阅读说明：本技术 一种手性3,4-二取代琥珀酰亚胺及其衍生物的制备方法 (Preparation method of chiral 3, 4-disubstituted succinimide and derivatives thereof ) 是由 王芳元 陈根强 张绪穆 于 2021-08-03 设计创作，主要内容包括：一种手性3,4-二取代琥珀酰亚胺及其衍生物的制备方法,手性3,4-二取代琥珀酰亚胺类化合物的制备方法,包括：在金属催化剂的存在下,使用式(I)所示的化合物反应得到式(II)所示的化合物。本发明提供的手性3,4-二取代琥珀酰亚胺的制备方法,通过将式(I)所示的化合物在特定的金属催化剂作用下反应,得到式(II)所示的化合物,通过实验发现,该反应通过采用不对称转移氢化反应,不仅具有反应条件温和、收率高、产物的非对映选择性和对映选择性优异等优点,且反应体系中催化剂用量少,催化效率高。(A preparation method of chiral 3, 4-disubstituted succinimide and derivatives thereof, a preparation method of chiral 3, 4-disubstituted succinimide compounds, comprises the following steps: reacting the compound shown in the formula (I) in the presence of a metal catalyst to obtain the compound shown in the formula (II). According to the preparation method of the chiral 3, 4-disubstituted succinimide, the compound shown in the formula (I) is reacted under the action of the specific metal catalyst to obtain the compound shown in the formula (II), and experiments show that the reaction adopts asymmetric transfer hydrogenation reaction, so that the preparation method has the advantages of mild reaction conditions, high yield, excellent diastereoselectivity and enantioselectivity of products and the like, and the catalyst consumption in a reaction system is small, and the catalytic efficiency is high.)

1. A method for preparing chiral 3, 4-disubstituted succinimide compounds is characterized by comprising the following steps:

reacting a compound shown in a formula (I) in the presence of a metal catalyst to obtain a compound shown in a formula (II);

wherein R is¹Independently represent unsubstituted aryl of C6-C30, substituted aryl of C6-C30, unsubstituted heteroaryl of C4-C20, substituted heteroaryl of C4-C20, alkyl of C1-C10 or cycloalkyl of C3-C10; r²Independently C6-C30 unsubstituted aryl, C6-C30 substituted aryl, C1-C10 alkyl without substituent or C1-C10 alkyl with substituent; or R¹、R²Together with the carbon on which they are located, form a cycloalkyl or cycloalkyl-containing fused or fused ring structure, the carbon atom marked with an asterisk (a) represents a chiral carbon atom.

2. The production method according to claim 1, wherein the metal catalyst is at least one selected from the group consisting of a ruthenium catalyst, an iridium catalyst and a rhodium catalyst.

3. The method according to claim 1, wherein the metal catalyst is at least one selected from the group consisting of (R, R) -cat.1, (S, S) -cat.2, (S, S) -cat.3, (R, R) -cat.4, (R, R) -cat.5, (R, R) -cat.6, and (S, S) -cat.6:

and/or the catalyst is selected from at least one of (R, R) -cat.6 and (S, S) -cat.6.

4. The method of claim 1, wherein the reaction is carried out in a solvent;

and/or the solvent is at least one selected from methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, dichloromethane, ethyl acetate, n-hexane and toluene;

and/or, the solvent is selected from ethyl acetate;

and/or the dosage ratio of the compound shown in the formula (I) to the solvent is 1 mmol: (10-20) mL.

5. The method of claim 1, wherein the starting materials for the reaction further comprise a hydrogen donor;

and/or, the hydrogen donor is selected from at least one of formic acid, sodium formate, isopropanol;

and/or the molar ratio of the compound represented by the formula (I) to the hydrogen donor is 1: (2-5);

and/or when the hydrogen donor of the reaction is formic acid, adding an azeotrope of the hydrogen donor in the reaction, wherein the azeotrope of the hydrogen donor is a mixed solution of formic acid and triethylamine;

and/or the molar ratio of formic acid to triethylamine is (2-200): (0-2);

and/or the molar ratio of formic acid to triethylamine is (5-200): (1-2);

and/or the molar ratio of formic acid to triethylamine is 5:2 or 100: 1;

and/or when the molar ratio of the formic acid to the triethylamine is (5-10): 1-2), the trans-isomer in the obtained product is excessive relative to the cis-isomer;

and/or the molar ratio of formic acid to triethylamine in the azeotrope containing the hydrogen donor is (100-200): (0-1), the cis-isomer in the obtained product is excessive relative to the trans-isomer;

and/or the amount ratio of the azeotrope of the compound shown in the formula (I) and the hydrogen donor or the hydrogen-containing donor is 0.1 mmol: (20-40) mu L.

