WO2020215357A1 - METHOD FOR PREPARING CHIRAL β-HYDROXYCARBOXYLATE COMPOUND - Google Patents

METHOD FOR PREPARING CHIRAL β-HYDROXYCARBOXYLATE COMPOUND Download PDF

Info

Publication number
WO2020215357A1
WO2020215357A1 PCT/CN2019/085490 CN2019085490W WO2020215357A1 WO 2020215357 A1 WO2020215357 A1 WO 2020215357A1 CN 2019085490 W CN2019085490 W CN 2019085490W WO 2020215357 A1 WO2020215357 A1 WO 2020215357A1
Authority
WO
WIPO (PCT)
Prior art keywords
containing functional
functional groups
group
chiral
substrate
Prior art date
Application number
PCT/CN2019/085490
Other languages
French (fr)
Chinese (zh)
Inventor
呼延旺
Original Assignee
呼延旺
上海欣海国际贸易有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 呼延旺, 上海欣海国际贸易有限公司 filed Critical 呼延旺
Publication of WO2020215357A1 publication Critical patent/WO2020215357A1/en

Links

Classifications

    • 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
    • B01J31/24—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • 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
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B01J2531/0244—Pincer-type complexes, i.e. consisting of a tridentate skeleton bound to a metal, e.g. by one to three metal-carbon sigma-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
    • B01J2531/80—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

Definitions

  • the invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a chiral ⁇ -hydroxy carboxylate compound.
  • Chiral ⁇ -hydroxy acid ester compounds are important organic synthesis intermediates and can be used to prepare various natural and non-natural compounds with biological activity.
  • L-carnitine is also known as vitamin BT, transliterated as L-carnitine, which is a compound naturally present in human cells, which promotes the conversion of fat into energy. It is often used in industry to start with chiral epichlorohydrin.
  • the chemical synthesis of raw materials, the reaction equation is as follows:
  • the method is simple, the raw materials are cheap, and the yield is good, but the production process requires a large amount of sodium cyanide aqueous solution, which causes serious environmental pollution.
  • Atorvastatin calcium is a statin lipid regulator.
  • the main part of atorvastatin calcium is in the liver, which can reduce the synthesis of cholesterol, increase the synthesis of low-density lipoprotein receptors, reduce blood cholesterol and low-density lipoprotein cholesterol levels, moderately reduce serum triglyceride levels and increase blood pressure Density lipoprotein level.
  • the protein binding rate of this product is 98%, most of which are excreted in bile in the form of metabolites. It is mainly used in patients with hypercholesterolemia and primary hypercholesterolemia. Its key intermediate (S)-4-chloro-3-hydroxybutyrate is industrially used in chemical synthesis with chiral epichlorohydrin as the starting material.
  • the reaction equation is as follows
  • the method has cheap raw materials and mature reaction, but the distillation yield is not high, the product cannot easily reach the required purity, and a large amount of sodium cyanide wastewater is produced during the production process, which causes serious pollution to the environment.
  • the present invention was made to solve the above-mentioned problems, and aims to provide a method for preparing chiral ⁇ -hydroxycarboxylate compounds with high activity, high stereoselectivity, wide substrate application range and low environmental pollution.
  • the present invention provides a method for preparing chiral ⁇ -hydroxy carboxylate compounds, which is characterized in that it comprises: step 1, preparing a catalyst, under the protection of nitrogen, combining [Ir(COD)Cl] 2 , ligand, alkali
  • step 1 preparing a catalyst, under the protection of nitrogen, combining [Ir(COD)Cl] 2 , ligand, alkali
  • the sexual additives are dissolved in the solvent and stirred at room temperature to generate the catalyst in situ.
  • Step 2 Dissolve the substrate ⁇ -carbonyl carboxylate compound in a solvent, and then add it to the catalyst prepared in step 1, and pass hydrogen to perform asymmetric catalytic hydrogenation of the substrate ⁇ -carbonyl carboxylate compound.
  • Reaction conditions The pressure is 10-100 atmospheres, the reaction temperature is 0-200°C, and the reaction time is 12-48 hours.
  • the molar ratio of iridium element to ligand in [Ir(COD)Cl] 2 is 1:1 to 5, and the total amount of [Ir(COD)Cl] 2 and ligand is the substrate ⁇ -carbonyl carboxylic acid
  • the amount of the alkaline additive is 5-20% of the amount of the substrate ⁇ -carbonyl carboxylate compound
  • step 1 The relationship between the total volume of the solvent and the substance of the substrate ⁇ -carbonyl carboxylate compound is 1-100 ml/mmol, that is, 1 mmol of the substrate ⁇ -carbonyl carboxylate compound corresponds to 1-100 ml of total solvent.
  • the substrate ⁇ -carbonyl carboxylate compound has the following structural formula:
  • R 1 is a C 1 -C 40 alkyl or cycloalkyl group, or is selected by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, P-containing functional groups, Cl-containing functional groups, and Br-containing functional groups.
  • N-containing functional groups can be amino groups, nitro groups, etc.; S-containing functional groups can be sulfonic acid groups -SO 3 H, etc.
  • the O-containing functional group can be hydroxyl, aldehyde, ketone, ester, etc.; the P-containing functional group can be phosphate, phosphite, etc.; the Cl-containing functional group can be chlorinated, etc.; the Br-containing functional group can be brominated, etc.
  • R 2 is H, or a C 1 -C 40 alkyl group, or a C 6 -C 40 aryl group,
  • the ligand is a phosphine-pyridine ligand, and the phosphine-pyridine ligand has the following structural formula:
  • R 3 is C 1 -C 40 alkyl or cycloalkyl, or C 1 -C 40 substituted by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, and P-containing functional groups Alkyl or cycloalkyl group, or C 7 -C 60 group containing benzyl, or C 6 -C 60 aromatic group, or contained in N-containing functional group, S-containing functional group, O-containing functional group, P-containing functional group One or more substituted C 6 -C 60 aromatic groups; N-containing functional groups can be amino, nitro, etc.; S-containing functional groups can be sulfonic acid groups -SO 3 H, etc.; O-containing functional groups can be hydroxyl, Aldehyde group, ketone group, ester group, etc.; P-containing functional group can be phosphate, phosphite, etc.
  • Ar is a C 6 -C 60 aromatic group, or a C 6 -C 60 aromatic group substituted by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, and P-containing functional groups.
  • the N-containing functional group can be an amino group, a nitro group, etc.
  • the S-containing functional group can be a sulfonic acid group -SO 3 H, etc.
  • the O-containing functional group can be a hydroxyl group, an aldehyde group, a ketone group, an ester group, etc.
  • the P-containing functional group can be a phosphate, Phosphite etc.
  • the solvent is dichloromethane, or 1,2-dichloroethane, or methanol, or Isopropanol, or toluene, or tetrahydrofuran, or ethanol.
  • the most preferred are methanol and ethanol.
  • the alkaline additive is sodium hydroxide, or potassium hydroxide, or potassium tert-butoxide, or carbonic acid Potassium.
  • the most preferred is potassium tert-butoxide.
  • the method for preparing chiral ⁇ -hydroxy carboxylate compounds may also have the feature that after adding the substrate ⁇ -carbonyl carboxylate compound to the catalyst prepared in step 1, it Put it in an autoclave, first replace it with hydrogen for at least 3 times, and then pass in hydrogen so that the pressure in the autoclave is 10-100 atmospheres.
  • the pressure in the autoclave is 20 atmospheres.
  • the method for preparing chiral ⁇ -hydroxy carboxylate compounds provided by the present invention, it may also have the feature: after the reaction is completed, the solvent is first removed, and then the product chiral ⁇ -hydroxyl group is obtained by the method of silica gel column separation. Carboxylate compound.
  • the reaction temperature is 60-100°C.
  • the reaction time is 24 hours.
  • step 1 stirring is performed at room temperature for 10-15 minutes.
  • the method for preparing chiral ⁇ -hydroxy carboxylate compounds according to the present invention adopts [Ir(COD)Cl] 2 and a ligand to generate a catalyst in situ under the condition of a basic additive, and under the catalyst condition,
  • the asymmetric catalytic hydrogenation reaction of ⁇ -carbonyl carboxylate compounds is carried out by introducing hydrogen.
  • the reaction conditions are: hydrogen pressure is 0-100 atmospheres, reaction temperature is 0-200°C, and reaction time is 12-48 hours.
  • This synthesis method has mild hydrogenation reaction conditions and is suitable for a variety of ⁇ -carbonyl carboxylic acids
  • the ester compound has a wide range of substrates, and the reaction process has little environmental pollution.
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the chiral phosphine-pyridine ligand is:
  • the method for preparing chiral ⁇ -hydroxy carboxylate compounds involved in the present invention is not limited to the scope of the specific examples.
  • the above content is only the basic description of the present invention, and any equivalent transformations made according to the technical solution of the present invention should belong to the protection scope of the present invention.

