WO2018090963A1 - 一种制备赖诺普利中间体的方法 - Google Patents

一种制备赖诺普利中间体的方法 Download PDF

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WO2018090963A1
WO2018090963A1 PCT/CN2017/111524 CN2017111524W WO2018090963A1 WO 2018090963 A1 WO2018090963 A1 WO 2018090963A1 CN 2017111524 W CN2017111524 W CN 2017111524W WO 2018090963 A1 WO2018090963 A1 WO 2018090963A1
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trifluoroacetyl
group
hydroxy
lysine
reaction
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PCT/CN2017/111524
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English (en)
French (fr)
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王松青
董鹏
郑扬
李全军
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浙江华海药业股份有限公司
浙江华海天诚药业有限公司
浙江华海立诚药业有限公司
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Priority to US16/461,589 priority Critical patent/US10633329B2/en
Priority to EP17870851.7A priority patent/EP3543225B1/en
Publication of WO2018090963A1 publication Critical patent/WO2018090963A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • 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

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  • the invention relates to the field of medicinal chemical industry, and in particular to a method for preparing lisinopril intermediates.
  • Lisinopril is a third-generation long-acting angiotensin-converting enzyme (ACE) inhibitor developed by Merk, USA, for the treatment of essential hypertension and renal vascular hypertension. . Its structural formula is as follows:
  • Lisinopril hydride the full name N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-lysine is important for the synthesis of lisinopril
  • the intermediate structure is as follows:
  • the main problem in this synthetic route is that the addition isomer is easily produced during the addition, and the isomer is hydrogenated to form an isomer of lisinopril hydride; the hydrogenation operation requirement and the catalyst cost are high, and Easy to produce impurities.
  • WO2005010028 reports that trifluoroacetyl lysine is protected by benzyl group, reacted with ethyl (R)-2-trifluoromethanesulfonate-4-phenylbutanoate, and then hydrogenated by palladium on carbon. Nopyl hydride.
  • the trifluoroacetyl lysine of the synthetic route needs to be protected by ester formation and then deprotected by hydrogenation, which increases the preparation steps and costs.
  • the object of the present invention is to provide a simple method for preparing N 2 -[1-(S)-alkoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-lysine (II) ,
  • the method provided by the invention comprises the following steps:
  • R 1 is selected from C 1 -C 5 alkyl; further preferably methyl, ethyl or isopropyl;
  • R 2 is selected from a C 1 -C 3 alkyl group or a substituted alkyl group, a C 6 -C 7 aryl group or a substituted aryl group.
  • the organic solvent described in the step (a) is selected from the group consisting of C 2 - C 7 ethers, C 2 - C 4 halogenated alkanes, C 7 - C 10 aromatic compounds or a mixed solvent of any two, and more preferably It is a mixed solvent of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, xylene or any two of them.
  • the mass-to-volume ratio of (R)-2-hydroxy-4-phenylbutyrate (I) to the above organic solvent is 1 g: 2 to 20 mL, preferably 1 g: 5 to 10 mL.
  • the base according to the step (a) is selected from the group consisting of alkali metal carbonates or hydrogencarbonates, C 5 to C 8 pyridine compounds, C 4 to C 9 secondary or tertiary amine compounds; further preferably sodium carbonate , potassium carbonate, sodium hydrogencarbonate, pyridine, 2,6-lutidine, triethylamine, diisopropylamine.
  • the molar ratio of the base to (R)-2-hydroxy-4-phenylbutyrate (I) is from 1 to 10:1, preferably from 2 to 4:1.
  • the sulfonyl chloride described in the step (a) is preferably methylsulfonyl chloride, trifluoromethylsulfonyl chloride, p-nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride.
  • the molar ratio of the sulfonyl chloride to the (R)-2-hydroxy-4-phenylbutyrate represented by the formula (I) is from 1 to 5:1, preferably from 1.1 to 3:1.
  • the temperature at which the sulfonyl chloride is added is preferably -5 to 15 ° C, more preferably -5 to 10 ° C, still more preferably 0 to 5 ° C.
  • the temperature of the reaction in the step (a) is preferably 20 to 60 ° C, more preferably 20 to 40 ° C, still more preferably 25 to 35 ° C.