6. The preparation method according to claim 1, wherein the reaction is carried out at a temperature of 15 to 80 ℃;

and/or, the reaction is carried out in an oxygen-free environment;

and/or the oxygen-free environment is obtained by filling inert gas and/or inert gas into the reaction environment;

and/or the inert gas comprises at least one of helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe) and nitrogen;

and/or the molar ratio of the compound represented by the formula (I) to the metal catalyst is 1: (0.0005 to 0.05);

and/or the molar ratio of the compound represented by the formula (I) to the metal catalyst is 1: (0.01 to 0.05);

and/or the molar ratio of the compound shown in the formula (I) to the metal catalyst is 1 (0.01-0.02);

and/or, in the compound represented by the formula (I), the R¹Independently selected from phenyl, alkyl substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, naphthyl, anthryl, phenanthryl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, pyridyl, thienyl, furyl, indolyl or alkyl substituted indolyl; the R is²Independently selected from phenyl, alkyl substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, naphthyl, anthracenyl, benzyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

and/or, said R¹、R²Form a C5-C8 cycloalkyl group together with the carbon on which they are located;

and/or, said R¹、R²Together with the carbon on which they are present form a cyclopentyl, cyclohexyl or cycloheptyl group;

and/or, said R¹、R²And the carbon atoms of the fused ring structure form a fused ring structure containing C5-C8 naphthenic base, wherein the fused ring is selected from: dicycloalkyl fused rings and cycloalkyl fused benzene rings, wherein the fused rings are formed by fusing cycloalkyl with naphthalene rings, anthracene rings, phenanthrene rings or fluorene rings;

and/or, the compound shown in the formula (I) is selected from at least one of the following compounds:

7. a compound produced by the production method according to any one of claims 1 to 6.

8. A method for preparing a compound of formula (III), comprising:

adding a protecting group to the compound shown in the formula (II) through a substitution reaction, and then obtaining the compound shown in the formula (III) through a reduction reaction;

wherein R is¹Independently selected from unsubstituted aryl of C6-C30, substituted aryl of C6-C30, unsubstituted heteroaryl of C4-C20, substituted heteroaryl of C4-C20, alkyl of C1-C10 or cycloalkyl of C3-C10; r²Independently selected from unsubstituted aryl of C6-C30, substituted aryl of C6-C30, alkyl without substituent of C1-C10 or alkyl with substituent of C1-C10; or R¹、R²Together with the carbon on which they are located to form a benzocycloalkyl group.

9. The method according to claim 8, wherein the compound represented by formula (II) is produced by the method according to any one of claims 1 to 6;

and/or the protecting group is selected from at least one of tert-butyldimethylsilyl (TBDMS), benzoyl, benzyl, methoxymethyl ether, beta-methoxyethoxymethyl ether, methoxytrityl (4-methoxyphenyl) diphenylmethyl, dimethoxytrityl (bis- (4-methoxyphenyl) phenylmethyl), p-methoxybenzyl ether, methylthiomethyl ether, pivaloyl, trityl (triphenylmethyl), 2-nitro-4, 5-dimethoxybenzyl, Trimethylsilyl (TMS), Triisopropylsilyloxymethyl (TOM), Triisopropylsilyl (TIPS), TBDPS ether;

and/or the substitution reaction and the reduction reaction are carried out in the presence of a protective reagent;

and/or, the protective reagent is a silicon reagent;

and/or the protective reagent is tert-butyldimethylsilyl trifluoromethanesulfonate;

and/or the molar ratio of the compound represented by the formula (II) to the protective agent is 1: (1.5-3);

and/or the substitution reaction and the reduction reaction are carried out in an oxygen-free environment;

and/or the substitution reaction is carried out at the temperature of 0-25 ℃;

and/or, the reduction reaction is carried out in the presence of a reducing agent;

and/or the molar ratio of the compound shown in the formula (II) to the reducing agent is 1 (3-10);

and/or the molar ratio of the compound represented by formula (II) to the reducing agent is 1: 5;

and/or, the reducing agent comprises NaBH₄；

And/or the system of the reduction reaction also contains Lewis acid;

and/or the Lewis acid is selected from at least one of aluminum trichloride, boron trifluoride, sulfur trioxide and ferric bromide;

and/or the reduction reaction is carried out at the temperature of 0-25 ℃;

and/or the reduction reaction is carried out in a temperature environment of 15 ℃;

and/or, the substitution reaction and the reduction reaction are carried out in an oxygen-free environment;

and/or the oxygen-free environment is obtained by filling inert gas and/or inert gas into the reaction environment;

and/or the inert gas is selected from at least one of helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe) and nitrogen.

10. A compound produced by the production method according to any one of claims 8 to 9.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of chiral 3, 4-disubstituted succinimide and derivatives thereof.

Background

3, 4-disubstituted succinimide is an important organic synthon; such chiral backbones are included in many natural products as well as in biological inhibitors. The derivatives of the 3, 4-disubstituted succinimide can be used as chiral phase transfer catalysts, chiral drug molecules and chiral ligands, so that the synthesis of the 3, 4-disubstituted succinimide compounds has very important significance.

In the prior art, few reports of synthetic methods of chiral 3, 4-disubstituted succinimide compounds exist, and no efficient high-stereoselectivity synthetic method exists at present.

Disclosure of Invention

According to a first aspect, there is provided in one embodiment a process for the preparation of a chiral 3, 4-disubstituted succinimide compound comprising:

reacting a compound shown in a formula (I) in the presence of a metal catalyst to obtain a compound shown in a formula (II);

wherein R is¹Independently represent unsubstituted aryl of C6-C30, substituted aryl of C6-C30, unsubstituted heteroaryl of C4-C20, substituted heteroaryl of C4-C20, alkyl of C1-C10 or cycloalkyl of C3-C10; r²Independently C6-C30 unsubstituted aryl, C6-C30 substituted aryl, C1-C10 alkyl without substituent or C1-C10 alkyl with substituent; or R¹、R²Form a cycloalkyl or a fused ring structure containing cycloalkyl together with the carbon on which they are located, and the carbon atom marked with an asterisk indicates a chiral carbon atom, indicating that the compound has stereoisomers.

According to a second aspect, there is provided a compound produced by the production method of the first aspect.

