CN105272861A

CN105272861A - Dopexamine hydrochloride and novel preparation method thereof

Info

Publication number: CN105272861A
Application number: CN201510777929.XA
Authority: CN
Inventors: 马占芝; 姚东民; 刘宇; 孙宇; 光海红
Original assignee: SHUANGDING PHARMACEUTICAL CO Ltd SHENYANG
Current assignee: SHUANGDING PHARMACEUTICAL CO Ltd SHENYANG
Priority date: 2015-11-16
Filing date: 2015-11-16
Publication date: 2016-01-27

Abstract

The invention discloses a preparation method of dopexamine hydrochloride. The preparation method comprises the steps that 1,6-hexamethylenediamine is taken as starting materials to react with beta-bromo-ethylbenzene and 3,4-dimethoxy-beta-bromo-ethylbenzene under catalysis of potassium hexafluoroaluminate; after reacting is finished, hydrolysis is performed with 36% hydrochloric acid to obtain crude dopexamine hydrochloride; recrystallization is performed with ethyl alcohol to obtain the dopexamine hydrochloride. According to the dopexamine hydrochloride and the novel preparation method thereof, the adopted raw materials are easy to obtain, the reacting conditions are mild, the reacting process time is short, the reacting yield is high, the by-product varieties are few, the by-product content is lower, and purification is easy.

Description

Dopexamine hydrochloride and novel preparation method thereof

Technical field

The invention belongs to medical art, relate to the novel method that medical material is produced, particularly relate to dopexamine hydrochloride novel preparation method.

Background technology

Dopexamine hydrochloride is that a kind of Catecholamine drugs chemical structure of synthesis is similar to Dopamine HCL, has very strong beta 2-adrenergic receptor excitation, and to dopamine D A1 and DA2 acceptor, and the excitation of β1-adrenergicreceptor is more weak; Energy inhibitory neuron is to the picked-up of catecholamine.The Positive Chronotropic Action of this product and positive inotropic action are by medicine indirect excitation β1-adrenergicreceptor, improve the activities of pressure receptor, suppress the re-uptake of norepinephrine, and direct excited heart beta 2-adrenergic receptor produces.The volume of blood flow of kidney, cardiac muscle and skeletal muscle can also be increased.

Dopexamine hydrochloride is a kind of medicine being mainly used in anti-heart failure.It has very strong beta 2-adrenergic receptor excitation, and the significant expansion artery blood vessel of energy, can increase the volume of blood flow of cardiac muscle, kidney, liver, skeletal muscle, reduce cardiac afterload; To heart beta 2-adrenergic receptor and Dopamine Receptors excitation more weak, myocardial contraction can be made to strengthen, increased heart rate, and have slight natriuretic diuretic effect.Be applicable to treat the patient that cardiac output after acute heart failure and heart operation is low.

Dopexamine hydrochloride does not also ratify listing at home as medicine, at present both at home and abroad disclosed production method with B-bromo ethylbenzene, 6-amino-hexanol, 3.4-dimethoxy-phenylethylamine for Material synthesis, deficiency is long reaction time, react under needing the high temperature more than 160 DEG C, complicated operation, the more content of by product kind is higher, for feed purification brings larger difficulty.

Summary of the invention

The object of the invention is, provide a kind of dopexamine hydrochloride novel preparation method, its raw material adopted is easy to get, and reaction conditions is gentle, and the reaction process time is short, and reaction yield is high, and by product kind is few, and by-products content is lower, and purifying is easy.

The technical scheme adopted is:

Dopexamine hydrochloride, is characterized in that: be with the own diamino of 1.6-, Beta-bromo ethylbenzene and 3.4-dimethoxy-Beta-bromo ethylbenzene for starting raw material, and 1:1:1 proportioning raw materials adds catalyst reaction and makes in reaction solvent in molar ratio.

Above-mentioned catalyzer is potassium hexafluoroaluminate, and catalyst levels is calculated in molar ratio as 0.02-0.25%.

Above-mentioned reaction solvent comprises a kind of acetonitrile, acetone, trichloromethane.