  • the reaction time of the step (a) is 2 to 10 hours.
  • the trifluoroacetyl lysine salt according to the step (b) is selected from the group consisting of alkali metal salts of trifluoroacetyl lysine, quaternary ammonium salts of C 4 to C 12 , further preferably lithium salt of trifluoroacetyl lysine, and three Fluoroacetyl lysine sodium salt, trifluoroacetyl lysine tetramethyl ammonium salt.
  • the molar ratio of the trifluoroacetyl lysinate to (R)-2-hydroxy-4-phenylbutyrate (I) is from 1 to 6:1, preferably from 1 to 4:1.
  • the temperature of the reaction in the step (b) is preferably from 10 to 80 ° C, more preferably from 20 to 60 ° C, still more preferably from 25 to 40 ° C.
  • the reaction time of the step (b) is preferably from 1 to 12 hours.
  • the reaction solvent may be removed, and the compound of the formula (II), which is selected from the group consisting of methanol, ethanol, ethyl acetate, isopropyl acetate, methyl group, may be isolated and purified in a suitable crystallization solvent.
  • the method for preparing lisinopril hydride and the like thereof provided by the invention has the advantages of short preparation route, simple operation, less impurity generation, low cost and the like, and is suitable for industrial production.
  • Figure 1 is an HPLC chromatogram of the product prepared in Example 1 of the present application, N 2 -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-N 6 -trifluoroacetyl-L-lysine.
  • the flow rate was 1.0 mL/min, the column temperature was 25 ° C, and the detection wavelength was 210 nm.
  • Peak number keep time Peak area Peak height Peak area% Theoretical plate number Resolution 1 2.595 11291 930 0.071 738.127 0.000 2 2.912 41363 3661 0.260 1742.500 0.959 3 4.707 3283 240 0.021 1215.483 4.383 4 4.931 3117 222 0.020 700.093 0.348 5 6.109 15671095 924068 98.634 3031.845 1.982 6 7.317 8360 652 0.053 278.804 1.099 7 7.654 103728 4708 0.653 3036.779 0.292 8 11.017 32718 1141 0.206 3,657.974 5.238 9 12.113 9111 301 0.057 3951.075 1.462 10 13.660 4140 124 0.026 4256.754 1.924 total 15888206 936048 100.000