According to a third aspect, in one embodiment, the present invention provides a process for the preparation of a compound of formula (III), comprising:

adding a protecting group to a compound shown in a formula (II) through a substitution reaction, and then obtaining a compound with a structure shown in a formula (III) through a reduction reaction;

wherein R is¹Independently selected from unsubstituted aryl of C6-C30, substituted aryl of C6-C30, unsubstituted heteroaryl of C4-C20, substituted heteroaryl of C4-C20, alkyl of C1-C10 or cycloalkyl of C3-C10; r²Independently selected from unsubstituted aryl of C6-C30, substituted aryl of C6-C30, alkyl without substituent of C1-C10 or alkyl with substituent of C1-C10; or R¹、R²Together with the carbon on which they are located to form a benzocycloalkyl group.

According to a fourth aspect, in one embodiment, there is provided a compound produced by the production method of the third aspect.

According to the preparation method of the chiral 3, 4-disubstituted succinimide and the derivative thereof in the embodiment, the compound shown in the formula (I) is reacted under the action of the specific metal catalyst to obtain the compound shown in the formula (II), and experiments show that the reaction has the advantages of mild reaction conditions, high yield, excellent diastereoselectivity and enantioselectivity of products and the like by adopting the asymmetric transfer hydrogenation reaction, and the catalyst consumption in a reaction system is small and the catalytic efficiency is high.

Detailed Description

The present invention will be described in further detail with reference to the following embodiments. Wherein like elements in different embodiments are numbered with like associated elements. In the following description, numerous details are set forth in order to provide a better understanding of the present application. However, those skilled in the art will readily recognize that some of the features may be omitted or replaced with other elements, materials, methods in different instances. In some instances, certain operations related to the present application have not been shown or described in detail in order to avoid obscuring the core of the present application from excessive description, and it is not necessary for those skilled in the art to describe these operations in detail, so that they may be fully understood from the description in the specification and the general knowledge in the art.

Furthermore, the features, operations, or characteristics described in the specification may be combined in any suitable manner to form various embodiments. Also, the various steps or actions in the method descriptions may be transposed or transposed in order, as will be apparent to one of ordinary skill in the art. Thus, the various sequences of the specification are for clarity only to describe certain embodiments and are not meant to imply a required sequence unless otherwise stated where a certain sequence must be followed.

The numbering of the components as such, e.g., "first", "second", etc., is used herein only to distinguish the objects as described, and does not have any sequential or technical meaning. The terms "connected" and "coupled" when used herein, unless otherwise indicated, include both direct and indirect connections (couplings).

Definition of

In this context, the solid wedge line is not specifically indicatedIndicating the chemical bond above the paper surface, dashed wedge lineThis chemical bond is shown below the paper.

Herein, Ts represents p-toluenesulfonoyl having the formula p-CH, unless otherwise specified₃-C₆H₄-SO₂-。

Herein, Ph represents a phenyl group, unless otherwise specified.

Herein, Bn represents a benzyl group, i.e., a benzyl group, unless otherwise specified.

Herein, Ru represents a ruthenium element, i.e., metallic ruthenium, unless otherwise specified.

Herein, Rh represents rhodium element, i.e., metal rhodium, unless otherwise specified.

Herein, Ir represents an iridium element, i.e., metallic iridium, unless otherwise specified.

Herein, Me represents a methyl group unless otherwise specified.

Herein, Et means ethyl unless otherwise specified.

Herein, DCM refers to dichloromethane unless otherwise specified.

Herein, THF means tetrahydrofuran unless otherwise specified.

As used herein, unless otherwise specified, dioxane refers to 1, 4-dioxane, the alias dioxane, 1, 4-dioxane, etc., and has the formula C₄H₈O₂And the molecular weight is 88.11.

Herein, tolumen refers to toluene, unless otherwise specified.

Herein, hexane means hexane unless otherwise specified.

Herein, iPrOH means isopropyl alcohol unless otherwise specified.

Herein, eq means a molar ratio unless otherwise specified.

Herein, r.t. means room temperature unless otherwise specified.

Herein, "room temperature" means 23 ℃. + -. 2 ℃ unless otherwise specified.

Derivatives of 3, 4-disubstituted succinimides include, but are not limited to, the following compounds:

in view of the important application of chiral 3, 4-disubstituted succinimide compounds in organic synthesis, the development of an effective synthetic route of 3, 4-disubstituted succinimide compounds with high stereoselectivity is urgently needed.

In view of the above, in some embodiments, the technical problem to be solved by the present invention is to provide a method for preparing chiral 3, 4-disubstituted succinimide and derivatives thereof, which has a wide substrate adaptability and can obtain both cis-trans isomers of the 3, 4-disubstituted succinimide compound.

According to a first aspect, in one embodiment, the present invention provides a method for preparing a chiral 3, 4-disubstituted succinimide compound, comprising:

reacting a compound shown in a formula (I) in the presence of a metal catalyst to obtain a compound shown in a formula (II);

wherein R is¹Independently represent unsubstituted aryl of C6-C30, substituted aryl of C6-C30, unsubstituted heteroaryl of C4-C20, substituted heteroaryl of C4-C20, alkyl of C1-C10 or cycloalkyl of C3-C10; r²Independently C6-C30 unsubstituted aryl, C6-C30 substituted aryl, C1-C10 alkyl without substituent or C1-C10 alkyl with substituent; or R¹、R²Form a cycloalkyl or a fused ring structure containing cycloalkyl together with the carbon on which they are located, and the carbon atom marked with an asterisk indicates a chiral carbon atom, indicating that the compound has stereoisomers.

