,1H),5.42(m,1H),5.30(m,1H),4.20(m,1H),4.15(m,2H),3.78(m,1H),2.06(m,1H),1.73(m,J＝4H),1.45(m,1H)。检测结果表明，得到的无色油状物为目标产物2-羟基-1-丙烯氧基环戊烷。
向反应瓶中依次加入13.4g上述步骤得到的2-羟基-1-丙烯氧基环戊烷，11.6g乙酸钠，1.3g DMAP和54mL二氯甲烷，搅拌均匀。降温至10℃，滴加乙酸酐11.6g。滴加完毕后，在20℃下搅拌12h。GC检测反应结束后，过滤。滤液加入20mL饮用水，分层，水相用30mL二氯甲烷萃取一次。有机相合并，减压浓缩得到2-乙酰氧基-1-丙烯氧基环戊烷(12g,70％)。
2-乙酰氧基-1-丙烯氧基环戊烷的核磁结果为：1HNMR(500MHz,CDCl3)δ6.06(m,1H),5.42(m,1H)5.36(m,1H),5.09(m,1H),4.13(d,2H),4.04(m,1H),2.15(m,1H),2.02(s,3H),1.90(m,1H),1.82–1.58(m,3H),1.45(m,1H).
向反应瓶中一次加入pH＝7.0的40L磷酸钾缓冲溶液，8L丙酮，3.4kg上述步骤得到的2-乙酰氧基-1-丙烯氧基环戊烷，400g Lipase PS。反应体系维持10℃，搅拌反应12h。GC检测反应完成后，过滤。滤液加入乙酸乙酯(10L x 2)萃取。合并有机相，浓缩有机相得到粗品，粗品不进行纯化直接用于下一步(ee值:99.0％)。
取少量产物样品经过硅胶纯化，检测鉴定为拆分后产物，核磁结果为：1H NMR(400MHz,CDCl3)δ6.06(m,1H),5.42(m,1H),5.30(m,1H),4.20(m,1H),4.15(m,2H),3.78(m,1H),2.06(m,1H),1.73(m,J＝4H),1.45(m,1H).)
氮气保护下，向三口瓶中加入3.0g CDI,19mL 2-甲基四氢呋喃，搅拌 均匀后。降温至0℃，滴加2.0g上述步骤得到的拆分产物的4mL 2-甲基四氢呋喃溶液。滴毕，升温至25℃搅拌2h。GC检测反应完全后，滴加冰水淬灭反应。加入正己烷10mL萃取。有机相浓缩干后，加入13g N-甲基吡咯烷酮稀释并转入到干净的三口瓶中。加入1.0g L-叔亮氨酸和0.27g 2-羟基吡啶氮氧化合物。在60℃下，搅拌反应12h。反应结束后，加入甲基叔丁基醚(15mL x 2)，用水(10mL)萃取。有机相水洗两次，饱和食盐水洗一次，有机相浓缩至3V-5V，停止浓缩，得到Glecaprevir合成中间体。
实施例2
向反应瓶中依次加入1.4L丙烯醇，82mL三氟化硼乙醚溶液，15L二氯甲烷，搅拌均匀。降温至20℃，滴加0.52L的环氧环戊烷，维持温度在20℃。滴加完成，在30℃下搅拌3h。GC跟踪反应完全后，滴加1.4L三乙胺淬灭反应，加压浓缩溶剂后蒸馏得到无色油状物2-羟基-1-丙烯氧基环戊烷。
向反应瓶中依次加入13.4g上述步骤得到的2-羟基-1-丙烯氧基环戊烷，11.6g乙酸钠，1.3gDMAP和54mL二氯甲烷，搅拌均匀。降温至0℃，滴加乙酸酐11.6g。滴加完毕后，在10℃下搅拌18h。GC检测反应结束后，过滤。滤液加入20mL饮用水，分层，水相用30mL二氯甲烷萃取一次。有机相合并，减压浓缩得到2-乙酰氧基-1-丙烯氧基环戊烷。