Landscapes

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

Abstract

The present invention provides a method for preparing a chiral β-hydroxycarboxylate compound: first, under nitrogen protection, dissolving [Ir(COD)Cl]2, a ligand, and an alkaline additive in a solvent, and stirring same at room temperature to generate a catalyst in situ; and then, dissolving a substrate β-hydroxycarboxylate compound in a solvent, adding the prepared catalyst, and introducing hydrogen to carry out an asymmetric catalytic hydrogenation reaction on the substrate β-hydroxycarboxylate compound, the reaction conditions being as follows: the pressure is 10-100 atmospheres, the reaction temperature is 0-200ºC, and the reaction time is 12-48 hours. The present invention has high reaction activity and selectivity, mild hydrogenation reaction conditions, a wide substrate application range, and low environmental pollution during the reaction process, and is suitable for a variety of β-hydroxycarboxylate compounds.

Description

制备手性β-羟基羧酸酯化合物的方法Method for preparing chiral β-hydroxy carboxylate compound 技术领域Technical field
本发明属于有机合成技术领域，具体涉及一种制备手性β-羟基羧酸酯化合物的方法。The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing a chiral β-hydroxy carboxylate compound.
背景技术Background technique
手性β-羟基酸酯化合物是重要的有机合成中间体，可用于制备具有生物活性的各种天然及非天然化合物。其中左旋肉碱又称为维生素BT，音译左卡尼丁，是人体细胞内天然存在的一种化合物，促使脂肪转化为能量的类氨基酸，工业上常采用以手性环氧氯丙烷为起始原料的化学合成法，反应方程式如下：Chiral β-hydroxy acid ester compounds are important organic synthesis intermediates and can be used to prepare various natural and non-natural compounds with biological activity. Among them, L-carnitine is also known as vitamin BT, transliterated as L-carnitine, which is a compound naturally present in human cells, which promotes the conversion of fat into energy. It is often used in industry to start with chiral epichlorohydrin. The chemical synthesis of raw materials, the reaction equation is as follows:
Figure PCTCN2019085490-appb-000001
Figure PCTCN2019085490-appb-000001
手性环氧氯丙烷为起始原料的化学合成法Chemical synthesis method with chiral epichlorohydrin as starting material
该方法简便，原料廉价，收率较好，但是生产过程需要大量的氰化钠水溶液，对环境造成严重的污染。The method is simple, the raw materials are cheap, and the yield is good, but the production process requires a large amount of sodium cyanide aqueous solution, which causes serious environmental pollution.
此外，阿托伐他汀钙(Atorvastatin calcium)为他汀类血脂调节药。阿托伐他汀钙主要作用部位在肝脏，可减少胆固醇的合成，增加低密度脂蛋白受体合成，使血胆固醇和低密度脂蛋白胆固醇水平降低，中度降低血清甘油三酯水平和增高血高密度脂蛋白水平。本品蛋 白结合率为98％，大部分以代谢物的形式经胆汁排出，主要应用于高胆固醇血症原发性高胆固醇血症患者。其关健中间体(S)-4-氯-3-羟基丁酸乙酯工业上采用以手性环氧氯丙烷为起始原料的化学合成法，反应方程式如下In addition, Atorvastatin calcium is a statin lipid regulator. The main part of atorvastatin calcium is in the liver, which can reduce the synthesis of cholesterol, increase the synthesis of low-density lipoprotein receptors, reduce blood cholesterol and low-density lipoprotein cholesterol levels, moderately reduce serum triglyceride levels and increase blood pressure Density lipoprotein level. The protein binding rate of this product is 98%, most of which are excreted in bile in the form of metabolites. It is mainly used in patients with hypercholesterolemia and primary hypercholesterolemia. Its key intermediate (S)-4-chloro-3-hydroxybutyrate is industrially used in chemical synthesis with chiral epichlorohydrin as the starting material. The reaction equation is as follows
Figure PCTCN2019085490-appb-000002
Figure PCTCN2019085490-appb-000002
阿托伐他汀钙关健中间体的化学合成Chemical synthesis of atorvastatin calcium key intermediate
该方法原料廉价，反应成熟，但精馏收率不高，产品不易达到要求的纯度，且生产过程产生大量的氰化钠废水，对环境造成严重的污染。The method has cheap raw materials and mature reaction, but the distillation yield is not high, the product cannot easily reach the required purity, and a large amount of sodium cyanide wastewater is produced during the production process, which causes serious pollution to the environment.
发明内容Summary of the invention
本发明是为了解决上述问题而进行的，目的在于提供一种发展高活性、高立体选择性、底物适用范围广，且对环境污染小的制备手性β-羟基羧酸酯化合物的方法。The present invention was made to solve the above-mentioned problems, and aims to provide a method for preparing chiral β-hydroxycarboxylate compounds with high activity, high stereoselectivity, wide substrate application range and low environmental pollution.
本发明提供了一种制备手性β-羟基羧酸酯化合物的方法，其特征在于，包括：步骤1，制备催化剂，在氮气保护下，将[Ir(COD)Cl] 2、配体、碱性添加物溶于溶剂中，在室温下搅拌，原位生成催化剂， The present invention provides a method for preparing chiral β-hydroxy carboxylate compounds, which is characterized in that it comprises: step 1, preparing a catalyst, under the protection of nitrogen, combining [Ir(COD)Cl] 2 , ligand, alkali The sexual additives are dissolved in the solvent and stirred at room temperature to generate the catalyst in situ.
步骤2，将底物β-羰基羧酸酯化合物溶于溶剂中，然后加入步骤1中制备的催化剂中，通入氢气对底物β-羰基羧酸酯化合物进行不对称催化氢化反应，反应条件：压力为10-100个大气压，反应温度为0-200℃，反应时间为12-48个小时，Step 2. Dissolve the substrate β-carbonyl carboxylate compound in a solvent, and then add it to the catalyst prepared in step 1, and pass hydrogen to perform asymmetric catalytic hydrogenation of the substrate β-carbonyl carboxylate compound. Reaction conditions : The pressure is 10-100 atmospheres, the reaction temperature is 0-200°C, and the reaction time is 12-48 hours.
其中，[Ir(COD)Cl] 2中铱元素与配体的摩尔比为1:1～5， [Ir(COD)Cl] 2和配体的总物质的量为底物β-羰基羧酸酯化合物的物质的量的万分之一到百分之一，碱性添加物的物质的量为底物β-羰基羧酸酯化合物的物质的量的5～20％，步骤1、步骤2中溶剂的总体积量对应底物β-羰基羧酸酯化合物的物质的量的关系为1-100ml/mmol，即1mmol底物β-羰基羧酸酯化合物对应1-100ml总溶剂。 Among them, the molar ratio of iridium element to ligand in [Ir(COD)Cl] 2 is 1:1 to 5, and the total amount of [Ir(COD)Cl] 2 and ligand is the substrate β-carbonyl carboxylic acid One ten thousandth to one hundredth of the amount of the ester compound, the amount of the alkaline additive is 5-20% of the amount of the substrate β-carbonyl carboxylate compound, step 1, step 2 The relationship between the total volume of the solvent and the substance of the substrate β-carbonyl carboxylate compound is 1-100 ml/mmol, that is, 1 mmol of the substrate β-carbonyl carboxylate compound corresponds to 1-100 ml of total solvent.
所述底物β-羰基羧酸酯化合物具有如下的结构式：The substrate β-carbonyl carboxylate compound has the following structural formula:
Figure PCTCN2019085490-appb-000003
Figure PCTCN2019085490-appb-000003
式中，R 1为C 1-C 40的烷基或环烷基，或被含N官能团、含S官能团、含O官能团、含P官能团、含Cl官能团、含Br官能团中的一种或多种取代的C 1-C 40的烷基或环烷基，或C 7-C 60包含苄基的基团，或C 6-C 60的芳香基团，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 6-C 60的芳香基团，含N官能团可以为氨基、硝基等；含S官能团可以为磺酸基-SO 3H等；含O官能团可以为羟基、醛基、酮基、酯基等；含P官能团可以为磷酸酯、亚磷酸酯等；含Cl官能团可以为氯代等；含Br官能团可以为溴代等。 In the formula, R 1 is a C 1 -C 40 alkyl or cycloalkyl group, or is selected by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, P-containing functional groups, Cl-containing functional groups, and Br-containing functional groups. A substituted C 1 -C 40 alkyl or cycloalkyl group, or a C 7 -C 60 group containing benzyl, or a C 6 -C 60 aromatic group, or N-containing functional group, S-containing functional group, One or more substituted C 6 -C 60 aromatic groups among O-containing functional groups and P-containing functional groups. N-containing functional groups can be amino groups, nitro groups, etc.; S-containing functional groups can be sulfonic acid groups -SO 3 H, etc. The O-containing functional group can be hydroxyl, aldehyde, ketone, ester, etc.; the P-containing functional group can be phosphate, phosphite, etc.; the Cl-containing functional group can be chlorinated, etc.; the Br-containing functional group can be brominated, etc.
R 2为H、或C 1-C 40的烷基、或C 6-C 40的芳基， R 2 is H, or a C 1 -C 40 alkyl group, or a C 6 -C 40 aryl group,
所述配体为膦-吡啶配体，所述膦-吡啶配体具有如下的结构式：The ligand is a phosphine-pyridine ligand, and the phosphine-pyridine ligand has the following structural formula:
Figure PCTCN2019085490-appb-000004
Figure PCTCN2019085490-appb-000004
式中，R 3为C 1-C 40的烷基或环烷基，或被含N官能团、含S官 能团、含O官能团、含P官能团中的一种或多种取代的C 1-C 40的烷基或环烷基，或C 7-C 60包含苄基的基团，或C 6-C 60的芳香基团，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 6-C 60的芳香基团；含N官能团可以为氨基、硝基等；含S官能团可以为磺酸基-SO 3H等；含O官能团可以为羟基、醛基、酮基、酯基等；含P官能团可以为磷酸酯、亚磷酸酯等。 In the formula, R 3 is C 1 -C 40 alkyl or cycloalkyl, or C 1 -C 40 substituted by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, and P-containing functional groups Alkyl or cycloalkyl group, or C 7 -C 60 group containing benzyl, or C 6 -C 60 aromatic group, or contained in N-containing functional group, S-containing functional group, O-containing functional group, P-containing functional group One or more substituted C 6 -C 60 aromatic groups; N-containing functional groups can be amino, nitro, etc.; S-containing functional groups can be sulfonic acid groups -SO 3 H, etc.; O-containing functional groups can be hydroxyl, Aldehyde group, ketone group, ester group, etc.; P-containing functional group can be phosphate, phosphite, etc.
Ar为C 6-C 60的芳香基团，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 6-C 60的芳香基团。含N官能团可以为氨基、硝基等；含S官能团可以为磺酸基-SO 3H等；含O官能团可以为羟基、醛基、酮基、酯基等；含P官能团可以为磷酸酯、亚磷酸酯等。 Ar is a C 6 -C 60 aromatic group, or a C 6 -C 60 aromatic group substituted by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, and P-containing functional groups. The N-containing functional group can be an amino group, a nitro group, etc.; the S-containing functional group can be a sulfonic acid group -SO 3 H, etc.; the O-containing functional group can be a hydroxyl group, an aldehyde group, a ketone group, an ester group, etc.; the P-containing functional group can be a phosphate, Phosphite etc.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：所述溶剂为二氯甲烷、或1,2-二氯乙烷、或甲醇、或异丙醇、或甲苯、或四氢呋喃、或乙醇。最优为甲醇、乙醇。Furthermore, in the method for preparing chiral β-hydroxy carboxylic acid ester compound provided by the present invention, it may also have the feature that the solvent is dichloromethane, or 1,2-dichloroethane, or methanol, or Isopropanol, or toluene, or tetrahydrofuran, or ethanol. The most preferred are methanol and ethanol.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：碱性添加物为氢氧化钠、或氢氧化钾、或叔丁醇钾、或碳酸钾。最优为叔丁醇钾。Further, in the method for preparing chiral β-hydroxy carboxylate compounds provided by the present invention, it may also have the feature that the alkaline additive is sodium hydroxide, or potassium hydroxide, or potassium tert-butoxide, or carbonic acid Potassium. The most preferred is potassium tert-butoxide.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：在步骤1中制备的催化剂中加入底物β-羰基羧酸酯化合物后，将其置于高压反应釜中，首先用氢气置换至少3次，然后再通入氢气使得高压反应釜中的压力为10-100个大气压。Furthermore, in the method for preparing chiral β-hydroxy carboxylate compounds provided by the present invention, it may also have the feature that after adding the substrate β-carbonyl carboxylate compound to the catalyst prepared in step 1, it Put it in an autoclave, first replace it with hydrogen for at least 3 times, and then pass in hydrogen so that the pressure in the autoclave is 10-100 atmospheres.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：最优的，高压反应釜中的压力为20个大气压。Furthermore, in the method for preparing chiral β-hydroxy carboxylic acid ester compounds provided by the present invention, it may also have the following characteristics: optimally, the pressure in the autoclave is 20 atmospheres.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：反应完成后，首先除去溶剂，然后采用硅胶柱分离的方法得到产物手性β-羟基羧酸酯化合物。Further, in the method for preparing chiral β-hydroxy carboxylate compounds provided by the present invention, it may also have the feature: after the reaction is completed, the solvent is first removed, and then the product chiral β-hydroxyl group is obtained by the method of silica gel column separation. Carboxylate compound.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：最优的，反应温度为60-100℃。Furthermore, in the method for preparing chiral β-hydroxy carboxylate compounds provided by the present invention, it may also have the following characteristics: optimally, the reaction temperature is 60-100°C.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：最优的，反应时间为24小时。Furthermore, in the method for preparing chiral β-hydroxy carboxylate compounds provided by the present invention, it may also have the following characteristics: optimally, the reaction time is 24 hours.