Compared with the prior art, in some embodiments, the compound with the structure of formula (II) is obtained by reacting the compound with the structure of formula (I) under the action of a specific metal catalyst, and experiments show that the reaction has the advantages of mild reaction conditions, high yield, excellent diastereoselectivity and enantioselectivity of the product and the like by adopting an asymmetric transfer hydrogenation reaction, and the catalyst dosage in the reaction system is small, and the catalytic efficiency is high.

In one embodiment, the metal catalyst includes, but is not limited to, at least one of a ruthenium catalyst, an iridium catalyst, and a rhodium catalyst.

In one embodiment, the metal catalyst is preferably at least one of (R, R) -cat.1, (S, S) -cat.2, (S, S) -cat.3, (R, R) -cat.4, R) -cat.5, (R, R) -cat.6, and (S, S) -cat.6:

in one embodiment, the metal catalyst is preferably at least one of (R, R) -cat.6 and (S, S) -cat.6.

In one embodiment, the reaction is carried out in a solvent.

In one embodiment, the solvent includes, but is not limited to, at least one of methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, dichloromethane, ethyl acetate, n-hexane, and toluene.

In one embodiment, the solvent is preferably ethyl acetate.

In one embodiment, the ratio of the amount of the compound of formula (I) to the solvent is 1 mmol: (10-20) mL.

In one embodiment, the feedstock for the reaction further comprises a hydrogen donor.

In one embodiment, the hydrogen donor is preferably at least one of formic acid, sodium formate, isopropanol, more preferably formic acid.

In one embodiment, the molar ratio of the compound of formula (I) to the hydrogen donor is preferably 1: (2-5).

In an embodiment, when the hydrogen donor of the reaction is formic acid, an azeotrope of the hydrogen donor is added in the reaction, and the azeotrope of the hydrogen donor is a mixed solution of formic acid and triethylamine, namely the hydrogen donor of the reaction of the invention can be mixed in advance to prepare an azeotrope, thereby avoiding the exothermic reaction of acid and base from affecting the selectivity of the product; in the hydrogen donor azeotrope in the reaction, such as the azeotrope of formic acid and triethylamine, the molar ratio of formic acid to triethylamine is preferably (2-200): (0-2), more preferably (5-200): (1-2), more preferably 5:1, 5:2 or 100: 1.

In one embodiment, when the molar ratio of formic acid to triethylamine is (5-10): (1-2), the trans-isomer in the obtained product is excessive relative to the cis-isomer, i.e., the obtained product is mainly the trans-isomer.

In one embodiment, the molar ratio of formic acid to triethylamine in the azeotrope containing the hydrogen donor is (100-200): (0-1), or adding no triethylamine, and only adding hydrogen donor formic acid, wherein the cis-isomer in the obtained product is excessive relative to the trans-isomer, namely the obtained product is mainly the cis-isomer.

In one embodiment, the azeotrope of the compound of formula (I) and the hydrogen donor or hydrogen-containing donor is used in a ratio of 0.1 mmol: (20-40) μ L, including but not limited to 0.1 mmol: 20 μ L, 0.1 mmol: 30 μ L, 0.1 mmol: 40 μ L, and so forth.

In one embodiment, the reaction is performed at a temperature of preferably 15 to 80 ℃, including but not limited to 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃,75 ℃, 80 ℃ and the like, more preferably 25 ℃.

In one embodiment, the reaction is preferably carried out in an oxygen-free environment.

In one embodiment, the oxygen-free environment is obtained by filling the reaction environment with an inert gas and/or an inert gas.

In an embodiment, the inert gas and/or the inert gas includes, but is not limited to, at least one of nitrogen, helium (He), neon (N e), argon (Ar), krypton (Kr), xenon (Xe).

In one embodiment, the oxygen-free environment may be an argon atmosphere glove box.

In one embodiment, the molar ratio of the compound of formula (I) to the metal catalyst is preferably 1: (0.0005 to 0.05), more preferably 1: (0.01 to 0.05), more preferably 1 (0.01 to 0.02), and may be 1: (0.02-0.05).

In one embodiment, after the reaction is finished, quenching the reaction solution with a quenching solution, wherein the quenching solution is a sodium bicarbonate solution or pure water; after the derivatization reaction is finished, quenching the reaction by adopting a quenching solution, wherein the quenching solution is a saturated salt solution or a NaOH (1M) aqueous solution; the amount of the quenching solution is preferably 5mL to 50mL per gram of the compound represented by the formula (I); or the quenching solution is used in an amount of 10mL to 30mL per gram of the compound represented by the formula (II).

In a preferred embodiment, in the compounds of formula (I), said R is¹Independently selected from phenyl, alkyl substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, naphthyl, anthryl, phenanthryl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, pyridyl, thienyl, furyl, indolyl or alkyl substituted indolyl; the R is²Independently selected from phenyl, alkyl substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, naphthyl, anthryl, benzyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In one embodiment, R is¹、R²Together with the carbon on which they are located form a C5-C8 cycloalkyl group, more preferably cyclopentyl, cyclohexyl or cycloheptyl.

In one embodiment, R is¹、R²And the carbon atoms of the fused ring structure form a fused ring structure containing C5-C8 naphthenic base, wherein the fused ring is selected from: bicyclic alkyl fused rings and cycloalkyl fused benzene rings, wherein the fused rings are formed by fusing cycloalkyl with naphthalene rings, anthracene rings, phenanthrene rings or fluorene rings.

