WO2023097691A1 - Method for obtaining high-selectivity b-chiral branched-chain chiral amino acid - Google Patents

Method for obtaining high-selectivity b-chiral branched-chain chiral amino acid Download PDF

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WO2023097691A1
WO2023097691A1 PCT/CN2021/135522 CN2021135522W WO2023097691A1 WO 2023097691 A1 WO2023097691 A1 WO 2023097691A1 CN 2021135522 W CN2021135522 W CN 2021135522W WO 2023097691 A1 WO2023097691 A1 WO 2023097691A1
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chiral
branched
amino acids
highly selective
obtaining highly
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周章涛
叶伟平
费安杰
王杨
王道功
罗富元
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广东莱佛士制药技术有限公司
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    • 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
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • 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

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  • the invention belongs to the field of organic chemical synthesis, and in particular relates to a method for obtaining highly selective ⁇ -chiral branched-chain chiral amino acids.
  • ⁇ -branched chiral amino acid compounds are an important class of organic synthesis intermediates, which play an extremely important role in the field of biopharmaceuticals, especially in the stability of polypeptide molecules and the modification of spatial structure. Due to the construction of multiple chiral centers, in order to efficiently obtain a single-configuration product, the preparation process of ⁇ -branched chiral amino acid compounds is highly demanding.
  • the methods for preparing ⁇ -branched chiral amino acid compounds are limited, and there are mainly the following two schemes: 1) enzyme-catalyzed fermentation and 2) asymmetric catalytic hydrogenation.
  • the enzyme-catalyzed fermentation method has high requirements on the activity and selectivity of the enzyme catalyst, and is only applicable to certain types of chiral amino acids, which makes the process development difficult and relatively low in efficiency;
  • the asymmetric catalytic hydrogenation method although also suitable for the catalyst
  • the requirements for activity, cost and selectivity are high, but the types of catalysts and chiral ligands that can be selected are wide, the condition screening is flexible and changeable, and the feasibility of later scale-up production is high, which is the current key research direction.
  • the preparation of unnatural ⁇ -branched chiral amino acids has always been an important research direction in the pharmaceutical field, especially ⁇ -chiral branched chain amino acids with multiple chiral centers.
  • the present invention starts from latent chiral olefin compounds and constructs ⁇ -chiral branched-chain chiral amino acids in one step with high selectivity through asymmetric hydrogenation.
  • the present invention has developed a new process route, which has better applicability, specifically
  • the synthetic route and reaction conditions are as follows:
  • R 1 is alkyl or aryl
  • R 2 is alkyl or aryl
  • R 3 is alkyl
  • R 4 is benzoyl or acetyl
  • R 1 and R 2 can form a ring; because R 1 and R 2 are essentially is not the site where the reaction occurs, and whether R 1 and R 2 form a ring will not have a substantial impact on the reaction.
  • R1 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40
  • R2 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40
  • R3 is below C30 the alkyl group
  • R 1 and R 2 are methyl, ethyl, phenyl or cycloalkyl
  • R 3 is methyl, ethyl or benzyl
  • R 4 is benzoyl, acetyl or tert-butyloxycarbonyl carbonate .
  • the required metal catalyst is a monovalent ruthenium catalyst.
  • the monovalent ruthenium catalyst is Rh(COD) 2 BF 4 and/or [Rh(COD)Cl] 2 .
  • the desired chiral ligand is a chiral ligand based on a chiral ferrocenephosphine ligand; preferably, the chiral ligand based on a chiral ferrocenephosphine ligand
  • the ligands are Josiphos series commercial catalysts.
  • the required solvent is one of dichloromethane, methanol or ethanol.
  • R 1 is an alkyl group, a cycloalkyl group, an aryl group, such as an alkyl group below C30, a cycloalkyl group below C40, or an aryl group below C40;
  • R 2 is Alkyl, cycloalkyl, aryl, such as alkyl below C30, cyclohydrocarbyl below C40, or aryl below C40;
  • R3 is alkyl, such as alkyl below C30;
  • R4 is benzoyl or acetyl .