向反应瓶中一次加入pH＝7.0的40mL磷酸钾缓冲溶液，8mL丙酮，4g上述步骤得到的2-乙酰氧基-1-丙烯氧基环戊烷，400mg Novozym 435。反应体系维持40℃，搅拌反应30h。GC检测反应完成后，过滤。滤液加入乙酸乙酯(20mL x 2)萃取。合并有机相，浓缩有机相得到粗品，粗品不进行纯化直接用于下一步(ee值:94.0％)。取少量产物样品经过硅胶纯化，检测鉴定为拆分后产物。
氮气保护下，向三口瓶中加入3.0g CDI,19mL 2-甲基四氢呋喃，搅拌均匀后。降温至5℃，滴加2.0g上述步骤得到的拆分产物的4mL 2-甲基四氢呋喃溶液。滴毕，升温至10℃搅拌2h。GC检测反应完全后，滴加冰水淬灭反应。加入正己烷10mL萃取。有机相浓缩干后，加入13g N-甲基吡咯烷酮稀释并转入到干净的三口瓶中。加入1.0g L-叔亮氨酸和 0.27g 2-羟基吡啶氮氧化合物。在100℃下，搅拌反应12h。反应结束后，加入甲基叔丁基醚(15mL x 2)，用水(10mL)萃取。有机相水洗两次，饱和食盐水洗一次，有机相浓缩至3V-5V，停止浓缩，得到Glecaprevir合成中间体。
实施例3
向反应瓶中依次加入1.4L丙烯醇，82mL三氟化硼乙醚溶液，15L二氯甲烷，搅拌均匀。降温至0℃，滴加0.52L的环氧环戊烷，维持温度在0℃。滴加完成，在10℃下搅拌3h。GC跟踪反应完全后，滴加1.4L三乙胺淬灭反应，加压浓缩溶剂后蒸馏得到无色油状物2-羟基-1-丙烯氧基环戊烷。
向反应瓶中依次加入13.4g上述步骤得到的2-羟基-1-丙烯氧基环戊烷，11.6g乙酸钠，1.3gDMAP和54mL二氯甲烷，搅拌均匀。降温至5℃，滴加乙酸酐11.6g。滴加完毕后，在30℃下搅拌14h。GC检测反应结束后，过滤。滤液加入20mL饮用水，分层，水相用30mL二氯甲烷萃取一次。有机相合并，减压浓缩得到2-乙酰氧基-1-丙烯氧基环戊烷。
向反应瓶中一次加入pH＝8.0的400mL磷酸钠缓冲溶液，80mL丙酮，40g上述步骤得到的2-乙酰氧基-1-丙烯氧基环戊烷，40mLAcalase 2.4L。反应体系维持30℃，搅拌反应72h。GC检测反应完成后，过滤。滤液加入乙酸乙酯(100mL x 2)萃取。合并有机相，浓缩有机相得到粗品，粗品不进行纯化直接用于下一步(ee值:95.0％)。取少量产物样品经过硅胶纯化，检测鉴定为拆分后产物。
氮气保护下，向三口瓶中加入3.0g CDI,19mL 2-甲基四氢呋喃，搅拌均匀后。降温至0℃，滴加2.0g上述步骤得到的拆分产物的4mL 2-甲基四氢呋喃溶液。滴毕，升温至0℃搅拌2h。GC检测反应完全后，滴加冰水淬灭反应。加入正己烷10mL萃取。有机相浓缩干后，加入13g N-甲基吡咯烷酮稀释并转入到干净的三口瓶中。加入1.0g L-叔亮氨酸和0.27g2-羟基吡啶氮氧化合物。在20℃下，搅拌反应12h。反应结束后，加入甲基叔丁基醚(15mL x 2)，用水(10mL)萃取。有机相水洗两次，饱和食盐水洗一次，有机相浓缩至3V-5V，停止浓缩，得到Glecaprevir合成中间体。
实施例4
以实施例1所得Glecaprevir合成中间体为原料，补加甲基叔丁基醚至10V，有机相转移至100mL反应瓶中。升温至45℃，滴加配制好的叔丁胺(1.2g)的甲基叔丁基醚(12mL)溶液。滴加结束后，45℃保温反应2h。缓慢降温至25℃并搅拌5h。保温结束后，在氮气保护下，过滤，滤饼用2.0g甲基叔丁基醚洗涤。滤饼于35℃下减压干燥9h，得到4.5gGlecaprevir合成中间体的叔丁胺盐，为白色固体，收率85％。
MS calcd for C15H25NO5(M+H)+300.0,found 300.0.