In one embodiment, the compound of formula (I) includes, but is not limited to, at least one of the following compounds:

according to a second aspect, in one embodiment, there is provided a compound produced by the method of the first aspect.

According to a third aspect, in one embodiment, the present invention provides a process for the preparation of a compound of formula (III), comprising:

adding a protecting group to the compound shown in the formula (II) through a substitution reaction, and then obtaining the compound shown in the formula (III) through a reduction reaction;

wherein R is¹Independently selected from unsubstituted aryl of C6-C30, substituted aryl of C6-C30, unsubstituted heteroaryl of C4-C20, substituted heteroaryl of C4-C20, alkyl of C1-C10 or cycloalkyl of C3-C10; r²Independently selected from unsubstituted aryl of C6-C30, substituted aryl of C6-C30, alkyl without substituent of C1-C10 or alkyl with substituent of C1-C10; or R¹、R²Together with the carbon on which they are located to form a benzocycloalkyl group.

In one embodiment, the protecting group includes, but is not limited to, at least one of tert-butyldimethylsilyl (TBDMS), benzoyl, benzyl, methoxymethyl ether, β -methoxyethoxymethyl ether, methoxytrityl (4-methoxyphenyl) diphenylmethyl, dimethoxytrityl (bis- (4-methoxyphenyl) phenylmethyl), p-methoxybenzyl ether, methylthiomethyl ether, pivaloyl, trityl (triphenylmethyl), 2-nitro-4, 5-dimethoxybenzyl, Trimethylsilyl (TMS), Triisopropylsilyloxymethyl (TOM), Triisopropylsilyl (TIPS), TBDPS ether, and the like.

In a preferred embodiment, the protecting group is tert-butyldimethylsilyl (TBDMS).

In one embodiment, the compound of formula (II) is prepared by the preparation method of the first aspect.

In one embodiment, the substitution reaction, reduction reaction, is carried out in the presence of a protecting reagent. Namely, the reaction raw materials are contacted with the protective reagent.

In one embodiment, the protecting reagent is preferably a silicon reagent, more preferably t-butyldimethylsilyl triflate.

In one embodiment, the molar ratio of the compound represented by the formula (II) to the protective agent is 1 (1.5-3), more preferably 1: 2.

In one embodiment, the substitution reaction is performed at a temperature of preferably 0 to 25 ℃, including but not limited to 0 ℃,5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, etc., more preferably 0 ℃.

In one embodiment, the reduction reaction is carried out in the presence of a reducing agent.

In one embodiment, the molar ratio of the compound represented by formula (II) to the reducing agent of the hydrolysis reagent is 1 (3-10), including but not limited to 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc., preferably 1: 5.

In one embodiment, the reducing agent includes, but is not limited to, NaBH₄。

In one embodiment, the system of the reduction reaction further contains a lewis acid. The lewis acid is an acid catalyst that promotes the reduction reaction.

In one embodiment, the lewis acid includes, but is not limited to, aluminum trichloride (AlCl)₃) At least one of boron trifluoride, sulfur trioxide and ferric bromide.

In one embodiment, the reduction reaction is performed at a temperature of preferably 0 to 25 ℃, and more preferably 15 ℃.

In one embodiment, the substitution reaction and the reduction reaction are preferably performed in an oxygen-free environment.

In one embodiment, the oxygen-free environment is obtained by filling the reaction environment with an inert gas and/or an inert gas.

In one embodiment, the inert gas and/or the inert gas includes, but is not limited to, at least one of helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe), and nitrogen.

According to a fourth aspect, in one embodiment, there is provided a compound produced by the method of the third aspect.

In an embodiment, according to the preparation method of the chiral 3, 4-disubstituted succinimide and the derivative thereof provided by the invention, the compound shown in the formula (I) is reacted under the action of a specific metal catalyst to obtain the compound shown in the formula (II), and the asymmetric transfer hydrogenation reaction is adopted in the reaction, so that the preparation method has the advantages of mild reaction conditions, high yield, excellent diastereoselectivity and enantioselectivity of products and the like, and the catalyst consumption in a reaction system is small, and the catalytic efficiency is high. The obtained compound of the formula (II) can be further prepared into a drug intermediate with a structure of a formula (III), and the discovery of the preparation method is significant.

The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

Under an argon atmosphere in a glove box, a metal catalyst cat.6(0.002mmol), a compound represented by formula I (0.1mmol), a formic acid/triethylamine (molar ratio of formic acid to triethylamine is 5:2) azeotrope (20. mu.L), and ethyl acetate (1mL) were added in a 10mL Schlenk bottle, respectively, and the system was stirred at room temperature until disappearance of the raw material (a compound represented by formula I) of the reaction was detected by TLC (thin layer chromatography, the detection method of the subsequent example was the same as that of the present example). After the reaction is finished, H is added into the system₂Quenching reaction, extracting twice with ethyl acetate, drying the obtained organic phase, concentrating, and performing flash column chromatography to obtain a pure product of the compound shown in the formula II. The purity and yield of the product were determined using HNMR (hydrogen nuclear magnetic resonance spectroscopy), and the enantioselectivity and diastereoselectivity of the reaction (crude detection) were determined using HPLC (High Performance Liquid Chromatography, all High Performance Liquid Chromatography in english).

The synthesis method of this example is specifically as follows:

under the argon atmosphere of a glove box, adding different metal catalysts cat.1-cat.6 into four 10mL Schlenk bottles respectively

(0.002mmol), the compound of formula 1a (0.1mmol) and formic acid/triethylamine (5:2 molar ratio of formic acid to triethylamine) azeotrope (20. mu.L) and MeOH (1mL) and the system was stirred at room temperature for 12h and the reaction was checked and the results are shown in Table 1.