  • the desired metal catalyst is Rh(COD) 2 BF 4 , [Rh(COD)Cl] 2 , preferably Rh(COD) 2 BF 4 ;
  • the desired chiral ligand is a chiral phosphine ligand, preferably a chiral ligand based on a chiral ferrocene phosphine ligand, preferably a commercial catalyst of the Jos iphos series, more preferably (R)-1-[(SP)- 2-(diphenylphosphino) ferrocene] ethyl di-tert-butylphosphine, its structure is as follows;
  • the required solvent is dichloromethane, methanol, preferably dichloromethane;
  • the required hydrogen pressure is 30-50atm, preferably 30atm; the reaction can be effectively completed within the range of 30-50atm, but because the greater the pressure, the higher the requirements for the reactor and the higher the risk factor, so in meeting the process requirements Under the precursor of , the reaction conditions with less pressure are preferred.
  • the desired reaction temperature is 60-80°C, preferably 80°C.
  • choosing a higher temperature can increase the reaction rate and reduce the reaction time.
  • the beneficial effect of the present invention is that: adopting the method for preparing ⁇ -chiral branched-chain chiral amino acid compounds of the present invention can efficiently construct ⁇ -chiral branched-chain chiral amino acids with multiple chiral centers in one step, which is different from traditional enzymes Catalyzed fermentation process, this scheme has better substrate universality, lower cost, and is more environmentally friendly, and can prepare a variety of ⁇ -chiral branched-chain chiral amino acid compounds with complex structures.
  • Fig. 1 is the chiral HPLC spectrum of the compound 2a racemate prepared in the example of the present invention.
  • Fig. 2 is the chiral HPLC spectrum of the compound optical alcohol 2a prepared in the example of the present invention.
  • Fig. 3 is the hydrogen spectrum of compound 2a prepared in the embodiment of the present invention.
  • the synthetic route is as follows:

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Abstract

Provided is a method for obtaining a high-selectivity β-chiral branched-chain chiral amino acid. The synthetic route of the method for obtaining a high-selectivity β-chiral branched-chain chiral amino acid is: R1 is an alkyl or an aryl; R2 is an alkyl or an aryl; R3 is an alkyl; and R4 is a benzoyl or an acetyl. By using the method for preparing a β-chiral branched-chain chiral amino acid compound, a β-chiral branched-chain chiral amino acid having multiple chiral centers can be efficiently constructed in one step. Different from a traditional enzymatically catalyzed fermentation process, the present solution has better substrate generality and a lower cost, is more environmentally friendly, and can prepare various β-chiral branched-chain chiral amino acid compounds with complex structures.

Description

一种获得高选择性β-手性支链手性氨基酸的方法A method for obtaining highly selective β-chiral branched chiral amino acids 技术领域technical field
本发明属于有机化学合成领域，具体涉及一种获得高选择性β-手性支链手性氨基酸的方法。The invention belongs to the field of organic chemical synthesis, and in particular relates to a method for obtaining highly selective β-chiral branched-chain chiral amino acids.
背景技术Background technique
如下所示，β-支链手性氨基酸化合物是一类重要的有机合成中间体，在生物制药领域具有极为重要的作用，特别是在多肽分子的稳定性、空间结构的修饰上有重要作用。由于涉及多个手性中心的构建，为了高效地得到单一构型产物，对β-支链手性氨基酸化合物制备工艺要求较高。As shown below, β-branched chiral amino acid compounds are an important class of organic synthesis intermediates, which play an extremely important role in the field of biopharmaceuticals, especially in the stability of polypeptide molecules and the modification of spatial structure. Due to the construction of multiple chiral centers, in order to efficiently obtain a single-configuration product, the preparation process of β-branched chiral amino acid compounds is highly demanding.