进一步，在本发明提供的制备手性β-羟基羧酸酯化合物的方法中，还可以具有这样的特征：步骤1中，在室温下搅拌10-15分钟。Furthermore, in the method for preparing chiral β-hydroxy carboxylic acid ester compounds provided by the present invention, it may also have the feature: in step 1, stirring is performed at room temperature for 10-15 minutes.
上述描述的被某官能团取代的某基团意为：基团中的H被官能团取代。The above description of a certain group substituted by a certain functional group means: H in the group is replaced by a functional group.
本发明提供了如下优点：The present invention provides the following advantages:
本发明所涉及的制备手性β-羟基羧酸酯化合物的方法，采用[Ir(COD)Cl] 2、配体在碱性添加物的条件下原位生成催化剂，在所述催化剂条件下，通入氢气对β-羰基羧酸酯化合物进行不对称催化氢化反应，反应条件为：氢气压力为0-100个大气压、反应温度为0-200℃、反应时间为12-48个小时，能够得到反应活性(反应的TONs高达100000)和选择性(ee值最高为99％)高的手性β-羟基羧酸酯化合物， 该种合成方法氢化反应条件温和，适用于多种β-羰基羧酸酯化合物，底物适用范围广，且反应过程对环境污染小。 The method for preparing chiral β-hydroxy carboxylate compounds according to the present invention adopts [Ir(COD)Cl] 2 and a ligand to generate a catalyst in situ under the condition of a basic additive, and under the catalyst condition, The asymmetric catalytic hydrogenation reaction of β-carbonyl carboxylate compounds is carried out by introducing hydrogen. The reaction conditions are: hydrogen pressure is 0-100 atmospheres, reaction temperature is 0-200°C, and reaction time is 12-48 hours. Chiral β-hydroxy carboxylic acid ester compound with high reactivity (the TONs of reaction is as high as 100,000) and selectivity (ee value is up to 99%). This synthesis method has mild hydrogenation reaction conditions and is suitable for a variety of β-carbonyl carboxylic acids The ester compound has a wide range of substrates, and the reaction process has little environmental pollution.
具体实施方式Detailed ways
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，以下结合实施例对本发明的制备手性β-羟基羧酸酯化合物的方法作具体阐述。In order to make it easy to understand the technical means, creative features, objectives and effects achieved by the present invention, the method for preparing chiral β-hydroxycarboxylate compounds of the present invention will be described in detail below in conjunction with examples.
<实施例一><Example One>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0025mmol,0.5mol％)，手性膦-吡啶配体(0.0055mmol,1.1mol％)和叔丁醇钾(0.025mmol,5.0mol％)溶于乙醇(1.0mL)，室温下搅拌10分钟，加入底物苯乙酰乙酸乙酯(0.5mmol)的乙醇(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20个大气压，100℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0025mmol, 0.5mol%), chiral phosphine-pyridine ligand (0.0055mmol, 1.1mol%) and potassium tert-butoxide ( 0.025mmol, 5.0mol%) dissolved in ethanol (1.0mL), stirred at room temperature for 10 minutes, added the substrate ethyl phenylacetoacetate (0.5mmol) in ethanol (1.0mL) solution, placed it in the autoclave, Hydrogen was replaced 3 times, then hydrogen was introduced to 20 atmospheres, and reacted at 100°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000005
Figure PCTCN2019085490-appb-000005
反应方程式如下：The reaction equation is as follows:
Figure PCTCN2019085490-appb-000006
Figure PCTCN2019085490-appb-000006
采用手性高效液相色谱检测产物的收率和选择性。产物3-羟基-3-苯基丙酸乙酯的收率为98％，选择性为97％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the product ethyl 3-hydroxy-3-phenylpropionate was 98%, and the selectivity was 97%.
手性高效液相色谱的条件如下：The conditions of chiral high performance liquid chromatography are as follows:
chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝90/10,0.8mL min -1,210nm,40℃):tR(S)＝11.5min,tR(R)＝16.8min.[a] 28 D＝45.5(c 1.01,CHCl 3). 1H NMR(400MHz,CDCl 3)d 7.44–7.27(m,5H),5.14(dd,J＝8.8,4.0Hz,1H),2.97–2.67(m,3H),2.60(dd,2H),1.32(t,3H). chiral HPLC (chiralcel OD-H, n-hexane/i-PrOH=90/10, 0.8mL min -1 , 210nm, 40℃): tR(S)=11.5min, tR(R)=16.8min.[a ] 28 D = 45.5 (c 1.01, CHCl 3 ). 1 H NMR (400MHz, CDCl 3 ) d 7.44–7.27 (m, 5H), 5.14 (dd, J = 8.8, 4.0 Hz, 1H), 2.97–2.67 ( m,3H), 2.60(dd,2H), 1.32(t,3H).
<实施例二><Example 2>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0025mmol,0.5mol％)，手性膦-吡啶配体(0.0055mmol,1.1mol％)和氢氧化钾(0.025mmol,5.0mol％)溶于乙醇(1.0mL)，室温下搅拌10分钟，加入底物苯乙酰乙酸乙酯(0.5mmol)的乙醇(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20个大气压，100℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0025mmol, 0.5mol%), chiral phosphine-pyridine ligand (0.0055mmol, 1.1mol%) and potassium hydroxide (0.025 mmol, 5.0 mol%) dissolved in ethanol (1.0 mL), stirred at room temperature for 10 minutes, added the substrate ethyl phenylacetoacetate (0.5 mmol) in ethanol (1.0 mL) solution, placed it in the autoclave, hydrogen Replace it for 3 times, then pass hydrogen to 20 atmospheres and react at 100°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000007
Figure PCTCN2019085490-appb-000007
采用手性高效液相色谱检测产物的收率和选择性。得到的产物3-羟基-3-苯基丙酸乙酯的收率为95％，选择性为92％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the obtained product, ethyl 3-hydroxy-3-phenylpropionate was 95%, and the selectivity was 92%.
手性高效液相色谱的条件与实施例一相同。The conditions of chiral high performance liquid chromatography are the same as in Example 1.