Table 1: effect of different catalysts on product stereoselectivity

In Table 1, the conversion rate is the percentage of the reactant 1a converted, and the conversion rate in the examples to be described later is defined similarly. The same symbols in the following embodiments as those in the present embodiment have the same meanings.

As can be seen from Table 1, the catalyst (S, S) -cat.6 has the best selectivity under the same conditions.

Example 2

In a 10mL Schlenk bottle, under an argon atmosphere in a glove box, a metal catalyst cat.6(0.002mmol), a compound represented by formula 1a (0.1mmol), a formic acid/triethylamine (molar ratio of formic acid to triethylamine is 5:2) azeotrope (20. mu.L) and an organic solvent (1mL) were added, stirred at room temperature for 12 hours, and the reaction was examined.

According to the above preparation method, the reaction was carried out by changing only the kind of the organic solvent, and the reaction condition was examined.

The results obtained are shown in Table 2.

Table 2: effect of different organic solvents on product stereoselectivity

As can be seen from Table 2, the effect of the reaction solvent is significant under the action of the catalyst (S, S) -cat.6, and ethyl acetate (EtOA c) is the most preferable reaction solvent.

Characterization of compound 2 a:

97％yield,99％ee,98:2dr；[α]²⁰ _D＝-88.8(c 0.5,CHCl₃)；HPLC(Chiralpak IE colu mn,hexane/isopropanol＝80/20；flow rate＝1.0mL/min；UV detection at 210nm；t₁＝8. 9min,t₂＝9.9min,t₃＝10.6min,t₄＝13.4min(major).¹H NMR(400MHz,Chlorofor m-d)δ7.46–7.25(m,8H),7.23–7.12(m,2H),4.69(q,J＝14.1Hz,2H),4.61–4.52 (m,1H),3.98(s,1H),3.91(d,J＝6.0Hz,1H).¹³C NMR(101MHz,Chloroform-d)δ1 76.6,174.1,135.2,134.6,129.0,128.7,128.2,128.1,128.0,74.7,54.7,42.7.HRMS(ESI- TOF)m/z:[M-H]^-Calcd for C₁₇H₁₄NO₃ ^-＝280.0979；Found 280.0978.

example 3

In a glove box argon atmosphere, a 10mL Schlenk bottle was charged with a metal catalyst cat.6(0.002mmol), a compound represented by formula 1a (0.1mmol), formic acid/triethylamine azeotrope and an organic solvent (1mL), stirred at room temperature for 12h, and the reaction was examined.

According to the preparation method, under the condition that the adding amount is not changed, the azeotrope (20 mu L) of formic acid/triethylamine (the molar ratio of formic acid to triethylamine is 5:2) is changed into formic acid/triethylamine (the molar ratio of formic acid to triethylamine is 5:1, 10:1, 100:1, 200: 1, 2:0 respectively), sodium formate or isopropanol, or an organic solvent is changed, reaction is carried out, and the obtained results are shown in a table 3.

Table 3: effect of different Hydrogen donors on product stereoselectivity

As can be seen from table 3, the amount of base (triethylamine) in the reaction was reduced as compared to table 2, and even with a catalytic amount of base or no base, the configuration of the product was inverted and the main product was 3 a.

Characterization of compound 3 a:

95％yield,96％ee,99:1 dr；[α]²⁰ _D＝-73.0(c 0.5,CHCl₃)；HPLC(Chiralpak IE colu mn,hexane/isopropanol＝80/20；flow rate＝1.0 mL/min；UV detection at 210 nm；t₁＝8. 9min,t₂＝9.9min(major),t₃＝10.6min,t₄＝13.4min.¹H NMR(400MHz,Chlorofor m-d)δ7.41–7.29(m,2H),7.29–7.21(m,3H),7.21–7.13(m,3H),6.99–6.82(m,2 H),4.66(s,2H),4.65–4.60(m,1H),4.11(d,J＝8.3Hz,1H),2.82(d,J＝5.0Hz,1 H).¹³C NMR(151MHz,Chloroform-d)δ177.1,175.0,135.2,131.4,129.2,128.9,128.8, 128.7,128.3,128.2,69.0,52.1,42.7.HRMS(ESI-TOF)m/z:[M-H]^-Calcd for C₁₇H₁₄NO₃ ^-＝280.0979；Found 280.0978.

example 4

Adding a metal catalyst cat.6(0.002mmol), a compound 1b (0.1mmol), formic acid/triethylamine (the molar ratio of formic acid to triethylamine is 5:2, and the total volume of formic acid and triethylamine is 20 mu L) and ethyl acetate (1mL) into a 10mL Schlenk bottle under an argon atmosphere in a glove box, stirring and reacting for 12h at room temperature, and detecting the reaction condition; after the reaction is finished, H is added into the system₂Quenching reaction, extracting twice with ethyl acetate, drying the obtained organic phase, concentrating, and performing flash column chromatography to obtain pure compound 2 b. The purity and yield of the product were determined using HNMR and the enantioselectivity and diastereoselectivity of the reaction were checked using HPLC (crude product detection).

Characterization of compound 2 b:

98％yield,>99％ee,99:1dr；[α]²⁰ _D＝-45.6(c 0.25,CHCl₃/MeOH(1v/1v))；HPLC (Chiralpak IE column,hexane/isopropanol＝80/20；flow rate＝1.0mL/min；UV detection at 210nm；t₁＝13.1min,t₂＝14.9min,t₃＝17.4min,t₄＝21.7min(major).¹H NMR (600MHz,DMSO-d₆)δ7.40–7.29(m,5H),7.24(d,J＝8.1Hz,2H),6.91(d,J＝8. 2Hz,2H),6.39(s,1H),4.70(d,J＝5.7Hz,1H),4.62–4.50(m,2H),4.01(d,J＝6. 4Hz,1H),3.74(s,3H).¹³C NMR(151MHz,DMSO-d₆)δ176.5,174.4,158.7,135.9,1 29.1,128.8,128.5,128.1,127.5,113.9,74.1,55.2,55.1,41.1.HRMS(ESI-TOF)m/z:[M- H]^-Calcd for C₁₈H₁₆NO₄ ^-＝310.1085；Found 310.1085.

example 5

Adding a metal catalyst cat.6(0.002mmol), a compound 1b (0.1mmol), formic acid (2eq, namely the molar ratio of formic acid to the compound 1b is 2: 1), triethylamine (0.02eq, namely the molar ratio of triethylamine to the compound 1b is 0.02: 1) and ethyl acetate (1mL) into a 10mL Schlenk bottle under an argon atmosphere of a glove box, stirring for reacting for 12 hours at room temperature, and detecting the reaction condition; after the reaction is finished, H is added into the system₂Quenching reaction, extracting twice with ethyl acetate, drying the obtained organic phase, concentrating, and performing flash column chromatography to obtain pure compound 3 b. The purity and yield of the product was determined using HN MR and the enantioselectivity and diastereoselectivity of the reaction were checked using HPLC (crude product detection).

Characterization of compound 3 b:

93％yield,95％ee,93:7dr；[α]²⁰ _D＝-54.4(c 0.5,CHCl₃)；HPLC(Chiralpak IE colu mn,hexane/isopropanol＝80/20；flow rate＝1.0mL/min；UV detection at 210nm；t₁＝1 3.1min,t₂＝14.7min(major),t₃＝17.3min,t₄＝21.6min.¹H NMR(400MHz,Chlor oform-d)δ7.43–7.27(m,5H),7.04–6.95(m,2H),6.85(d,J＝8.6Hz,2H),4.80– 4.73(m,1H),4.70(d,J＝1.9Hz,2H),4.21(d,J＝8.3Hz,1H),3.79(s,3H),2.51– 2.39(m,1H).¹³C NMR(101MHz,Chloroform-d)δ176.9,174.9,159.5,131.4,130.5,12 9.2,129.0,128.4,127.6,114.1,69.2,55.3,52.2,42.2.HRMS(ESI-TOF)m/z:[M-H]^-Cal cd for C₁₈H₁₆NO₄ ^-＝310.1085；Found 310.1086.

example 6

Adding a metal catalyst cat.6(0.002mmol), a compound 1u (0.1mmol), formic acid/triethylamine (5:2, the total volume of formic acid and triethylamine is 20 mu L) and ethyl acetate (1m L) into a 10mL Schlenk bottle under an argon atmosphere in a glove box, stirring and reacting for 12h at room temperature, and detecting the reaction condition; after the reaction is finished, H is added into the system₂Quenching reaction, extracting twice with ethyl acetate, drying the obtained organic phase, concentrating, and performing flash column chromatography to obtain pure compound 3 u. The purity and yield of the product were determined using HNMR and the enantioselectivity and diastereoselectivity of the reaction were measured using HPLC (crude product detection).

Characterization of compound 3 u:

97％yield,97％ee,>20:1dr；{[α]20D＝-57.0(c 0.5,CHCl3)；HPLC(Chiralpak IC column,hexane/isopropanol＝85/15；flow rate＝1.0mL/min；UV detection at 210nm；t1 ＝11.5min(major),t2＝12.5min.1H NMR(400MHz,Chloroform-d)δ7.25–7.17 (m,2H),6.79–6.71(m,2H),4.50(s,2H),4.48(s,1H),3.70(s,3H),3.65(s,1H),2.92 (p,J＝7.7Hz,1H),1.17(d,J＝7.6Hz,3H).13C NMR(101MHz,Chloroform-d)δ1 78.4,178.2,159.3,130.1,127.6,114.0,68.5,55.2,41.7,40.1,10.2.HRMS(ESI-TOF)m/z: [M-H]-Calcd for C13H14NO4-＝248.0928；Found 248.0926.

example 7

Adding a metal catalyst cat.6(0.002mmol), a compound 1w (0.1mmol), formic acid (2eq.), triethylamine (0.02eq.) and ethyl acetate (1mL) into a 10mL Schlenk bottle under an argon atmosphere in a glove box, stirring at room temperature for 12 hours, and detecting the reaction condition; after the reaction is finished, H is added into the system₂Quenching reaction, extracting twice with ethyl acetate, drying the obtained organic phase, concentrating, and performing flash column chromatography to obtain a compound 3 w. The purity and yield of the product were determined using HNMR and the enantioselectivity and diastereoselectivity of the reaction were measured using HPLC (crude product detection).

