阅读说明：本技术 （s）-3-羟基-1-苄基吡咯烷的合成方法 (Synthesis method of (S) -3-hydroxy-1-benzylpyrrolidine ) 是由 高元 崔槐杰 宗杨磊 于 2019-11-18 设计创作，主要内容包括：本发明公开了一种(S)-3-羟基-1-苄基吡咯烷的合成方法,包括以下加工步骤：S1、将苄胺溶于溶剂中,并加入(S)-3羟基-4氯丁酸乙酯,升温至20~65℃回流,将溶剂拉干得到4-苄基氨基-(S)3-羟基丁酸乙酯；S2、将(S)4-苄基氨基-3-羟基丁酸乙酯加入到溶剂中完全溶解,滴加碱反应,滴加完毕后,在温度10~65℃的条件下回流10~12h；S3、回流结束后,将反应液滴加到水中,冷却到室温过滤得到(S)-1-苄基-4-羟基-2吡咯烷酮；S4、将(S)-1-苄基-4-羟基-2吡咯烷酮加入到四氢呋喃中,并加还原剂,在温度0~65℃的条件下回流12~20h；S5、回流结束后,将反应液滴加到水中,搅拌后抽滤得到(S)-3-羟基-1-苄基吡咯烷。本发明所用原料易得,环境污染极小,操作安全性高。(The invention discloses a synthesis method of (S) -3-hydroxy-1-benzyl pyrrolidine, which comprises the following processing steps of S1, dissolving benzylamine in a solvent, adding ethyl (S) -3-hydroxy-4-chlorobutyrate, heating to 20 ~ 65 ℃ for refluxing, drying the solvent to obtain ethyl 4-benzylamino- (S) 3-hydroxybutyrate, S2, adding ethyl (S) 4-benzylamino-3-hydroxybutyrate into the solvent for complete dissolution, dropwise adding alkali for reaction, refluxing for 10 ~ 12h at 10 ~ 65 ℃ after dropwise adding is finished, S3, adding reaction liquid drops into water after refluxing is finished, cooling to room temperature, filtering to obtain (S) -1-benzyl-4-hydroxy-2 pyrrolidone, S4, adding (S) -1-benzyl-4-hydroxy-2 pyrrolidone into tetrahydrofuran, adding a reducing agent, refluxing for 12 ~ 20h at 0 ~ 65 ℃, stirring after S5 and refluxing are finished, adding the reaction liquid drops into water, performing suction filtration, and obtaining the high safety of the (S) -3-hydroxy-1-benzyl pyrrolidine after the reflux is finished, and the pollution of the environment is very low.)

1. A method for synthesizing (S) -3-hydroxy-1-benzyl pyrrolidine is characterized in that: the method comprises the following processing steps:

s1, dissolving benzylamine in a solvent, adding (S) -3-hydroxy-4-chlorobutyric acid ethyl ester, heating to 20 ~ 65 ℃, refluxing, and drying the solvent to obtain 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester;

s2, adding (S) 4-benzylamino-3-hydroxy ethyl butyrate into a solvent to be completely dissolved, dropwise adding alkali to react, and refluxing for 10 ~ 12h at the temperature of 10 ~ 65 ℃ after dropwise adding is finished;

s3, after the reflux is finished, dropwise adding the reaction liquid into water, cooling to room temperature, and filtering to obtain (S) -1-benzyl-4-hydroxy-2-pyrrolidone;

s4, adding (S) -1-benzyl-4-hydroxy-2-pyrrolidone into tetrahydrofuran, adding a reducing agent, and refluxing for 12 ~ 20h at the temperature of 0 ~ 65 ℃;

s5, after the reflux is finished, dropwise adding the reaction liquid into water, stirring and carrying out suction filtration to obtain the (S) -3-hydroxy-1-benzyl pyrrolidine.

2. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: the molar ratio of benzylamine, (S) -3-hydroxy-4-chlorobutyric acid ethyl ester in the step S1 is 1: 0.1 to 2.

3. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: in the step S1, the solvent is one or more of methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and the amount of the solvent is 4-5 times of the mass of benzylamine.

4. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: in the step S1, the solubility of the methanol solution of the ethyl (S) -3-hydroxy-4-chlorobutyrate is 15-20%, and the dosage of the methanol solution is 70-75% of the mass of benzylamine.

5. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: in the step S2, the alkali is one or more of sodium hydroxide, sodium methoxide, potassium carbonate, sodium bicarbonate, sodium carbonate and sodium ethoxide, and the amount of the alkali is 65-70% of the mass of the 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester.

6. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: the solvent in the step S2 is one or more of dichloromethane, chloroform, tetrachloromethane, tetrahydrofuran, acetone, butanone, toluene, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and water.

7. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: the adding molar ratio of the 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester to the base in the step S2 is 1: 1 to 20.

8. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: in the step S4, the molar ratio of the (S) -1-benzyl-4-hydroxy-2-pyrrolidone to the reducing agent is 1: 1 to 20.

9. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: and in the step S4, the reducing agent is one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, boron trifluoride diethyl etherate and cyano sodium borohydride.

