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WO2018059427A1 - 一种苯丙氨酸类化合物的制备方法 - Google Patents

一种苯丙氨酸类化合物的制备方法 Download PDF

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WO2018059427A1
WO2018059427A1 PCT/CN2017/103618 CN2017103618W WO2018059427A1 WO 2018059427 A1 WO2018059427 A1 WO 2018059427A1 CN 2017103618 W CN2017103618 W CN 2017103618W WO 2018059427 A1 WO2018059427 A1 WO 2018059427A1
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phenyl
fluorobenzoyl
carried out
process according
reaction
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PCT/CN2017/103618
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English (en)
French (fr)
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鲁先平
李志斌
王祥辉
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深圳微芯生物科技有限责任公司
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Priority to DK17854877.2T priority Critical patent/DK3524592T3/da
Priority to KR1020197011254A priority patent/KR102264868B1/ko
Priority to ES17854877T priority patent/ES2930284T3/es
Priority to PL17854877.2T priority patent/PL3524592T3/pl
Priority to MX2019003459A priority patent/MX2019003459A/es
Priority to EP17854877.2A priority patent/EP3524592B1/en
Priority to JP2019517775A priority patent/JP6884857B2/ja
Priority to AU2017333054A priority patent/AU2017333054B2/en
Priority to US16/337,207 priority patent/US10640465B2/en
Priority to BR112019005986-5A priority patent/BR112019005986B1/pt
Priority to CA3038381A priority patent/CA3038381C/en
Priority to RU2019112470A priority patent/RU2708243C1/ru
Publication of WO2018059427A1 publication Critical patent/WO2018059427A1/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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system

Definitions

  • the invention relates to the field of medicinal chemistry, and in particular to a method for preparing a phenylalanine compound.
  • 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid is a type of metabolism
  • a phenylalanine compound with therapeutic and prophylactic activity which has the following chemical structural formula:
  • the method has many side reactions, and the obtained product has many kinds of impurities and high impurity content, and impurities in the product are difficult to be removed by conventional treatment methods (including recrystallization), and purification by chromatography is required, and large-scale cannot be performed. Industrial production.
  • the object of the present invention is to overcome the disadvantages of the prior art and to provide a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazole-9-yl) group) An industrially acceptable process for the preparation of ethoxy)phenyl)propionic acid.
  • the reaction step (a) is a condensation reaction.
  • the reacting step (a) is preferably carried out in the presence of a catalyst of cesium carbonate.
  • step (a) is carried out at a reaction temperature of from 80 to 120 °C.
  • the reaction time of the step (a) may be 2 to 3 hours.
  • the reaction temperature of the condensation reaction in step (a) is 90 ° C and the reaction time is 3 hours.
  • the crude product of the compound (III) obtained in the condensation reaction of the step (a) can be used in the next reaction without further purification.
  • Step (b) is a hydrolysis reaction.
  • Step (b) is preferably in the presence of a base, especially an inorganic base get on. More preferably, the base is lithium hydroxide.
  • reaction of step (b) is preferably carried out using N,N-dimethylformamide and water or tetrahydrofuran and water as a solvent.
  • the hydrolysis is carried out using lithium hydroxide, N,N-dimethylformamide and water or tetrahydrofuran and water as a solvent, the reaction temperature is 15 to 45 ° C, and the reaction time is 4 to 8 hours.
  • the hydrolysis reaction uses tetrahydrofuran and water as a solvent.
  • the reaction step (c) is an acidification reaction, and the compound (IV) is acidified with an acid to obtain the target compound 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-). Carbazole-9-yl)ethoxy)phenyl)propanoic acid.
  • the acid used in the acidification reaction is a mineral acid; more preferably, the acid is hydrochloric acid.
  • the acidification reaction may be carried out by any suitable solvent, preferably ethyl acetate and water.
  • the product of the acidification reaction can optionally be recrystallized from an organic solvent.
  • the organic solvent used for recrystallization is acetonitrile.
  • the preparation method of the invention does not require chromatographic separation and purification, and is suitable for industrial production; the obtained reaction product is allowed to be purified by simple recrystallization, and the obtained target compound has high purity and can reach 99% or more.
  • 9-carbazole ethanol mesylate produced by Beijing Lewei Taike Pharmaceutical Technology Co., Ltd., purity >99%.
  • Methyl 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propanoate produced by Beijing Lewei Taike Pharmaceutical Technology Co., Ltd., purity >96%.
  • HPLC test conditions instrument: Dai An UltiMate 3000; column: Shim-pack VP-ODS 5 ⁇ m 250 L ⁇ 4.6; detector: VWD-3100.
  • the filter cake was added to the reaction flask, 550 mL of ethyl acetate and 306 mL of water were added, 210 mL of 4 mmol/L hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for about 4 hours, allowed to stand for separation, and the upper organic phase was concentrated in vacuo to give 2-[(2- (4-Fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propanoic acid crude product, 41.46 g.
  • the crude product was recrystallized from about 373 mL of acetonitrile.
  • the filter cake was added to the reaction flask, 54 mL of ethyl acetate and 28 mL of water were added, 21 mL of 4 mmol/L hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for about 4.5 hours, allowed to stand for separation, and the upper organic phase was concentrated in vacuo to give 2-[(2- (4-Fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propanoic acid crude product, weight 4.79 g.
  • the crude product was recrystallized from ca. 48 mL of acetonitrile.
  • the filter cake was added to the reaction flask, 54 mL of ethyl acetate and 30 mL of water were added, 21 mL of 4 mmol/L hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for about 4.5 hours, allowed to stand for separation, and the upper organic phase was concentrated in vacuo to give 2-[(2- (4-Fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propanoic acid crude product, weight 5.25 g.
  • the crude product was recrystallized from about 53 mL of acetonitrile.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)