Characterization of compound 3 w:

95％yield,99％ee,>20:1dr；[α]²⁰ _D＝-37.3(c 1.5,CHCl₃)；HPLC(Chiralpak IC co lumn,hexane/isopropanol＝85/15；flow rate＝0.8mL/min；UV detection at 210nm；t₁＝ 8.3min(major),t₂＝8.8min.¹H NMR(600MHz,Chloroform-d)δ7.32–7.25(m,5 H),7.23–7.21(m,4H),7.20–7.15(m,1H),4.59–4.50(m,2H),4.50–4.47(m,1 H),3.62(d,J＝3.1Hz,1H),3.22–3.16(m,1H),3.14–3.06(m,2H).¹³C NMR(151 MHz,Chloroform-d)δ177.6,176.6,138.0,135.2,129.1,128.7,128.6,128.4,128.0,126. 6,68.1,46.9,42.2,30.4.HRMS(ESI-TOF)m/z:[M-H]^-Calcd for C₁₈H₁₆NO₃ ^-＝294.113 6；Found 294.1136.

example 8

Adding a metal catalyst cat.6(0.005mmol), a compound 1y (0.1mmol) and formic acid/triethylamine (the molar ratio of formic acid to triethylamine is 5:2, and the total volume of formic acid and triethylamine is 40 mu L) and ethyl acetate (1mL) into a 10mL Schlenk bottle under an argon atmosphere in a glove box, stirring and reacting for 24h at room temperature, and detecting the reaction condition; after the reaction is finished, H is added into the system₂Quenching reaction, extracting twice with ethyl acetate, drying the obtained organic phase, concentrating, and performing flash column chromatography to obtain pure productCompound 4 y. The purity and yield of the product were determined using HNMR and the enantioselectivity and diastereoselectivity of the reaction were measured using HPLC (crude product detection).

Characterization of compound 4 y:

91％yield,>99％ee；[α]²⁰ _D＝-73.6(c 0.5,MeOH)；HPLC(Chiralpak IAcolumn,he xane/isopropanol＝85/15；flow rate＝1.0mL/min；UV detection at 210nm；t₁＝8.9min, t₂＝10.1min(major).¹H NMR(600MHz,Methanol-d₄)δ7.32–7.28(m,2H),7.27– 7.23(m,2H),7.18–7.12(m,1H),5.10(d,J＝4.1Hz,1H),4.09(dd,J＝5.6,4.1Hz, 1H),3.04–2.93(m,2H),2.73–2.66(m,1H).¹³C NMR(151MHz,Methanol-d₄)δ1 78.6,141.8,129.9,129.3,127.0,80.6,70.3,50.2,30.8.HRMS(ESI-TOF)m/z:[M-H]^-Ca lcd for C₁₁H₁₂NO₃ ^-＝206.0823；Found 206.0817.

example 9

Step 1: under an argon atmosphere, compound 3w (0.6g, 2mmol) and 1H-imidazole (6mmol) were added to a 50mL schlenk bottle, followed by the addition of a solution of acetonitrile (20 mL). Placing the bottle at 0 ℃, stirring for 5 minutes, slowly dripping tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf, 3mmol) into the system, naturally heating to room temperature, and adding H into the system after detecting that the raw materials are completely consumed₂O (5mL), then extracted twice with ethyl acetate. The obtained organic phase is combined, dried and concentrated, and a pure product can be obtained by simple silica gel filtration (>99% yield).

Step 2: the product obtained in step 1 (0.8g,1eq.) was dissolved in THF, cooled to 0 ℃ and Al Cl was added₃(5.0eq.) NaBH is added₄(5.0eq.) was added to the system in portions, the temperature was slowly raised to 10 ℃ and the system was stirred until the consumption of the starting material was complete, and after completion of the reaction saturated NaHCO was added₃The solution (10mL) was extracted with ethyl acetate (5 mL. times.3)) The organic phases were combined, dried and concentrated to give a crude product, which was purified by column chromatography (8% EtOAc in petroleum ether) to give pure product 6w (1.24g, 75% yield, 97% ee) as a colorless liquid.

The structure identification result is as follows:¹H NMR(400MHz,Chloroform-d)δ7.41–7.35(m,2H),7.3 5–7.29(m,3H),7.25–7.19(m,2H),7.17–7.06(m,3H),4.39(q,J＝4.7Hz,1H),4. 07–3.95(m,2H),3.37–3.28(m,1H),3.08–2.85(m,4H),2.82–2.74(m,1H),2.55 –2.42(m,1H),0.86(s,9H),-0.00(s,3H),-0.06(s,3H).¹³C NMR(101MHz,Chlorof orm-d)δ139.7,132.8,132.1,128.8,128.5,128.4,128.0,126.2,72.6,68.3,68.0,63.9,43.2, 33.4,25.8,18.0,-4.5,-5.3.[α]²⁵ _D＝+26.8(c 0.25,CHCl₃)；HPLC(Chiralpak IC column, hexane/isopropanol＝85/15；flow rate＝1.0mL/min；UV detection at 210nm；t₁＝5.5min(maj or),t₂＝6.1min.

in one embodiment, the invention provides a preparation method of chiral 3, 4-disubstituted succinimide and derivatives thereof, which comprises the steps of reacting a compound with a structure shown in formula (I) under the action of a specific metal catalyst to obtain a compound with a structure shown in formula (II), and as a result, controlling the dosage of a base in the reaction to respectively obtain cis-trans isomers of the compound with the structure shown in formula (II). The reaction adopts asymmetric transfer hydrogenation reaction, and has the advantages of mild reaction conditions, high yield, excellent diastereoselectivity and enantioselectivity of the product and the like, and the catalyst in the reaction system is less in dosage and high in catalysis efficiency.

The present invention has been described in terms of specific examples, which are provided to aid understanding of the invention and are not intended to be limiting. For a person skilled in the art to which the invention pertains, several simple deductions, modifications or substitutions may be made according to the idea of the invention.