Figure PCTCN2021135522-appb-000001
Figure PCTCN2021135522-appb-000001
β-支链手性氨基酸化合物结构式Structural formula of β-branched chiral amino acid compound
目前，制备β-支链手性氨基酸化合物的方法有限，主要有以下两种方案：1)酶催化发酵法和2)不对称催化氢化。其中，酶催化发酵法对酶催化剂活性、选择性要求较高，且只对特定几类手性氨基酸适用，工艺开发难度大、效率相对较低；而不对称催化氢化法，虽然同样对催化剂的活性、成本、选择性要求高，但可选择的催化剂种类、手性配体类型较广，条件筛选灵活、多变，后期放大生产可行性高，是目前重点的研究方向。At present, the methods for preparing β-branched chiral amino acid compounds are limited, and there are mainly the following two schemes: 1) enzyme-catalyzed fermentation and 2) asymmetric catalytic hydrogenation. Among them, the enzyme-catalyzed fermentation method has high requirements on the activity and selectivity of the enzyme catalyst, and is only applicable to certain types of chiral amino acids, which makes the process development difficult and relatively low in efficiency; the asymmetric catalytic hydrogenation method, although also suitable for the catalyst The requirements for activity, cost and selectivity are high, but the types of catalysts and chiral ligands that can be selected are wide, the condition screening is flexible and changeable, and the feasibility of later scale-up production is high, which is the current key research direction.
Figure PCTCN2021135522-appb-000002
Figure PCTCN2021135522-appb-000002
β-支链手性氨基酸制备Preparation of β-branched chiral amino acids
日本千叶大学的Atsushi Ohashi教授(Eur.J.Org.Chem.2002,2535-2546)采用其设计的手性双膦配体尝试β-支链手性氨基酸的制备。虽然此催化体系的对映异构选择性较高(达到98.2％，见上图)，但对于手性β-支链的研究没有过多涉及，其合成的多为非手性的β-支链。Professor Atsushi Ohashi of Chiba University in Japan (Eur.J.Org.Chem.2002, 2535-2546) used his designed chiral bisphosphine ligands to try to prepare β-branched chiral amino acids. Although the enantioselectivity of this catalytic system is high (up to 98.2%, see the figure above), there is not much research on chiral β-branched chains, and most of the synthesized ones are achiral β-branched chain.
Figure PCTCN2021135522-appb-000003
Figure PCTCN2021135522-appb-000003
β-手性支链手性氨基酸制备Preparation of β-Chiral Branched Chiral Amino Acids
美国的研究人员(J.Org.Chem.2017,82,10376-10387)为了制备一个丙型肝炎病毒的抑制剂，开发了一个β-手性支链手性氨基酸的合成方法(路线见上)，但其对映异构选择性较差，无法一步得到单一构型的目标分子，且分离难度较大，需要通过色谱柱进行分离，后期放大生产工艺难度大。Researchers in the United States (J.Org.Chem.2017, 82, 10376-10387) developed a synthesis method of β-chiral branched chiral amino acids in order to prepare an inhibitor of hepatitis C virus (see above for the route) , but its enantiomeric selectivity is poor, and it is impossible to obtain a single-configuration target molecule in one step, and the separation is difficult. It needs to be separated by a chromatographic column, and the subsequent scale-up production process is difficult.
发明内容Contents of the invention
因此，为了同时解决对映异构选择性与非对映异构选择性的难题，一步得到高选择性的β-手性支链手性氨基酸，并兼顾后期商业化放大生产的需求，需要开发一种高效的催化体系来制备β-手性支链手性氨基酸。Therefore, in order to solve the problems of enantioselectivity and diastereoselectivity at the same time, obtain highly selective β-chiral branched chiral amino acids in one step, and take into account the needs of commercial scale-up production in the later stage, it is necessary to develop An efficient catalytic system to prepare β-chiral branched chiral amino acids.
非天然类β-支链手性氨基酸的制备一直是制药领域重要的研究方向，特别是具有多个手性中心的β-手性支链氨基酸。本发明从潜手性的烯烃化合物出发，通过不对称氢化的方式高选择性地一步构建β-手性支链手性氨基酸，本发明开发了新的工艺路线，具有较好的适用性，具体合成路线及反应条件如下：The preparation of unnatural β-branched chiral amino acids has always been an important research direction in the pharmaceutical field, especially β-chiral branched chain amino acids with multiple chiral centers. The present invention starts from latent chiral olefin compounds and constructs β-chiral branched-chain chiral amino acids in one step with high selectivity through asymmetric hydrogenation. The present invention has developed a new process route, which has better applicability, specifically The synthetic route and reaction conditions are as follows:
Figure PCTCN2021135522-appb-000004
Figure PCTCN2021135522-appb-000004
根据本发明的一种实施方式，例如，在上述合成路线中，According to one embodiment of the present invention, for example, in the above synthetic route,
R 1为烷基或芳基；R 2为烷基或芳基；R 3为烷基；R 4为苯甲酰基或者乙酰基；R 1、R 2可以成环；由于R 1、R 2实质上并不是反应发生位点，R 1、R 2是否成环并不会对反应造成实质性影响。 R 1 is alkyl or aryl; R 2 is alkyl or aryl; R 3 is alkyl; R 4 is benzoyl or acetyl; R 1 and R 2 can form a ring; because R 1 and R 2 are essentially is not the site where the reaction occurs, and whether R 1 and R 2 form a ring will not have a substantial impact on the reaction.
优选的，R 1为C30以下的烷基、C40以下的环烃基或C40以下的芳基；R 2为C30以下的烷基、C40以下的环烃基或C40以下的芳基；R 3为C30以下的烷基； Preferably, R1 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40; R2 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40; R3 is below C30 the alkyl group;
进一步优选的，R 1与R 2为甲基、乙基、苯基或者环烃基，R 3为甲基、乙基或苄基，R 4为苯甲酰基、乙酰基或者碳酸叔丁基氧羰基。 Further preferably, R 1 and R 2 are methyl, ethyl, phenyl or cycloalkyl, R 3 is methyl, ethyl or benzyl, R 4 is benzoyl, acetyl or tert-butyloxycarbonyl carbonate .
根据本发明的一种实施方式，例如，在上述合成路线中，所需金属催化剂为一价钌催化 剂。优选的，所述一价钌催化剂为Rh(COD) 2BF 4和/或[Rh(COD)Cl] 2。 According to one embodiment of the present invention, for example, in the above synthesis route, the required metal catalyst is a monovalent ruthenium catalyst. Preferably, the monovalent ruthenium catalyst is Rh(COD) 2 BF 4 and/or [Rh(COD)Cl] 2 .
根据本发明的一种实施方式，例如，所需手性配体为基于手性二茂铁膦配体的手性配体；优选的，所述基于手性二茂铁膦配体的手性配体为Jos iphos系列商业化催化剂。According to one embodiment of the present invention, for example, the desired chiral ligand is a chiral ligand based on a chiral ferrocenephosphine ligand; preferably, the chiral ligand based on a chiral ferrocenephosphine ligand The ligands are Josiphos series commercial catalysts.
根据本发明的一种实施方式，例如，所需溶剂为二氯甲烷、甲醇或乙醇中的一种。According to one embodiment of the present invention, for example, the required solvent is one of dichloromethane, methanol or ethanol.
Figure PCTCN2021135522-appb-000005
Figure PCTCN2021135522-appb-000005
根据本发明的一种实施方式，例如，底物骨架中，R 1为烷基、环烃基、芳基，例如C30以下的烷基、C40以下的环烃基或C40以下的芳基；R 2为烷基、环烃基、芳基，例如C30以下的烷基、C40以下的环烃基或C40以下的芳基；R 3为烷基，例如C30以下的烷基；R 4为苯甲酰基或乙酰基。 According to one embodiment of the present invention, for example, in the substrate skeleton, R 1 is an alkyl group, a cycloalkyl group, an aryl group, such as an alkyl group below C30, a cycloalkyl group below C40, or an aryl group below C40; R 2 is Alkyl, cycloalkyl, aryl, such as alkyl below C30, cyclohydrocarbyl below C40, or aryl below C40; R3 is alkyl, such as alkyl below C30; R4 is benzoyl or acetyl .
