阅读说明：本技术 一种盐酸安非他酮的制备工艺 (Preparation process of bupropion hydrochloride ) 是由 宋文波 肖永鹏 李国良 黄栋 马超 沈剑锋 于 2021-01-08 设计创作，主要内容包括：本发明公开了一种盐酸安非他酮的制备工艺。现有的盐酸安非他酮的制备方法多所采用的溴代反应,溴素毒害性强,同时具有腐蚀性。为克服上述缺点,本发明提供一种新的盐酸安非他酮的制备工艺,本工艺采用浓度为30%的盐酸代替溴素进行反应。本工艺大致的方法为：取用30%盐酸与双氧水进行氧化反应,得到中间体1；中间体1与间氯苯丙酮发生氯代反应得到中间体2；中间体2进一步与叔丁胺发生胺化反应得到中间体3；中间体3最后经过成盐和纯化操作,得到目标盐酸安非他酮纯品。(The invention discloses a preparation process of bupropion hydrochloride. Most of the existing methods for preparing bupropion hydrochloride adopt bromination reaction, and bromine has strong toxicity and corrosiveness. In order to overcome the defects, the invention provides a novel preparation process of bupropion hydrochloride, which adopts hydrochloric acid with the concentration of 30% to replace bromine for reaction. The method of the process comprises the following steps: carrying out oxidation reaction on 30% hydrochloric acid and hydrogen peroxide to obtain an intermediate 1; the intermediate 1 and m-chloropropiophenone are subjected to chlorination reaction to obtain an intermediate 2; the intermediate 2 further reacts with tert-butylamine to generate amination reaction to obtain an intermediate 3; and finally, salifying and purifying the intermediate 3 to obtain a pure target bupropion hydrochloride product.)

1. A preparation process of bupropion hydrochloride is characterized by comprising the following steps:

(1) adding hydrogen peroxide into hydrochloric acid, wherein the reaction molar ratio of the hydrochloric acid to the hydrogen peroxide is 1-1.2, controlling the temperature at 20-30 ℃, and reacting to obtain an intermediate 1 reaction solution;

(2) adding m-chloropropiophenone into the reaction liquid of the intermediate 1, wherein the reaction molar ratio of the intermediate 1 to the m-chloropropiophenone is 1-1.3, controlling the temperature to be 60-65 ℃ for reaction to obtain reaction liquid of an intermediate 2, extracting the intermediate 2 from the reaction liquid of the intermediate 2, and leaving extract liquid of the intermediate 2 for later use;

(3) under the condition of stirring at room temperature, adding tert-butylamine into the intermediate 2 extract, wherein the reaction molar ratio of the intermediate 2 to the tert-butylamine is 1-9, after the reaction is finished, adding purified water for stirring, standing for layering, and removing a water layer to obtain an intermediate 3 extract; evaporating the intermediate 3 extract to dryness at normal pressure, and dissolving in organic solvent to obtain intermediate 3 solution;

(4) salifying the intermediate 3 to obtain a crude bupropion hydrochloride product;

(5) and (4) refining the crude bupropion hydrochloride product to obtain a pure bupropion hydrochloride product.

2. The preparation process of bupropion hydrochloride according to claim 1, wherein the step (4) is specifically: cooling the intermediate 3 solution to 0-5 ℃, and adding hydrochloric acid, wherein the salifying molar ratio of the intermediate 3 to the hydrochloric acid is 1-1.8; adjusting the pH value to 2-3, stirring, carrying out suction filtration and evaporation to dryness to obtain a crude bupropion hydrochloride product.

3. The process for preparing bupropion hydrochloride according to claim 1, wherein the step (5) is specifically as follows: adding purified water into the bupropion hydrochloride crude product, wherein the weight ratio of the bupropion hydrochloride crude product to the water is 1-6; stirring and heating to 80-85 ℃, keeping the temperature to dissolve and clear, cooling to 10-15 ℃ for crystallization, and performing suction filtration and drying to obtain a pure bupropion hydrochloride product.

4. The process of claim 1, wherein the step of preparing bupropion hydrochloride comprises the following steps: the reaction molar ratio of the hydrochloric acid to the hydrogen peroxide in the step (1) is 1-1.1.

5. The process of claim 1, wherein the step of preparing bupropion hydrochloride comprises the following steps: in the step (2), the reaction molar ratio of the intermediate 1 to the m-chloropropiophenone is 1-1.1.

6. The process of claim 1, wherein the step of preparing bupropion hydrochloride comprises the following steps: the reaction molar ratio of the intermediate 2 to the tert-butylamine in the step (3) is 1-7.

7. The process of claim 2, wherein the step of preparing bupropion hydrochloride comprises the following steps: in the step (4), the salifying molar ratio of the intermediate 3 to 30% hydrochloric acid is 1-1.2.

8. The process of claim 1, wherein the step of preparing bupropion hydrochloride comprises the following steps: the weight ratio of the bupropion hydrochloride crude product to the water in the step (5) is 1-4.

9. The process of claim 1, wherein the step of preparing bupropion hydrochloride comprises the following steps: the extraction solvent used in the step (2) is one or two of dichloromethane and toluene.

10. The process of claim 1, wherein the step of preparing bupropion hydrochloride comprises the following steps: in the step (3), the organic solvent is one or more than two of dichloromethane, chloroform and toluene.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation process of bupropion hydrochloride.

Background

Bupropion hydrochloride is an aminoketone antidepressant, is also the only market variety of the current antidepressant drugs, and is successfully developed by the American Baowei company in the 70 s as a selective depression preparation of dopamine transmitter. The bupropion hydrochloride belongs to central nervous system medication, has weak inhibition effect on reuptake of norepinephrine, 5-HT and dopamine, and has no effect on monoamine oxidase. The antidepressant action mechanism of the product is not clear, and may be related to the action of norepinephrine and/or dopaminergic, but the effect of bupropion is stronger than that of other antidepressants. In addition, bupropion hydrochloride was first marketed in 1997 in the united states as an aid for smoking cessation, which was the first non-nicotine prescription drug on the U.S. market for smoking cessation.

Bupropion hydrochloride is a racemic mixture and thus the pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The pharmacokinetic curve of bupropion hydrochloride is in a two-chamber model, the mean half-life of the terminal phase is 21 hours (+ -20%), and the mean half-life of the distribution phase is 3-4 hours. Only a small fraction of the drug can be absorbed after oral administration, reaching peak blood concentration within 2 hours.

Most of the existing methods for preparing bupropion hydrochloride adopt bromination reaction, and bromine has strong toxicity and corrosiveness. In order to overcome the defects, the invention provides a novel preparation process of bupropion hydrochloride, which adopts hydrochloric acid to replace bromine for reaction.

Disclosure of Invention

The invention aims to provide a preparation process of bupropion hydrochloride, which aims to solve the problems in the background technology.

A preparation process of bupropion hydrochloride comprises the following steps:

(1) adding hydrogen peroxide into hydrochloric acid, wherein the reaction molar ratio of the hydrochloric acid to the hydrogen peroxide is 1-1.2, controlling the temperature at 20-30 ℃, and reacting to obtain an intermediate 1 reaction solution;

(2) adding m-chloropropiophenone into the reaction liquid of the intermediate 1, wherein the reaction molar ratio of the intermediate 1 to the m-chloropropiophenone is 1-1.3, controlling the temperature to be 60-65 ℃ for reaction to obtain reaction liquid of an intermediate 2, extracting the intermediate 2 from the reaction liquid of the intermediate 2, and leaving extract liquid of the intermediate 2 for later use;

(3) under the condition of stirring at room temperature, adding tert-butylamine into the intermediate 2 extract, wherein the reaction molar ratio of the intermediate 2 to the tert-butylamine is 1-9, after the reaction is finished, adding purified water for stirring, standing for layering, and removing a water layer to obtain an intermediate 3 extract; evaporating the intermediate 3 extract to dryness at normal pressure, and dissolving in organic solvent to obtain intermediate 3 solution;

(4) salifying the intermediate 3 to obtain a crude bupropion hydrochloride product;

(5) refining the bupropion hydrochloride crude product to obtain a bupropion hydrochloride pure product;

preferably, the step (4) is specifically: cooling the intermediate 3 solution to 0-5 ℃, and adding hydrochloric acid, wherein the salifying molar ratio of the intermediate 3 to the hydrochloric acid is 1-1.8; adjusting the pH value to 2-3, stirring, carrying out suction filtration and evaporation to dryness to obtain a crude bupropion hydrochloride product.

Preferably, the step (5) is specifically: adding purified water into the bupropion hydrochloride crude product, wherein the weight ratio of the bupropion hydrochloride crude product to the water is 1-6; stirring and heating to 80-85 ℃, keeping the temperature to dissolve and clear, cooling to 10-15 ℃ for crystallization, and performing suction filtration and drying to obtain a pure bupropion hydrochloride product.

Preferably, the reaction molar ratio of the hydrochloric acid to the hydrogen peroxide in the step (1) is 1-1.1.

Preferably, the reaction molar ratio of the intermediate 1 to the m-chloropropiophenone in the step (2) is 1-1.1.

Preferably, the reaction molar ratio of the intermediate 2 to the tert-butylamine in the step (3) is 1-7.

Preferably, the salifying molar ratio of the intermediate 3 to the hydrochloric acid in the step (4) is 1-1.2.

Preferably, the weight ratio of the crude bupropion hydrochloride product to the water in the step (5) is 1-4.

Preferably, the extraction solvent used in step (2) is one or both of dichloromethane and toluene.

Preferably, the organic solvent in step (3) is one or more of dichloromethane, chloroform and toluene.

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

(1) according to the preparation process of bupropion hydrochloride provided by the invention, the adopted raw materials are low in toxicity and corrosivity, and the pollution of the traditional bromination reaction to the environment is reduced;

(2) the preparation process of bupropion hydrochloride provided by the invention has the advantages of high chlorination reaction rate, less impurities and high yield.

Drawings

FIG. 1 is a scheme showing the synthesis of bupropion hydrochloride according to the present invention;

description of reference numerals: 1. intermediate 1; 2. intermediate 2; 3. intermediate 3.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below with reference to fig. 1 of the specification, 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

Step (1): adding 41g of hydrochloric acid (0.38mol) with the concentration of 30% into a reaction bottle, dropwise adding 46g of hydrogen peroxide (0.456mol) at the temperature of 20-30 ℃, finishing dropwise adding within 4 hours, and reacting for 8 hours after dropwise adding to obtain an intermediate 1 reaction solution, wherein the calculated molar yield is 95%.

Step (2): heating the reaction liquid of the intermediate 1 to 65 ℃, adding 38g of m-chloropropiophenone (0.226mol) through an oscillating feeder, and carrying out chlorination reaction on the m-chloropropiophenone in the intermediate 1; controlling the temperature at 60-65 ℃, reacting for 4 hours, cooling to 10-15 ℃, adding 50ml of dichloromethane for extraction and layering, and extracting to obtain an intermediate 2 extract; 20ml of purified water was added to the intermediate 2 extract for washing, and after washing, the intermediate 2 extract was left for further use.

And (3): under the condition of room temperature, 138g of tert-butylamine (1.9mol) is added into the extract liquor of the intermediate 2 while stirring, after 24 hours of reaction, 100ml of purified water is added and stirred for 10 minutes; standing for layering, and removing a water layer to obtain an intermediate 3 extract; and (3) evaporating the intermediate 3 extract to dryness at normal pressure, adding 200ml of isopropanol solution, and stirring for 1h until the solution is clear to obtain an intermediate 3 solution.

And (4): and (3) cooling the intermediate 3 solution to 0-5 ℃, adding hydrochloric acid with the concentration of 30%, adjusting the pH to 2-3, stirring for 4h, performing suction filtration, and drying the product obtained by suction filtration for 12h to obtain 40g of bupropion hydrochloride crude product.

And (5): taking 40g of bupropion hydrochloride crude product, adding 240ml of purified water, heating the solution to 80-85 ℃ while stirring, preserving heat for 1h, cooling to 10-15 ℃ for crystallization for 4h, carrying out suction filtration and drying on the obtained crystals to obtain 38g of bupropion hydrochloride pure product, wherein the calculated molar yield is 95%.

Examples 2 to 4

The reaction is the same as the example 1 except that the reaction molar ratio of the 30 percent hydrochloric acid to the hydrogen peroxide in the step (1) is different from the example 1.

Reaction molar ratio of 30% hydrochloric acid to hydrogen peroxide	Yield of
		0.38mol：0.494mol	92.4％
0.38mol：0.418mol	94.6％
		0.38mol：0.38mol	90.2％

Examples 5 to 7

The reaction was carried out in the same manner as in example 1 except that the reaction molar ratio of the intermediate 1 to m-chloropropiophenone in step (2) was changed from that in example 1.

Examples 8 to 10

The reaction is the same as example 1 except that the molar ratio of the intermediate 2 to tert-butylamine in step (3) is different from that in example 1.

Reaction molar ratio of intermediate 2 to tert-butylamine	Yield of
		0.38mol：1.9mol	95％
0.27mol：1.9mol	99.2％
		0.21mol：1.9mol	97.2％

Examples 11 to 13

The same procedure as in example 1 was repeated except that the reaction molar ratio of the intermediate 3 to 30% hydrochloric acid in step (4) was changed from that in example 1.

Reaction molar ratio of intermediate 3 to 30% hydrochloric acid	Yield of
		0.208mol：0.229mol	85.4％
0.208mol：0.25mol	90.5％
		0.208mol：0.27mol	87.2％

Examples 14 to 16

The process is the same as example 1 except that the weight ratio of the crude bupropion hydrochloride product to water in step (5) is different from that in example 1.

Weight ratio of bupropion hydrochloride crude product to water	Yield of
		40g：160g	91.6％
40g：240g	95％
		40g：320g	90％

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.