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Trimetazidine and production method for hydrochloride of trimetazidine

A technology of trimetazidine and its production method, which is applied in the field of production of trimetazidine and its hydrochloride, can solve the problems of difficult preparation, high risk, unfavorable production, etc., and is beneficial to large-scale production and reduces synthesis Cost, Effect of Enhanced Safety

Inactive Publication Date: 2011-08-03
LIAONING BENYUAN PHARMACY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 2. In French Patent No: 2493316, 2,3,4-trimethoxybenzyl chloride and 2-piperazinone are used as raw materials, and the product is then reduced with LiAlH4 to obtain trimetazidine, with a low yield. Simultaneously raw material 2-piperazinone is not easy to prepare
[0014] 5. In U.S. Patent No. 5,142,053, 2,3,4-trimethoxybenzaldehyde and piperazine are used as raw materials, and LiAlH4 or NaHB4 is prepared by reductive amination reaction. The yield is high, but the dangerous LiAlH4 is used and NaHB4, not conducive to large-scale production
[0016] The biggest defect of the first four methods is that the yield is low. Although the fifth method has improved the yield of the reaction, it uses LiAlH4 and NaHB4 which are dangerous, which is unfavorable for the amplification of synthesis. The main purpose of this application is to develop a A more complete and practical method for producing trimetazidine

Method used

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  • Trimetazidine and production method for hydrochloride of trimetazidine
  • Trimetazidine and production method for hydrochloride of trimetazidine
  • Trimetazidine and production method for hydrochloride of trimetazidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Under the protection of nitrogen, put 78.4g2,3,4-trimethoxybenzaldehyde, 68.8g piperazine, 400mL methyl tert-butyl ether, 4gPd / C into the reactor, quickly raise the temperature of the reaction system to 50-55°C, and then The reaction system was fed with 10 bar hydrogen, and then the temperature was continued to rise to 70°C and maintained at this temperature for about 2 hours, and then the reaction liquid was cooled to 50°C and the catalyst was filtered. Then cool the filtrate to 10°C to filter unreacted piperazine, then add 200mL water to the filtrate, adjust the pH of the filtrate to 7.9-8 with 7N hydrochloric acid at 13-18°C, and add 600mL water to the filtrate, stir for half an hour Separation, the organic phase was extracted twice with 100mL toluene and discarded, the aqueous phase was cooled with an ice-water bath, 42g sodium hydroxide was slowly added, stirred and extracted three times with 120mL toluene, dried over anhydrous magnesium sulfate, and rotary evaporat...

Embodiment 2

[0027] Under the protection of nitrogen, put 78.4g 2,3,4-trimethoxybenzaldehyde, 90.6g piperazine, 400mL ethanol, 4gPd / C into the reactor, quickly raise the temperature of the reaction system to 70°C, and then inject 10bar hydrogen into the reaction system, Then continue to heat up to 70°C and maintain this temperature for about 2 hours, then cool the reaction solution to 20°C and filter the catalyst. Then the filtrate was spin-dried under reduced pressure, added 200mL of toluene cooled to -10°C and stirred, filtered off unreacted piperazine, then added 200mL of water to the filtrate, adjusted the pH of the filtrate to 6 with concentrated hydrochloric acid, and extracted the two parts with 120mL of toluene. Discarded once, the water phase was cooled with an ice-water bath, slowly added 42g of sodium hydroxide, stirred and extracted three times with 120mL of toluene, dried over anhydrous magnesium sulfate, and rotary evaporated under reduced pressure to obtain trimetazidine, yie...

Embodiment 3

[0029] Under nitrogen protection, the trimetazidine 100.1g that example 1 obtains is stirred and dissolved in 216.0g isopropanol, and the filtrate after filtering is transferred to the stainless steel reactor rinsed with isopropanol, and slowly added to fill 79.2g concentrated hydrochloric acid In 348g of isopropanol solution, the temperature was controlled not to exceed 40°C and stirred for half an hour, the reaction solution was distilled to 270g at room temperature and stirred at 0°C for 2 hours, filtered to obtain trimetazidine hydrochloride, and rinsed twice with isopropanol , Yield: 98%.

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Abstract

The invention discloses trimetazidine and a production method for hydrochloride of trimetazidine, belonging to the technical field of chemical synthesis. The invention is characterized in that under nitrogen protection, the trimetazidine is prepared by taking 2, 3, 4-trimethoxybenzaldehyde and piperazine as raw materials and Pd / C as a catalyst in the present of H2. The trimetazidine and the production method for hydrochloride of trimetazidine have the advantages of low cost, high yield, good environmental protection and the like.

Description

technical field [0001] The present invention relates to a kind of use Pd / C as catalyst to prepare anti-angina medicine trimetazidine chemical name is 1-(2,3,4-trimethoxybenzyl)piperazine formula (3) and the production of its hydrochloride method. [0002] [0003] Formula (3) technical background [0004] Trimetazidine is an anti-anginal drug (EP: 453365, US: 5142053) successfully developed by the French company Servier. long. It has anti-epinephrine, norepinephrine and vasopressin effects, can reduce vascular resistance, increase coronary blood flow and peripheral blood flow, and promote myocardial metabolism and myocardial energy production. At the same time, it can reduce the workload of the heart. Reduce myocardial oxygen consumption and myocardial energy consumption, thereby improving the balance between supply and demand of myocardial oxygen. Controlled trials in patients with angina pectoris have shown that trimetazidine can increase coronary blood flow reserv...

Claims

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Application Information

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IPC IPC(8): C07D295/096
Inventor 颜文革漆新国李昕昊赵树明刘念
Owner LIAONING BENYUAN PHARMACY CO LTD
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