WO2021227641A1 - 一种手性4-芳基-β-氨基酸衍生物的制备方法 - Google Patents

一种手性4-芳基-β-氨基酸衍生物的制备方法 Download PDF

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WO2021227641A1
WO2021227641A1 PCT/CN2021/080631 CN2021080631W WO2021227641A1 WO 2021227641 A1 WO2021227641 A1 WO 2021227641A1 CN 2021080631 W CN2021080631 W CN 2021080631W WO 2021227641 A1 WO2021227641 A1 WO 2021227641A1
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preparation
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trifluorophenyl
aryl
amino acid
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盛力
吴旭锋
沈大冬
范钢
刘鹏程
董登峰
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浙江医药股份有限公司新昌制药厂
浙江昌海制药有限公司
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Priority to US17/924,261 priority Critical patent/US20230174461A1/en
Priority to EP21803733.1A priority patent/EP4151620A4/en
Publication of WO2021227641A1 publication Critical patent/WO2021227641A1/zh

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    • C—CHEMISTRY; METALLURGY
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    • 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
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
    • B01J31/2471—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom
    • B01J31/2476—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/827—Iridium
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/24—Phosphines

Definitions

  • the present invention relates to a method for preparing enantiomerically enriched ⁇ -amino acid derivatives, which are important intermediates in pharmacy. Specifically, it relates to a new method for preparing enantiomerically enriched ⁇ -amino acid derivatives for Synthetic treatment of diabetes medicine sitagliptin.
  • the general structure II is a dipeptidyl peptidase-IV (DPP-IV) inhibitor, a commercial drug used to treat type II diabetes (Sitagliptin , Januvia).
  • DPP-IV dipeptidyl peptidase-IV
  • enamine is asymmetrically catalyzed in the presence of a rhodium catalyst and Joshiphos ligand.
  • a special solvent is required, the amount of catalyst is relatively large, and the ee value of the obtained chiral product is relatively low, making this method Uneconomical.
  • the intermediate chiral ⁇ -amino acid derivatives are prepared by using BINAP-RuCl 2 as a catalyst for the asymmetric hydrogenation of enamine.
  • the ee value and yield of the obtained chiral products are relatively low.
  • the intermediate chiral ⁇ -amino acid derivative is prepared by using TangPhosRh(COD)BF 4 as a catalyst for the asymmetric hydrogenation of enamine.
  • the ee value and yield of the chiral product obtained are relatively high, but the catalyst The cost of ligands is relatively high, commercial sources are unstable, and industrial applications are at risk.
  • the present invention provides a method for preparing a chiral 4-aryl- ⁇ -amino acid derivative in an effective enantioselective manner.
  • the chiral 4-aryl- ⁇ -amino acid derivative has the formula ⁇ -amino acid derivative of the structure shown in ⁇ ,
  • the preparation method includes hydrogenating an enamine compound having a structure as shown in formula III in the presence of a transition metal catalyst containing rhodium and BIBOPs in an organic solvent;
  • Ar is phenyl, which is substituted with one to five or one to five mixed substituents independently selected from halogen, trifluoromethyl, and alkoxy;
  • PG is hydrogen, aldehyde, acetyl, benzyl, Boc, Cbz, PMB, Fmoc, COOR 1 , CONR 2 ;
  • the chiral ligands are BIBOPs (for the preparation method, please refer to US8552212, Org. Lett., 2010, 12(1): 176), which has formula IV Structure:
  • the ligand BIBOPs has the structure shown in formula IV:
  • R' is hydrogen, alkyl, halogen, hydroxy, alkoxy, or aryl.
  • the preferred configuration is formula IVa, and R is methoxy.
  • formula IV is formula (S, S, S', S')-IVa and formula (R, R, R', R ')-IVb,
  • the transition metal comprises [M(NBD) 2 ]X, [M(COD) 2 ]X, wherein: X is selected from tetrafluoroborate, hexafluoro Non-coordinating anions of antimonate and trifluoromethanesulfonate; M is rhodium, iridium, and ruthenium. Among them: COD is 1,5-cyclooctadiene, and NBD is norbornadiene.
  • Preferred transition metals are [Rh(NBD) 2 ]BF 4 and [Rh(COD) 2 ]BF 4 .
  • the organic solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, butyl acetate, tetrahydrofuran, methyl tert-butyl ether, One or more of isopropyl ether, toluene, acetone, acetonitrile, dichloromethane, and n-heptane.
  • Preferred organic solvents are methanol and ethanol.
  • the amount of chiral ligand and transition metal is 0.001 to 1 mol%.
  • the pressure of hydrogen is 0.1-10 MPa. Preferably, it is 0.1 to 2.5 MPa.
  • the reaction temperature of the hydrogenation is room temperature to 100°C. Preferably, room temperature to 80°C.
  • the reaction time of the hydrogenation is 2 to 36 hours. Preferably 6-24h.
  • the preparation method of the chiral ⁇ -amino acid derivative (formula I) provided by the present invention has the following beneficial effects: the amount of selected asymmetric catalyst is small, the operation is simple, the reaction conditions are mild, the yield is high, the purity is as high as 99.9%, and the three-dimensional High selectivity, good industrial application and economic value.