Abstract

本发明公开了2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的制备方法，该方法以9-咔唑乙醇甲磺酸酯和2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯为起始原料，经缩合、水解、酸化得到目标化合物。本发明所述制备方法适合工业化生产，所得目标化合物纯度高。

Description

一种苯丙氨酸类化合物的制备方法
本申请要求于2016年09月27日提交中国专利局、申请号为201610855107.3、发明名称为“一种苯丙氨酸类化合物的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学领域，具体涉及一种苯丙氨酸类化合物的制备方法。
背景技术
2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸是一种对于代谢性疾病具有治疗和预防活性的苯丙氨酸类化合物，其化学结构式如下：
Figure PCTCN2017103618-appb-000001
在中国专利申请CN03126974.5和美国专利申请US7,268,157中均记载了该化合物的药理活性。2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸具有选择性激活PPAR-α、PPAR-γ和PPAR-δ的能力，可以用于治疗与代谢综合征相关的疾病，如糖尿病、高血压、肥胖、胰岛 素抵抗、高甘油三酯血症、高血糖、高胆固醇、动脉粥样硬化、冠心病等。
在中国专利申请CN03126974.5和美国专利申请US7,268,157中公开了2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的一种制备方法，其合成路线如下：
Figure PCTCN2017103618-appb-000002
但该方法副反应多，所得产品杂质种类多、杂质含量高，而且所述产品中的杂质难以通过常规处理方法(包括重结晶)除去，需要用层析分离的方法进行纯化，无法进行大规模工业化生产。
因此，探索2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的可工业化的制备方法仍具有极其重要的意义。
发明内容
本发明的目的在于克服现有技术的缺点，提供一种2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的可工业化的制备方法。
本发明提供的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的制备方法如下：
Figure PCTCN2017103618-appb-000003
反应步骤(a)是缩合反应。优选地，反应步骤(a)优选在催化剂碳酸铯存在下进行。
优选地，步骤(a)在80～120℃的反应温度下进行。步骤(a)的反应时间可以是2至3小时。
步骤(a)可以采用任何适用的有机溶剂；优选地，采用甲苯作为反应溶剂。
在一个更优选的实施方案中，所述步骤(a)缩合反应的反应温度为90℃，反应时间为3小时。
所述步骤(a)缩合反应所得化合物(III)的粗产品可以未经进一步纯化，直接用于下一步反应。
步骤(b)是水解反应。步骤(b)优选在碱、特别是无机碱存在下 进行。更优选地，所述碱为氢氧化锂。
在另一个方面，步骤(b)的反应优选以N,N-二甲基甲酰胺和水或四氢呋喃和水为溶剂。
更优选地，所述水解采用氢氧化锂，以N,N-二甲基甲酰胺和水或四氢呋喃和水为溶剂，反应温度为15～45℃，反应时间为4～8小时。
更优选地，所述水解反应以四氢呋喃和水为溶剂。
反应步骤(c)为酸化反应，将化合物(IV)利用酸进行酸化得到目标化合物2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸。
优选的，该酸化反应中所用的酸为无机酸；更优选地，所述酸为盐酸。该酸化反应可以采用任何合适的溶剂，优选以乙酸乙酯和水为溶剂。
所述酸化反应的产物可以任选地用有机溶剂进行重结晶。
优选的，所述用于重结晶的有机溶剂为乙腈。
本发明的上述各个反应步骤的优选条件可以组合进行。
在本发明的另一方面，还提供了化合物(II)用作2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的合成中间体的用途
Figure PCTCN2017103618-appb-000004
本发明所述制备方法不需要层析分离纯化，适合工业化生产；所得反应产物允许通过简便的重结晶进行纯化，所得目标化合物纯度高，可以达到99％以上。
具体实施方式
下面结合实例进一步阐明本发明的内容，但本发明的保护范围并不仅仅局限于这些实例。本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位或百分比，均是为了提供明白无误的书面参考。本领域熟练技术人员在实践本专利时，基于本发明的教导和原则，使用在此范围之外或有别于单个数值的温度、浓度、数量等，仍然可以得到预期的结果。
起始原料和实验仪器：
9-咔唑乙醇甲磺酸酯：北京乐威泰克医药科技有限公司生产，纯度>99％。
2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯：北京乐威泰克医药科技有限公司生产，纯度>96％。
质子核磁共振测试条件：仪器：AV-400(德国Bruker公司)；溶剂：DMSO-d6。
HPLC测试条件：仪器：戴安UltiMate3000；色谱柱：Shim-pack VP-ODS 5μm 250L×4.6；检测器：VWD-3100。
LC-MS测试条件：仪器：Waters 2695/ZQ4000；色谱柱：Shim-pack VP-ODS 5μm 150L×2.0；检测器：Waters 2996DAD。
实施例1：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的制备
Figure PCTCN2017103618-appb-000005
在反应瓶中依次加入400mL甲苯、39.34g(100mmol)2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯、43.40g(150mmol)9-咔唑乙醇甲磺酸酯和39.40g(120mmol)碳酸铯，于90℃反应3小时，过滤，将滤液真空浓缩除去溶剂甲苯，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品，纯度(HPLC)69.8％，LC-MS(m/z)587(M+1)。所得粗产品未经进一步纯化，直接用于下一步反应。
在反应瓶中加入上述2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品和400mL四氢呋喃，室温搅拌溶解。将16.78g(400mmol)LiOH.H2O溶于200mL水，加入上述溶液中，室温搅拌反应8小时，静置分层，将上层有机相真空浓缩。将浓缩物用800mL乙酸乙酯打浆、过滤，重复4次。将滤饼加入反应瓶中，加入550mL乙酸乙酯和306mL水，滴加210mL 4mmol/L盐酸，室温搅拌约4小时，静置分层，将上层有机相真空浓缩，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸粗产品，重量41.46g。将粗产品用约373mL乙腈重结晶。重复3次，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸纯产品，重量23.88g，收率41.7％，纯度(HPLC)99.4％。LC-MS(m/z)573(M+1)。1H NMR(DMSO-d6)δ2.98(dd,1H,CH2)，3.11(dd,1H,CH2)，4.28(t,1H,CH)，4.48(m,2H,CH2)，4.73(t,2H,CH2)，6.59(d,1H,Ar-H)，6.68(d,2H,Ar-H)，，6.60(d,1H,Ar-H)，7.05(d,2H,Ar-H)，7.18(d,2H,Ar-H)，7.31(m,3H,Ar-H)，7.42(m,3H,Ar-H)，7.61(m,4H,Ar-H)，8.13(d,2H,Ar-H)，8.50(d,1H,NH)。
实施例2：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的制备
Figure PCTCN2017103618-appb-000006
在反应瓶中依次加入40mL甲苯、3.93g(10mmol)2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯、4.34g(15mmol)9-咔唑乙醇甲磺酸酯和3.95g(12mmol)碳酸铯，于80℃反应2小时，过滤，将滤液真空浓缩除去溶剂甲苯，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品，LC-MS(m/z)587(M+1)。所得粗产品未经进一步纯化，直接用于下一步反应。
在反应瓶中加入上述2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品和40mL四氢呋喃，室温搅拌溶解。将1.68g(40mmol)LiOH.H2O溶于20mL水，加入上述溶液中，于15℃搅拌反应8小时，静置分层，将上层有机相真空浓缩。将浓缩物用70mL乙酸乙酯打浆、过滤，重复4次。将滤饼加入反应瓶中，加入54mL乙酸乙酯和28mL水，滴加21mL 4mmol/L盐酸，室温搅拌约4.5小时，静置分层，将上层有机相真空浓缩，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸粗产品，重量4.79g。将粗产品用约48mL乙腈重结晶。重复4次，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸纯产品，重量2.20g，收率38.5％，纯度(HPLC)99.4％。
实施例3：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧 基)苯基)丙酸的制备
Figure PCTCN2017103618-appb-000007
在反应瓶中依次加入40mL甲苯、3.93g(10mmol)2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯、4.34g(15mmol)9-咔唑乙醇甲磺酸酯和3.95g(12mmol)碳酸铯，于120℃反应2小时，过滤，将滤液真空浓缩除去溶剂甲苯，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品，LC-MS(m/z)587(M+1)。所得粗产品未经进一步纯化，直接用于下一步反应。
在反应瓶中加入上述2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品和40mL四氢呋喃，室温搅拌溶解。将1.68g(40mmol)LiOH.H2O溶于20mL水，加入上述溶液中，于45℃搅拌反应8小时，静置分层，将上层有机相真空浓缩。将浓缩物用80mL乙酸乙酯打浆、过滤，重复4次。将滤饼加入反应瓶中，加入54mL乙酸乙酯和30mL水，滴加21mL 4mmol/L盐酸，室温搅拌约4.5小时，静置分层，将上层有机相真空浓缩，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸粗产品，重量5.25g。将粗产品用约53mL乙腈重结晶。重复4次，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸纯产品，重量2.31g，收率40.4％，纯度(HPLC)99.4％。
实施例4：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的制备
Figure PCTCN2017103618-appb-000008
在反应瓶中依次加入40mL甲苯、3.93g(10mmol)2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯、4.34g(15mmol)9-咔唑乙醇甲磺酸酯和3.90g(12mmol)碳酸铯，于90℃反应2.5小时，过滤，将滤液真空浓缩除去溶剂甲苯，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品，LC-MS(m/z)587(M+1)。所得粗产品未经进一步纯化，直接用于下一步反应。
在反应瓶中加入上述2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯粗产品和40mL N,N-二甲基甲酰胺，室温搅拌溶解。将1.67g(40mmol)LiOH.H2O溶于20mL水，加入上述溶液中，室温搅拌反应4小时，过滤。将滤饼用55mL乙酸乙酯打浆、过滤，重复4次。将滤饼加入反应瓶中，加入40mL乙酸乙酯和22mL水，滴加18mL 4mmol/L盐酸，室温搅拌约1.5小时，静置分层，将上层有机相真空浓缩，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸粗产品，重量3.48g。将粗产品用约35mL乙腈重结晶，重复2次，得2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸，重量2.22g，收率38.8％，纯度(HPLC)99.3％。
上述实施例只是对本发明的示例性说明。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和权利要求中所要求保护的本发明范围之内。

Claims (11)

  1. 2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的制备方法，包括如下反应步骤：
    (a)使化合物(I)与化合物(II)反应，得到化合物(III)；
    Figure PCTCN2017103618-appb-100001
    (b)将化合物(III)水解得到化合物(IV)；
    Figure PCTCN2017103618-appb-100002
    (c)将化合物(IV)用酸酸化，得到2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸。
    Figure PCTCN2017103618-appb-100003
  2. 如权利要求1所述的制备方法，其中反应步骤(a)在碳酸铯存在下进行。
  3. 如权利要求1或2所述的制备方法，其中反应步骤(a)在80～120℃的反应温度下进行。
  4. 如权利要求1至3中任一项所述的制备方法，其中反应步骤(a)以甲苯为溶剂进行。
  5. 如权利要求1至4中任一项所述的制备方法，其中反应步骤(b)的水解在碱存在下进行。
  6. 如权利要求1至5中任一项所述的制备方法，其中反应步骤(b)的水解在氢氧化锂存在下进行。
  7. 如权利要求1至6中任一项所述的制备方法，其中反应步骤(b)以N,N-二甲基甲酰胺和水或四氢呋喃和水为溶剂进行。
  8. 如权利要求1至7中任一项所述的制备方法，其中反应步骤(c)在无机酸存在下进行。
  9. 如权利要求1至8中任一项所述的制备方法，其中反应步骤(c)在盐酸存在下进行。
  10. 如权利要求1至9中任一项所述的制备方法，其中反应步骤(c)以乙酸乙酯和水为溶剂进行。
  11. 化合物(II)用作2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的合成中间体的用途
    Figure PCTCN2017103618-appb-100004
PCT/CN2017/103618 2016-09-27 2017-09-27 一种苯丙氨酸类化合物的制备方法 WO2018059427A1 (zh)

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