  • reaction liquid was filtered, and the filtrate was evaporated to dryness to dryness to dryness, and the residue was evaporated to dryness, and the residue was added to 195 mL of n-heptane and stirred at 25 ° C for 10 hours to obtain 33.8 g of product N 2 -[1-(S)-methoxycarbonyl-3 -Phenylpropyl]-N 6 -trifluoroacetyl-L-lysine, yield 80.9%, HPLC purity 98.1%.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供了一种制备赖诺普利中间体的方法，包括在有机溶剂中在碱存在下将(R)-羟基-4-苯基丁酸酯用磺酰氯处理得到磺酸酯的溶液；将上述制得的溶液与三氟乙酰赖氨酸盐反应，反应结束后分离得到N2-[1-(S)-烷氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸。本发明提供的制备赖诺普利中间体方法，合成路线较短、操作简便、成本低，适于工业化生产。

Description

一种制备赖诺普利中间体的方法 技术领域
本发明涉及医药化工领域，具体涉及一种制备赖诺普利中间体的方法。
背景技术
赖诺普利(Lisinopril)是由美国默克(Merk)公司开发的第三代长效血管紧张素转化酶(ACE)抑制剂，临床用于治疗原发性高血压及肾血管性高血压疾病。其结构式如下所示：
Figure PCTCN2017111524-appb-000001
赖诺普利氢化物，全称N2-[1-(S)-乙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸是合成赖诺普利重要的中间体，结构式如下所示：
Figure PCTCN2017111524-appb-000002
赖诺普利氢化物的制备方法主要有以下两种：
1.US4925969报道了以4-氧代4-苯基-2-丁烯酸乙酯为原料，依次与三氟乙酰赖氨酸盐加成、再经钯碳作用下氢化还原制得赖诺普利氢化物，合成路线如下所示：
Figure PCTCN2017111524-appb-000003
该合成路线存在的主要问题：加成时易产生加成物异构体，该异构体经氢化还原生成赖诺普利氢化物的异构体；氢化操作要求和催化剂成本均较高，且易于产生杂质。
2.WO2005010028报道了以三氟乙酰赖氨酸经苄基保护，与(R)-2-三氟甲磺酸酯基-4-苯丁酸乙酯反应，再经钯碳催化氢化制得赖诺普利氢化物。
Figure PCTCN2017111524-appb-000004
该合成路线的三氟乙酰赖氨酸需先经成酯保护、再经氢化脱保护，增加了制备步骤和成本。
目前文献报道的赖诺普利氢化物的制备方法存在收率较低、成本较高、路线的原子利用率较低等缺点。
发明内容
本发明的目的在于提供一种简便的制备N2-[1-(S)-烷氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸(II)的方法，
Figure PCTCN2017111524-appb-000005
本发明提供的方法包括以下步骤：
(a)在有机溶剂中在碱存在下将(R)-2-羟基-4-苯基丁酸酯(I)用磺酰氯(III)处理得到式(I)的磺酸酯溶液；
Figure PCTCN2017111524-appb-000006
(b)上述制得的溶液与三氟乙酰赖氨酸盐反应，反应结束后分离得到式(II)所示的化合物,
上述式中:
R1选自C1-C5的烷基；进一步优选为甲基，乙基或异丙基；
R2选自C1～C3的烷基或取代烷基、C6～C7的芳香基或取代芳香基。
步骤(a)所述的有机溶剂选自：C2～C7的醚类、C2～C4的卤代烷烃、C7～C10 的芳香族化合物或其任意两者的混合溶剂，进一步优选为：四氢呋喃、2-甲基四氢呋喃、二氯甲烷、甲苯、二甲苯或其任意两者的混合溶剂。(R)-2-羟基-4-苯基丁酸酯(I)与所述的有机溶剂的质量体积比为1g：2～20mL，优选为1g：5～10mL。