10. The method for synthesizing (S) -3-hydroxy-1-benzylpyrrolidine according to claim 1, wherein: the dosage of the reducing agent in the step S4 is 40-50% of the mass of the (S) -1-benzyl-4-hydroxy-2-pyrrolidone.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of (S) -3-hydroxy-1-benzyl pyrrolidine.

Background

(S) -3-hydroxy-1-benzylpyrrolidine, of formula:

(S) -1-benzyl-3-hydroxypyrrolidine is a key intermediate for synthesizing medicaments for treating overactive bladder, such as darifenacin, antihypertensive medicaments, barnidipine and the like.

Disclosure of Invention

The invention aims to provide a synthesis method of (S) -3-hydroxy-1-benzylpyrrolidine, which greatly improves the environmental friendliness, reduces the production cost, avoids the risk of using peroxide in the production and is suitable for industrial production.

In order to achieve the purpose, the invention adopts the technical scheme that: a synthetic method of (S) -3-hydroxy-1-benzylpyrrolidine comprises the following processing steps:

s1, dissolving benzylamine in a solvent, adding (S) -3-hydroxy-4-chlorobutyric acid ethyl ester, heating to 20 ~ 65 ℃, refluxing, and drying the solvent to obtain 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester;

s2, adding (S) 4-benzylamino-3-hydroxy ethyl butyrate into a solvent to be completely dissolved, dropwise adding alkali to react, and refluxing for 10 ~ 12h at the temperature of 10 ~ 65 ℃ after dropwise adding is finished;

s3, after the reflux is finished, dropwise adding the reaction liquid into water, cooling to room temperature, and filtering to obtain (S) -1-benzyl-4-hydroxy-2-pyrrolidone;

s4, adding (S) -1-benzyl-4-hydroxy-2-pyrrolidone into tetrahydrofuran, adding a reducing agent, and refluxing for 12 ~ 20h at the temperature of 0 ~ 65 ℃;

s5, after the reflux is finished, dropwise adding the reaction liquid into water, stirring and carrying out suction filtration to obtain the (S) -3-hydroxy-1-benzyl pyrrolidine.

The technical scheme of further improvement in the technical scheme is as follows:

1. in the above scheme, the molar ratio of benzylamine, (S) -3 hydroxy-4 chlorobutyric acid ethyl ester in the step S1 is 1: 0.1 to 2.

2. In the scheme, the solvent in the step S1 is one or more of methanol, ethanol, propanol, isopropanol, butanol and tert-butanol, and the amount of the solvent is 4-5 times of the mass of benzylamine.

3. In the above scheme, the solubility of the methanol solution of (S) -3-hydroxy-4-chlorobutyric acid ethyl ester in the step S1 is 15% to 20%, and the amount of the methanol solution is 70% to 75% of the mass of benzylamine.

4. In the above scheme, the reaction temperature in the step S1 is preferably 30 ℃.

5. In the scheme, the alkali in the step S2 is one or more of sodium hydroxide, sodium methoxide, potassium carbonate, sodium bicarbonate, sodium carbonate and sodium ethoxide, and the amount of the alkali is 65-70% of the mass of the 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester.

6. In the above scheme, the solvent in step S2 is one or more of dichloromethane, chloroform, tetrachloromethane, tetrahydrofuran, acetone, butanone, toluene, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and water, preferably methanol, and the amount of the solvent is 4 to 5 times of the mass of 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester.

7. In the above scheme, the molar ratio of the 4-benzylamino- (S) 3-hydroxybutyric acid ethyl ester and the base added in step S2 is 1: 1 to 20.

8. In the above scheme, the reaction temperature in the step S2 is 20 ℃.

9. In the above scheme, the molar ratio of (S) -1-benzyl-4-hydroxy-2-pyrrolidone and the reducing agent in step S4 is 1: 1 to 20.

10. In the above scheme, the reducing agent in step S4 is one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, boron trifluoride diethyl etherate, and sodium cyanoborohydride.

11. In the above scheme, the reaction temperature in the step S4 is 0 ~ 10 ℃.

12. In the scheme, the amount of the reducing agent used in the step S4 is 40-50% of the mass of the (S) -1-benzyl-4-hydroxy-2-pyrrolidone.

The chemical reaction formula of the synthetic method is as follows:

due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

1. the synthesis method has the advantages of easily available raw materials, mild conditions, strong process operation and controllability, low cost, high yield, no generation of a large amount of three wastes, and capability of achieving high purity of the (S) -3-hydroxy-1-benzylpyrrolidine without complex post-treatment.

2. The step S1 is a substitution reaction, methanol is used as a reaction medium in the reaction, the cost is reduced, and the post-treatment is simple; the reactions of the steps S2 and S3 are ring-closing reactions, methanol is used as a solvent, and the post-treatment is simple; the reactions of the steps S4 and S5 are reduction reactions with classical reduction reaction types, high reaction purity and high yield.

Drawings

FIG. 1 is a liquid chromatogram of (S) -3-hydroxy-1-benzylpyrrolidine prepared by the synthetic method of example 1 of the present invention.

Detailed Description

In the description of this patent, it is noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the present invention; the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance; furthermore, unless expressly stated or limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, as they may be fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The meaning of the above terms in this patent may be specifically understood by those of ordinary skill in the art.

The invention is further described below with reference to the following examples: