阅读说明：本技术 一种高纯度盐酸多巴胺的合成方法 (Synthesis method of high-purity dopamine hydrochloride ) 是由 盛遵田 邓义蒙 田成艳 刘发文 李广乾 王海峰 尹凤学 丁凤娟 杨荣 于 2020-08-24 设计创作，主要内容包括：本发明提供了一种盐酸多巴胺的合成方法,属于药物合成领域。本发明以3,4-二甲氧基苯乙胺为起始原料,先与酸反应成盐,重结晶精制得到3,4-二甲氧基苯乙胺盐,与氢溴酸反应脱去甲基,生成多巴胺氢溴酸盐,最后与盐酸反应成盐得到盐酸多巴胺。本发明提供的制备方法起始原料廉价易得,工艺简单,无高温高压氢化步骤,成本低,纯度、收率高,适用于工业化生产。(The invention provides a synthesis method of dopamine hydrochloride, belonging to the field of drug synthesis. The method comprises the steps of taking 3, 4-dimethoxy phenethylamine as a starting raw material, reacting with acid to form salt, recrystallizing and refining to obtain 3, 4-dimethoxy phenethylamine salt, reacting with hydrobromic acid to remove methyl to generate dopamine hydrobromide, and finally reacting with hydrochloric acid to form salt to obtain dopamine hydrochloride. The preparation method provided by the invention has the advantages of cheap and easily available starting materials, simple process, no high-temperature and high-pressure hydrogenation step, low cost, high purity and high yield, and is suitable for industrial production.)

1. A method for synthesizing high-purity dopamine hydrochloride is characterized by comprising the following steps:

the method comprises the following specific steps:

a) reacting 3, 4-dimethoxy phenethylamine with acid HX in a solvent to form salt so as to obtain a crude product of the 3, 4-dimethoxy phenethylamine salt; recrystallizing the crude product to obtain a refined product of the 3, 4-dimethoxyphenethylamine salt;

b) reacting the refined product of the 3, 4-dimethoxy phenethylamine salt with hydrobromic acid to obtain dopamine hydrobromide;

c) reacting the dopamine hydrobromide with hydrochloric acid to change the salt to obtain the target product dopamine hydrochloride.

2. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: the acid HX in the step a is hydrobromic acid or hydrochloric acid, the concentration of the hydrobromic acid is 40-48%, and the concentration of the hydrochloric acid is 36-38%.

3. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: the solvent in the step a is one of methanol, ethanol, isopropanol or ethyl acetate.

4. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: in the step a, the molar ratio of the 3, 4-dimethoxyphenethylamine to the acid HX is 1: 1-1: 2.

5. the method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: in the step a, the recrystallization solvent of the crude product of the 3, 4-dimethoxyphenethylamine salt is one of methanol, ethanol, isopropanol, acetone HX solution and methanol HX solution.

6. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: in the step b, the dosage of the hydrobromic acid is 5 to 10 times of the mass of the refined product of the 3, 4-dimethoxy phenethylamine salt.

7. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: the concentration of hydrobromic acid used in the step b is 40-48%.

8. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: the reaction temperature of the step b is 100-120 ℃.

9. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: and c, the solvent is one or a mixture of two of methanol, ethanol, isopropanol and water.

10. The method for synthesizing high-purity dopamine hydrochloride according to claim 1, characterized in that: in the step c, the mass ratio of the dopamine hydrobromide to the hydrochloric acid is 1: 1-1: 5.

Technical Field

The invention belongs to the technical field of medical chemistry, and particularly relates to a synthesis method of high-purity dopamine hydrochloride.

Background

Dopamine Hydrochloride (Dopamine Hydrochloride), chemical name 4- (2-aminoethyl) -1, 2-benzenediol Hydrochloride. Dopamine has beta receptor agonism and certain alpha receptor agonism, can enhance myocardial contractility, increase cardiac output, accelerate heart rate slightly, slightly contract peripheral blood vessels, increase arterial pressure, dilate visceral blood vessels, increase blood flow, increase renal blood flow and glomerular filtration rate, thereby promoting increase of urine volume and sodium excretion, improving peripheral circulation, obviously increasing urine volume, having no obvious influence on heart rate, and being clinically mainly used for various types of shock in places superior to other vasoconstrictors or vasodilators. The structural formula is as follows:

the main synthetic routes of dopamine hydrochloride in the prior reports are as follows:

route one: (China journal of medical industry 1977, 2, 21-22) piperonyl cyanide is used as a starting material, dopamine is obtained through catalytic hydrogenation and ring-opening deprotection, the purity is 99%, the total yield is 70%, the catalytic hydrogenation needs high-pressure (1MPa) operation, the requirement on equipment is high, expensive and flammable palladium-carbon or Raney nickel is needed as a catalyst, the reaction temperature of the second deprotection is high, and the industrial production difficulty is high. The reaction formula is as follows:

and a second route: (proceedings of Shandong light industry academy of sciences, 1990, 4(3), 1-3; Chemical & pharmaceutical bulletin,36(2), 837-40; 1988) 3-methoxy-4-hydroxybenzaldehyde (vanillin) is used as a raw material, and is firstly condensed with nitromethane under the catalysis of methylamine to obtain 4-hydroxy-3-methoxy-beta-nitroethylbenzene, 4-hydroxy-3-methoxyphenethylamine hydrochloride is obtained by reduction, and the dopamine hydrobromide is obtained by removing the methyl group under the catalysis of hydrogen bromide, then reacts with hydrochloric acid to obtain the dopamine hydrochloride, and the finished product is obtained after refining, wherein the purity is 98%, and the total yield is 40%. The method is characterized in that a flammable and explosive hazardous chemical substance nitromethane is used in the first step, but the reaction condition in the step is mild, the reaction can be carried out at room temperature, a large amount of zinc powder and hydrochloric acid are used in the second step, hydrogen is discharged through the reaction, the industrial production risk is high, and the zinc powder belongs to explosive chemicals. The reaction formula is as follows:

and a third route: (S.G.Lee et al, enzyme and microbiological Technology 25(1999) 298- & lt302 & gt; Metabolic Engineering,14 & lt6 & gt, 603- & lt610 & gt, 2012) the route uses catechol or L-tyrosine as raw materials, and firstly, levodopa is obtained through reaction, and then dopamine is obtained through decarboxylation. The intermediate levodopa is a commercial product, and the levodopa is directly used as a starting material in literature reports. Most of the routes use enzyme as a catalyst, the reaction conditions are harsh, the price of the enzyme is high, the reaction yield is low, the product purity is low, a large number of byproducts are generated, the purification is difficult, the cost control is not facilitated, and the industrial production is difficult to realize. The reaction formula is as follows:

disclosure of Invention

The invention provides a method for synthesizing high-purity dopamine hydrochloride, which is characterized in that 3, 4-dimethoxy phenethylamine is used as a starting material, the starting material is firstly reacted with acid to form salt, recrystallized to obtain 3, 4-dimethoxy phenethylamine salt, the salt is reacted with hydrobromic acid to remove methyl, dopamine hydrobromide is generated, and finally the salt is reacted with hydrochloric acid to form salt, so that dopamine hydrochloride is obtained.

The technical scheme adopted by the invention for solving the technical problems is as follows:

a synthesis method of dopamine hydrochloride comprises the following steps:

a) reacting 3, 4-dimethoxy phenethylamine with acid HX in a solvent to form salt so as to obtain a crude product of the 3, 4-dimethoxy phenethylamine salt; recrystallizing the crude product to obtain a refined product of the 3, 4-dimethoxyphenethylamine salt;

b) reacting the refined product of the 3, 4-dimethoxy phenethylamine salt with hydrobromic acid to obtain dopamine hydrobromide;

c) reacting the dopamine hydrobromide with hydrochloric acid to change the salt to obtain the standard product dopamine hydrochloride.

Further preferably, the acid HX used in the step a is hydrobromic acid or hydrochloric acid, the concentration of the hydrobromic acid is 40-48%, the concentration of the hydrochloric acid is 36-38%, and hydrobromic acid is preferred; more preferably hydrobromic acid at a concentration of 48%.

Further preferably, the solvent used in step a is one of methanol, ethanol, isopropanol or ethyl acetate, the methanol solubility is high, the yield is low, and the impurity removal effect of the isopropanol and the ethyl acetate is general, so that ethanol is preferred;

further preferably, the molar ratio of the 3, 4-dimethoxyphenethylamine to the acid HX in the step a is 1: 1-1: 2, preferably 1: 1.1;

further preferably, in the step a, a recrystallization solvent of the crude 3, 4-dimethoxyphenethylamine salt is methanol, ethanol, isopropanol, acetone HX solution or methanol HX solution, the isopropanol has low solubility to the crude 3, 4-dimethoxyphenethylamine salt, the required solvent amount is large, the impurity removal effect of the acid solution of acetone and methanol is general, and ethanol is preferred;

further preferably, the dosage of the hydrobromic acid in the step b is 5 to 10 times, preferably 8 times of the mass of the refined product of the 3, 4-dimethoxyphenethylamine salt;

further preferably, the concentration of hydrobromic acid used in step b is 40-48%, preferably 48%;

further preferably, the reaction temperature in the step b is 100-120 ℃, preferably 110-115 ℃, and the reaction time is prolonged due to low temperature;

further preferably, the solvent used in step c is one or a mixture of two of methanol, ethanol, isopropanol and water, wherein the solubility of dopamine hydrobromide in methanol, ethanol and water is high, the yield is low, and isopropanol is preferred;

further preferably, the mass ratio of dopamine hydrobromide to hydrochloric acid in step c is 1: 1-1: 5, preferably 1: 2.

compared with the prior art, the invention has the following beneficial effects:

1. the synthesis method of dopamine hydrochloride provided by the invention takes 3, 4-dimethoxy phenethylamine as a starting material and 3, 4-dimethoxy phenethylamine as a common medical intermediate, is widely applied to synthesis of medicines such as verapamil, bevantolol, papaverine, palmatine, tetrahydropalmatine and the like, is cheap and easy to obtain, and has a market price of 300-400 yuan/kg.

2. According to the synthesis method of dopamine hydrochloride, the selected 3, 4-dimethoxy phenethylamine is oily and is obtained by evaporating the solvent, the purity is low, in the process, the 3, 4-dimethoxy phenethylamine is salified to obtain solid, and recrystallization purification is carried out, so that the purity is improved, and the preparation of high-purity dopamine hydrochloride is guaranteed.

3. The synthesis method of dopamine hydrochloride provided by the invention avoids special reaction conditions such as high-pressure hydrogenation and the like, obtains a target product by reacting under mild conditions, avoids the use of nitromethane, zinc powder and the like which are easily explosive chemicals, has a simple post-treatment method and fewer three wastes, and is more suitable for industrial scale-up production.

4. The purity of the dopamine hydrochloride prepared by the process can reach more than 99.9 percent, and the dopamine hydrochloride meets the standards of pharmacopoeia at home and abroad.

Drawings

FIG. 1: example one liquid chromatogram of the obtained dopamine hydrochloride.

Detailed Description

The present application will be described in further detail with reference to examples. It is to be understood that the specific embodiments described herein are merely illustrative of the relevant invention and not restrictive of the invention.