阅读说明：本技术 一种7-氨基庚酸盐酸盐的合成方法 (Synthesis method of 7-aminoheptanoic acid hydrochloride ) 是由 王灏 张智慧 王达彤 郭鹏 冯维春 于 2019-11-18 设计创作，主要内容包括：本发明公开一种7-氨基庚酸盐酸盐的合成方法,属于有机合成领域：将环庚酮加入到甲醇溶液中,加入盐酸羟胺,升温反应得到庚内酰胺,将得到的反应液中加入浓盐酸,回流反应,将反应液减压脱除溶剂后用二氯甲烷降温析晶,得到7-氨基庚酸盐酸盐。本发明具本发明操作简便,生产中绿色环保,所得的产品收率较高,更适于规模化生产。(The invention discloses a synthesis method of 7-aminoheptanoic acid hydrochloride, belonging to the field of organic synthesis: adding cycloheptanone into methanol solution, adding hydroxylamine hydrochloride, heating to react to obtain enantholactam, adding concentrated hydrochloric acid into the obtained reaction liquid, refluxing to react, decompressing the reaction liquid, removing the solvent, cooling with dichloromethane, and crystallizing to obtain 7-aminoheptanoic acid hydrochloride. The method has the advantages of simple and convenient operation, green and environment-friendly production, higher product yield and suitability for large-scale production.)

1. A method for synthesizing 7-amino heptanoic acid hydrochloride is characterized by comprising the following steps:

(a) adding cycloheptanone into organic solvent, stirring to dissolve, and cooling to 0-10 deg.C to form solution;

(b) adding hydroxylamine hydrochloride into the solution obtained in the step (a) in batches, and finishing the adding within 0.5-2.5 h;

(c) after the dropwise adding is finished, heating to 60-80 ℃, and reacting for 2-4 h;

(d) after the reaction is finished, adding concentrated hydrochloric acid;

(e) after the addition is finished, heating to 60-80 ℃, and reacting for 1-2 hours;

(f) after the reaction is finished, removing methanol and water under reduced pressure;

(g) and f, adding an organic solvent into the solution obtained in the step f, cooling to 0-5 ℃, crystallizing, and filtering to obtain 7-aminoheptanoic acid hydrochloride.

2. The method for synthesizing 7-aminoheptanoic acid hydrochloride according to claim 1, wherein the organic solvent in step (a) is one or more selected from the group consisting of ethanol, methanol, acetonitrile, acetone, dichloromethane, ethyl acetate, isopropyl ether, isopropanol, and tetrahydrofuran.

3. The method of synthesizing 7-aminoheptanoic acid hydrochloride according to claim 1, wherein the mass ratio of the cycloheptanone to the organic solvent in the step (a) is: 1: 5-10.

4. The method of synthesizing 7-aminoheptanoic acid hydrochloride according to claim 1 wherein the molar ratio of the cycloheptanone of step (b) to hydroxylamine hydrochloride is: 1: 1-5.

5. The method of synthesizing 7-aminoheptanoic acid hydrochloride according to claim 1 wherein the molar ratio of cycloheptanone to concentrated hydrochloric acid added in step (d) is: 1:1-5.

6. The method for synthesizing 7-aminoheptanoic acid hydrochloride according to claim 1, wherein the organic solvent in step (g) is one or more selected from the group consisting of ethanol, methanol, acetonitrile, acetone, dichloromethane, ethyl acetate, isopropyl ether, isopropanol, and tetrahydrofuran.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method.

Background

The synthesis method of 7-amino heptanoic acid hydrochloride has the molecular formula: c₆H₁₅NO₂HCl, molecular weight: 181.66.

7-aminoheptanoic acid is an important medical intermediate, and is mainly used for synthesizing tianeptine sodium. The chemical name of the Tianeptine Sodium (Tianeptine Sodium) is 7- [ (3-chloro-6, 11-dihydro-5, 5-dioxo-6-methyl dibenzo- [ c, f ] thiazepine-11-ylamino ] heptanoic acid Sodium salt, the Tianeptine Sodium salt is a novel antidepressant developed by France Schvea company, is marketed in France in 2001, and the commercial name of the Tianeptine Sodium is Stablon.

The literature reports that there are three main methods for synthesizing 7-aminoheptanoic acid: 1. 7-amino heptanoic acid is obtained by the reaction of 7-bromo heptanoic acid and strong ammonia water. This method has two disadvantages: firstly, the raw material 7-bromoheptanoic acid is not easy to obtain, and the purification of the 7-bromoheptanoic acid needs distillation under high vacuum and high temperature; secondly, the product generated after the 7-bromoheptanoic acid reacts with ammonia water is actually a mixture of aminoheptanoic acid and ammonium bromide, the mixture needs to be purified by ion exchange resin, a large amount of water and acid and alkali are needed, and the pollution is large. 2.1, 5-dibromopentane reacts with phthalimide and diethyl malonate, and then the mixture is refluxed in concentrated hydrochloric acid to obtain 7-aminoheptanoic acid hydrochloride. Because the intermediate is insoluble in water, long-term reflux is required to remove phthalic acid and carboxyl. The long-time backflow of the concentrated hydrochloric acid causes too much corrosion to equipment, and industrial production is difficult to realize. 3. 7-amino-heptanoic acid hydrochloride is obtained by refluxing and hydrolyzing concentrated hydrochloric acid after 7-bromoheptanonitrile reacts with phthalimide. The raw material 7-bromoheptanitrile is not easy to obtain, the preparation process needs hydride with poor safety, high vacuum distillation and long-time hydrochloric acid reflux are also needed, and the industrialization is difficult to realize. The patent application 201310288413.X reports a method for synthesizing 7-aminoheptanoic acid by taking 6-bromoethyl hexanoate and nitromethane as starting materials, wherein nitromethane is introduced in the reaction process, and the substance is extremely easy to cause explosion in the transportation and reaction processes, belongs to dangerous chemicals and is extremely not beneficial to industrial production.

