WO2005011863A1 - A chiral ligand metalcomplex catalyst system and its preparation and applications - Google Patents

A chiral ligand metalcomplex catalyst system and its preparation and applications Download PDF

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Publication number
WO2005011863A1
WO2005011863A1 PCT/CN2004/000777 CN2004000777W WO2005011863A1 WO 2005011863 A1 WO2005011863 A1 WO 2005011863A1 CN 2004000777 W CN2004000777 W CN 2004000777W WO 2005011863 A1 WO2005011863 A1 WO 2005011863A1
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ligand
reaction
chiral
room temperature
solid
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PCT/CN2004/000777
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French (fr)
Chinese (zh)
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Zhuo Zheng
Hanmin Hang
Huilin Chen
Huili Luo
Changmin Bai
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Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
    • B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0269—Complexes comprising ligands derived from the natural chiral pool or otherwise having a characteristic structure or geometry
    • B01J2531/0272—Complexes comprising ligands derived from the natural chiral pool or otherwise having a characteristic structure or geometry derived from carbohydrates, including e.g. tartrates or DIOP
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B01J2531/822—Rhodium

Definitions

  • the invention relates to a chiral ligand metal complex catalytic system
  • the invention also relates to a method for preparing the above-mentioned catalytic system
  • the invention also relates to the application of the above-mentioned catalytic system in asymmetric hydrogenation reaction. Background technique
  • Catalytic asymmetric hydrogenation is the core technology in asymmetric synthesis, and it is one of the most effective methods for synthesizing optically pure chiral drugs, pesticides, food additives, and spices.
  • the design and synthesis of chiral ligands is the key to achieving this core technology. factor.
  • many chiral bidentate phosphine ligands have been developed in succession.
  • most of the ligands are difficult to synthesize, have poor stability, and are expensive to synthesize. It is difficult to apply them to industrial production, so they have been successfully applied to industrial production.
  • the purpose of the present invention is to provide a chiral ligand metal complex catalyst system
  • Another object of the present invention is to provide a method for preparing the above-mentioned catalytic system, in particular, a method for preparing a ligand in the catalytic system.
  • the chiral ligand metal complex catalyst system provided by the present invention is composed of a complex or ligand formed by a ligand and a metal Rla, Ru, Ir, Pt or Pd and a corresponding metal precursor in a molar ratio of 1 to 2 System; where the ligand has the following structure and structural formula name:
  • the R, and 'groups in the ligand are: hydrogen, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl in C 6 -C M , containing N, S, 0, P or not Aromatic groups containing N, S, 0, P; methyl, ethyl, propyl or butyl ⁇
  • the groups in the ligand are:
  • a high-efficiency chiral phosphite ligand is synthesized by using a D-type mannitol or an L-type mannitol as a chiral source through a triple reaction, and the structure and synthesis of the ligand
  • the technical route is as follows:
  • the aldehyde mannitol: concentrated sulfuric acid (molar ratio) is 1: 4.4: 2;
  • the preparation steps of the ligand in the catalytic system are:
  • step 2 b) adding the solid obtained in step 1, sodium hydride and halogenated fat to DMF at a molar ratio of 1: 1: 1.1, and stirring the reaction at room temperature for 0.5-3 hours; extracting the reaction mixture with ether and washing with brine, Dry over anhydrous sodium sulfate and remove the solvent to obtain a solid;
  • the aldehyde used in step a of the preparation method is an aliphatic aldehyde or a C 6 -C 3 () aromatic.
  • the aldehyde used in step a of the preparation method is formaldehyde, acetaldehyde, or benzaldehyde.
  • the halogenated aliphatic hydrocarbon used in step b of the preparation method is methyl iodide, an aromatic hydrocarbon-substituted halomethyl group, an aromatic hydrocarbon-substituted halomethylene group, or an aromatic hydrocarbon-substituted halomethine group.
  • the diphenol used in step c of the preparation method is 2,2'-binaphthol, 2,3'-binaphthol substituted at the 3,3 'position, 2,2'-biphenyldiol or Substituted 2,2'-biphenol.
  • the reaction is carried out at a temperature of 1-100atm, -20 ⁇ 200 ° C.
  • a protic alcohol solvent can be selected, and aprotic C 6 to C lfl hydrocarbons, CH 2 C1 2 , C C1C3 ⁇ 4CI, C3 ⁇ 4C1, CC1 4 , tetrahydrofuran, etc. as solvents.
  • Invention effect
  • the catalyst formed by the designed and synthesized chiral ligand ManniPhos and the rhodium metal compound has a wide application range and can be applied to asymmetric hydrogenation reactions of various types of CC double bonds.
  • the catalyst formed by ManniPhos and [Rh (COD) 2 ] BF 4 under in situ conditions is mainly used in the following types of substrates to catalyze asymmetric hydrogenation:
  • the chiral ligand ManniPhos designed by the present invention is stable to the air, easy to operate and save; the synthetic route of the ligand is simple, and no severe operating conditions such as high temperature and high pressure are required during the synthesis process; the cost of the synthesis of the ligand is low, and the raw materials mannitol and aldehyde are synthesized , Phosphorus trichloride, etc. are cheap and readily available.
  • the catalysts formed by ManniPhos and rhodium metal compounds have high stereoselectivity. The enantioselectivity can be as high as 99.9% for the above four types of substrates.
  • the catalysts formed by ManniPhos and rhodium metal compounds have high activity, and the TON can be as high as 10,000.
  • the asymmetric hydrogenation reaction involving the catalyst formed by the chiral ligand ManniPhos and the rhodium metal compound designed and synthesized by the present invention has mild conditions and can react at room temperature.
  • the pressure of hydrogen can be used in a wide range and does not affect the activity of the catalyst from normal pressure to high pressure.
  • Stereoselectivity, the reaction time is 1 to 24 hours, the molar ratio of the ligand to the metal rhodium compound is 1: 1 to 4: 1, and the ratio of the reaction substrate to the catalyst is 100 to 10,000.
  • the catalysts formed by chiral ligands and rhodium metal compounds have high catalytic activity and stereoselectivity for ⁇ -dehydroamino acids, ⁇ -dehydroamino acids, itaconic acid and its ⁇ -substituted itaconic acid substrates.
  • TON Under the reaction conditions of temperature 0 ⁇ 100 ° C and pressure 1 ⁇ 100 ato, TON can reach as high as 10,000, Enantioselectivity can be as high as 99.9%.
  • various types of chiral products such as chiral drugs, chiral pesticides, and chiral amino acids can be prepared through asymmetric hydrogenation reactions, which have important applications in the industries of medicine, pesticides, spices, food and feed additives, etc. value.
  • the existing monodentate phosphine ligands such as Reete are relatively simple to synthesize, the chemical properties of the ligands are stable and they can be stably stored in the air, but the Rh complexes are only active against itaconic acid derivatives.
  • Example 1 a monodentate phosphinate ligand such as Reetz, etc. was used to make Rh catalyst to catalyze the asymmetric hydrogenation of ⁇ -dehydroamino acid ester, and only 95.5% ee was obtained.
  • Example 7 the use of monodentate phosphinate ligands such as Reetz and others to make the enamine catalyzed by Rh catalyst It is called hydrogenation, and it can only react at a higher pressure, 60atni, and only 95.3% ee is obtained.

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  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A chiral phosphine ligand containing metal complex catalyst system, which was constitute of the complex formed from the ligand with Rh, Ru, Pt or Pd, or formed from the corresponding metal with the ligand in term of 1~2 molar ratio; the phosphine ligand in this catalyst system was a highly active chiral phosphite ester ligand, which was obtained by the reaction of chiral D-mannite or L-mannite chiral sources. The asymmetry hydrogenation reaction, which was catalyzed by the catalyst formed by the chiral phosphine ligand and rhodium, has facile reaction conditions, that can react at room temperature; and has wide hydric press, without infect the catalyst activity and solid selectivity, from atmospheric pressure to high pressure; the reaction time is 1~24 hour, the molor ratio of ligand to rhodium compound is 1:1~2:1, the ratio of reaction substrate to the catalyst is 100~10,000.

Description

-种手性配体金属络合物催化体系及制法和应用  -A kind of chiral ligand metal complex catalytic system, its preparation method and application
技术领域 Technical field
本发明涉及一种手性配体金属络合物催化体系；  The invention relates to a chiral ligand metal complex catalytic system;
本发明还涉及上述催化体系的制备方法；  The invention also relates to a method for preparing the above-mentioned catalytic system;
本发明还涉及上述催化体系在不对称氢化反应中的应用。 背景技术  The invention also relates to the application of the above-mentioned catalytic system in asymmetric hydrogenation reaction. Background technique
催化不对称氢化是不对称合成中的核心技术， 是合成光学纯手性药物、 农药、 食 品添加剂、 香料的最有效方法之一， 而手性配体的设计合成是实现这一核心技术的关 键因素。 目前， 已有许多手性双齿膦配体相继被人们开发出來， 但是由于绝大多数配 体合成难度大， 稳定性差， 合成价格昂贵难以应用于工业生产中， 因此真正的成功应 用于工业生产的手性膦配体不多。 目前文献报道的用于工业应用的仅有美国孟山都公 司的 DIP AMP, R本高砂香料的 BINAP等屈指可数的几类。最近， 单齿手性亚磷酸酯、 亚磷酰胺类配体也已被人们相继开发出来， 虽然此类配体合成简便， 结构稳定， 但是 此类配体的手性诱导能力， 配体底物适用范围比较窄， 也限制了其在工业上的应用。 发明内容  Catalytic asymmetric hydrogenation is the core technology in asymmetric synthesis, and it is one of the most effective methods for synthesizing optically pure chiral drugs, pesticides, food additives, and spices. The design and synthesis of chiral ligands is the key to achieving this core technology. factor. At present, many chiral bidentate phosphine ligands have been developed in succession. However, most of the ligands are difficult to synthesize, have poor stability, and are expensive to synthesize. It is difficult to apply them to industrial production, so they have been successfully applied to industrial production. There are not many chiral phosphine ligands. At present, only a few of the types reported in the literature for industrial applications are DIP AMP from Monsanto, Inc., BINAP, R. Takasago. Recently, monodentate chiral phosphites and phosphoramidite-based ligands have also been successively developed. Although such ligands are simple to synthesize and structurally stable, the chirality-inducing ability of such ligands and ligand substrates The relatively narrow scope of application also limits its industrial application. Summary of the invention
本发明的目的在于提供一种手性配体金属络合物催化体系；  The purpose of the present invention is to provide a chiral ligand metal complex catalyst system;
本发明的又一目的在于提供上述催化体系的制备方法，具体地说是催化体系中配 体的制备方法。  Another object of the present invention is to provide a method for preparing the above-mentioned catalytic system, in particular, a method for preparing a ligand in the catalytic system.
本发明提供的手性配体金属络合物催化体系， 是由配体与金属 Rla、 Ru、 Ir、 Pt或 Pd形成的络合物或配体与相应金属前体按 1〜2摩尔比组成的体系； 其中配体具有如 下结构及结构式名称：
Figure imgf000003_0001
The chiral ligand metal complex catalyst system provided by the present invention is composed of a complex or ligand formed by a ligand and a metal Rla, Ru, Ir, Pt or Pd and a corresponding metal precursor in a molar ratio of 1 to 2 System; where the ligand has the following structure and structural formula name:
Figure imgf000003_0001
L-ManniPhos  L-ManniPhos
其中， 配体中的 R,、 '基团为： 氢、 苯基、 取代苯基、 1-萘基或 2-萘基的 C6-CM 内的含 N、 S、 0、 P或不含 N、 S、 0、 P的芳香基团； 甲基、 乙基、 丙基或丁基的 〜Wherein, the R, and 'groups in the ligand are: hydrogen, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl in C 6 -C M , containing N, S, 0, P or not Aromatic groups containing N, S, 0, P; methyl, ethyl, propyl or butyl ~
C40内的含 N、 S、 0、 P的脂肪基团； Within the N-containing C 40, S, 0, P aliphatic group;
-o  -o
配体中的 基团为:  The groups in the ligand are:
-o  -o
Figure imgf000003_0002
Figure imgf000003_0002
本发明制备上述催化体系中配体的方法，以 D-型甘露醇或 L-型甘露醇为手性源经 过三歩反应合成一种高效的手性亚磷酸酯配体， 配体的结构及合成技术路线如下： In the method for preparing a ligand in the above catalytic system, a high-efficiency chiral phosphite ligand is synthesized by using a D-type mannitol or an L-type mannitol as a chiral source through a triple reaction, and the structure and synthesis of the ligand The technical route is as follows:
Figure imgf000003_0003
或
Figure imgf000004_0001
Figure imgf000003_0003
or
Figure imgf000004_0001
L-甘 S醇  L-Glycol
其中： among them:
第一歩反应中， 醛:甘露醇：浓硫酸 (摩尔比)为 1 :4.4:2;  In the first reaction, the aldehyde: mannitol: concentrated sulfuric acid (molar ratio) is 1: 4.4: 2;
第二步反应中， 物料 (l):NaH: R (摩尔比) =1 :1:1.1 ;  In the second reaction step, the material (l): NaH: R (molar ratio) = 1: 1: 1.1;
第三歩反应中， 物料 (2):二酚: PCl3:Et3N (摩尔比) =1:1.2:1 :2.2。 In the third reaction, the material (2): diphenol: PCl 3 : Et 3 N (molar ratio) = 1: 1.2: 1: 2.2.
具体地说， 催化体系中配体的制备步骤为：  Specifically, the preparation steps of the ligand in the catalytic system are:
a) 按摩尔比醛：甘露醇：浓硫酸为 1:4.4:2, 加入到与上述总体积相等的溶剂 DMF 中， 室温搅拌下反应 10-80小时， 将反应混合物过滤得到固体并用石油醚洗涤， 固体 物用沸腾的氯仿抽提， 过滤得到的固体物经甲醇重结晶；  a) The molar ratio of aldehyde: mannitol: concentrated sulfuric acid is 1: 4.4: 2, and it is added to the solvent equal to the above total volume of DMF. The reaction is stirred at room temperature for 10-80 hours. The reaction mixture is filtered to obtain a solid and washed with petroleum ether. , The solid was extracted with boiling chloroform, and the solid obtained by filtration was recrystallized from methanol;
b) 将步骤 1得到的固体物、 氢化钠与卤代脂肪经按摩尔比为 1 :1 :1.1加入到 DMF 中， 室温下搅拌反应 0.5-3小时， 反应混合物用***萃取， 食盐水洗涤， 无水硫酸钠干 燥， 去除溶剂得到固体物；  b) adding the solid obtained in step 1, sodium hydride and halogenated fat to DMF at a molar ratio of 1: 1: 1.1, and stirring the reaction at room temperature for 0.5-3 hours; extracting the reaction mixture with ether and washing with brine, Dry over anhydrous sodium sulfate and remove the solvent to obtain a solid;
c) 氮气保护下， 将步聚 2得到的固体物于 0-5°C滴加三乙胺， 滴加完毕后在室温 搅拌反应 5-30分钟， 再加入二酚于室温下搅拌反应 1-3小时， 过滤， 去除溶剂经*** 重结晶得到所需的配体； 该歩骤中的摩尔比为固体物:二酚:三氯化磷 (PC13):三乙胺 =1:1.2:1 :2.2。 c) Triethylamine was added dropwise to the solid obtained in Step 2 under the protection of nitrogen at 0-5 ° C. After the dropwise addition, the reaction was stirred at room temperature for 5-30 minutes, and then diphenol was added to stir the reaction at room temperature. 3 hours, filtered, removed the solvent and recrystallized from ether to obtain the desired ligand; the molar ratio in this step is solid: diphenol: phosphorus trichloride (PC1 3 ): triethylamine = 1: 1.2: 1 : 2.2.
所述的制备方法歩骤 a中所用的的醛为 的脂肪醛或 C6-C3()的芳香 所述的制备方法步骤 a中所用的醛为甲醛、 乙醛或苯甲醛。 The aldehyde used in step a of the preparation method is an aliphatic aldehyde or a C 6 -C 3 () aromatic. The aldehyde used in step a of the preparation method is formaldehyde, acetaldehyde, or benzaldehyde.
所述的制备方法歩骤 b中所用的卤代脂肪烃为碘甲烷、 芳烃取代卤代甲基、 芳烃 取代卤代亚甲基或芳烃取代卤代次甲基。  The halogenated aliphatic hydrocarbon used in step b of the preparation method is methyl iodide, an aromatic hydrocarbon-substituted halomethyl group, an aromatic hydrocarbon-substituted halomethylene group, or an aromatic hydrocarbon-substituted halomethine group.
所述的制备方法步骤 c中所用的二酚为 2，2'-联萘二酚、 3,3' 位取代的 2,2'-联萘二 酚、 2,2'-联苯二酚或取代的 2,2'-联苯二酚。  The diphenol used in step c of the preparation method is 2,2'-binaphthol, 2,3'-binaphthol substituted at the 3,3 'position, 2,2'-biphenyldiol or Substituted 2,2'-biphenol.
本发明的手性膦配体 ManniPhos与金属前体原位形成的的金属络合物对 C=C键、 C=N键、 C=0键的氢化反应具有高的催化活性和光学选择性。反应在 1-lOOatm, -20〜 200°C的温度下进行， 根据原料类别可选用质子性的醇类溶剂， 也可以选择非质子性的 C6〜Clfl的垸烃、 CH2C12、 C C1C¾CI、 C¾C1、 CC14、 四氢呋喃等作溶剂。
Figure imgf000005_0001
发明效果 The metal complex formed in situ between the chiral phosphine ligand ManniPhos and the metal precursor of the present invention has high catalytic activity and optical selectivity for the hydrogenation reaction of C = C bond, C = N bond, and C = 0 bond. The reaction is carried out at a temperature of 1-100atm, -20 ~ 200 ° C. Depending on the type of raw material, a protic alcohol solvent can be selected, and aprotic C 6 to C lfl hydrocarbons, CH 2 C1 2 , C C1C¾CI, C¾C1, CC1 4 , tetrahydrofuran, etc. as solvents.
Figure imgf000005_0001
Invention effect
本发明设计合成的手性配体 ManniPhos与铑金属化合物形成的催化剂适用范围 广， 可以应用于多类 C-C双键的不对称氢化反应。 ManniPhos与 [Rh(COD)2]BF4在原 位条件下形成的催化剂主要用于以下几类底物催化不对称氢化反应中： The catalyst formed by the designed and synthesized chiral ligand ManniPhos and the rhodium metal compound has a wide application range and can be applied to asymmetric hydrogenation reactions of various types of CC double bonds. The catalyst formed by ManniPhos and [Rh (COD) 2 ] BF 4 under in situ conditions is mainly used in the following types of substrates to catalyze asymmetric hydrogenation:
(1) ex-脱氢氨基酸的催化不对称氢化反应；  (1) catalytic asymmetric hydrogenation of ex-dehydroamino acids;
(2) β-脱氢氨基酸的催化不对称氢化反应；  (2) catalytic asymmetric hydrogenation of β-dehydroamino acids;
(3)衣康酸及其 β-取代的衣康酸类化合物的催化不对称氢化反应；  (3) Asymmetric hydrogenation of itaconic acid and its β-substituted itaconic acid compounds;
(4)α-取代非环状及环状烯胺的催化不对称氢化反应。  (4) Asymmetric hydrogenation of α-substituted acyclic and cyclic enamines.
本发明设计的手性配体 ManniPhos对空气稳定、 易于操作、 保存； 配体合成工艺 路线简单， 合成过程中无须高温、 高压等剧烈的操作条件； 配体合成成本低廉， 合成 原料甘露醇、 醛、 三氯化磷等便宜易得。 ManniPhos与铑金属化合物形成的催化剂立 体选择性高，对映体选择性对于以上四类底物均可以高达 99.9%; ManniPhos与铑金属 化合物形成的催化剂活性高， TON可以高达 10，000。  The chiral ligand ManniPhos designed by the present invention is stable to the air, easy to operate and save; the synthetic route of the ligand is simple, and no severe operating conditions such as high temperature and high pressure are required during the synthesis process; the cost of the synthesis of the ligand is low, and the raw materials mannitol and aldehyde are synthesized , Phosphorus trichloride, etc. are cheap and readily available. The catalysts formed by ManniPhos and rhodium metal compounds have high stereoselectivity. The enantioselectivity can be as high as 99.9% for the above four types of substrates. The catalysts formed by ManniPhos and rhodium metal compounds have high activity, and the TON can be as high as 10,000.
本发明设计合成的手性配体 ManniPhos与铑金属化合物形成的催化剂参与的不对 称氢化反应条件温和， 可以在室温下反应； 氢气的压力应用范围广， 从常压到高压均 不影响催化剂的活性， 立体选择性， 反应时间为 1〜24小时， 配体与金属铑化合物的 摩尔比为 1 :1〜4:1， 反应底物与催化剂的比为 100〜10,000。  The asymmetric hydrogenation reaction involving the catalyst formed by the chiral ligand ManniPhos and the rhodium metal compound designed and synthesized by the present invention has mild conditions and can react at room temperature. The pressure of hydrogen can be used in a wide range and does not affect the activity of the catalyst from normal pressure to high pressure. Stereoselectivity, the reaction time is 1 to 24 hours, the molar ratio of the ligand to the metal rhodium compound is 1: 1 to 4: 1, and the ratio of the reaction substrate to the catalyst is 100 to 10,000.
本发明所提出的手性单膦配体 ManniPhos具有合成路线简单、 成本低、 在空气中 稳定等特点， 其金属 Rh、 Ru、 Ir、 Pd、 Pt络合物对 G=C、 C=0、 C=N键的加氢反应 有极高的催化活性和光学选择性。 手性配体与铑金属化合物形成的催化剂对 α-脱氢氨 基酸、 β-脱氢氨基酸、 衣康酸及其 β-取代的衣康酸四类底物具有高催化活性和立体选 择性， 在温度为 0〜100°C , 压力 l〜100 ato的反应条件下， TON可以高达 10,000, 对映体选择性可以高达 99.9%。 应用该手性配体， 通过不对称氢化反应可制备出手性 药物、 手性农药、 手性氨基酸等多种类型的手性产品， 在医药、 农药、 香料、 食品饲 料添加剂等行业具有重要的应用价值。 The chiral monophosphine ligand ManniPhos proposed by the present invention has the characteristics of simple synthetic route, low cost, and stability in the air, and its metal Rh, Ru, Ir, Pd, and Pt complexes have G = C, C = 0, C = N bond hydrogenation has extremely high catalytic activity and optical selectivity. The catalysts formed by chiral ligands and rhodium metal compounds have high catalytic activity and stereoselectivity for α-dehydroamino acids, β-dehydroamino acids, itaconic acid and its β-substituted itaconic acid substrates. Under the reaction conditions of temperature 0 ~ 100 ° C and pressure 1 ~ 100 ato, TON can reach as high as 10,000, Enantioselectivity can be as high as 99.9%. By using this chiral ligand, various types of chiral products such as chiral drugs, chiral pesticides, and chiral amino acids can be prepared through asymmetric hydrogenation reactions, which have important applications in the industries of medicine, pesticides, spices, food and feed additives, etc. value.
与之相比， 虽然现有的 Reete等的单齿膦配体合成比较简单， 配体的化学性质稳 定, 在空气中能稳定存放， 但 Rh络合物只对衣康酸类衍生物的活性、 对映选择性较 好 （S/C=5000， e.e=99.6%), 但对 α-脱氢氨基酸、 烯胺类、 β-脱氢氨基酸类底物的活 性、 对映选择性较差或极差。 具体实施方式  In contrast, although the existing monodentate phosphine ligands such as Reete are relatively simple to synthesize, the chemical properties of the ligands are stable and they can be stably stored in the air, but the Rh complexes are only active against itaconic acid derivatives. The enantioselectivity is good (S / C = 5000, ee = 99.6%), but the activity and enantioselectivity of α-dehydroamino acids, enamines and β-dehydroamino acids are poor or Very poor. detailed description
(一)配体的合成  (I) Synthesis of Ligand
实施例 1  Example 1
在 1000ml的带有机械搅拌的三口瓶中加入浓硫酸 (20ml)， D-甘露醇 (100g)， 苯甲 醛 (120ml)和溶剂 DMF(300ml)， 此反应混合物在室温搅拌反应 3天后， 将反应混合物 倒入含有 30克碳酸钾和 500ml石袖醚的冰水中剧烈搅拌直到冰融化，过滤得到固体并 用石油醚洗涤， 固体物用 400ml沸腾的氯仿抽提 2次， 过滤得到的固体物经甲醇重结 晶即可得到产品白色固体 1 (86g， 42%)  Concentrated sulfuric acid (20 ml), D-mannitol (100 g), benzaldehyde (120 ml), and solvent DMF (300 ml) were added to a three-necked flask of 1000 ml with mechanical stirring. The reaction mixture was stirred at room temperature for 3 days. The mixture was poured into ice-water containing 30 g of potassium carbonate and 500 ml of stone sleeve ether and stirred vigorously until the ice melted, filtered to obtain a solid and washed with petroleum ether. The solid was extracted twice with 400 ml of boiling chloroform. Crystallize to obtain the product as a white solid 1 (86g, 42%)
在一 250ml的圆底烧瓶中加入氢化钠 (12mmol，含量 80%的融于矿物油的氢化钠)， 上^合成的化合物 l(l Ommol), 溶剂 DMF (40mI), 将此反应混合物在室温下搅拌反应 1小时后， 加入碘甲烷 (lOmmol)继续在室温下反应 1小时。 反应混合物用 20ml水稀释 ***萃取， 饱食盐水洗涤， 无水硫酸钠干燥， 经减压去除溶剂得到固体物， 经二氯甲 烷 /正己烷重结晶得白色晶体 2 (3.54 g, 95%)  In a 250 ml round bottom flask was added sodium hydride (12 mmol, 80% sodium hydride dissolved in mineral oil), and synthesized compound l (10 mmol), solvent DMF (40 ml), and the reaction mixture was at room temperature. After the reaction was stirred for 1 hour, methyl iodide (10 mmol) was added to continue the reaction at room temperature for 1 hour. The reaction mixture was diluted with 20 ml of water and extracted with diethyl ether, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a solid. Recrystallization from dichloromethane / n-hexane gave white crystals 2 (3.54 g, 95%)
