CN111153807B

CN111153807B - Preparation method of N, N-dimethylamino chloropropane hydrochloride

Info

Publication number: CN111153807B
Application number: CN202010046724.5A
Authority: CN
Inventors: 李闪闪; 魏利强; 张元峰; 程丽红; 罗明; 周金龙; 张莹
Original assignee: Henan Yuchen Pharmaceutical Co ltd
Current assignee: Henan Yuchen Pharmaceutical Co ltd
Priority date: 2020-01-16
Filing date: 2020-01-16
Publication date: 2023-01-06
Anticipated expiration: 2040-01-16
Also published as: CN111153807A

Abstract

The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a preparation method of N, N-dimethylamino chloropropane hydrochloride. The preparation method has the advantages of high reaction speed, high conversion rate, good selectivity, simple post-treatment and the like, and the product purity is over 99.0 percent and the molar yield is over 88 percent.

Description

Preparation method of N, N-dimethylamino chloropropane hydrochloride

Technical Field

The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a preparation method of N, N-dimethylamino chloropropane hydrochloride.

Background

The N, N-dimethylamino hydrochloride is used for synthesizing chlorpromazine which is a psychotropic drug and imipramine which is an antidepressant, and is also a key intermediate of Telden, doxepin, amitriptyline and the like. The medicaments have the functions of resisting mental disorder, depression and anxiety, and also have obvious curative effects on the aspects of diminishing inflammation, relieving fever, easing pain and the like, and the structural formula of the medicaments is as follows:

according to the prior literature reports, the following main synthetic routes are available:

the first synthetic route is as follows:

the reaction conditions of the method are harsh, a large amount of SO2 gas can be generated by using thionyl chloride in the chlorination process of the hydroxyl in the second step, a special absorption tower is needed for tail gas absorption, the equipment investment is large, the three wastes are high, and the method is not environment-friendly.

The second synthetic route is as follows:

according to the method, chloropropene is used as a raw material, the chloropropene and dimethylamine gas are subjected to high-temperature pressurization reaction under the action of strong alkali through gasification, and then hydrogen chloride gas is introduced to perform addition and salt formation, so that the reaction steps are complex, a large number of byproducts are produced, and the yield is low.

The third synthetic route is as follows:

the method takes 1,3-bromochloropropane and dimethylamine as reaction raw materials, and performs amine alkylation substitution reaction under the action of a catalyst, but by-products N, N, N ', N' tetramethyl-1,3-propane diamine are generated in the reaction process of the process, which brings trouble to the purification of products in the post-treatment process, directly influences the yield and quality of the products, and simultaneously generates a large amount of by-products hydrogen bromide or hydrogen chloride gas, so that the method has many three wastes and is not beneficial to energy conservation and environmental protection.

Disclosure of Invention

Based on the related technical problems, the invention aims to provide a preparation method of N, N-dimethylamino chloropropane hydrochloride, which aims to solve the problems that the existing preparation method of N, N-dimethylamino chloropropane hydrochloride is relatively complex and has more byproducts.

In order to achieve the purpose, the invention adopts the following technical scheme:

the preparation method of the N, N-dimethylamino chloropropane hydrochloride comprises the following synthetic route:

the method specifically comprises the following steps:

1) Reacting the chloropropene solution with dimethylamine for 1-10h at 35-45 ℃ under the action of a catalyst (the content of chloropropene in the raw material is less than or equal to 2 percent through gas phase tracking detection), and then terminating the reaction;

2) Carrying out reduced pressure distillation on the reaction product obtained in the step 1), washing and layering, adding acid into the obtained organic layer until the pH value is 2-3, reacting for 1-2 h at the temperature of 95-112 ℃, refluxing and carrying water for 8-10h, cooling to normal temperature, filtering, and drying to obtain the N, N-dimethylamino chloropropane hydrochloride.

Specifically, the chloropropene solution in the step 1) is obtained by dissolving chloropropene in toluene, ethanol or water, and the chloropropene solution is preferably obtained by dissolving chloropropene in toluene or ethanol.

In particular, the catalyst in step 1) may be a metal catalyst such as TiCl ₄ Or SnCl ₄ Can be a supported catalyst such as CeCl ₃ ·7H ₂ O or NaI, or a recoverable catalyst formed by mixing with silica gel, such as diatomaceous earth.

Specifically, the molar ratio of dimethylamine to chloropropene in the step 1) is (1.1-1.5): 1.

specifically, the mass of the catalyst added in the step 1) is 0.2-1.0% of that of chloropropene.

Compared with the prior art, the invention has the beneficial effects that:

the invention takes dimethylamine as raw material, carries out aza Michael addition with chloropropene under the action of catalyst, obtains N, N-dimethylamino chloropropane by separation and purification after the reaction is finished, obtains N, N-dimethylamino chloropropane hydrochloride by acidification and salt forming reaction, has no by-product, has the advantages of simple reaction process, simple and convenient post-treatment process, high conversion rate of main raw material, high reaction speed and the like, and the obtained product has high purity (more than 99.0 percent).