Disclosure of Invention

In order to solve the technical problem, the invention provides a method for synthesizing 7-aminoheptanoic acid hydrochloride. The preparation method solves the problems of large wastewater amount, high production cost and poor product purity in the traditional 7-aminoheptanoic acid synthesis process, and has the advantages of simple operation, environmental friendliness, high yield and good product purity.

The invention is realized by the following technical scheme:

a method for synthesizing 7-aminoheptanoic acid hydrochloride comprises the following steps:

(a) adding cycloheptanone into organic solvent, stirring to dissolve, and cooling to 0-10 deg.C to form solution;

the temperature is kept between 0 and 10 ℃ because the hydroxylamine hydrochloride is dripped to cause heat release, so that the violent initiation in the adding process is prevented;

(b) adding hydroxylamine hydrochloride into the solution obtained in the step (a) in batches, and finishing the adding within 0.5-2.5 h;

(c) after the dropwise adding is finished, heating to 60-80 ℃, and reacting for 2-4 h;

the conversion rate of the cycloheptanone and the hydroxylamine hydrochloride is higher at the temperature of 60-80 ℃, the conversion rate is lower at low temperature, and the byproducts are increased at the temperature of more than 80 DEG C

(d) After the reaction is finished, adding concentrated hydrochloric acid;

adding concentrated hydrochloric acid, heating and hydrolyzing under strong acid to generate 7-aminoheptanoic acid hydrochloride from enantholactam;

(e) after the addition is finished, heating to 60-80 ℃, and reacting for 1-2 hours;

(f) after the reaction is finished, removing methanol and water under reduced pressure;

(g) and f, adding an organic solvent into the solution obtained in the step f, cooling to 0-5 ℃, crystallizing, and filtering to obtain 7-aminoheptanoic acid hydrochloride.

The organic solvent in the step (a) is one or more of ethanol, methanol, acetonitrile, acetone, dichloromethane, ethyl acetate, isopropyl ether, isopropanol and tetrahydrofuran;

the mass ratio of the cycloheptanone to the organic solvent in the step (a) is as follows: 1: 5-10;

the molar ratio of the cycloheptanone in the step (b) to the hydroxylamine hydrochloride is as follows: 1: 1-5;

the molar ratio of the cycloheptanone to the concentrated hydrochloric acid added in the step (d) is as follows: 1: 1-5; .

The organic solvent in the step (g) is one or more of ethanol, methanol, acetonitrile, acetone, dichloromethane, ethyl acetate, isopropyl ether, isopropanol and tetrahydrofuran;

the mechanism of the synthesis method is as follows: reacting cycloheptanone with hydroxylamine hydrochloride to form cycloheptanone oxime, rephotoping to obtain enantholactam, which is unstable and hydrolyzed under strong acidic condition to obtain 7-amino heptanoate hydrochloride

The invention has the beneficial effects that:

(1) the synthesis method of the 7-amino heptanoic acid hydrochloride reduces the requirements on reaction equipment, and the improvement can greatly reduce the investment in industrial production. The traditional process takes 7-bromoheptanoic acid as a raw material, the purification of the 7-bromoheptanoic acid needs distillation under high vacuum and high temperature, a large amount of rectification and vacuum equipment needs to be added, and the process can be completed only by a traditional reaction kettle.

(2) The synthesis method of the 7-amino heptanoic acid hydrochloride improves the yield of the product and virtually reduces the production cost of the product. The hydroxylamine hydrochloride and cycloheptanone used as raw materials in the process route are common bulk chemicals, the price is low, the reaction yield reaches 80 percent, and the process has obvious cost advantage compared with the prior process.

(3) The synthesis method of the 7-aminoheptanoic acid hydrochloride reduces reaction steps and saves production cost of enterprises.

(4) The synthetic method of the 7-amino heptanoic acid hydrochloride reduces the generation of waste water in the reaction process and reduces the environmental protection pressure of enterprises. The product obtained after the reaction of the 7-bromoheptanoic acid and the ammonia water is actually a mixture of the aminoheptanoic acid and the ammonium bromide, the purification is carried out by using ion exchange resin, a large amount of water and acid and alkali are required to be used, the pollution is large, the production of waste water is reduced by the process, and only the hydrochloric acid solution is added in the hydrolysis, so that the consumption of the waste water is relatively reduced.

(5) The synthesis method of the 7-aminoheptanoic acid hydrochloride has the advantages of short time, less used equipment and high product purity, and is suitable for industrial mass production. The process achieves the purity of the crude product after recrystallization to reach 99.3 percent, and the obtained product basically has no introduction of byproducts.

(6) The synthesis method of the 7-aminoheptanoic acid hydrochloride improves the product purity, reduces the generation of side reactions and improves the quality of finished products.

Detailed Description

The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.