步骤(a)所述的碱选自碱金属的碳酸盐或碳酸氢盐、C5～C8的吡啶类化合物、C4～C9的仲胺或叔胺类化合物；进一步优选为碳酸钠、碳酸钾、碳酸氢钠、吡啶、2,6-二甲基吡啶、三乙胺、二异丙基胺。所述碱与(R)-2-羟基-4-苯基丁酸酯(I)的摩尔比为1～10：1，优选为2～4：1。
步骤(a)所述的磺酰氯优选为甲基磺酰氯、三氟甲基磺酰氯、对硝基苯磺酰氯或对甲苯磺酰氯。所述磺酰氯与式(I)所示的(R)-2-羟基-4-苯基丁酸酯的摩尔比为1～5：1，优选为1.1～3：1。所述磺酰氯的加入温度范围优选为-5～15℃,进一步优选为-5～10℃，更优选为0-5℃。
步骤(a)反应的温度范围优选为20～60℃，进一步优选为20～40℃，更优选为25～35℃。
步骤(a)的反应时间为2～10小时。
步骤(b)所述的三氟乙酰赖氨酸盐选自三氟乙酰赖氨酸的碱金属盐、C4～C12的季铵盐，进一步优选为三氟乙酰赖氨酸锂盐、三氟乙酰赖氨酸钠盐、三氟乙酰赖氨酸四甲基铵盐。其中所述三氟乙酰赖氨酸盐与(R)-2-羟基-4-苯基丁酸酯(I)的摩尔比为1～6：1，优选为1～4：1。
步骤(b)反应的温度范围优选为10～80℃，进一步优选为20～60℃，更优选为25～40℃。
步骤(b)的反应时间优选为1～12小时。
步骤(b)反应结束后，可以除去反应溶剂，再在合适的结晶溶剂中分离纯化式(II)化合物，所述结晶溶剂选自：甲醇、乙醇、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚、正己烷、正庚烷、环己烷或其任意两者的混合溶剂；(R)-2-羟基-4-苯基丁酸酯(I)与所用结晶溶剂的质量体积比为1g：2～20mL，优选为1g：4～12mL；所述的结晶温度范围优选为-5～60℃，进一步优选为-5～40℃、更优选为0-25℃；结晶时间优选为5～12小时。
进一步地，制备式(II)化合物的过程如下：
(a)往(R)-2-羟基-4-苯基丁酸酯(I)中加入有机溶剂和碱，于-5～15℃缓慢加入磺酰氯(III)，料液升温至20～60℃搅拌反应2～10小时；反应完全后，过滤反应液；
(b)往上述滤液中加入三氟乙酰赖氨酸盐，在10～80℃搅拌反应1～12小时，过滤反应液，滤液减压蒸馏除去反应溶剂；
(c)往上述蒸馏底物加入结晶溶剂，于-5～60℃结晶5～12小时，过滤，滤饼干燥得式(II)化合物。
本发明提供的制备赖诺普利氢化物及其类似物的方法，具有制备路线较短、操作简便、杂质生成较少、成本较低等优点，适于工业化生产。
附图说明
图1为本申请实施例1制备的产物，N2-[1-(S)-乙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸的HPLC图谱。
具体实施方式
下面结合实施例对本发明做进一步阐述，但是这些实例不对本发明构成任何限制。
HPLC仪器型号：Shimadzu LC-20A
HPLC条件：
色谱柱：Agilent Zorbax SB-18 150×3.0mm，3.5μm；
流动相：2.5‰KH2PO4溶液∶乙腈＝60∶40；
流速1.0mL/min，柱温：25℃，检测波长：210nm。
实施例1：
250mL三口瓶中加入20.8g(R)-2-羟基-4-苯基丁酸乙酯、110mL二氯甲烷和42.4g碳酸钠，于0℃缓慢加入26.6g对甲苯磺酰氯，料液升温至25℃搅拌反应8小时；过滤反应液，往滤液中加入62.3g三氟乙酰赖氨酸四甲基铵盐于15℃搅拌反应10小时。反应液过滤，滤液减压蒸除二氯甲烷，剩余物加入240mL正己烷，于0～5℃搅拌5小时，制得37.2g产物，经过HPLC图谱确定为N2-[1-(S)-乙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，收率86.0％，HPLC纯度98.6％，其HPLC相关数据见下表1。
表1
峰编号 保留时间 峰面积 峰高 峰面积％ 理论塔板数 分离度
1 2.595 11291 930 0.071 738.127 0.000
2 2.912 41363 3661 0.260 1742.500 0.959
3 4.707 3283 240 0.021 1215.483 4.383
4 4.931 3117 222 0.020 700.093 0.348
5 6.109 15671095 924068 98.634 3031.845 1.982
6 7.317 8360 652 0.053 278.804 1.099
7 7.654 103728 4708 0.653 3036.779 0.292
8 11.017 32718 1141 0.206 3657.974 5.238