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

Abstract

本发明提供了一种手性4-芳基-β-氨基酸衍生物的制备方法，所述制备方法包括在有机溶剂中，在包含过渡金属和BIBOPs的催化剂的存在下，氢化具有如式Ⅲ所示结构的烯胺化合物。本发明的制备方法具有选用的不对称催化剂用量少、操作简单、反应条件温和、收率高，立体选择性高，具有较好的工业应用和经济价值。

Description

一种手性4-芳基-β-氨基酸衍生物的制备方法 技术领域
本发明涉及制备对映体富集的β-氨基酸衍生物的方法，其是药学中重要的中间体，具体地说，涉及制备对映体富集的β-氨基酸衍生物的新方法，用于合成治疗糖尿病药物西格列汀。
背景技术
如J.Med.Chem.2005,48(1):141所公开，通式结构Ⅱ是二肽基肽酶-Ⅳ(DPP-Ⅳ)抑制剂，用来治疗Ⅱ型糖尿病的商购药物(Sitagliptin，Januvia)。
Figure PCTCN2021080631-appb-000001
如WO2004085378，WO2005097733，WO2006065826所公开，在铑催化剂和Joshiphos配体存在下不对称催化烯胺，然而需要使用特殊溶剂，催化剂用量相对较多，所得手性产物的ee值相对较低，使得该法不经济。
如WO2009064476所公开，中间体手性β-氨基酸衍生物由BINAP-RuCl 2作催化剂不对称氢化烯胺所制备。所得手性产物的ee值 和收率相对较低。
如US8278486/CN102271504所公开，中间体手性β-氨基酸衍生物由TangPhosRh(COD)BF 4作催化剂不对称氢化烯胺所制备，所得手性产物的ee值和收率相对较高，但该催化剂配体成本较高，商业来源不稳定，工业应用存在风险。
发明内容
本发明提供以有效的对映选择性方式，提供了一种手性4-芳基-β-氨基酸衍生物的制备方法，所述手性4-芳基-β-氨基酸衍生物为具有如式Ι所示结构的β-氨基酸衍生物，
Figure PCTCN2021080631-appb-000002
其中：立体中心用*标记的R-构型或S-构型；
所述制备方法包括在有机溶剂中，在包含铑和BIBOPs的过渡金属催化剂的存在下，氢化具有如式Ⅲ所示结构的烯胺化合物；
Figure PCTCN2021080631-appb-000003
其中：Ar为苯基，其用一至五个或一至五个混合独立选自卤素、三氟甲基、烷氧基的取代基取代；PG是氢、醛基、乙酰基、苄基、Boc、Cbz、PMB、Fmoc、COOR 1、CONR 2；Z是OR 1、SR 1和NR 3R 4；其中：R 1＝H、C 1-6烷基；R 2＝H、C 1-6烷基或含有氮、氧、硫的三至六元杂环；R 3和R 4是各自独立H、C 1-6烷基、C 4-10环烷基、芳基或R 3和R 4与它 们连接至氮原子形成的任选含有选自O、S、N-C 1-5烷基的额外杂原子的C 4-7元杂环。
在本发明的制备方法的优选技术方案中，优选地，所述手性配体为BIBOPs(其制备方法可参考US8552212，Org.Lett.,2010,12(1):176)，其具有式Ⅳ结构：所述配体BIBOPs具有如式Ⅳ所示的结构：
Figure PCTCN2021080631-appb-000004
其中，R’是氢、烷基、卤素、羟基、烷氧基、芳基。优选的构型为式Ⅳa，R为甲氧基。
在本发明的制备方法的优选技术方案中，优选地，如式Ⅳ所示的结构构型为式(S,S,S’,S’)-IVa和式(R,R,R’,R’)-IVb，
Figure PCTCN2021080631-appb-000005
在本发明的制备方法的优选技术方案中，优选地，所述过渡金属包含[M(NBD) 2]X、[M(COD) 2]X，其中：X选自四氟硼酸根、六氟锑酸根、三氟甲磺酸根的非配位阴离子；M是铑、铱、钌。其中：COD为1,5-环辛二烯，和NBD为降冰片二烯。优选的过渡金属为[Rh(NBD) 2]BF 4、[Rh(COD) 2]BF 4。
在本发明的制备方法的优选技术方案中，优选地，所述有机溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸甲酯、乙酸丁酯、四氢呋喃、甲基叔丁基醚、异丙醚、甲苯、丙酮、乙腈、二氯甲烷、正庚烷中的一种或两种以上。优选的有机溶剂为甲醇、乙醇。
在本发明的制备方法的优选技术方案中，优选地，手性配体和过渡金属的用量为0.001～1mol％。
在本发明的制备方法的优选技术方案中，优选地，氢气的压力为0.1～10MPa。优选地0.1～2.5MPa。
在本发明的制备方法的优选技术方案中，优选地，所述氢化的反应温度为室温至100℃。优选地，室温至80℃。
在本发明的制备方法的优选技术方案中，优选地，所述氢化的反应时间2～36h。优选地6～24h。
本发明提供的手性β-氨基酸衍生物(式Ι)的制备方法，具有以下有益效果：选用的不对称催化剂用量少、操作简单、反应条件温和、收率高，纯度高达99.9％，立体选择性高，具有较好的工业应用和经济价值。
具体实施方式
为了更好地理解本发明的技术方案，下面结合具体实施例作进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1：5-[1-羟基-2-(2,4,5-三氟苯基)-亚乙基]-2,2-二甲基-1,3-二氧六 环-4,6-二酮
Figure PCTCN2021080631-appb-000006
250mL反应釜中加入四氢呋喃(40.0g)、三氟苯乙酸(10.0g)，控温在0～5℃，分批加入N,N-羰基二咪唑(CDI，9.4g)，加毕后室温反应3h，加入米氏酸(8.4g)，室温搅拌16h。减压蒸除溶剂，加入水(20.0g)、用1N盐酸调pH至2左右，二氯甲烷萃取、洗涤、干燥得到类白色固体[5-[1-羟基-2-(2,4,5-三氟苯基)-亚乙基]-2,2-二甲基-1,3-二氧六环-4,6-二酮]14.6g，收率88％。HRMS[M+H] +：317.0628； 1H-NMR(400MHz，CDCl 3)：15.50(s，1H)，7.13-7.19(m，1H)，6.93-6.99(m，1H)，4.54(s，2H)，1.77(s，6H)。
实施例2：(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯
Figure PCTCN2021080631-appb-000007
250mL反应釜中加入甲醇(48.0g)、实施例1的产品5-[1-羟基-2-(2,4,5-三氟苯基)-亚乙基]-2,2-二甲基-1,3-二氧六环-4,6-二酮(14.0g)，60℃反应4h，加入乙酸铵(5.0g)，60℃反应10h小时，减压浓缩，加入二氯甲烷、水，萃取、洗涤、干燥，减压回收溶剂至干，得到淡黄色固体[(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯]10.0g，收率92％。 HRMS[M+H] +：246.0735； 1H-NMR(400MHz，CDCl 3)：7.05-7.12(m，1H)，6.92-6.98(m，1H)，4.57(s，1H)，3.65(s，3H)，3.41(s，2H)。
实施例3：(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯
Figure PCTCN2021080631-appb-000008
100mL反应瓶中加入四氢呋喃(40.0g)，实施例2的产品(Z)-3-氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(10.0g)、醋酐(8.0g)、吡啶(9.0g)，回流反应20h，用盐酸调pH至3左右。减压蒸除溶剂至近干，硅胶纯化得到9.3g白色固体[(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯](79％，HPLC纯度99.8％)。HRMS[M+H] +：288.0838； 1H-NMR(400MHz，CDCl 3)：11.14(s，1H)，7.03-7.09(m，1H)，6.89-6.96(m，1H)，4.82(s，1H)，4.15(s，2H)，3.71(s，3H)，2.15(s，3H)。
实施例4：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000009
氢化釜中加入甲醇(16.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(4.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(2.0mg)，先后用氮气、氢气置换，氢气压力至1.0Mpa，室温反应36h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸 甲酯定量收率98.8％ee，纯度99.4％。HRMS[M+H] +：290.0998； 1H-NMR(400MHz，CDCl 3)：7.02-7.09(m，1H)，6.87-6.93(m，1H)，6.31-6.33(m，1H)，4.44-4.45(m，1H)，3.71(s，3H)，2.87-2.89(m，2H)，2.49-2.61(m，2H)1.93(s，3H)。
实施例5：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000010
氢化釜中加入乙醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(1.0mg)，先后用氮气、氢气置换，氢气压力至1.0Mpa，60℃反应18h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.5％ee，纯度99.4％。
实施例6：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000011
氢化釜中加入四氢呋喃(10.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(1.0mg)，先后用氮气、氢气置换，氢气压力至1.5Mpa，50℃反应10h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.8％ee，纯度高达99.7％。
实施例7：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000012
氢化釜中加入甲醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(1.0mg)，先后用氮气、氢气置换，氢气压力至2.5Mpa，60℃反应6h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.2％ee，纯度99.8％。
实施例8：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000013
氢化釜中加入甲醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(COD) 2]BF 4(1.5mg)，先后用氮气、氢气置换，氢气压力至1.0Mpa，40℃反应24h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.5％ee，纯度高达99.5％。
实施例9：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸乙酯
Figure PCTCN2021080631-appb-000014
氢化釜中加入甲醇(16.0g)、(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸乙酯(4.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(2.0mg)，先后用氮气、氢气置换，氢气压力至1.0Mpa，50℃反应14h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸乙酯定量收率98.7％ee，纯度99.8％。HRMS[M+H] +：304.1150； 1H-NMR(400MHz，CDCl 3)：7.04-7.10(m，1H)，6.88-6.93(m，1H)，6.30-6.33(m，1H)，4.42-4.45(m，1H)，4.10(q，J＝7.2Hz，2H)3.72(s，3H)，2.87-2.90(m，2H)，2.49-2.61(m，2H)1.26(t，J＝6.8Hz，3H)。
