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Trimetazidine and production method of hydrochloride thereof

A technology of trimetazidine and a production method, which is applied in the field of preparing anti-angina pectoris drugs, can solve the problems of high risk, high production cost, low product yield and the like, and achieve the effects of reducing production cost and enhancing safety

Active Publication Date: 2009-11-11
BEIJING JIALIN PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The product yield of the first four methods is very low, the production cost is high, and the fourth method also needs to use the more dangerous LiAlH 4 and NaBH 4 reducing agent, and the fifth route that is often used at present mostly uses noble metal catalysts, and there are some defects

Method used

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  • Trimetazidine and production method of hydrochloride thereof
  • Trimetazidine and production method of hydrochloride thereof
  • Trimetazidine and production method of hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] In the autoclave, throw 196 grams (1.0 moles) of 2,3,4-trimethoxybenzaldehyde, 215 grams (2.5 moles) of anhydrous piperazine, 1500 milliliters of dimethoxyethyl ether and 25 grams of 5% nickel / silicon For algal earth catalyst, after purging the system with nitrogen, fill the hydrogen to 1.5MPa, raise the temperature to 75-85°C, stir and react for 6-8 hours until the reactant no longer absorbs hydrogen, cool and release the pressure, filter the reaction mixture, and pour into the filtrate Add 500 milliliters of water, adjust the pH value to 3-4 with hydrochloric acid with a concentration of 6M, separate the organic phase, wash the water phase with 150 milliliters of dichloroethane three times, and then wash the water phase with 460 grams of 50% sodium hydroxide After the solution was neutralized to pH=12, it was extracted three times with 120 ml of benzene each, the benzene extracts were combined, and the benzene was evaporated to obtain 239 g (~90%) of trimetazidine.

Embodiment 2

[0031] In the autoclave, throw 98 grams (0.5 mole) 2,3,4-trimethoxybenzaldehyde, 86 grams (1.0 mole) anhydrous piperazine, 500 milliliters of diisopropyl ether and 15 grams of 8% nickel / oxide Aluminum catalyst, after purging the system with nitrogen, fill hydrogen to 1.8MPa, heat up to 85-95°C, stir and react for 8 hours until the reactant no longer absorbs hydrogen, cool and release the pressure, filter the product, add 250 Milliliter of water, adjust the pH value to 3-4 with hydrochloric acid with a concentration of 6M, separate the organic phase, wash the aqueous phase with 100 ml of dichloroethane for 3 times, and then neutralize it with 220 grams of 50% sodium hydroxide solution. pH=12, the aqueous phase was extracted three times with 80 ml of toluene each, the toluene extracts were combined, and the toluene was evaporated to obtain 108 g (81%) of trimetazidine.

Embodiment 3

[0033] In the there-necked flask, add 400 milliliters of ethanol, 65 milliliters of 35% concentrated hydrochloric acid, under stirring, the solution of 133 grams of trimetazidine (0.5 mole) of embodiment 1 gained in 280 milliliters of ethanols is added dropwise to above-mentioned hydrochloric acid solution After the addition, stir for another 1 hour, and evaporate part of the solvent under normal pressure. After the distillate reaches 260 grams, the reaction system is cooled to 0 ° C, filtered, and the filter cake is washed with ethanol and dried to obtain 155.6 grams of trimetaz. The yield of oxazine dihydrochloride was 92%.

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Abstract

The invention discloses trimetazidine and a production method of hydrochloride thereof, which belongs to the technical field of chemical synthesis and is characterized by adopting 2,3,4-3-methoxybenzaldehyde and piperazine as raw materials. The method comprises the following steps of: adding a solvent, 2,3,4-3-methoxybenzaldehyde and anhydrous piperazine with the molar ratio of 1:1 to 1:3, and a nickel-based catalyst accounting for 3 to 10% of the mass percentage of the 2,3,4-3-methoxybenzaldehyde and the anhydrous piperazine to a pressure kettle; using nitrogen for purging before hydrogen is led in, with hydrogen pressure maintained within the range of 0.7MPa to 2.0MPa, reaction temperature within the range of 50 DEG C to 95 DEG C, reaction time within the range of 4 hours to 10 hours, and pH value regulated to 3 to 4; separating out organic phase; and recovering the solvent. The water phase is washed with chlorinated hydrocarbon extraction, and the pH value is regulated to 12, then the water phase is extracted with aromatic hydrocarbon, and the aromatic hydrocarbon in the aromatic hydrocarbon extraction liquid is steamed out, thus obtaining the trimetazidine. The invention has the advantages of low production cost, high yield, and good environmental protection.

Description

technical field [0001] The invention relates to a production method for preparing the antianginal drug trimetazidine with the chemical name of 1-(2,3,4-trimethoxybenzyl)piperazine (Formula 1) and its hydrochloride by using a nickel catalyst. [0002] [0003] Formula 1 technical background [0004] Trimetazidine has been reported in the literature since 1961 (Fr M805; 1961.10.16), and was successfully developed by France Servier (Souvie) company until 1991 (EP 453365; US 5142053 ), it can promote myocardial metabolism and myocardial energy production, and at the same time reduce myocardial oxygen consumption, thereby improving the balance of myocardial oxygen supply and demand, and can also increase the tolerance to cardiac glycosides. It has anti-epinephrine, norepinephrine and vasopressin effects, can reduce vascular resistance, and increase coronary and circulatory blood flow. In particular, trimetazidine can increase exercise test tolerance in patients with angina p...

Claims

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Application Information

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IPC IPC(8): C07D295/096
Inventor 齐陈泽姚献东孙旭东曾敏峰沈永淼肖慧泉
Owner BEIJING JIALIN PHARM INC
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