<实施例三><Example Three>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0025mmol,0.5mol％)，手性膦-吡啶配体(0.0055mmol,1.1mol％)和叔丁醇钾(0.025mmol,5.0mol％)溶于乙醇(1.0mL)，室温下搅拌10分钟，加入底物苯乙酰乙酸乙酯(0.5mmol)的乙醇(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至60个大气压，100℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0025mmol, 0.5mol%), chiral phosphine-pyridine ligand (0.0055mmol, 1.1mol%) and potassium tert-butoxide ( 0.025mmol, 5.0mol%) dissolved in ethanol (1.0mL), stirred at room temperature for 10 minutes, added the substrate ethyl phenylacetoacetate (0.5mmol) in ethanol (1.0mL) solution, placed it in the autoclave, Hydrogen was replaced 3 times, then hydrogen was introduced to 60 atmospheres, and reacted at 100°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000008
Figure PCTCN2019085490-appb-000008
采用手性高效液相色谱检测产物的收率和选择性。得到的产物3-羟基-3-苯基丙酸乙酯的收率为96％，选择性为95％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the obtained product, ethyl 3-hydroxy-3-phenylpropionate was 96%, and the selectivity was 95%.
手性高效液相色谱的条件与实施例一相同。The conditions of chiral high performance liquid chromatography are the same as in Example 1.
<实施例四><Example Four>
在氮气保护下，将[Ir(COD)Cl] 2(0.00025mmol,0.05mol％)，手性膦-吡啶配体(0.00055mmol,0.11mol％)和叔丁醇钾(0.025mmol,0.50mol％)溶于乙醇(1.0mL)，室温下搅拌10分钟，加入底物苯乙酰乙酸乙酯(0.5mmol)的乙醇(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20个大气压，100℃下反应24小时，慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 Under the protection of nitrogen, [Ir(COD)Cl] 2 (0.00025mmol, 0.05mol%), chiral phosphine-pyridine ligand (0.00055mmol, 0.11mol%) and potassium tert-butoxide (0.025mmol, 0.50mol%) ) Was dissolved in ethanol (1.0 mL), stirred at room temperature for 10 minutes, added the substrate ethyl phenylacetoacetate (0.5 mmol) in ethanol (1.0 mL) solution, placed it in an autoclave, replaced with hydrogen 3 times, and then Pass hydrogen to 20 atmospheres, react at 100°C for 24 hours, slowly release hydrogen, remove the solvent and separate with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000009
Figure PCTCN2019085490-appb-000009
采用手性高效液相色谱检测产物的收率和选择性。得到的产物3-羟基-3-苯基丙酸乙酯的收率为93％，选择性为95％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the obtained product, ethyl 3-hydroxy-3-phenylpropionate was 93%, and the selectivity was 95%.
手性高效液相色谱的条件与实施例一相同。The conditions of chiral high performance liquid chromatography are the same as in Example 1.
<实施例五><Example 5>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0025mmol,0.5mol％)，手性膦-吡啶配体(0.0055mmol,1.1mol％)和氢氧化钾(0.025mmol,5.0mol％)溶于甲苯(1.0mL)，室温下搅拌10分钟，加入底物4’-氯苯乙酰乙酸乙酯(0.5mmol)的甲苯(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20个大气压，100℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-(4-氯苯基)丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0025mmol, 0.5mol%), chiral phosphine-pyridine ligand (0.0055mmol, 1.1mol%) and potassium hydroxide (0.025 mmol, 5.0mol%) dissolved in toluene (1.0mL), stirred at room temperature for 10 minutes, added the substrate 4'-chlorophenyl acetoacetate (0.5mmol) in toluene (1.0mL) solution, placed it under high pressure for reaction In the kettle, hydrogen was replaced 3 times, and then hydrogen was introduced to 20 atmospheres and reacted at 100°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-(4-chlorophenyl)propionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000010
Figure PCTCN2019085490-appb-000010
采用手性高效液相色谱检测产物的收率和选择性。得到的产物3-羟基-3-(4-氯苯基)丙酸乙酯的收率为99％，选择性为96％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The resulting product, ethyl 3-hydroxy-3-(4-chlorophenyl)propionate, has a yield of 99% and a selectivity of 96%.
手性高效液相色谱的条件如下：The conditions of chiral high performance liquid chromatography are as follows:
chiral HPLC(chiralpak AS-H,n-hexane/i-PrOH＝95/5,0.8mL  min -1,210nm,40℃):tR(R)＝18.4min,tR(S)＝20.2min.[a] 28 D＝37.6(c 1.02,CHCl 3). 1H NMR(400MHz,CDCl 3)d 7.35–7.28(m,4H),5.11(dd,J＝8.1,4.7Hz,1H),2.75–2.67(m,2H),2.63(dd,2H),1.30(t,3H). chiral HPLC (chiralpak AS-H, n-hexane/i-PrOH=95/5, 0.8mL min -1 , 210nm, 40℃): tR(R)=18.4min, tR(S)=20.2min.[a ] 28 D ＝37.6(c 1.02,CHCl 3 ). 1 H NMR(400MHz, CDCl 3 )d 7.35–7.28(m,4H), 5.11(dd,J＝8.1,4.7Hz,1H), 2.75–2.67( m, 2H), 2.63 (dd, 2H), 1.30 (t, 3H).
<实施例六><Example 6>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0025mmol,0.5mol％)，手性膦-吡啶配体(0.0055mmol,1.1mol％)和叔丁醇钾(0.025mmol,5.0mol％)溶于甲醇(1.0mL)，室温下搅拌10分钟，加入底物4’-甲基苯乙酰乙酸乙酯(0.5mmol)的甲醇(1.0mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至20个大气压，60℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-(4-甲基苯基)丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0025mmol, 0.5mol%), chiral phosphine-pyridine ligand (0.0055mmol, 1.1mol%) and potassium tert-butoxide ( 0.025mmol, 5.0mol%) was dissolved in methanol (1.0mL), stirred at room temperature for 10 minutes, and the substrate 4'-methylphenylacetoacetate (0.5mmol) in methanol (1.0mL) solution was added and placed in In the autoclave, hydrogen was replaced 3 times, and then hydrogen was introduced to 20 atmospheres and reacted at 60°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-(4-methylphenyl)propionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000011
Figure PCTCN2019085490-appb-000011
采用手性高效液相色谱检测产物的收率和选择性。得到的产物3-羟基-3-(4-甲基苯基)丙酸乙酯的收率为98％，选择性为99％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The resulting product, ethyl 3-hydroxy-3-(4-methylphenyl)propionate, has a yield of 98% and a selectivity of 99%.
手性高效液相色谱的条件如下：The conditions of chiral high performance liquid chromatography are as follows:
chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝90/10,0.8mL min -1,210nm,40℃):tR(R)＝9.0min,tR(S)＝9.8min.[a] 28 D＝44.7(c 1.04,CHCl 3). 1H NMR(400MHz,CDCl 3)d 7.30–7.23(m,2H),7.16(d,J＝7.9Hz,2H),5.09(dd,J＝9.2,3.8Hz,1H),3.70(s,3H),2.87–2.62 (m,2H),2.66(dd,2H),1.29(t,3H). chiral HPLC (chiralcel OD-H, n-hexane/i-PrOH=90/10, 0.8mL min -1 , 210nm, 40℃): tR(R)=9.0min, tR(S)=9.8min.[a ] 28 D = 44.7 (c 1.04, CHCl 3 ). 1 H NMR (400MHz, CDCl 3 ) d 7.30–7.23 (m, 2H), 7.16 (d, J = 7.9 Hz, 2H), 5.09 (dd, J = 9.2, 3.8Hz, 1H), 3.70 (s, 3H), 2.87-2.62 (m, 2H), 2.66 (dd, 2H), 1.29 (t, 3H).