在氮气保护下， 向 100ml 带有滴液漏斗和搅拌的三口瓶中加入上步合成化合物 (5mmol), 在 0°C下滴加三氯化磷（5 mrnol), 滴加完毕后撤去冰浴并在室温搅拌反应 1 小时后， 于 O'C下加入三乙胺 (15.5mm0l)， 滴加完毕后撤去冰浴并在室温搅拌反应 15 分钟，固体 R型的 2,2'-联萘二酚 (i?-BINOL)加入到反应混合物中于室温下搅拌反应 1〜 3 小时。 加入***稀释并用硅藻土助滤， 经减压去除溶剂得到泡沫状固体物， 经*** 重结晶得到白色固体即为所需的配体 (2.74g， 80%)。 Under nitrogen protection, add the synthetic compound (5mmol) from the previous step to a 100ml three-necked flask with a dropping funnel and stirring, and add phosphorus trichloride (5 mrnol) dropwise at 0 ° C. After the addition is complete, remove the ice bath. After stirring for 1 hour at room temperature, triethylamine (15.5mm 0 l) was added under O'C. After the dropwise addition was completed, the ice bath was removed and the reaction was stirred at room temperature for 15 minutes. The solid R-shaped 2,2'-linked Naphthol (i? -BINOL) was added to the reaction mixture and the reaction was stirred at room temperature for 1 to 3 hours. Diethyl ether was added to dilute and filtered with diatomaceous earth. The solvent was removed under reduced pressure to obtain a foamy solid. Recrystallization from ether gave a white solid as the desired ligand (2.74 g, 80%).
(二）催化不对称氢化反应  (2) Catalytic asymmetric hydrogenation reaction
实施例 1  Example 1
在氮气保护下， 2.0mg(0.005mmol) [Rh(COD)2]BF4 , 与上述合成的手性配体 ManniPhos (O.OlOmmol),溶剂二氯甲垸 (lml)在室温下于 10ml 的反应器中，反应 10-30 分钟制成催化剂， 将加氢反应底物 2-乙酰氨基丙烯酸甲酯 (0.5mmol )转移到该反应器 中， 氢气置换 3次后持续通入氢气， 维持常压反应 30分钟后终止反应， 用短硅胶柱过 滤， 将过滤所得滤液浓縮后， 用 GC进行含量及光学纯度测定， 得 S-乙酰氨基丙酸甲 酯收率 100% (以 2-乙酰氨基丙烯酸甲酯计)， 对映体过量为 97.7%ee。 Under the protection of nitrogen, 2.0 mg (0.005 mmol) of [Rh (COD) 2 ] BF 4 , and the synthesized chiral ligand ManniPhos (O.OlOmmol), the solvent dichloromethane (lml) in a 10ml reactor at room temperature, react for 10-30 minutes to make a catalyst, hydrogenation reaction substrate methyl 2-acetamidoacrylate (0.5mmol ) Transferred to the reactor, after hydrogen replacement for 3 times, hydrogen was continuously passed in. After the reaction was maintained at normal pressure for 30 minutes, the reaction was terminated, filtered through a short silica gel column, and the filtrate obtained after the filtration was concentrated. The content and optical purity were determined by GC. The yield of methyl S-acetopropionate was 100% (based on methyl 2-acetaminoacrylate), and the enantiomeric excess was 97.7% ee.
实施例 2  Example 2
在氮气保护下， 2.0mg(0.005mmol) [Rh(COD)2]BF4， 与上述合成的手性配体 ManniPhos (O.OlOmmol),溶剂二氯甲烷 (lml)在室温下于 10ml 的反应器中，反应 10-30 分钟制成催化剂， 将加氢反应底物 2-乙酰氨基肉桂酸甲酯 (0.5mmol )转移到该反应器 中， 氢气置换 3次后持续通入氢气， 维持常压反应 30分钟后终止反应， 用短硅胶柱过 滤， 将过滤所得滤液浓缩后， 用 GC进行含量及光学纯度测定， 得 S-乙酰氨基苯丙酸 甲酯收率 100% (以 2-乙酰氨基肉桂酸甲酯计)， 对映体过量为 98.0%ee。 Reaction of 2.0 mg (0.005 mmol) [Rh (COD) 2 ] BF 4 with the chiral ligand ManniPhos (0.10 mmol) synthesized above, the solvent dichloromethane (1 ml) at room temperature in 10 ml under the protection of nitrogen In the reactor, the reaction was made for 10-30 minutes to prepare a catalyst. The hydrogenation reaction substrate methyl 2-acetylaminocinnamate (0.5 mmol) was transferred to the reactor. After the hydrogen was replaced 3 times, hydrogen was continuously passed in to maintain the normal pressure. After 30 minutes of reaction, the reaction was terminated, filtered through a short silica gel column, and the filtrate obtained after the filtration was concentrated. The content and optical purity of the filtrate were measured by GC. The yield of methyl S-acetaminophenpropionate was 100% (with 2-acetylaminocinnamon Methyl ester), enantiomeric excess was 98.0% ee.
实施例 3  Example 3
在氮气保护下， 2.0mg(0.005mmol) [Rh(COD)2]BF4， 与上述合成的手性配体 ManniPhos (O.OlOmmol),溶剂二氯甲烷 (lml)在室温下于 10ml 的反应器中，反应 10-30 分钟制成催化剂， 将加氢反应底物多巴的前体 (0.5mmol)转移到该反应器中， 氢气置换 3次后持续通入氢气， 维持常压反应 30分钟后终止反应， 用短硅胶柱过滤， 将过滤所 得滤液浓缩后， 用 GC进行含量及光学纯度测定， 得 L-多巴收率 100% (以多巴的前体 计)， 对映体过量为 98.0%ee。 Reaction of 2.0 mg (0.005 mmol) [Rh (COD) 2 ] BF 4 with the chiral ligand ManniPhos (0.10 mmol) synthesized above, the solvent dichloromethane (1 ml) at room temperature in 10 ml under the protection of nitrogen In the reactor, the reaction was made for 10-30 minutes to make a catalyst. The precursor of the hydrogenation reaction substrate dopa (0.5 mmol) was transferred to the reactor. After the hydrogen was replaced 3 times, hydrogen was continuously passed in to maintain the reaction at normal pressure for 30 minutes. The reaction was terminated, filtered through a short silica gel column, and the filtrate obtained after the filtration was concentrated. The content and optical purity were determined by GC. The yield of L-dopa was 100% (based on the precursor of dopa). The enantiomeric excess was 98.0% ee.