Dopexamine hydrochloride preparation method, comprises the following steps:

preparation N-3,4-Dimethoxyphenethyl-N '-styroyl-1, the ratio of 6-hexanediamine 1:1 in molar ratio gets Beta-bromo ethylbenzene, 1.6-hexanediamine, in solvent, acetonitrile or acetone or trichloromethane add potassium hexafluoroaluminate and mineral alkali potassium hydroxide or sodium hydroxide or salt of wormwood, in stirring at normal temperature 4-8 hour; The ratio of 1:1 adds 3.4-dimethoxy-Beta-bromo ethylbenzene in molar ratio again, continues at stirring at normal temperature 4-8 hour; Cross and filter potassium hexafluoroaluminate and excessive alkali;

preparation dopexamine hydrochloride crude product:

Above-mentioned filtrate, not treated, directly add 36% hydrochloric acid, stirring at normal temperature 0.5 hour, intensification water trap removes organic solvent, in 100-105 DEG C of insulated and stirred 4 hours, cools to 0--4 DEG C of insulation 8 hours, filters to obtain dopexamine hydrochloride crude product;

preparation dopexamine hydrochloride:

95% ethanol of above-mentioned crude product and 5 times of (W/V) volumes heats, and dissolves completely, adds dopexamine hydrochloride crude product 0.5%(W/w) needle-use activated carbon, reflux 30 minutes, filtration carbon removal; Filtrate is lowered the temperature, and in 0--4 DEG C of crystallization 8 hours, collecting by filtration crystal, 50-55 DEG C of drying 8 hours, obtained dopexamine hydrochloride.

The raw material that the present invention adopts is easy to get, and reaction conditions is gentle, and the reaction process time is short, and reaction yield is high, and by product kind is few, and by-products content is lower, and purifying is easy.

Embodiment

Embodiment 1:

In 1000ml there-necked flask, add 500ml acetonitrile, 58.1g1,6-hexanediamine respectively, 92.8g Beta-bromo ethylbenzene, 6g potassium hexafluoroaluminate, 70g potassium hydroxide, stir lower 25 DEG C of reactions 2 hours, be warmed up to 45 DEG C of back flow reaction 2 hours; Cool to 25 DEG C, add 109.5g3.4-dimethoxy-Beta-bromo ethylbenzene, stir lower 25 DEG C of reactions 2 hours, be warmed up to 45 DEG C of back flow reaction 2 hours, cool to 25; Cross and filter potassium hexafluoroaluminate and excessive alkali; Filtrate is refunded in 1000ml there-necked flask, adds 300ml36% hydrochloric acid, and stir lower 25 DEG C of insulations 0.5 hour, intensification water trap divides acetonitrile, adds into 100ml36% hydrochloric acid, is warmed up to 100 DEG C in 100-105 DEG C of insulation 4 hours; Cool to 0--4 DEG C, insulation crystallization 8 hours, collected by filtration, obtains wet dopexamine hydrochloride crude product 202g; Dopexamine hydrochloride crude product 202.7g adds the heating of 1000ml95% ethanol, dissolves completely, adds 1g needle-use activated carbon, reflux 30 minutes, filter carbon removal; Filtrate is lowered the temperature, and in 0--4 DEG C of crystallization 8 hours, collecting by filtration crystal, 50-55 DEG C of drying 8 hours, obtained dopexamine hydrochloride 147.5g, yield 69.5%.

Embodiment 2:

In 1000ml there-necked flask, add 500ml acetone, 58.1g1,6-hexanediamine respectively, 92.8g Beta-bromo ethylbenzene, 12g potassium hexafluoroaluminate, 50g sodium hydroxide, stir lower 25 DEG C of reactions 2 hours, be warmed up to 60 DEG C of back flow reaction 2 hours; Cool to 25 DEG C, add 109.5g3.4-dimethoxy-Beta-bromo ethylbenzene, stir lower 25 DEG C of reactions 2 hours, be warmed up to 60 DEG C of back flow reaction 2 hours, cool to 25; Cross and filter potassium hexafluoroaluminate and excessive alkali; Filtrate is refunded in 1000ml there-necked flask, adds 300ml36% hydrochloric acid, and stir lower 25 DEG C of insulations 0.5 hour, intensification water trap divides acetonitrile, adds into 100ml36% hydrochloric acid, is warmed up to 100 DEG C in 100-105 DEG C of insulation 4 hours; Cool to 0--4 DEG C, insulation crystallization 8 hours, collected by filtration, obtains wet dopexamine hydrochloride crude product 202g; Dopexamine hydrochloride crude product 212.0g adds the heating of 1000ml95% ethanol, dissolves completely, adds 1g needle-use activated carbon, reflux 30 minutes, filter carbon removal; Filtrate is lowered the temperature, and in 0--4 DEG C of crystallization 8 hours, collecting by filtration crystal, 50-55 DEG C of drying 8 hours, obtained dopexamine hydrochloride 149.8g, yield 70.6%.