1H NMR(400MHz,CDCl3)δ5.88(ddd,J＝22.6,10.6,5.4Hz,1H),5.41(d,J＝9.0Hz,1H),5.25(dd,J＝17.2,1.6Hz,1H),5.18–5.12(m,1H),4.92(d,J＝5.9Hz,1H),4.02(m,2H),3.80(t,J＝7.0Hz,2H),2.31–1.83(m,2H),1.64(m,4H),1.32(s,9H),0.98(s,9H)。
经计算可知，本申请实施例1～3制备Glecaprevir合成中间体的收率均高于50％，远远高于现有技术中30％的水平。
由以上实施例可知，本发明提供了一种Glecaprevir合成中间体的制备方法，以环氧环戊烷为原始材料，进行开环反应生成2-羟基-1-丙烯氧基环戊烷，乙酰化得到2-乙酰氧基-1-丙烯氧基环戊烷，拆分后再顺次进行活化和氨基缩合，得到Glecaprevir合成中间体。本发明提供的方法反应步骤少，收率较高，总收率均高于30％，远远高于现有技术中的10％；同时成本低、环境友好、反应条件温和、操作简便、适于工业化生产。本发明还提供了一种Glecaprevir合成中间体胺盐的制备方法，同样具有收率高、反应温和、操作简便的特点。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。对这些实施例的多种修改对本领域的专业技术人员来说是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下在其它实施例中实现。因此，本发明将不会被限制于 本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (21)

  1. 一种Glecaprevir合成中间体的制备方法，包含如下步骤：
    (1)将环氧环戊烷、丙烯醇、催化剂和溶剂混合，进行开环反应，加入三乙胺淬灭后得到2-羟基-1-丙烯氧基环戊烷；
    所述催化剂为三氟化硼乙醚络合物和/或三(五氟苯基)硼乙醚络合物；
    (2)所述2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂混合进行乙酰化反应，得到2-乙酰氧基-1-丙烯氧基环戊烷；
    所述乙酰化试剂为乙酸酐和/或乙酰氯；
    所述碱为乙酸钠、乙酸钾、三乙胺、二异丙基乙胺和吡啶中的一种或几种；
    (3)将所述2-乙酰氧基-1-丙烯氧基环戊烷在生物酶和缓冲液的作用下进行水解拆分，分别得到(-)-2-羟基-1-丙烯氧基环戊烷；
    所述生物酶为Lipase PS、Novozym435、Acalase2.4L和Acalase2.5L中的一种或几种；
    所述缓冲液为磷酸盐溶液；
    (4)惰性气氛下，将所述(-)-2-羟基-1-丙烯氧基环戊烷与活化试剂和溶剂混合，发生活化反应，加入冰水淬灭后得到活性中间体；
    所述活化试剂为N,N'-羰基二咪唑、光气和三光气中的一种或几种；
    (5)将所述活性中间体与L-叔亮氨酸、2-羟基吡啶氮氧化合物和溶剂混合，进行氨基酸缩合反应，得到Glecaprevir合成中间体。
  2. 根据权利要求1所述的制备方法，其特征在于，所述开环反应的温度为-10～30℃，时间为1～3h。
  3. 根据权利要求1或2所述的制备方法，其特征在于，所述步骤(1)中溶剂为二氯甲烷、氯仿、四氢呋喃、2-甲基四氢呋喃和乙腈中的一种或几种。
  4. 根据权利要求1或2所述的制备方法，其特征在于，所述步骤(1)中环氧环戊烷、丙烯醇、催化剂、溶剂和三乙胺的质量比为1:(1.2～10):(0.1～1):(5～10):(1.5～2.5)。
  5. 根据权利要求1所述的制备方法，其特征在于，所述乙酰化反应 的温度为0～30℃，时间为12～18h。
  6. 根据权利要求1或5所述的制备方法，其特征在于，所述步骤(2)中的溶剂为二氯甲烷、氯仿、四氢呋喃、甲基叔丁基醚、乙腈和丙酮中的一种或几种。
  7. 根据权利要求1或5所述的制备方法，其特征在于，所述步骤(2)中2-羟基-1-丙烯氧基环戊烷、乙酰化试剂、碱和溶剂的质量比为1:(1～2):(1.2～5):(5～10)。