实施例 4  Example 4
在氮气保护下， 2.0mg(0.005mmol) [R (COD)2]BF4 , 与上述合成的手性配体 ManniPhos (O.OlOmmol) ,溶剂二氯甲烷 (lml)在室温下于 10ml 的反应器中，反应 10-30 分钟制成催化剂， 将加氢反应底物衣康酸二甲酯 (0.5mmol)转移到该反应器中， 氢气置 换 3次后持续通入氢气， 维持常压反应 3小时后终止反应， 用短硅胶柱过滤， 将过滤 所得滤液浓縮后，用 GC进行含量及光学纯度测定，得 (R)-2-甲基丁二酸二甲酯 100°/o(以 衣康酸二甲酯计)， 对映体过量为 99.0%ee。 Reaction of 2.0 mg (0.005 mmol) [R (COD) 2 ] BF 4 with the chiral ligand ManniPhos (O.OlOmmol) synthesized above, and a solvent of dichloromethane (1 ml) at room temperature in 10 ml under a nitrogen atmosphere. In the reactor, the reaction was made for 10-30 minutes to prepare a catalyst. The hydrogenation reaction substrate dimethyl itaconic acid (0.5 mmol) was transferred to the reactor. After the hydrogen was replaced 3 times, hydrogen was continuously passed in to maintain the atmospheric reaction 3 After an hour, the reaction was terminated, and the mixture was filtered through a short silica gel column. After the filtrate was concentrated, the content and optical purity were measured by GC to obtain (R) -2-methyl succinate 100 ° / o Based on dimethyl taurate), the enantiomeric excess was 99.0% ee.
实施例 5  Example 5
在氮气保护下， 2.0 mg (0.005 mmol) [Rh(COD)2]BF4 , 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲烷 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30分钟制成催化剂， 将催化剂转移到反应釜中， 加氢反应底物衣康酸二甲酯 （0.5 mmol )加入到该反应釜中， 氢气置换 3次后持续通入氢气， 维持 10公斤压力反应 3 小时后终止反应， 用短硅胶柱过滤， 将过滤所得滤液浓缩后， 用 GC进行含量及光学 纯度测定， 得 (R 2-甲基丁二酸二甲酯 100°/。（以衣康酸二甲酯计）， 对映体过量为 98.8%ee. Under the protection of nitrogen, 2.0 mg (0.005 mmol) [Rh (COD) 2 ] BF 4 , and the synthesized chiral ligand ManniPhos (0.010 mmol), a solvent of dichloromethane (1 ml) at room temperature in 10 ml of In the reactor, react for 10-30 minutes to make a catalyst, transfer the catalyst to the reaction kettle, and hydrogenate the reaction substrate dimethyl itaconic acid (0.5 mmol) was added to the reaction kettle, hydrogen was continuously introduced after 3 times of hydrogen replacement, and the reaction was stopped after maintaining a pressure of 10 kg for 3 hours. The reaction was terminated by short silica gel column filtration, and the filtrate obtained after the filtration was concentrated, and the content and optical purity were measured by GC. Determination of (R 2-methyl succinate 100 ° /. (Based on dimethyl itaconic acid), the enantiomeric excess was 98.8% ee.
'实施例 6  'Example 6
在氮气保护下， 2.0tng (0.005mmol) [Rh(COD)2]BF4 , 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲垸 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30分钟制成催化剂， 将催化剂转移到反应釜中， 加氢反应底物 2-乙酰氨基 -2-丁烯 酸甲酯 (0.5 mmol )加入到该反应釜中， 氢气置换 3次后持续通入氢气， 维持 40公斤 压力反应 24小时后终止反应， 用短硅胶柱过滤， 将过滤所得滤液浓缩后， 用 GC进行 含量及光学纯度测定， 得 (S)- 2-乙酰氨基 -2-丁酸甲酯 100°/。（以 2-乙酰氨基 -2-丁烯酸甲 酯计)， 对映体过量为 99.1%ee。 Under nitrogen protection, 2.0tng (0.005mmol) [Rh (COD) 2 ] BF 4 and the synthesized chiral ligand ManniPhos (0.010 mmol), the solvent dichloroformamidine (1 ml) at room temperature in 10 ml In a reactor, react for 10-30 minutes to make a catalyst, transfer the catalyst to a reaction kettle, and add hydrogenation reaction substrate 2-acetamino-2-butenoic acid methyl ester (0.5 mmol) to the reaction kettle. After three replacements of hydrogen, hydrogen was continuously passed in, and the reaction was maintained at a pressure of 40 kg for 24 hours. The reaction was terminated, filtered through a short silica gel column, the filtrate obtained after the filtration was concentrated, and the content and optical purity were measured by GC to obtain (S)-2- Acetamino-2-butyric acid methyl ester 100 ° /. (Based on methyl 2-acetylamino-2-butenoate), the enantiomeric excess was 99.1% ee.
实施例 7  Example 7
在氮气保护下， 2.0 mg (0.005 mmol) [Rh(COD)2]BF4 , 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲烷 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30分钟制成催化剂，将催化剂转移到反应釜中，加氢反应底物乙酰氨基苯乙烯（0.5 mmol ) 加入到该反应釜中， 氢气置换 3次后持续通入氢气， 维持 10公斤压力反应 3 小时后终止反应， 用短硅胶柱过滤， 将过滤所得滤液浓缩后， 用 GC进行含量及光学 纯度测定，得 (S)-乙酰氨基苯乙烷 100% (以乙酰氨基苯乙烯计)，对映体过量为 99.8%ee。 Under the protection of nitrogen, 2.0 mg (0.005 mmol) [Rh (COD) 2 ] BF 4 , and the synthesized chiral ligand ManniPhos (0.010 mmol), a solvent of dichloromethane (1 ml) at room temperature in 10 ml of In the reactor, a catalyst is prepared for 10-30 minutes, and the catalyst is transferred to a reaction kettle. Hydrogenation reaction substrate acetaminostyrene (0.5 mmol) is added to the reaction kettle, and hydrogen is continuously passed through after 3 times of hydrogen substitution. After maintaining the pressure of 10 kg for 3 hours, the reaction was terminated, and the reaction was filtered through a short silica gel column. The filtrate obtained after the filtration was concentrated, and the content and optical purity were determined by GC to obtain (S) -acetaminophenethane 100% (as acetamino acid) Based on styrene), the enantiomeric excess was 99.8% ee.