9 12.113 9111 301 0.057 3951.075 1.462
10 13.660 4140 124 0.026 4256.754 1.924
合计   15888206 936048 100.000    
实施例2：
250mL三口瓶中加入20.8g(R)-2-羟基-4-苯基丁酸乙酯、150mL四氢呋喃和20.2g三乙胺，于0℃缓慢加入12.6g甲基磺酰氯，料液升温至25℃搅拌反应8小时；过滤反应液，往滤液中加入37.2g三氟乙酰赖氨酸锂盐，于25℃搅拌反应10小时。反应液过滤，滤液减压蒸除四氢呋喃，剩余物加入85mL乙醇，于0℃搅拌5小时，制得35.9g产物N2-[1-(S)-乙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，其HPLC图谱与图1一致，收率83.0％，HPLC纯度98.9％。
实施例3：
250mL三口瓶中加入20.8g(R)-2-羟基-4-苯基丁酸乙酯、150mL四氢呋喃和19.8g吡啶，于0℃缓慢加入13.5g甲基磺酰氯，料液升温至35℃搅拌反应6小时；过滤反应液，往滤液中加入39.6g三氟乙酰赖氨酸钠盐，于25℃搅拌反应10小时。反应液过滤，滤液减压蒸除四氢呋喃，剩余物加入40mL正己烷和200mL环己烷，于0℃搅拌8小时，制得36.6g产物N2-[1-(S)-乙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，其HPLC图谱与图1一致，收率84.7％，HPLC纯度98.8％。
实施例4：
250mL三口瓶中加入9.7g(R)-2-羟基-4-苯基丁酸甲酯、95mL甲苯和20.2g三乙胺，于0℃加入28.6g对甲苯磺酰氯，料液升温至35℃搅拌反应10小时；过滤反应液，往滤液中加入49.6g三氟乙酰赖氨酸锂盐，于40℃搅拌反应12小时。反应液过滤，滤液减压蒸除甲苯，剩余物加入115mL乙酸乙酯，于25℃搅拌12小时，制得16.4g产物N2-[1-(S)-甲氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，收率78.6％，HPLC纯度99.1％。
实施例5：
250mL三口瓶中加入19.4g(R)-2-羟基-4-苯基丁酸甲酯、160mL 2-甲基四氢呋喃和33.6g碳酸氢钠，于5℃加入18.5g三氟甲基磺酰氯，料液升温至25℃搅拌反应10小时；过滤反应液，往滤液中加入37.2g三氟乙酰赖氨酸锂盐，于30℃搅拌反应12小时。反应液过滤，滤液减压蒸除2-甲基四氢呋喃，剩余物加入195mL正庚烷，于25℃搅拌10小时，制得33.8g产物N2-[1-(S)-甲氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，收率80.9％，HPLC纯度98.1％。
实施例6：
250mL三口瓶中加入19.4g(R)-2-羟基-4-苯基丁酸甲酯、160mL 2-甲基四氢呋喃和26.8g 2,6-二甲基吡啶，于0℃加入17.2g甲基磺酰氯，料液升温至30℃搅拌反应7小时；过滤反应液，往滤液中加入37.2g三氟乙酰赖氨酸锂盐，于30℃搅拌反应12小时。反应液过滤，滤液减压蒸除2-甲基四氢呋喃，剩余物加入80mL甲醇，于0℃搅拌8小时，制得35.2g产物N2-[1-(S)-甲氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，收率84.2％，HPLC纯度98.6％。
实施例7：
250mL三口瓶中加入22.2g(R)-2-羟基-4-苯基丁酸异丙酯、180mL二氯甲烷和28.4g二异丙基胺，于0℃加入28.8g对硝基苯磺酰氯，料液升温至30℃搅拌反应10小时；过滤反应液，往滤液中加入34.6g三氟乙酰赖氨酸四甲基铵盐，于30℃搅拌反应10小时。反应液过滤，滤液减压蒸除二氯甲烷，剩余物加入100mL甲基叔丁基醚，于5℃搅拌析晶8小时，过滤、滤饼干燥制得36.4g产物N2-[1-(S)-异丙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，收率81.4％，HPLC纯度98.7％。
实施例8：
250mL三口瓶中加入22.2g(R)-2-羟基-4-苯基丁酸异丙酯、120mL四氢呋喃和41.7g碳酸钾，于10℃加入28.6g对甲基苯磺酰氯，料液升温至35℃搅拌反应8小时；过滤反应液，往滤液中加入37.2g三氟乙酰赖氨酸锂盐，于30℃搅拌反应10小时。反应液过滤，滤液减压蒸除四氢呋喃，剩余物加入200mL正庚烷，于5℃搅拌析晶8小时，过滤、滤饼干燥制得34.3g产物N2-[1-(S)-异丙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，收率76.8％，HPLC纯度97.4％。