所需金属催化剂为Rh(COD) 2BF 4，[Rh(COD)Cl] 2，优选Rh(COD) 2BF 4； The desired metal catalyst is Rh(COD) 2 BF 4 , [Rh(COD)Cl] 2 , preferably Rh(COD) 2 BF 4 ;
所需手性配体为手性膦配体，优选基于手性二茂铁膦配体的手性配体，优选Jos iphos系列商品化催化剂，进一步优选(R)-1-[(SP)-2-(二苯基膦基)二茂铁]乙基二叔丁基膦，其结构如下所示；The desired chiral ligand is a chiral phosphine ligand, preferably a chiral ligand based on a chiral ferrocene phosphine ligand, preferably a commercial catalyst of the Jos iphos series, more preferably (R)-1-[(SP)- 2-(diphenylphosphino) ferrocene] ethyl di-tert-butylphosphine, its structure is as follows;
Figure PCTCN2021135522-appb-000006
Figure PCTCN2021135522-appb-000006
所需溶剂为二氯甲烷、甲醇，优选二氯甲烷；The required solvent is dichloromethane, methanol, preferably dichloromethane;
所需氢气压力为30-50atm，优选30atm；在30-50atm这个范围内可以有效的完成反应，但由于压力越大，对反应釜的要求越高，风险系数也越高，因此在满足工艺需求的前体下，优选压力较小的反应条件。The required hydrogen pressure is 30-50atm, preferably 30atm; the reaction can be effectively completed within the range of 30-50atm, but because the greater the pressure, the higher the requirements for the reactor and the higher the risk factor, so in meeting the process requirements Under the precursor of , the reaction conditions with less pressure are preferred.
所需反应温度为60-80℃，优选80℃。在保证反应体系品质不被破坏的前提下，选择较高温度，可以提高反应速率、减少反应时间。The desired reaction temperature is 60-80°C, preferably 80°C. On the premise of ensuring that the quality of the reaction system is not damaged, choosing a higher temperature can increase the reaction rate and reduce the reaction time.
本发明的有益效果在于：采用本发明制备β-手性支链手性氨基酸类化合物的方法，可高效地一步构建多手性中心的β-手性支链手性氨基酸，区别于传统的酶催化发酵工艺，此方案底物普适性更佳、成本更低、更环保，可以制备多种结构复杂的β-手性支链手性氨基酸类化合物。The beneficial effect of the present invention is that: adopting the method for preparing β-chiral branched-chain chiral amino acid compounds of the present invention can efficiently construct β-chiral branched-chain chiral amino acids with multiple chiral centers in one step, which is different from traditional enzymes Catalyzed fermentation process, this scheme has better substrate universality, lower cost, and is more environmentally friendly, and can prepare a variety of β-chiral branched-chain chiral amino acid compounds with complex structures.
附图说明Description of drawings
为了更清楚地说明本发明实施例的技术方案，下面将对实施例的附图作简单地介绍，显然，下面描述中的附图仅仅涉及本发明的一些实施例，而非对本发明的限制。In order to illustrate the technical solutions of the embodiments of the present invention more clearly, the drawings of the embodiments will be briefly introduced below. Apparently, the drawings in the following description only relate to some embodiments of the present invention, rather than limiting the present invention.
图1是本发明实施例制备的化合物2a消旋体手性HPLC图谱。Fig. 1 is the chiral HPLC spectrum of the compound 2a racemate prepared in the example of the present invention.
图2是本发明实施例制备的化合物光学醇2a手性HPLC图谱。Fig. 2 is the chiral HPLC spectrum of the compound optical alcohol 2a prepared in the example of the present invention.
图3是本发明实施例制备的化合物2a氢谱图。Fig. 3 is the hydrogen spectrum of compound 2a prepared in the embodiment of the present invention.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的获得高选择性β-手性支链手性氨基酸的方法做更进一步的说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The method for obtaining highly selective β-chiral branched chiral amino acids of the present invention will be further described below in conjunction with specific examples. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.
