Novel synthesis path of trimetazidine hydrochloride

A technology of trimetazidine hydrochloride and its synthesis method, which is applied in the field of synthesis of anti-anginal drug trimetazidine hydrochloride, can solve problems such as nickel activation and post-processing trouble, difficult preparation of 2-piperazinone, unfavorable industrial production, etc. Achieve the effect of low cost, easy industrialization, and simple post-processing

Active Publication Date: 2013-03-27
WUHAN WUYAO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In the first two methods, the first method has a lower yield of only 44%, and 2-piperazinone is more difficult to prepare in the second method; the third scheme uses dangerous lithium aluminum hydride or sodium borohydride Reduction is not conducive to industrial production; catalytic hydrogenation with noble metal palladium carbon is relatively expensive; catalytic hydrogenation with nickel is troublesome for activation and post-treatment of nickel

Method used

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  • Novel synthesis path of trimetazidine hydrochloride
  • Novel synthesis path of trimetazidine hydrochloride
  • Novel synthesis path of trimetazidine hydrochloride

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Effect test

Embodiment 1

[0033] Embodiment 1: the preparation method 1 of compound III

[0034] Add 12.6g (0.1mol) of 1.2.3-hydroxybenzene (compound II) into a 100ml single-necked bottle, then add 50ml of ethanol, cool to 10°C in an ice-water bath and stir to dissolve. After dissolving, add 2.2g (0.05mol) of paraformaldehyde at 0-5°C, then add 9.4g (0.05mol) of Boc-piperazine in 20ml of ethanol dropwise into the reaction system, and heat up to room temperature for 1.5-2 hours. After the reaction, the reaction solution was poured into 300ml of purified water, and a white solid was precipitated, which was filtered and dried to obtain 12.8g of compound III as a solid, with a yield of 80%.

[0035]

Embodiment 2

[0036] Embodiment 2: The preparation method 2 of compound III

[0037] Add 12.6g (0.1mol) of 1.2.3-hydroxybenzene (compound II) into a 100ml single-necked bottle, then add 50ml of methanol and cool to 10°C in an ice-water bath and stir to dissolve. After dissolving, add 6.0g of formaldehyde (0.05mol) saturated solution dropwise at 0-5°C, then add 9.4g (0.05mol) of Boc-piperazine in 20ml of methanol-alcohol solution dropwise into the reaction system, heat up to room temperature and react for 1.5-2 hours. After the reaction, the reaction solution was poured into 300ml of purified water, and a white solid was precipitated, which was filtered and dried to obtain 12.5 g of compound III as a solid, with a yield of 77%.

Embodiment 3

[0038] Embodiment 3: the preparation of compound IV

[0039] Add 16.2g (0.05mol) of compound III and 37.8g (0.3mol) of dimethyl sulfate into a 250ml three-necked flask, and slowly add aqueous sodium hydroxide solution (12g (0.3mol) of sodium hydroxide, 70g of water), the dropwise addition was completed, and the temperature was raised to 60-70°C and stirred for 2-6 hours. After the reaction was completed, the reaction solution was poured into 300ml of water, filtered by suction, and dried to obtain 16g of compound IV solid, with a yield of 87%.

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Abstract

The invention provides a novel synthesis path of trimetazidine hydrochloride. The novel synthesis path comprises the steps of: reacting 1,2,3-phenol (II) react with Boc piperazine to generate a compound III, reacting the compound III react with dimethyl sulfate to generate a compound IV, and carrying out deprotection and salifying on the compound IV to obtain trimetazidine hydrochloride. The novel synthesis path has the advantages of simple process, high yield and low cost and is easy for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for synthesizing an anti-angina drug trimetazidine hydrochloride. Background technique [0002] Trimetazidine hydrochloride, the chemical name is 1-[(2,3,4-trimethoxyphenyl)methyl]-piperazine hydrochloride, the chemical structure is as follows: [0003] [0004] Trimetazidine hydrochloride was reported in the literature in 1961 (Fr M805; 1961.10.16), and it was not until 1991 that the French company Servier (souvie) successfully developed a coronary artery vasodilator (EP453365; US 5142053). It can promote myocardial metabolism and myocardial energy production, while reducing myocardial oxygen consumption, thereby improving the balance of myocardial oxygen supply and demand, and can also increase the tolerance to cardiac glycosides, and can balance the heart rate and reduce the frequency of angina pectoris. [0005] The method of the reported synthetic trimetazidin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
Inventor 皮金红岳荣耀丁友友魏金维潘文清谢国范
Owner WUHAN WUYAO PHARMA
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