实施例9：
250mL三口瓶中加入20.8g(R)-2-羟基-4-苯基丁酸乙酯、90mL二甲苯、60mL四氢呋喃和20.0g三乙胺，于0℃加入13.0g甲基磺酰氯，料液升温至35℃搅拌反应8小时；过滤反应液，往滤液中加入37.5g三氟乙酰赖氨酸锂盐，于30℃搅拌反应10小时。反应液过滤，滤液减压蒸除溶剂，剩余物加入30mL乙酸异丙酯和120mL正庚烷，于5℃搅拌10小时，制得35.5g产物N2-[1-(S)-乙氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸，其HPLC图谱与图1一致，收率82.3％，HPLC纯度97.5％。

Claims (13)

  1. 一种制备N2-[1-(S)-烷氧羰基-3-苯丙基]-N6-三氟乙酰基-L-赖氨酸(II)的方法，
    Figure PCTCN2017111524-appb-100001
    其特征在于包括以下步骤：
    (a)在有机溶剂中在碱存在下将(R)-2-羟基-4-苯基丁酸酯(I)用磺酰氯(III)处理得到式(I)的磺酸酯溶液；
    Figure PCTCN2017111524-appb-100002
    (b)上述制得的溶液与三氟乙酰赖氨酸盐反应，反应结束后分离得到式(II)化合物；
    上述式中：
    R1选自C1-C5的烷基；
    R2选自C1～C3的烷基或取代烷基、C6～C7的芳香基或取代芳香基。
  2. 根据权利要求1所述的制备方法，其中R1选自甲基，乙基或异丙基。
  3. 根据权利要求1或2所述的制备方法，其中步骤(a)所述的有机溶剂选自：C2～C7的醚类、C2～C4的卤代烷烃、C7～C10的芳香族化合物或其任意两者的混合溶剂；进一步优选为四氢呋喃、2-甲基四氢呋喃、二氯甲烷、甲苯、二甲苯或其任意两者的混合溶剂。
  4. 根据权利要求1或2所述的制备方法，其中步骤(a)中的(R)-2-羟基-4-苯基丁酸酯(I)与所述的有机溶剂的质量体积比为1g：2～20mL，优选为1g：5～10mL。
  5. 根据权利要求1或2所述的制备方法，其中所述的碱选自碱金属的碳酸盐或碳酸氢盐、C5～C8的吡啶类化合物、C4～C9的仲胺或叔胺类化合物；进一步优选为碳酸钠、碳酸钾、碳酸氢钠、吡啶、2,6-二甲基吡啶、三乙胺、二异丙基 胺。
  6. 根据权利要求1或2所述的制备方法，其中所述碱与(R)-2-羟基-4-苯基丁酸酯(I)的摩尔比为1～10：1，优选为2～4：1。
  7. 根据权利要求1或2所述的制备方法，其中所述的磺酰氯(III)选自甲基磺酰氯、三氟甲基磺酰氯、对硝基苯磺酰氯或对甲苯磺酰氯。
  8. 根据权利要求1或2所述的制备方法，其中所述磺酰氯(III)与式(I)所示的(R)-2-羟基-4-苯基丁酸酯的摩尔比为1～5：1，优选为1.1～3：1。
  9. 根据权利要求1或2所述的制备方法，其特征在于所述的磺酰氯的加入温度范围为-5～15℃，优选为-5～10℃，进一步优选为0-5℃；步骤(a)反应的温度范围为20～60℃，优选为20～40℃，进一步优选为25～35℃。
  10. 根据权利要求1或2所述的制备方法，其特征在于所述的三氟乙酰赖氨酸盐选自三氟乙酰赖氨酸的碱金属盐、C4～C12的季铵盐，进一步优选为三氟乙酰赖氨酸锂盐、三氟乙酰赖氨酸钠盐、三氟乙酰赖氨酸四甲基铵盐。
  11. 根据权利要求1或2所述的制备方法，其中所述三氟乙酰赖氨酸盐与(R)-2-羟基-4-苯基丁酸酯(I)的摩尔比为1～6：1，优选为1～4：1。
  12. 根据权利要求1或2所述的制备方法，其中步骤(b)反应的温度范围为10～80℃，优选为20～60℃，更优选为25～40℃。
  13. 根据权利要求1或2所述的制备方法，进一步包括将所分离得到的式(II)化合物粗品在结晶溶剂中结晶，所述结晶溶剂选自：甲醇、乙醇、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚、正己烷、正庚烷、环己烷或其任意两者的混合溶剂；(R)-2-羟基-4-苯基丁酸酯(I)与所用结晶溶剂的质量体积比为1g：2～20mL，优选为1g：4～12mL；所述的结晶温度范围为-5～60℃，优选为-5～40℃、更优选为0-25℃。
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