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Preparation method of trimetazidine

A technology of trimetazidine and piperazine, which is applied in the field of preparation of pharmaceutical compounds, can solve the problems of difficult industrial production, unfavorable scale-up, unfavorable production, etc., and achieve the effects of high yield, enhanced safety, and reduced synthesis cost

Active Publication Date: 2013-01-02
REYOUNG PHARMA
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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 were reacted to generate 4-(2,3,4-trimethoxybenzyl)-2-piper azinones, followed by LiAlH 4 Reduction to 2,3,4-trimethoxybenzylpiperazine (i.e. trimetazidine) with low yield
[0014] 5. In U.S. Patent US5142053, LiAlH is made of 2,3,4-trimethoxybenzaldehyde and piperazine 4 or NaBH 4 prepared by the reductive amination reaction, the yield is high, but the dangerous LiAlH is used 4 and NaBH 4 , 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 improves the yield of the reaction, it uses the more dangerous LiAlH 4 and NaBH 4 , is not conducive to the amplification of synthesis, and is difficult to industrialized production

Method used

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  • Preparation method of trimetazidine
  • Preparation method of trimetazidine
  • Preparation method of trimetazidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Put 180g of 2,3,4-trimethoxybenzaldehyde, 553g of piperazine, and 800mL of methanol into the reactor, quickly raise the temperature of the reaction system to 63±3°C, then add 733g of formic acid into the reaction system, raise the temperature to 85°C and keep At this temperature for 3 hours, methanol was distilled off under reduced pressure, then 800mL of 40% sodium hydroxide solution was added to the reaction system, the temperature was raised to 100°C and kept at this temperature for 1 hour, the pH was adjusted to 11, the temperature was lowered, and used at 12±2°C 8N hydrochloric acid to adjust the pH value of the material liquid to 1, wash 3 times with 200mL of dichloromethane each, and then neutralize the aqueous phase with 520g40% sodium hydroxide to a pH value of 12, extract 3 times with 100mL of toluene each, anhydrous sulfuric acid Magnesium drying, vacuum rotary evaporation to obtain trimetazidine 217.3g, yield: 89%.

Embodiment 2

[0038] Put 180g of 2,3,4-trimethoxybenzaldehyde, 620g of piperazine, and 800mL of toluene into the reactor, quickly raise the temperature of the reaction system to 103±3°C, then add 648g of formic acid into the reaction system, raise the temperature to 105°C and keep At this temperature for 3.5 hours, toluene was evaporated under reduced pressure, then 800mL of 40% sodium hydroxide solution was added to the reaction system, the temperature was raised to 105°C and kept at this temperature for 1.5 hours, the pH was adjusted to 12, the temperature was lowered, and used at 8±3°C Adjust the pH value of the feed solution to 1.5 with concentrated hydrochloric acid, wash with 200mL of chloroform three times, neutralize the water phase with 490g of 40% sodium hydroxide to pH 10, extract with 100mL of toluene three times, and dry over anhydrous magnesium sulfate , 202.7 g of trimetazidine was obtained by rotary evaporation under reduced pressure, yield: 83%.

Embodiment 3

[0040] Put 180g of 2,3,4-trimethoxybenzaldehyde, 720g of piperazine, and 800mL of toluene into the reactor, quickly raise the temperature of the reaction system to 103±3°C, then add 648g of formic acid into the reaction system, raise the temperature to 110°C and keep At this temperature for 5 hours, toluene was evaporated under reduced pressure, then 800mL of 40% sodium hydroxide solution was added to the reaction system, the temperature was raised to 105°C and maintained at this temperature for 1.5 hours, the pH was adjusted to 13, the temperature was lowered, and used at 5-10°C Concentrated hydrochloric acid to adjust the pH value of the feed solution to 2, wash with 200mL of chloroform for 3 times, then neutralize the water phase with 490g of 40% sodium hydroxide until the pH value is 10, extract with 100mL of toluene for 3 times, and dry over anhydrous magnesium sulfate , 202.7 g of trimetazidine was obtained by rotary evaporation under reduced pressure, yield: 83%.

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Abstract

The invention relates to a preparation method of trimetazidine, belonging to the preparation field of medicine compound. The method comprises the steps of: by taking 2, 3, 4-trimethoxy benzaldehyde and piperazine as raw materials and formic acid as a catalyst; adding a solvent and formic acid in the 2, 3, 4-trimethoxy benzaldehyde and the piperazine for reaction; removing the solvent by steaming, and adjusting the pH value of reaction liquid to be 11-13; and then, carrying out reflux, acidification and rotary steaming to obtain the trimetazidine. In the method, the reductive amination reaction is adopted and the trimetazidine is synthesized in one step under the condition that the formic acid is taken as the catalyst, and the yield reaches up to 83-92%; meanwhile, precious metal palladium catalyst is not used, so that the synthesis cost is reduced. The LiAlH4 and NaBH4 which are high in danger are not used, so that the experimental safety is improved; and the method is beneficial to the large-scale production of the trimetazidine.

Description

technical field [0001] The invention relates to a preparation method of trimetazidine, which belongs to the field of preparation of pharmaceutical compounds. Background technique [0002] [0003] Formula 1 [0004] The chemical name of trimetazidine is 1-(2,3,4-trimethoxybenzyl)piperazine (Formula 1), which is an anti-anginal drug successfully developed by Servier Company in France (EP:453365, US: 5142053), is a stronger anti-anginal drug, its onset is slower than that of nitroglycerin, but its duration of action is longer. 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
Inventor 何茂群苗得足王龙科黄文涛曹光伟刘洋张鹏
Owner REYOUNG PHARMA
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