  8. 根据权利要求1所述的制备方法，其特征在于，所述水解拆分的温度为0～40℃，时间为12～72h。
  9. 根据权利要求1或8所述的制备方法，其特征在于，所述步骤(3)中2-乙酰氧基-1-丙烯氧基环戊烷、生物酶和缓冲液的质量比为1:(0.1～1):(5～20)。
  10. 根据权利要求1所述的制备方法，其特征在于，所述步骤(4)中活化反应的温度为-10～30℃，时间为1～3h。
  11. 根据权利要求1或10所述的制备方法，其特征在于，所述步骤(4)中溶剂为二甲基四氢呋喃、四氢呋喃、二甲基甲酰胺和二氯甲烷中的一种或几种。
  12. 根据权利要求1或10所述的制备方法，其特征在于，所述步骤(4)中(-)-2-羟基-1-丙烯氧基环戊烷、活化试剂、溶剂和冰水的质量比为1:(1.5～2):(5～12):(1～5)。
  13. 根据权利要求1或10所述的制备方法，其特征在于，所述步骤(5)中氨基酸缩合反应的温度为20～100℃，时间为12～16h。
  14. 根据权利要求13所述的制备方法，其特征在于，所述步骤(5)中溶剂为N-甲基吡咯烷酮、四氢呋喃、二甲基甲酰胺和二甲亚砜中的一种或几种。
  15. 根据权利要求13所述的制备方法，其特征在于，所述步骤(5)中(-)-2-羟基-1-丙烯氧基环戊烷、L-叔亮氨酸、2-羟基吡啶氮氧化合物的质量比为1:(0.8～2):(0.8～2)。
  16. 根据权利要求15所述的制备方法，其特征在于，所述步骤(5)中活性中间体和溶剂的质量比为1:(5～15)。
  17. 一种Glecaprevir合成中间体胺盐的制备方法，包含如下步骤：
    按照权利要求1～16任意一项所述制备方法的步骤(1)～(5)制备得到Glecaprevir合成中间体；
    将所述Glecaprevir合成中间体和胺进行成盐反应，得到Glecaprevir合成中间体胺盐。
  18. 根据权利要求17所述的制备方法，其特征在于，所述胺优选为叔丁胺、二环已基胺、R-苯乙胺和2-丁胺中的一种或几种。
  19. 根据权利要求17或18所述的制备方法，其特征在于，所述胺和L-叔亮氨酸的质量比为(1～1.5):1。
  20. 根据权利要求17或18所述的制备方法，其特征在于，所述成盐反应在甲基叔丁基醚溶剂中进行，所述胺的质量和甲基叔丁基醚溶剂的体积比为(1～1.5)g:(10～15)mL。
  21. 根据权利要求17或18所述的制备方法，其特征在于，所述成盐反应包含顺次进行的一级保温阶段和二级保温阶段；
    所述一级保温阶段的温度为40～50℃，时间为1～3h；
    所述二级保温阶段的温度为20～30℃，时间为5～6h。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103209703A (zh) * 2010-09-21 2013-07-17 益安药业 大环脯氨酸衍生的hcv丝氨酸蛋白酶抑制剂
CN105849118A (zh) * 2013-12-23 2016-08-10 吉利德科学公司 大环hcv ns3抑制三肽的合成
US9809576B1 (en) * 2014-07-18 2017-11-07 Abbvie Inc. Synthetic route to anti-viral agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103209703A (zh) * 2010-09-21 2013-07-17 益安药业 大环脯氨酸衍生的hcv丝氨酸蛋白酶抑制剂
CN105849118A (zh) * 2013-12-23 2016-08-10 吉利德科学公司 大环hcv ns3抑制三肽的合成
US9809576B1 (en) * 2014-07-18 2017-11-07 Abbvie Inc. Synthetic route to anti-viral agents

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