阅读说明：本技术 一种制备4位手性取代的γ-丁内酯的方法 (Method for preparing 4-bit chiral substituted gamma-butyrolactone ) 是由 吴璇 向威 胡振宇 于 2019-09-04 设计创作，主要内容包括：本发明公开了一种制备4位手性取代的γ-丁内酯的方法,包括以下步骤：(a)以取代琥珀酸酐为原料经手性还原得到化合物2；(b)化合物2经羟基转为氨基的反应制备成相应的化合物3；(c)化合物3通过一些手性拆分酸进行手性拆分得到化合物4；(d)化合物4经脱氨基反应得到最终产物化合物5。取代基R选自C1-C8直链或支链烷基、3-8元脂环族基团、芳基、杂芳基、Ar(CH<Sub>2</Sub>)<Sub>n</Sub>-基团,其中,Ar代表芳基、杂芳基,n=1-6。本发明提供了一种新的合成路线,原料易得,一般取代琥珀酸酐均有大量生产；操作步骤均为常规的化学反应,简易,可操作性强；最终产品的手性选择性好,产品ee值在85~99.5%之间,纯度高。(the invention discloses a method for preparing 4-bit chiral substituted gamma-butyrolactone, which comprises the following steps: (a) substituted succinic anhydride is taken as a raw material, and a compound 2 is obtained through manual reduction; (b) the compound 2 is converted into a corresponding compound 3 through a reaction of converting hydroxyl into amino; (c) carrying out chiral resolution on the compound 3 by using some chiral resolving acids to obtain a compound 4; (d) the compound 4 is subjected to deamination reaction to obtain a final product compound 5. The substituent R is selected from C1-C8 straight chain or branched chain alkyl, 3-8 membered alicyclic group, aryl, heteroaryl, Ar (CH) 2 ) n the invention provides a new synthetic route, raw materials are easy to obtain, general substituted succinic anhydride is produced in large quantity, operation steps are conventional chemical reactions, simplicity and easiness are realized, operability is strong, the chiral selectivity of a final product is good, the ee value of the product is 85 ~ 99.5%, and the purity is high.)

1. A method for preparing 4-position chirality substituted gamma-butyrolactone is characterized in that the reaction route is as follows:

wherein, the configuration shown by the star position is R type and S type;

The method specifically comprises the following steps:

(a) Adding a chiral CBS catalyst and borane dimethyl sulfide into an organic solvent, and dropwise adding substituted succinic anhydride (compound 1) for reaction to obtain a compound 2;

(b) In an organic solvent, the compound 2 is converted into a corresponding compound 3 through a reaction of converting hydroxyl into amino;

(c) in an organic solvent, salifying the compound 3 and a corresponding chiral resolving acid, separating out, filtering, and adding alkali to the solid for dissociation to obtain a compound 4;

(d) In an organic solvent, the compound 4 is subjected to deamination reaction to obtain a final product compound 5.

2. A process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: the substituent R is C1-C8 straight-chain or branched alkyl, 3-8-membered alicyclic group, aryl, heteroaryl, Ar (CH)₂)_n-group, wherein Ar represents aryl, heteroaryl and n-1-6.

3. A process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: the chiral CBS catalyst in step (a) is selected from (R) -2-methyl-CBS-oxazaborolidine, (S) -2-methyl-CBS-oxazaborolidine, (R) -2-phenyl-CBS-oxazaborolidine, (S) -2-phenyl-CBS-oxazaborolidine, (R) -2- (O-methyl) benzene-CBS-oxazaborolidine, (S) -2- (O-methyl) benzene-CBS-oxazaborolidine.

4. A process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: the temperature of the process of dropwise adding the substituted succinic anhydride (compound 1) in the step (a) is-80 ℃ to 40 ℃.

5. A process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: the chiral resolving acid in the step (c) is selected from tartaric acid, malic acid, camphoric acid, camphorsulfonic acid and mandelic acid.

6. A process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: in the step (c), the solvent is selected from tetrahydrofuran, acetonitrile, 1, 4-dioxane, dichloromethane, methyl tertiary butyl ether, diethyl ether, methanol and ethanol.

7. A process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: the equivalent ratio of the CBS catalyst to the substituted succinic anhydride in step (a) is between 0.1:1 and 1: 1.

8. a process for the preparation of 4-chirally substituted γ -butyrolactone according to claim 1, characterized in that: the equivalent ratio of borane dimethyl sulfide and substituted succinic acid in step (a) is between 1:1 and 2: 1.

Technical Field

the invention relates to a method for chemically synthesizing a chiral drug intermediate, in particular to a method for preparing 4-bit chiral substituted gamma-butyrolactone.

Background

chirally substituted gamma-butyrolactones, as a very important class of building blocks, are found in a wide variety of molecules with important biological activities. For example, lignin enterolactone 6, which inhibits breast and colon cancer, arctiin 7 and arctiin 8, which have the potential to inhibit class I hiv integrase, parthenolide 9, which has potential activity against pancreatic cancer, leukemia, melanoma, and parabaconic acid 10 and 11, which has antifungal and bacterial activity.

In addition, as important pharmaceutical intermediates, chirally substituted γ -butyrolactones, especially 4-chirally substituted γ -butyrolactones, are also widely used in pharmaceutical synthesis. For example, the synthesis of a new generation of the antiepileptic drug, namely, the busulfan 12, and the synthesis of the drug, namely, the pregabalin 13, which is used for treating peripheral neuralgia and assisting in treating the seizures of the focal partial epilepsy.

Since the chiral substituted gamma-butyrolactone is not only an important active group, but also has wide application in drug synthesis, the research on the synthesis method of the chiral substituted gamma-butyrolactone has important significance.

The patent focuses on the synthesis method of the 4-chiral substituted gamma-butyrolactone, and the comprehensive reference of the literature shows that the synthesis method of the 4-chiral substituted gamma-butyrolactone mainly has the following routes:

Asymmetric Baeyer-Villiger oxidation, reported by Ding group 2008, asymmetric BV oxidation of cyclobutanone catalyzed by chiral phosphoric acid, followed by other groups that found more catalysts available for this reaction. The method has the advantages of simple process, simple raw material structure, yield of 90-99% and ee value of 55-93%, and has the defect that catalysts are too expensive and are not beneficial to industrialization.

asymmetric hydrogenation, Starodubtseva group developed an asymmetric hydrogenation based on RuCl3- (R) -BINAP-HCl catalyzed γ -keto ester, allowing one-step synthesis of a variety of γ -substituted-butyrolactones. Subsequent other groups designed other high affinity catalysts and prepared gamma-butyrolactone with multiple chiral centers.

Asymmetric metal carbene conversion reactions, Doyle et al first reported that in situ generated metal carbenes promoted the conversion of diazoesters to butyrolactone. Over the years, the catalytic conversion of asymmetric metal carbenes has become a key step in the synthesis of various biologically active cyclic and bicyclic lactones.

Asymmetric cyclocarbonylation, Alper et al 1997 reported that the first enantioselective palladium catalyzed cyclocarbonylation of allyl alcohol to gamma-butyrolactone. Subsequent further development, other groups designed more stable catalysts, simpler operating modes.

There are also some preparations of the 4-position chirally substituted gamma-butyrolactone from more complex (or less readily available) starting materials, although the target product is obtained, which is clearly of little practical interest, the simple route is as follows:

In order to overcome the problems of the known route, the inventor designs a new 4-position chirality substituted gamma-butyrolactone synthesis process route and verifies the feasibility of the gamma-butyrolactone synthesis process through experiments. The new process route has the advantages of easily obtained starting materials, simple operation, good chiral selectivity and the like, and has wide industrial application prospect.

disclosure of Invention

The invention aims to overcome various problems in the existing 4-chiral substituted gamma-butyrolactone synthesis process, and provides a novel preparation method, which has the advantages of easily available raw materials, controllable process and industrial production conditions.

The technical scheme of the invention is as follows:

A method for preparing 4-position chirally substituted gamma-butyrolactone, comprising the steps of:

(a) adding a chiral CBS catalyst and borane dimethyl sulfide into an organic solvent, and dropwise adding substituted succinic anhydride (compound 1) under an acidic condition to react to obtain a compound 2;

(b) In an organic solvent, halogenating and ammoniating the compound 2 to prepare a corresponding compound 3;

(c) In an organic solvent, salifying the compound 3 and a corresponding chiral resolving acid, separating out, filtering, and adding alkali to the solid for dissociation to obtain a compound 4;

(d) In an organic solvent, the compound 4 and a reducing agent undergo a reduction reaction to obtain a final product compound 5.

The reaction route is as follows:

wherein, the configuration shown by the star position is R type and S type;

The substituent R is selected from C1-C8 straight-chain or branched-chain alkyl, 3-8-membered alicyclic group, aryl, heteroaryl and Ar (CH2) n-group, wherein Ar represents aryl and heteroaryl, and n is 1-6.

In the synthetic route of 4-position chirally substituted gamma-butyrolactone described in the present invention, the chiral CBS catalyst in step (a) is selected from (R) -2-methyl-CBS-oxazaborolidine, (S) -2-methyl-CBS-oxazaborolidine, (R) -2-phenyl-CBS-oxazaborolidine, (S) -2-phenyl-CBS-oxazaborolidine, (R) -2- (O-methyl) benzene-CBS-oxazaborolidine, (S) -2- (O-methyl) benzene-CBS-oxazaborolidine.

In the synthetic route of the 4-chiral substituted gamma-butyrolactone, the temperature of the process of dropwise adding the substituted succinic anhydride (compound 1) in the step (a) is-80 ℃ to 40 ℃.

The equivalent ratio of the CBS catalyst to the substituted succinic anhydride is between 0.1:1 and 1: 1.

The equivalent ratio of the borane dimethyl sulfide and the substituted succinic acid is between 1:1 and 2: 1.

In the step b, the amination reaction after the halogenation of the compound 2 is a reaction for converting a hydroxyl group into an amino group, and a method commonly used in the art is adopted.

in the synthetic route of 4-position chirally substituted gamma-butyrolactone, the chiral resolving acid in step (c) is selected from tartaric acid, malic acid, camphoric acid, camphorsulfonic acid and mandelic acid.

Deamination of compound 4 in step d is carried out by methods commonly used in the art.

In the synthetic route of the 4-chiral substituted gamma-butyrolactone, the solvent in the step (c) is selected from tetrahydrofuran, acetonitrile, 1, 4-dioxane, dichloromethane, methyl tertiary butyl ether, diethyl ether, methanol and ethanol.

Has the advantages that:

the invention provides a new synthetic route, the raw materials are easy to obtain, and the general substituted succinic anhydride is produced in large quantity; the operation steps are conventional chemical reactions, and the method is simple and easy and has strong operability; the final product has good chiral selectivity, the ee value of the product is between 85 and 99.5 percent, and the purity is high.

Detailed Description

In order that the invention may be better understood, the following detailed description will proceed with reference being made to specific examples, it being understood that the following examples are not intended to limit the scope of the invention, but that various changes and modifications within the scope of the invention will become apparent to those skilled in the art from this description, and such changes and modifications are intended to be included within the scope of the invention.