<实施例七><Example 7>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.00125mmol,0.0005mol％)，手性膦-吡啶配体(0.00275mmol,0.0011mol％)和叔丁醇钾(0.0125mmol,0.005mol％)溶于异丙醇(10mL)，室温下搅拌10分钟，加入底物4-氯乙酰乙酸乙酯(0.25mol)的异丙醇(10mL)溶液，将其置于高压反应釜中，氢气置换3次，然后通入氢气至50个大气压，80℃反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-4-氯丁酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.00125mmol, 0.0005mol%), chiral phosphine-pyridine ligand (0.00275mmol, 0.0011mol%) and potassium tert-butoxide ( 0.0125mmol, 0.005mol%) dissolved in isopropanol (10mL), stirred at room temperature for 10 minutes, added the substrate 4-chloroacetoacetate (0.25mol) in isopropanol (10mL) solution, and placed it under high pressure In the reaction kettle, hydrogen was replaced 3 times, and then hydrogen was introduced to 50 atmospheres and reacted at 80°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-4-chlorobutyrate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000012
Figure PCTCN2019085490-appb-000012
采用手性高效液相色谱检测产物的收率和选择性。产物3-羟基-4-氯丁酸乙酯的收率为95％，选择性为98％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the product ethyl 3-hydroxy-4-chlorobutyrate was 95%, and the selectivity was 98%.
手性高效液相色谱的条件如下：The conditions of chiral high performance liquid chromatography are as follows:
chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝95/5,0.8mL min -1,210nm,40℃):tR(S)＝10.2min,tR(R)＝11.3min.[a] 28 D＝13.9(neat). 1H NMR(400MHz,CDCl 3)d 4.27(m,1H),4.19(q,4H),3.61(dt,2H),2.63(dd,2H),1.28(t,3H). chiral HPLC (chiralcel OD-H, n-hexane/i-PrOH=95/5, 0.8mL min -1 , 210nm, 40℃): tR(S)=10.2min, tR(R)=11.3min.[a ] 28 D ＝13.9(neat). 1 H NMR(400MHz,CDCl 3 )d 4.27(m,1H),4.19(q,4H),3.61(dt,2H),2.63(dd,2H),1.28(t ,3H).
<实施例八><Example 8>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0005mmol)，手性膦-吡啶配体(0.005mmol)和氢氧化钠(0.055mmol)溶于二氯 甲烷(1.0mL)，室温下搅拌15分钟，加入底物苯乙酰乙酸乙酯(0.55mmol)的二氯甲烷(1.0mL)溶液，将其置于高压反应釜中，氢气置换4次，然后通入氢气至100个大气压，200℃下反应12小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0005mmol), chiral phosphine-pyridine ligand (0.005mmol) and sodium hydroxide (0.055mmol) were dissolved in dichloromethane ( 1.0mL), stir at room temperature for 15 minutes, add the substrate ethyl phenylacetoacetate (0.55mmol) in dichloromethane (1.0mL) solution, place it in the autoclave, replace with hydrogen 4 times, and then add hydrogen To 100 atmospheres, react at 200°C for 12 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000013
Figure PCTCN2019085490-appb-000013
采用手性高效液相色谱检测产物的收率和选择性。产物3-羟基-3-苯基丙酸乙酯的收率为97％，选择性为80％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the product ethyl 3-hydroxy-3-phenylpropionate was 97%, and the selectivity was 80%.
手性高效液相色谱的条件与实施例一相同。The conditions of chiral high performance liquid chromatography are the same as in Example 1.
<实施例九><Example 9>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.00002mmol)，手性膦-吡啶配体(0.00013mmol)和碳酸钾(0.3mmol)溶于1,2-二氯乙烷(0.5mL)，室温下搅拌12分钟，加入底物苯乙酰乙酸乙酯(1.5mmol)的1,2-二氯乙烷(1.0mL)溶液，将其置于高压反应釜中，氢气置换4次，然后通入氢气至10个大气压，60℃下反应24小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.00002mmol), chiral phosphine-pyridine ligand (0.00013mmol) and potassium carbonate (0.3mmol) were dissolved in 1,2-di Chloroethane (0.5mL), stirred at room temperature for 12 minutes, added the substrate ethyl phenylacetoacetate (1.5mmol) in 1,2-dichloroethane (1.0mL) solution, placed it in the autoclave, Hydrogen was replaced 4 times, then hydrogen was introduced to 10 atmospheres, and reacted at 60°C for 24 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000014
Figure PCTCN2019085490-appb-000014
采用手性高效液相色谱检测产物的收率和选择性。产物3-羟基-3-苯基丙酸乙酯的收率为80％，选择性为87％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the product ethyl 3-hydroxy-3-phenylpropionate was 80%, and the selectivity was 87%.
手性高效液相色谱的条件与实施例一相同。The conditions of chiral high performance liquid chromatography are the same as in Example 1.
<实施例十><Example ten>
在本实施例中，在氮气保护下，将[Ir(COD)Cl] 2(0.0025mmol)，手性膦-吡啶配体(0.0055mmol)和叔丁醇钾(0.025mmol)溶于四氢呋喃(20mL)，室温下搅拌13分钟，加入底物苯乙酰乙酸乙酯(0.5mmol)的四氢呋喃(30mL)溶液，将其置于高压反应釜中，氢气置换5次，然后通入氢气至20个大气压，0℃下反应48小时。慢慢释放氢气，除去溶剂后用硅胶柱分离得到产物3-羟基-3-苯基丙酸乙酯。 In this example, under the protection of nitrogen, [Ir(COD)Cl] 2 (0.0025mmol), chiral phosphine-pyridine ligand (0.0055mmol) and potassium tert-butoxide (0.025mmol) were dissolved in tetrahydrofuran (20mL ), stir at room temperature for 13 minutes, add the substrate ethyl phenylacetoacetate (0.5mmol) in tetrahydrofuran (30mL) solution, place it in an autoclave, replace with hydrogen 5 times, and then pass hydrogen to 20 atmospheres. React at 0°C for 48 hours. The hydrogen is slowly released, the solvent is removed, and the product is separated with a silica gel column to obtain the product ethyl 3-hydroxy-3-phenylpropionate.
其中，手性膦-吡啶配体为：Among them, the chiral phosphine-pyridine ligand is:
Figure PCTCN2019085490-appb-000015
Figure PCTCN2019085490-appb-000015
采用手性高效液相色谱检测产物的收率和选择性。产物3-羟基-3-苯基丙酸乙酯的收率为82％，选择性为78％。Chiral high performance liquid chromatography was used to detect the yield and selectivity of the product. The yield of the product ethyl 3-hydroxy-3-phenylpropionate was 82%, and the selectivity was 78%.
手性高效液相色谱的条件与实施例一相同。The conditions of chiral high performance liquid chromatography are the same as in Example 1.
本发明所涉及的制备手性β-羟基羧酸酯化合物的方法并不限于 具体实施例的范围。以上内容仅为本发明的基本说明，而依据本发明的技术方案所作的任何等效变换，均应属于本发明的保护范围。The method for preparing chiral β-hydroxy carboxylate compounds involved in the present invention is not limited to the scope of the specific examples. The above content is only the basic description of the present invention, and any equivalent transformations made according to the technical solution of the present invention should belong to the protection scope of the present invention.

Claims (9)

  1. 一种制备手性β-羟基羧酸酯化合物的方法，其特征在于：A method for preparing chiral β-hydroxy carboxylate compounds, characterized in that:
    步骤1，制备催化剂，在氮气保护下，将[Ir(COD)Cl] 2、配体、碱性添加物溶于溶剂中，在室温下搅拌，原位生成催化剂， Step 1. Prepare a catalyst. Under the protection of nitrogen, dissolve [Ir(COD)Cl] 2 , ligands, and basic additives in a solvent, stir at room temperature, and generate the catalyst in situ.
    步骤2，将底物β-羰基羧酸酯化合物溶于溶剂中，然后加入步骤1中制备的催化剂中，通入氢气对底物β-羰基羧酸酯化合物进行不对称催化氢化反应，反应条件：压力为10-100个大气压，反应温度为0-200℃，反应时间为12-48个小时，Step 2. Dissolve the substrate β-carbonyl carboxylate compound in a solvent, and then add it to the catalyst prepared in step 1, and pass hydrogen to perform asymmetric catalytic hydrogenation of the substrate β-carbonyl carboxylate compound. Reaction conditions : The pressure is 10-100 atmospheres, the reaction temperature is 0-200°C, and the reaction time is 12-48 hours.
    其中，[Ir(COD)Cl] 2中铱元素与配体的摩尔比为1:1～5，[Ir(COD)Cl] 2和配体的总物质的量为底物β-羰基羧酸酯化合物的物质的量的万分之一到百分之一，碱性添加物的物质的量为底物β-羰基羧酸酯化合物的物质的量的5～20％，步骤1、步骤2中溶剂的总体积量对应底物β-羰基羧酸酯化合物的物质的量的关系为1-100ml/mmol， Among them, the molar ratio of iridium element to ligand in [Ir(COD)Cl] 2 is 1:1 to 5, and the total amount of [Ir(COD)Cl] 2 and ligand is the substrate β-carbonyl carboxylic acid One ten thousandth to one hundredth of the amount of the ester compound, the amount of the alkaline additive is 5-20% of the amount of the substrate β-carbonyl carboxylate compound, step 1, step 2 The relationship between the total volume of the solvent and the substance of the substrate β-carbonyl carboxylate compound is 1-100ml/mmol,
    所述底物β-羰基羧酸酯化合物具有如下的结构式：The substrate β-carbonyl carboxylate compound has the following structural formula:
    Figure PCTCN2019085490-appb-100001
    Figure PCTCN2019085490-appb-100001
    式中，R 1为C 1-C 40的烷基或环烷基，或被含N官能团、含S官能团、含O官能团、含P官能团、含Cl官能团、含Br官能团中的一种或多种取代的C 1-C 40的烷基或环烷基，或C 7-C 60包含苄基的基团，或C 6-C 60的芳香基团，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 6-C 60的芳香基团， In the formula, R 1 is a C 1 -C 40 alkyl or cycloalkyl group, or is selected by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, P-containing functional groups, Cl-containing functional groups, and Br-containing functional groups. A substituted C 1 -C 40 alkyl or cycloalkyl group, or a C 7 -C 60 group containing benzyl, or a C 6 -C 60 aromatic group, or N-containing functional group, S-containing functional group, One or more substituted C 6 -C 60 aromatic groups in O-containing functional groups and P-containing functional groups,
    R 2为H、或C 1-C 40的烷基、或C 6-C 40的芳基， R 2 is H, or a C 1 -C 40 alkyl group, or a C 6 -C 40 aryl group,
    所述配体为膦-吡啶配体，所述膦-吡啶配体具有如下的结构式：The ligand is a phosphine-pyridine ligand, and the phosphine-pyridine ligand has the following structural formula:
    Figure PCTCN2019085490-appb-100002
    Figure PCTCN2019085490-appb-100002
    式中，R 3为C 1-C 40的烷基或环烷基，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 1-C 40的烷基或环烷基，或C 7-C 60包含苄基的基团，或C 6-C 60的芳香基团，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 6-C 60的芳香基团； In the formula, R 3 is C 1 -C 40 alkyl or cycloalkyl, or C 1 -C 40 substituted by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, and P-containing functional groups Alkyl or cycloalkyl group, or C 7 -C 60 group containing benzyl, or C 6 -C 60 aromatic group, or contained in N-containing functional group, S-containing functional group, O-containing functional group, P-containing functional group One or more substituted C 6 -C 60 aromatic groups;
    Ar为C 6-C 60的芳香基团，或被含N官能团、含S官能团、含O官能团、含P官能团中的一种或多种取代的C 6-C 60的芳香基团。 Ar is a C 6 -C 60 aromatic group, or a C 6 -C 60 aromatic group substituted by one or more of N-containing functional groups, S-containing functional groups, O-containing functional groups, and P-containing functional groups.
  2. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法的方法，其特征在于：The method for preparing a chiral β-hydroxycarboxylate compound according to claim 1, wherein:
    所述溶剂为二氯甲烷、或1,2-二氯乙烷、或甲醇、或异丙醇、或甲苯、或四氢呋喃、或乙醇。The solvent is dichloromethane, or 1,2-dichloroethane, or methanol, or isopropanol, or toluene, or tetrahydrofuran, or ethanol.
  3. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 1, wherein:
    所述碱性添加物为氢氧化钠、或氢氧化钾、或叔丁醇钾、或碳酸钾。The alkaline additive is sodium hydroxide, or potassium hydroxide, or potassium tert-butoxide, or potassium carbonate.
  4. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 1, wherein:
    在步骤1中制备的催化剂中加入底物β-羰基羧酸酯化合物后，将其置于高压反应釜中，首先用氢气置换至少3次，然后再通入氢气使 得高压反应釜中的压力为10-100个大气压。After adding the substrate β-carbonyl carboxylate compound to the catalyst prepared in step 1, place it in the autoclave, first replace it with hydrogen for at least 3 times, and then add hydrogen so that the pressure in the autoclave is 10-100 atmospheres.
  5. 根据权利要求4所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 4, characterized in that:
    高压反应釜中的压力为20个大气压。The pressure in the autoclave was 20 atmospheres.
  6. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 1, wherein:
    反应完成后，首先除去溶剂，然后采用硅胶柱分离的方法得到产物手性β-羟基羧酸酯化合物。After the reaction is completed, the solvent is first removed, and then a silica gel column separation method is used to obtain the product chiral β-hydroxycarboxylate compound.
  7. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 1, wherein:
    反应温度为60-100℃。The reaction temperature is 60-100°C.
  8. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 1, wherein:
    反应时间为24小时。The reaction time is 24 hours.
  9. 根据权利要求1所述的制备手性β-羟基羧酸酯化合物的方法，其特征在于：The method for preparing chiral β-hydroxy carboxylate compounds according to claim 1, wherein:
    步骤1中，在室温下搅拌10-15分钟。In step 1, stir at room temperature for 10-15 minutes.
PCT/CN2019/085490 2019-04-22 2019-05-05 METHOD FOR PREPARING CHIRAL β-HYDROXYCARBOXYLATE COMPOUND WO2020215357A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910324607.8 2019-04-22
CN201910324607.8A CN110003005A (en) 2019-04-22 2019-04-22 The method for preparing chiral beta-hydroxy carboxylate compound

Publications (1)

Publication Number Publication Date
WO2020215357A1 true WO2020215357A1 (en) 2020-10-29

Family

ID=67173620

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/085490 WO2020215357A1 (en) 2019-04-22 2019-05-05 METHOD FOR PREPARING CHIRAL β-HYDROXYCARBOXYLATE COMPOUND

Country Status (2)

Country Link
CN (1) CN110003005A (en)
WO (1) WO2020215357A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110003005A (en) * 2019-04-22 2019-07-12 上海欣海国际贸易有限公司 The method for preparing chiral beta-hydroxy carboxylate compound
CN110330429A (en) * 2019-08-22 2019-10-15 上海欣海国际贸易有限公司 A kind of preparation method of chiral beta-hydroxy ester compound
CN110396072B (en) * 2019-09-02 2022-09-13 上海欣海健伟实业有限公司 Method for producing(s) -3-hydroxytetrahydrofuran

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029259A1 (en) * 2001-09-28 2003-04-10 Synkem Novel disphospines, their complexes with transition metals and their use in asymmetric synthesis
WO2009065784A1 (en) * 2007-11-20 2009-05-28 Solvias Ag Bidentate chiral ligands for use in catalytic asymmetric addition reactions
CN106853378A (en) * 2015-12-08 2017-06-16 中国科学院大连化学物理研究所 The ternary catalyst systems of the part of structural framework containing PNN and its application
CN108101785A (en) * 2016-11-24 2018-06-01 中国科学院大连化学物理研究所 A kind of method that iridium catalysis asymmetric hydrogenation prepares chiral beta-hydroxy ester
CN110003005A (en) * 2019-04-22 2019-07-12 上海欣海国际贸易有限公司 The method for preparing chiral beta-hydroxy carboxylate compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029259A1 (en) * 2001-09-28 2003-04-10 Synkem Novel disphospines, their complexes with transition metals and their use in asymmetric synthesis
WO2009065784A1 (en) * 2007-11-20 2009-05-28 Solvias Ag Bidentate chiral ligands for use in catalytic asymmetric addition reactions
CN106853378A (en) * 2015-12-08 2017-06-16 中国科学院大连化学物理研究所 The ternary catalyst systems of the part of structural framework containing PNN and its application
CN108101785A (en) * 2016-11-24 2018-06-01 中国科学院大连化学物理研究所 A kind of method that iridium catalysis asymmetric hydrogenation prepares chiral beta-hydroxy ester
CN110003005A (en) * 2019-04-22 2019-07-12 上海欣海国际贸易有限公司 The method for preparing chiral beta-hydroxy carboxylate compound

Also Published As

Publication number Publication date
CN110003005A (en) 2019-07-12

Similar Documents

Publication Publication Date Title
WO2020215357A1 (en) METHOD FOR PREPARING CHIRAL β-HYDROXYCARBOXYLATE COMPOUND
US8471048B2 (en) Ruthenium carbonyl complex having tridentate ligand, its production method and use
WO2007052383A1 (en) Process for producing 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one
DE60208305T2 (en) Process for the preparation of optically active amino alcohols
CN109734600B (en) Synthesis method of chiral beta-hydroxy acid ester compound
WO2003078366A1 (en) Process for trifluoromethylation of sulfates
CN110642718B (en) Heterogeneous catalyst for synthesizing diphenyl carbonate and preparation method thereof
WO2006137195A1 (en) Sulfonate catalyst and process for producing alcohol compound with the same
CN113788766B (en) Preparation method of atorvastatin calcium intermediate
WO1989006225A1 (en) Ligand-accelerated catalytic asymmetric dihydroxylation
WO2021031246A1 (en) METHOD FOR PREPARING CHIRAL β-HYDROXYLCARBOXYLATE COMPOUND
CN113549062A (en) Chiral quaternary ammonium salt phase transfer catalyst with high steric hindrance derived from cinchona alkaloid and synthesis method thereof
CN109970560B (en) Preparation method of tri-substituted 1, 3-diene compound
CN114436831A (en) Synthesis method of chiral 1-phenylpropyl acetate compound
US6780812B2 (en) Chiral lead catalyst and method of asymmetric aldol reaction
Lee et al. Highly Enantioselective Rh-Catalyzed Transfer Hydrogenation of α-Functionalized Arylketones
JP2688528B2 (en) Process for producing optically active 2-hydroxy-4-phenylbutyric acid alkyl ester
IE47907B1 (en) Process for preparing aromatic aldehydes
CN115583874B (en) Method for catalyzing asymmetric tandem reaction of internal alkyne by rhodium metal
KR20050010050A (en) Process for production of 1,2,4-butanetriol
CN109180496B (en) Method for synthesizing cinacalcet by using chemical-enzymatic method
JP2006206550A (en) METHOD FOR PRODUCING delta-IMINOMALONIC ACID DERIVATIVE, AND CATALYST THEREFOR
JP2006076935A (en) Asymmetric ruthenium catalyst and manufacturing method of optically active alcohol using the same
JPS6160822B2 (en)
JP2009242390A (en) Method for producing homoallyl hydrazide, and asymmetric catalyst for use therein

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19926670

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19926670

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 25/02/2022)