Embodiment 3:

In 1000ml there-necked flask, add 500ml trichloromethane, 58.1g1,6-hexanediamine respectively, 92.8g Beta-bromo ethylbenzene, 6g potassium hexafluoroaluminate, 150g Anhydrous potassium carbonate, stir lower 25 DEG C of reactions 2 hours, be warmed up to 60 DEG C of back flow reaction 2 hours; Cool to 25 DEG C, add 109.5g3.4-dimethoxy-Beta-bromo ethylbenzene, stir lower 25 DEG C of reactions 2 hours, be warmed up to 60 DEG C of back flow reaction 2 hours, cool to 25; Cross and filter potassium hexafluoroaluminate and excessive alkali; Filtrate is refunded in 1000ml there-necked flask, adds 300ml36% hydrochloric acid, and stir lower 25 DEG C of insulations 0.5 hour, intensification water trap divides acetonitrile, adds into 100ml36% hydrochloric acid, is warmed up to 100 DEG C in 100-105 DEG C of insulation 4 hours; Cool to 0--4 DEG C, insulation crystallization 8 hours, collected by filtration, obtains wet dopexamine hydrochloride crude product 202g; Dopexamine hydrochloride crude product 195.6g adds the heating of 1000ml95% ethanol, dissolves completely, adds 1g needle-use activated carbon, reflux 30 minutes, filter carbon removal; Filtrate is lowered the temperature, and in 0--4 DEG C of crystallization 8 hours, collecting by filtration crystal, 50-55 DEG C of drying 8 hours, obtained dopexamine hydrochloride 125.8g, yield 59.3%.

Preparation method of the present invention, its reaction formula is as follows:

。

Claims

1. a dopexamine hydrochloride, is characterized in that: be starting raw material by the own diamino of 1.6-, Beta-bromo ethylbenzene and 3.4-dimethoxy-Beta-bromo ethylbenzene, and 1:1:1 proportioning raw materials adds catalyst reaction and makes in reaction solvent in molar ratio.

2. dopexamine hydrochloride according to claim 1, is characterized in that described catalyzer is potassium hexafluoroaluminate, and catalyst levels take molar ratio computing as 0.02-0.25%.

3. dopexamine hydrochloride according to claim 1, is characterized in that described reaction solvent comprises acetonitrile, acetone, trichloromethane.

4. a dopexamine hydrochloride preparation method, is characterized in that comprising the following steps:

preparation N-3,4-Dimethoxyphenethyl-N '-styroyl-1,6-hexanediamine: the ratio of 1:1 gets Beta-bromo ethylbenzene, 1.6-hexanediamine in molar ratio, in solvent, acetonitrile or acetone or trichloromethane add potassium hexafluoroaluminate and mineral alkali potassium hydroxide or sodium hydroxide or salt of wormwood, in stirring at normal temperature 4-8 hour; The ratio of 1:1 adds 3.4-dimethoxy-Beta-bromo ethylbenzene in molar ratio again, continues at stirring at normal temperature 4-8 hour; Cross and filter potassium hexafluoroaluminate and excessive alkali;

preparation dopexamine hydrochloride crude product:

preparation dopexamine hydrochloride:

95% ethanol of above-mentioned crude product and 5 times of volumes heats, and dissolves completely, add dopexamine hydrochloride crude product by weight 0.5% needle-use activated carbon, reflux 30 minutes, filtration carbon removal; Filtrate is lowered the temperature, and in 0--4 DEG C of crystallization 8 hours, collecting by filtration crystal, 50-55 DEG C of drying 8 hours, obtained dopexamine hydrochloride.