Detailed Description

In order to make the objects, technical solutions and effects of the present invention clearer and clearer, the present invention is described in further detail below. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The molar yield calculation method of the invention comprises the following steps: taking chloropropene as a reference, the material input is 50.0g, the molar weight is 0.65mol, the theoretical product yield is 103.3g, and the actual yield is divided by the theoretical yield to obtain the molar yield.

Example 1

A preparation method of N, N-dimethylamino chloropropane hydrochloride comprises the following specific steps:

1) Adding 50.0g of chloropropene and 150g of toluene into a four-mouth reaction bottle, stirring, and adding a catalyst TiCl ₄ 0.5g, 33g of dimethylamine gas introduced at 35 ℃, reaction is stopped after heat preservation at 35 ℃ for 7h, and the chloropropene content is less than or equal to 2% by gas phase tracking detection analysis;

2) Distilling the reaction product in the step 1) under reduced pressure, recovering 45.2g of toluene and unreacted vinyl chloride, washing with 100g of water for layering, and removing the catalyst TiCl ₄ (catalyst TiCl) ₄ Dissolved in a water layer), hydrochloric acid is dripped into the organic layer, the pH value is adjusted to 2-3, the reaction and the reflux carry water for 10 hours at the temperature of 95 ℃, the temperature is reduced to normal temperature, the filtration and the drying are carried out, and 92.1g of N, N-dimethylamino chloropropane hydrochloride with the purity of 99.2 percent and the molar yield of 89.2 percent are obtained.

Example 2

1) Adding 50.0g of chloropropene and 150g of ethanol into a four-mouth reaction bottle, stirring, and adding a catalyst TiCl ₄ Introducing 36g of dimethylamine gas at the temperature of 40 ℃ in 1.0g, keeping the temperature at the temperature of 40 ℃ for reaction for 8 hours, and then terminating the reaction, wherein the chloropropene content is less than or equal to 2% by gas phase tracking detection analysis;

2) Distilling the reaction product in the step 1) under reduced pressure, recovering 36.4g of toluene and unreacted vinyl chloride, washing with 100g of water for layering, and removing the catalyst TiCl ₄ (catalyst TiCl) ₄ Dissolved in a water layer), hydrogen chloride gas is introduced into the organic layer, the pH value is adjusted to 2-3, the reaction and the reflux are carried out for 10 hours at the temperature of 100 ℃, the temperature is reduced to normal temperature, the filtration and the drying are carried out, and 91.5g of N, N-dimethylamino chloropropane hydrochloride with the purity of 99.4 percent and the molar yield of 88.6 percent are obtained.

Example 3

1) Adding 50.0g of chloropropene and 150g of toluene into a four-opening reaction bottle, stirring, adding 1.0g of catalyst diatomite, introducing 38g of dimethylamine gas at 45 ℃, keeping the temperature at 45 ℃ for reaction for 10 hours, and then terminating the reaction, wherein the content of chloropropene is less than or equal to 2% by gas phase tracking detection analysis;

2) And (2) carrying out reduced pressure distillation on the reaction product in the step 1), recovering 42.1g of toluene and unreacted vinyl chloride, washing with 100g of water, filtering to remove catalyst diatomite, dropwise adding hydrochloric acid into the organic layer, adjusting the pH value to 2-3, carrying out reaction and reflux at 112 ℃ for 12h with water, cooling to normal temperature, filtering, and drying to obtain 93.0g of N, N-dimethylamino chloropropane hydrochloride, wherein the purity is 99.1%, and the molar yield is 90.0%.

While particular embodiments of the present invention have been described, it is to be understood that the present invention is not limited to the precise embodiments described above, and that various changes and modifications may be effected therein by one skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims.

Claims

1. The preparation method of the N, N-dimethylamino chloropropane hydrochloride is characterized by comprising the following steps:

1) Reacting chloropropene solution with dimethylamine for 1-10h at 35-45 ℃ under the action of a catalyst, and terminating the reaction;

2) Carrying out reduced pressure distillation on the reaction product obtained in the step 1), washing and layering, adding acid into the obtained organic layer until the pH value is 2-3, reacting for 1-2 h at the temperature of 95-112 ℃, refluxing for 8-10h with water, cooling to normal temperature, filtering, and drying to obtain N, N-dimethylamino chloropropane hydrochloride;

the catalyst in the step 1) is TiCl ₄ Or diatomaceous earth;

the chloropropene solution in the step 1) is obtained by dissolving chloropropene in toluene or ethanol.

2. The preparation method according to claim 1, wherein the molar ratio of dimethylamine to chloropropene in step 1) is (1.1-1.5): 1.

3. the process according to claim 1, wherein the amount of the catalyst added in step 1) is 0.2 to 1.0% by mass or 2.0% by mass based on the amount of the chloropropene.