实施例10：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000015
氢化釜中加入甲醇(10.0g)、实施例3的产品(Z)-3-乙酰氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD)]SbF 6(1.5mg)，先后用氮气、氢气置换，氢气压力至1.0Mpa，50℃反应24h，减压蒸除溶剂至干，得到(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯定量收率98.0％ee，纯度高达99.0％。
实施例11：(3R)-N-叔丁氧羰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000016
50mL反应瓶中加入(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯(3.0g)，盐酸(9.0g)，回流过夜，减压浓缩，加入2mol/L NaOH溶液调pH＞13.5，滴加Boc酸酐(2.7g)，室温反应5h。加入乙酸乙酯(9.0g)，用2N盐酸调节pH至2.5～3.5，分层、萃取、洗涤，减压至干，得到类白色固体(3R)-N-叔丁氧羰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯3.1g，收率90％，纯度99.7％。HRMS[M+H] +：334.1276； 1H-NMR(400MHz，DMSO-d 6)：12.19(s，1H)7.41-7.48(m，1H)，7.24-7.31(m，1H)，6.77-6.79(d，1H，J＝8.8Hz)，4.00-4.02(m，1H)，2.57(dd，1H，J＝3.2，13.2Hz)，2.83(dd，1H，J＝4.4，15.2Hz)，2.40(d，2H，J＝6.4Hz)1.27(s，9H)。
实施例12：N-Boc西格列汀
Figure PCTCN2021080631-appb-000017
250mL反应瓶加入二氯甲烷(30.0g)、(3R)-N-叔丁氧羰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯(3.0g)、3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐(2.4g)，加入HOBT(1.4g)、EDC·HCl(1.9g)，温度控制在0.0～10.0℃，缓慢加入DIPEA(3.5g)，室温反应12h，加入水(70.0g)，减压蒸除溶剂，加入无水乙醇(24.0g)升温至溶解后 过滤，冷却结晶，干燥得到白色固体3.75g(收率82％)。HRMS[M+H] +：508.1666； 1H-NMR(400MHz，DMSO-d 6)：7.40-7.47(m，1H)，7.29-7.36(m，1H)，6.74-6.77(m，1H)，4.88-5.04(m，2H)，4.22-4.32(m，1H)，3.96-4.10(m，2H)，2.61-2.89(m，4H)1.24(s，9H)。
实施例13：西格列汀
Figure PCTCN2021080631-appb-000018
100mL反应瓶依次投入甲醇(10.0g)、N-Boc西格列汀(2.0g)，缓慢加入盐酸(4.5g)，室温反应14h，减压浓缩后，加入水(2.5g)搅拌，氢氧化钠溶液调节pH值8.0～9.0，加入乙酸乙酯萃取，减压浓缩，异丙醇(10.0g)重结晶，得到白色固体1.3g(收率80％，≥99.9％ee)。HRMS[M+H] +：408.1260； 1H-NMR(400MHz，D 2O)：7.17-7.24(m，1H)，7.01-7.11(m，1H)，4.82-5.00(m，2H)，4.14-4.27(m，2H)，3.93-4.01(m，1H)，2.91-3.09(m，2H)，2.79-2.97(m，2H)。
实施例14：N-Boc西格列汀
Figure PCTCN2021080631-appb-000019
氢化釜中加入甲醇(10.0g)、(Z)-叔丁氧羰基-4-氧代-[3-(三氟甲 基)-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)-丁-2-烯-2-基氨基甲酸酯(2.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(2.0mg)，先后用氮气、氢气置换，氢气压力至1.5Mpa，50℃反应16h，减压蒸除溶剂至干，得到定量收率90.0％ee。
实施例15：(3R)-N-乙酰基-3-氨基-4-(2,4,5-三氟苯基)丁酸甲酯
Figure PCTCN2021080631-appb-000020
氢化釜中加入甲醇(10.0g)、(Z)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)-2-丁烯酸甲酯(2.0g)、MeO-BIBOP/[Rh(NBD) 2]BF 4(1.0mg)，先后用氮气、氢气置换，氢气压力至1.0Mpa，50℃反应14h，过滤、减压蒸除溶剂至干，得到定量收率99.3％ee，纯度99.9％。HRMS[M+H] +：348.1421； 1H-NMR(400MHz，CDCl 3)：7.04-7.12(m，1H)，6.84-6.93(m，1H)，5.09-5.12(m，1H)，4.10-4.22(m，1H)，3.70(s，3H)，2.85-2.90(m，1H)，2.50-2.61(m，1H)，1.40(s，9H)。
本发明不受上述实施例的限制，上述实施例和说明书中描述的只是为了说明原理，在阅读了本发明的上述内容后，本领域技术人员可以对本发明做各种修改而不背离本发明的精神和范围，这些等同形式的修改同样落在本发明的保护范围之内。

