Synthesis method of trimetazidine hydrochloride

A technology of trimetazidine hydrochloride and its synthesis method, which is applied in the field of synthesis of antiangina pectoris drugs, can solve problems such as unfavorable production, cumbersome operation steps, and unsuitability for industrial production, so as to improve yield and purity, reduce production cost, and easily The effect of recycling

Active Publication Date: 2020-01-21
BEIJING WINSUNNY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] 4. In the U.S. Patent US5142053, 2,3,4-trimethoxybenzaldehyde and piperazine are used as raw materials, and the reductive amination reaction of LiAlH4 or NaBH4 is prepared. The yield is high, but the dangerous LiAlH4 is used and NaBH4, not conducive to large-scale production
[0015] 5. In the patent of CN102140084A, 2,3,4-trimethoxybenzaldehyde and piperazine were used as raw materials, and Pd / C was used as a catalyst to reductively aminate with hydrogen to prepare trimetazidine, and then further transform In the form of hydrochloride, the operation steps of this patent are cumbersome and not suitable for industrial production

Method used

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  • Synthesis method of trimetazidine hydrochloride
  • Synthesis method of trimetazidine hydrochloride
  • Synthesis method of trimetazidine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Add 500kg of ethanol, 120kg of 2,3,4-trimethoxybenzaldehyde, 150kg of anhydrous piperazine, and 2kg of Lindella catalyst (Pd-CaCO3-PbO containing 10% palladium) to the 2000L hydrogenation reactor, and the addition is completed. The hydrogen pressure was 2.0MPa, and the temperature was raised to 60°C and kept stirring for 16 hours, during which the hydrogen pressure was controlled at 2.0Mpa until the reaction was complete. The reaction solution was lowered to room temperature, filtered to remove the Lindella catalyst, concentrated under reduced pressure at 30-40°C until there was no distillate, added 1000kg of acetone, stirred for 10 minutes, added concentrated hydrochloric acid to 125kg, cooled to 10°C for crystallization and stirred for 5 hours, and centrifuged to obtain Trimetazidine hydrochloride was 191.3kg, the yield was 92.5%, and the purity was 100%, and the trimetazidine hydrochloride impurity B was not detected.

Embodiment 2

[0041] In the 2000L hydrogenation reactor, add 450kg methanol, 120kg 2,3,4-trimethoxybenzaldehyde, 210kg anhydrous piperazine, 2.4kg Lindela catalyst (Pd-CaCO3-PbAc2 containing palladium 5%), finish . The hydrogen pressure was 2.0MPa, and the temperature was raised to 65°C and kept stirring for 16 hours, during which the hydrogen pressure was controlled at 1.0Mpa until the reaction was complete. The reaction solution was lowered to room temperature, filtered to remove the Lindella catalyst, concentrated under reduced pressure at 30-40°C until there was no distillate, added 1000kg of acetone, stirred for 10 minutes, added 125kg of concentrated hydrochloric acid, cooled to 20°C for crystallization and stirred for 5 hours, and centrifuged to obtain Trimetazidine hydrochloride was 189.6 kg, the yield was 91.7%, and the purity was 99.9%, and trimetazidine hydrochloride impurity B was not detected.

Embodiment 3

[0043] In the 2000L hydrogenation reactor, add 550kg Virahol, 120kg 2,3,4-trimethoxybenzaldehyde successively, 184kg anhydrous piperazine, 3.6kg Lindela catalyst (Pd-CaCO3-PbO contains palladium 7%), Gabi. The hydrogen pressure was 2.0MPa, and the temperature was raised to 50°C and kept stirring for 17 hours, during which the hydrogen pressure was controlled at 2.5Mpa until the reaction was complete. The reaction solution was lowered to room temperature, filtered to remove the Lindella catalyst, concentrated under reduced pressure at 30-40°C until there was no distillate, added 1000kg of ethyl acetate, stirred for 10 minutes, added 125kg of concentrated hydrochloric acid, cooled to 15°C for crystallization and stirred for 5 hours. 190.5 kg of trimetazidine hydrochloride was obtained by centrifugation, with a yield of 92.1% and a purity of 99.8%, and trimetazidine hydrochloride impurity B was not detected.

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Abstract

The invention provides a synthesis method of trimetazidine hydrochloride, which comprises the following steps: carrying out hydroamination reaction by using 2,3,4-trimethoxybenzaldehyde and piperazineanhydrous as raw materials, and catalyzing by using a Lindlar catalyst. The trimetazidine hydrochloride produced by the method does not contains trimetazidine hydrochloride impurity B and has high purity.

Description

technical field [0001] The invention relates to a synthesis method of an antiangina drug, in particular to a synthesis method of trimetazidine hydrochloride. Background technique [0002] Angina pectoris is a common cardiovascular disease, which is caused by coronary artery atherosclerosis and stenosis, coronary artery insufficiency, temporary myocardial ischemia and hypoxia, and a group of comprehensive symptoms with precordial pain as the main clinical manifestation. It is one of the coronary heart diseases with the highest incidence rate, which seriously threatens human health and life. It is mainly divided into stable angina and unstable angina. Angina pectoris can occur at any time in 24 hours, but most of them are from early morning to morning, and variant angina pectoris often occurs regularly at night. Therefore, it is required that the therapeutic drug can maintain an effective therapeutic concentration within 24 hours to ensure the effectiveness, safety and stabi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 刘志东王力李迎春马德彪李正杰
Owner BEIJING WINSUNNY PHARMA CO LTD
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