实施例 S  Example S
在氮气保护下， 2.0 mg (0.005 mmol) [RJi(COD)2]BF4 , 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲垸 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30分钟制成催化剂，将加氢反应底物 2-乙酰氨基苯乙烯 （0.5 mmol )转移到该反应 器中， 氢气置换 3次后持续通入氢气， 维持常压反应 3小时后终止反应， 用短硅胶柱 过滤， 将过滤所得滤液浓缩后， 用 GC进行含量及光学纯度测定， 得 (S)-乙酰氨基苯乙 烷 100% (以 2-乙酰氨基苯乙烯计)， 对映体过量为 99.8%ee。 Under the protection of nitrogen, 2.0 mg (0.005 mmol) [RJi (COD) 2 ] BF 4 , and the synthesized chiral ligand ManniPhos (0.010 mmol), the solvent dichloroformamidine (1 ml) at room temperature in 10 ml In the reactor, the reaction was made for 10-30 minutes to make a catalyst, and the hydrogenation reaction substrate 2-acetylaminostyrene (0.5 mmol) was transferred to the reactor. After the hydrogen was replaced 3 times, hydrogen was continuously passed in to maintain normal pressure. After 3 hours of reaction, the reaction was terminated, filtered through a short silica gel column, and the filtrate obtained after the filtration was concentrated. The content and optical purity were measured by GC to obtain (S) -acetaminophenethane 100% (calculated as 2-acetaminostyrene). ), The enantiomeric excess was 99.8% ee.
实施例 9  Example 9
在氮气保护下， 2.0 mg (0.005 mmol) [R (COD)2]BF4 , 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲烷 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30分钟制成催化剂， 将催化剂转移到反应釜中， 加氢反应底物乙酰氨基苯乙烯（50 mmol )和 20 ml溶剂加入到该反应釜中， 氢气置换 3次后持续通入氢气， 维持 10公 斤压力反应 6小时后终止反应， 用短硅胶柱过滤， 将过滤所得滤液浓缩后， 用 GC进 行含量及光学纯度测定， 得 (S)-乙酰氨基苯乙烷 100°/。（以乙酰氨基苯乙烯计)， 对映体 过量为％.0°/oee。 Under the protection of nitrogen, 2.0 mg (0.005 mmol) [R (COD) 2 ] BF 4 and the synthesized chiral ligand ManniPhos (0.010 mmol), the solvent dichloromethane (1 ml) at room temperature in 10 ml of In the reactor, react for 10-30 minutes to make a catalyst, transfer the catalyst to a reaction kettle, and hydrogenate the reaction substrate acetaminostyrene (50 mmol) and 20 ml of solvent were added to the reaction kettle. After the hydrogen was replaced three times, hydrogen was continuously passed in, and the reaction was terminated after maintaining the pressure of 10 kg for 6 hours. The reaction was filtered through a short silica gel column, and the filtrate obtained after the filtration was concentrated and then performed by GC. Determination of content and optical purity, (S) -acetaminophenethane 100 ° /. (Calculated as acetaminostyrene), the enantiomeric excess is% .0 ° / oee.
实施例 10  Example 10
在氮气保护下， 2.0 rag (0.005 mmol) [Ir(COD)2]BF4 , 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲烷 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30 分钟制成催化剂， 将催化剂转移到反应釜中， 加氢反应底物苯丙甲亚胺 （0.5 mmol )和 2 ml溶剂加入到该反应釜中， 氢气置换 3次后持续通入氢气， 维持 60公斤 压力反应 6小时后终止反应。 用短硅胶柱过滤， 将过滤所得滤液浓缩后， 用 GC进行 含量及光学纯度测定， 得苯丙甲胺收率 100% (以苯丙甲亚胺计）， 对映体过量为 98.0°/oee。 Under nitrogen protection, 2.0 rag (0.005 mmol) [Ir (COD) 2] BF 4 , together with the synthesized chiral ligand ManniPhos (0.010 mmol), the solvent dichloromethane (1 ml) at room temperature in 10 ml of In the reactor, react for 10-30 minutes to make a catalyst, transfer the catalyst to the reaction kettle, add hydrogenation reaction substrate amphetamine (0.5 mmol) and 2 ml of solvent to the reaction kettle, and replace with hydrogen 3 times After that, hydrogen was continuously introduced, and the reaction was terminated after maintaining the pressure of 60 kg for 6 hours. It was filtered through a short silica gel column. After the filtrate was concentrated, the content and optical purity were measured by GC. The yield of amphetamine was 100% (based on amphetamine). The enantiomeric excess was 98.0 ° / oee. .
实施例 11  Example 11
在氮气保护下， 2.0 mg (0.005 mmol) 水芹烯氯化钌， 与上述合成的手性配体 ManniPhos (0.010 mmol), 溶剂二氯甲垸 (1 ml)在室温下于 10 ml 的反应器中， 反应 10-30分钟制成催化剂，将催化剂转移到反应釜中，加氢反应底物丙酮酸甲酯 (0.5 mmol) 和 2ml溶剂加入到该反应釜中 , 将加氢底物转移到该反应器中， 氢气置换 3次后持续 通入氢气， 维持 60公斤压力于 60°C反应 6小时后终止反应。 用短硅胶柱过滤， 将过 滤所得滤液浓缩后， 用 GC进行含量及光学纯度测定， 得 S-乳酸甲酯收率 100% (以 丙酮酸甲酯计)， 对映体过量为 99.0%ee。  Under the protection of nitrogen, 2.0 mg (0.005 mmol) of ruthenium chloride, with the chiral ligand ManniPhos (0.010 mmol) synthesized above, the solvent dichloroformamidine (1 ml) at room temperature in a 10 ml reactor In the reaction, a catalyst is prepared for 10-30 minutes, and the catalyst is transferred to the reaction kettle. The hydrogenation reaction substrate methyl pyruvate (0.5 mmol) and 2 ml of solvent are added to the reaction kettle, and the hydrogenation substrate is transferred to the reaction kettle. In the reactor, hydrogen was continuously introduced after replacing the hydrogen 3 times, and the reaction was terminated after maintaining the pressure of 60 kg at 60 ° C for 6 hours. It was filtered through a short silica gel column, and the filtrate obtained after the filtration was concentrated, and the content and optical purity were measured by GC. The yield of S-methyl lactate was 100% (based on methyl pyruvate), and the enantiomeric excess was 99.0% ee.