Claims (10)

  1. 一种手性4-芳基-β-氨基酸衍生物的制备方法，所述手性4-芳基-β-氨基酸衍生物为具有如式Ι所示结构的β-氨基酸衍生物，
    Figure PCTCN2021080631-appb-100001
    其中：立体中心用*标记的R-构型或S-构型；
    所述制备方法包括在有机溶剂中，在包含过渡金属和BIBOPs的催化剂的存在下，氢化具有如式Ⅲ所示结构的烯胺化合物；
    Figure PCTCN2021080631-appb-100002
    其中：Ar为苯基，其用一至五个或一至五个混合独立选自卤素、三氟甲基、烷氧基的取代基取代；PG是氢、醛基、乙酰基、苄基、Boc、Cbz、PMB、Fmoc、COOR 1、CONR 2；Z是OR 1、SR 1和NR 3R 4；其中：
    R 1＝H、C 1-6烷基；
    R 2＝H、C 1-6烷基或含有氮、氧、硫的三至六元杂环；
    R 3和R 4是各自独立H、C 1-6烷基、C 4-10环烷基、芳基或R 3和R 4与它们连接至氮原子形成的任选含有选自O、S、N-C 1-5烷基的额外杂原子的C 4-7元杂环。
  2. 根据权利要求1的制备方法，其中，所述过渡金属包含[M(NBD) 2]X、[M(COD) 2]X，其中：X选自四氟硼酸根、六氟锑酸根、 三氟甲磺酸根的非配位阴离子；M是铑、铱、钌。
  3. 根据权利要求1的制备方法，其中，所述配体BIBOPs具有如式Ⅳ所示的结构：
    Figure PCTCN2021080631-appb-100003
    其中，R’是氢、烷基、卤素、羟基、烷氧基、芳基。
  4. 根据权利要求3的制备方法，其中，如式Ⅳ所示的结构构型为式(S,S,S’,S’)-IVa和式(R,R,R’,R’)-IVb，
    Figure PCTCN2021080631-appb-100004
  5. 根据权利要求1的制备方法，其中，所述有机溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸甲酯、乙酸丁酯、四氢呋喃、甲基叔丁基醚、异丙醚、甲苯、丙酮、乙腈、二氯甲烷、正庚烷中的一种或两种以上。
  6. 根据权利要求1的制备方法，其中，式Ⅲ中Ar是2,4,5-三氟苯基，PG是乙酰基，Z是OCH 3。
  7. 根据权利要求1的制备方法，其中，式Ⅲ中Ar是2,4,5-三氟苯基，PG是Boc，Z是
    Figure PCTCN2021080631-appb-100005
  8. 根据权利要求1所述的制备方法，其中，氢气的压力为0.1～10MPa。
  9. 根据权利要求1所述的制备方法，其中，所述氢化的反应温度为室温至100℃。
  10. 根据权利要求1所述的制备方法，其中，所述氢化的反应时间为2～36h。
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