合成路线如下：The synthetic route is as follows:
Figure PCTCN2021135522-appb-000007
Figure PCTCN2021135522-appb-000007
向50-mL Fischer&Porter耐压反应管里加入化合物1a(0.32g，1.0mmol)、Rh(COD) 2BF 4(2.5mg，10μmol)以及Josiphos(R)-1-1[(S)-2-(二苯基膦)二茂铁]乙基二叔丁基膦(CAS No.155830-69-6,5.4mg，10μmol)。然后，将反应管与氢气钢瓶用不锈钢气管相连，用高纯氢气对反应管进行氢气置换三次，然后再加入二氯甲烷(2mL)。之后，再对反应管进行4次氢气置换，然后维持30atm的压力，关闭阀门。再升温到80℃搅拌反应24小时。反应结束后，将反应液经硅胶过滤除去催化剂后，滤液浓缩后得到产品2a(3.0g)，92％ee，非对映异构体选择性大于99/1，收率95％。对比技术路线背景路线2中描述的非对映异构选择性，此方案的非对映异构选择性和收率都大大优于此前方案。 1H NMR(400MHz,CDCl 3)δ1.76-1.85(3H,m),2.03-2.07(1H,m),2.76-2.86(2H,m),3.41-3.44(1H,dd),3.64(1H,s),5.29-5.31(1H,dd),6.45-6.47(1H,d),7.09-7.12(3H,m),7.19-7.24(1H,dd),7.38-7.40(2H,t),7.46-7.47(1H,t),7.66-7.68(2H,d)。产品2a的相关表征结果见附图1-3。 Add compound 1a (0.32g, 1.0mmol), Rh(COD) 2 BF 4 (2.5mg, 10μmol) and Josiphos(R)-1-1[(S)-2- (Diphenylphosphine)ferrocene]ethyldi-tert-butylphosphine (CAS No. 155830-69-6, 5.4 mg, 10 μmol). Then, the reaction tube was connected to the hydrogen cylinder with a stainless steel gas tube, and the reaction tube was replaced with high-purity hydrogen for three times, and then dichloromethane (2 mL) was added. After that, the reaction tube was replaced with hydrogen 4 times, and then the pressure was maintained at 30 atm, and the valve was closed. Then the temperature was raised to 80° C. and the reaction was stirred for 24 hours. After the reaction, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated to obtain product 2a (3.0 g), 92% ee, diastereoisomer selectivity greater than 99/1, and a yield of 95%. Compared with the diastereoselectivity described in the technical route background route 2, the diastereoselectivity and yield of this scheme are much better than the previous scheme. 1 H NMR (400MHz, CDCl 3 ) δ1.76-1.85(3H,m),2.03-2.07(1H,m),2.76-2.86(2H,m),3.41-3.44(1H,dd),3.64(1H ,s),5.29-5.31(1H,dd),6.45-6.47(1H,d),7.09-7.12(3H,m),7.19-7.24(1H,dd),7.38-7.40(2H,t),7.46 -7.47(1H,t),7.66-7.68(2H,d). The relevant characterization results of product 2a are shown in Figures 1-3.

Claims (9)

  1. 一种获得高选择性β-手性支链手性氨基酸的方法，其特征在于，所述获得高选择性β-手性支链手性氨基酸的方法的合成路线为：A method for obtaining highly selective β-chiral branched chiral amino acids, characterized in that the synthetic route of the method for obtaining highly selective β-chiral branched chiral amino acids is:
    Figure PCTCN2021135522-appb-100001
    Figure PCTCN2021135522-appb-100001
    ，其中，R 1为烷基或芳基；R 2为烷基或芳基；R 3为烷基；R 4为苯甲酰基或者乙酰基； , wherein, R 1 is alkyl or aryl; R 2 is alkyl or aryl; R 3 is alkyl; R 4 is benzoyl or acetyl;
    优选的，R 1、R 2可以成环； Preferably, R 1 and R 2 can form a ring;
    优选的，R 1为C30以下的烷基、C40以下的环烃基或C40以下的芳基；R 2为C30以下的烷基、C40以下的环烃基或C40以下的芳基；R 3为C30以下的烷基； Preferably, R1 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40; R2 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40; R3 is below C30 the alkyl group;
    进一步优选的，R 1与R 2为甲基、乙基、苯基或者(C40以下的)环烃基，R 3为甲基、乙基或苄基，R 4为苯甲酰基、乙酰基或者碳酸叔丁基氧羰基。 Further preferably, R 1 and R 2 are methyl, ethyl, phenyl or (below C40) cycloalkyl, R 3 is methyl, ethyl or benzyl, R 4 is benzoyl, acetyl or carbonic acid tert-butyloxycarbonyl.
  2. 根据权利要求1所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，所述获得高选择性β-手性支链手性氨基酸的方法的合成路线为：The method for obtaining highly selective β-chiral branched chiral amino acids according to claim 1, characterized in that, the synthetic route of the method for obtaining highly selective β-chiral branched chiral amino acids is:
    Figure PCTCN2021135522-appb-100002
    Figure PCTCN2021135522-appb-100002
  3. 根据权利要求2所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，所述催化剂为一价钌催化剂，优选的，所述一价钌催化剂为Rh(COD) 2BF 4和/或[Rh(COD)Cl] 2。 The method for obtaining highly selective β-chiral branched chiral amino acids according to claim 2, wherein the catalyst is a monovalent ruthenium catalyst, preferably, the monovalent ruthenium catalyst is Rh(COD) 2 BF 4 and/or [Rh(COD)Cl] 2 .