相关的比较例 1  Related Comparative Example 1
按实施例 1，使用 Reetz等的单齿亚膦酸酯配体制成 Rh催化剂催化 α-脱氢氨基酸 酯的不对称氢化， 仅能得到 95.5%ee。  According to Example 1, a monodentate phosphinate ligand such as Reetz, etc. was used to make Rh catalyst to catalyze the asymmetric hydrogenation of α-dehydroamino acid ester, and only 95.5% ee was obtained.
Figure imgf000009_0001
相关的比较例 2
Figure imgf000009_0001
Related Comparative Example 2
按实施例 7， 使用 Reetz等的单齿亚膦酸酯配体制成 Rh催化剂催化的烯胺的不对 称氢化， 只能在较高的压力， 60atni下反应， 且仅得到 95.3%ee。 According to Example 7, the use of monodentate phosphinate ligands such as Reetz and others to make the enamine catalyzed by Rh catalyst It is called hydrogenation, and it can only react at a higher pressure, 60atni, and only 95.3% ee is obtained.
Figure imgf000010_0001
Figure imgf000010_0001

Claims

权 利 要 求 Rights request
1、 一种手性配体金属络合物催化体系， ώ配体与金属 Rh、 Ru、 Ir、 Pt或 Pd金属 形成的络合物或配体与相应金属前体按 1〜2摩尔比组成的体系；其中配体具有如下结 构及结构式名字- 1. A chiral ligand metal complex catalyst system. The complex or ligand formed by the ligand and the metal Rh, Ru, Ir, Pt or Pd metal and the corresponding metal precursor is composed in a molar ratio of 1 to 2 System; where the ligand has the following structure and structural formula name-
Figure imgf000011_0001
L-WlanniPhos
Figure imgf000011_0001
L-WlanniPhos
其中， 配体中的 、 基团为： 氢、 苯基、 取代苯基、 1-萘基或 2-萘基的 C6-C6I 内的含 N、 S、 0、 P的芳香基团； 甲基、 乙基、 丙基或丁基的 Cto内的含 N、 S、 0、 P的脂肪基团； Wherein, the groups in the ligand are: hydrogen, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl in C 6 -C 6I containing N, S, 0, P aromatic groups; N, S, 0, P-containing aliphatic groups in Cto of methyl, ethyl, propyl or butyl;
Figure imgf000011_0002
Figure imgf000011_0002
2、 一种制备权利要求 1所述催化体系中配体的方法， 其步骤为：  2. A method for preparing a ligand in the catalytic system according to claim 1, wherein the steps are:
a)按摩尔比醛:甘露醇：浓硫酸为 1 :4.4:2，加入到与上述总体积相等的有机溶剂中， 室温搅袢下反应 10-80小时， 将反应混合物过滤得到固体并用石油醚洗涤， 固体物用 沸腾的氯仿抽提， 过滤得到的固体物经甲醇重结晶；  a) The molar ratio of molaldehyde: mannitol: concentrated sulfuric acid is 1: 4.4: 2, and it is added to an organic solvent equal to the above total volume, and the reaction is carried out under stirring at room temperature for 10-80 hours. The reaction mixture is filtered to obtain a solid and petroleum ether is used. After washing, the solid was extracted with boiling chloroform, and the solid obtained by filtration was recrystallized from methanol;
b)将歩骤 1得到的固体物、氢化钠与卤代脂肪'烃按摩尔比为 1 :1 1加入到有机溶 剂中， 室温下搅拌反应 0.5-3小时， 反应混合物用***萃取， 食盐水洗搽， 无水硫酸钠 干燥， 去除溶剂得到固体物；  b) Add the solid obtained in step 1, sodium hydride and halogenated fatty hydrocarbons in a molar ratio of 1: 1 to an organic solvent, stir the reaction at room temperature for 0.5-3 hours, and extract the reaction mixture with ether and wash with brine.搽, drying over anhydrous sodium sulfate, removing the solvent to obtain a solid;
c)氮气保护下， 将步聚 2得到的固体物于 0-5°C滴加三乙胺， 滴加完毕后在室温 搅拌反应 5-30分钟， 再加入二酚于室温下搅拌反应 1-3小时， 过滤， 去除溶剂经*** 重结晶得到所需的配体； 该步骤中的摩尔比为固体物：二酚:三氯化磷：三乙胺 =1 :1.2:1 :2.2。 c) Triethylamine was added dropwise to the solid obtained in Step 2 under nitrogen protection at 0-5 ° C. After the addition was complete, the reaction was stirred at room temperature for 5-30 minutes, and then diphenol was added to stir the reaction at room temperature. 3 hours, filtered, solvent removed via ether The desired ligand is obtained by recrystallization; the molar ratio in this step is solid: diphenol: phosphorus trichloride: triethylamine = 1: 1.2: 1: 2.2.
3、 如权利要求 2所述的制备方法， 其特征在于， 步骤 a中所用的的醛为 d-Ceo 的脂肪醛或 C6-C3Q的芳香醛； 3. The production method according to claim 2, characterized in that, step a is used in d-Ceo aldehyde aliphatic aldehyde or aromatic aldehyde C 6 -C 3Q of;
.  .
4、 如权利要求 3所述的制备方法， 其特征在于， 歩骤 a中所用的醛为甲醛、 乙 醛或苯甲醛。 4. The method according to claim 3, wherein the aldehyde used in step a is formaldehyde, acetaldehyde or benzaldehyde.
5、 如权利要求 2所述的制备方法， 其特征在于， 步骤 b中所用的卤代脂肪烃为 碘甲烷、 芳烃取代卤代甲基、 芳烃取代卤代亚甲基或芳烃取代卤代次甲基。  5. The preparation method according to claim 2, characterized in that the halogenated aliphatic hydrocarbon used in step b is methyl iodide, aromatic substituted halomethyl, aromatic substituted halomethylene or aromatic substituted halomethine. base.
6、如权利要求 1所述的制备方法，其特征在于， 步骤 c中所用的二酚为 2,2'-联萘 二酚、. 3,3'位取代的 2,2'-联萘二酚、 2,2'-联苯二酚或取代的 2,2'-联苯二酚。  6. The preparation method according to claim 1, wherein the diphenol used in step c is 2,2'-binaphthol, 2,3'-binaphtadiene substituted at 3,3 'position Phenol, 2,2'-biphenol, or substituted 2,2'-biphenol.
7、 上述任一项权利要求所述的手性单齿磷配体在 C=C、 C=0、 C=N键中不对称 氢化反应的应用。  7. Application of the chiral monodentate phosphorus ligand according to any one of the preceding claims to asymmetric hydrogenation reactions in C = C, C = 0, C = N bonds.
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