  4. 根据权利要求2或3所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，所述手性配体为基于手性二茂铁膦配体的手性配体；The method for obtaining highly selective β-chiral branched chiral amino acids according to claim 2 or 3, wherein the chiral ligand is a chiral ligand based on a chiral ferrocene phosphine ligand ;
    优选的，所述基于手性二茂铁膦配体的手性配体为Josiphos系列商业化催化剂。Preferably, the chiral ligand based on the chiral ferrocene phosphine ligand is a commercial catalyst of the Josiphos series.
  5. 根据权利要求2-4任一项所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，反应在有机溶剂中进行；The method for obtaining highly selective β-chiral branched chiral amino acids according to any one of claims 2-4, characterized in that the reaction is carried out in an organic solvent;
    优选的，所述有机溶剂为二氯甲烷或甲醇；Preferably, the organic solvent is methylene chloride or methanol;
    进一步优选的，所述有机溶剂为二氯甲烷。Further preferably, the organic solvent is dichloromethane.
  6. 根据权利要求2-5任一项所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，反应在还原性气氛下进行；The method for obtaining highly selective β-chiral branched chiral amino acids according to any one of claims 2-5, characterized in that the reaction is carried out under a reducing atmosphere;
    优选的，所述还原性气氛为氢气；Preferably, the reducing atmosphere is hydrogen;
    优选的，所述氢气压力为30-50atm，进一步优选30atm。Preferably, the hydrogen pressure is 30-50 atm, more preferably 30 atm.
  7. 根据权利要求2-6任一项所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，反应在60-80℃下进行；The method for obtaining highly selective β-chiral branched chiral amino acids according to any one of claims 2-6, characterized in that the reaction is carried out at 60-80°C;
    优选的，反应在80℃下进行。Preferably, the reaction is carried out at 80°C.
  8. 根据权利要求2-7任一项所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，所述获得高选择性β-手性支链手性氨基酸的方法包括：The method for obtaining highly selective β-chiral branched chiral amino acids according to any one of claims 2-7, wherein the method for obtaining highly selective β-chiral branched chiral amino acids comprises :
    向反应器里加入化合物反应原料、催化剂Rh(COD) 2BF 4以及手性配体Josiphos(R)-1-1[(S)-2-(二苯基膦)二茂铁]乙基二叔丁基膦； Add the compound reaction raw materials, the catalyst Rh(COD) 2 BF 4 and the chiral ligand Josiphos(R)-1-1[(S)-2-(diphenylphosphino)ferrocene]ethyl di tert-butylphosphine;
    然后，将反应器与氢气钢瓶用不锈钢气管相连，用高纯氢气对反应管进行氢气置换三次，然后再加入二氯甲烷；Then, connect the reactor to the hydrogen cylinder with a stainless steel gas pipe, replace the reaction tube with hydrogen three times with high-purity hydrogen, and then add dichloromethane;
    之后，再对反应器进行4次氢气置换，然后维持30atm的压力，关闭阀门；After that, the reactor was replaced with hydrogen 4 times, and then the pressure of 30atm was maintained, and the valve was closed;
    再升温到80℃搅拌反应24小时；Then the temperature was raised to 80° C. and the reaction was stirred for 24 hours;
    反应结束后，将反应液经硅胶过滤除去催化剂后，滤液浓缩后得到产品。After the reaction is finished, the reaction solution is filtered through silica gel to remove the catalyst, and the filtrate is concentrated to obtain the product.
  9. 根据权利要求2-8任一项所述的获得高选择性β-手性支链手性氨基酸的方法，其特征在于，所述手性配体的结构为：The method for obtaining highly selective β-chiral branched chiral amino acids according to any one of claims 2-8, wherein the structure of the chiral ligand is:
    Figure PCTCN2021135522-appb-100003
    Figure PCTCN2021135522-appb-100003
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