CN102140084A - Trimetazidine and production method for hydrochloride of trimetazidine - Google Patents
Trimetazidine and production method for hydrochloride of trimetazidine Download PDFInfo
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- CN102140084A CN102140084A CN2010101062007A CN201010106200A CN102140084A CN 102140084 A CN102140084 A CN 102140084A CN 2010101062007 A CN2010101062007 A CN 2010101062007A CN 201010106200 A CN201010106200 A CN 201010106200A CN 102140084 A CN102140084 A CN 102140084A
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- trimetazidine
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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
The present invention relates to a kind of is that Preparation of Catalyst antianginal drug trimetazidine chemical name is the production method of 1-(2,3,4-trimethoxy benzyl) piperazine formula (3) and hydrochloride thereof with Pd/C.
Formula (3)
Technical background
Trimetazidine is that French Shi Weiya company researches and develops successful a kind of antianginal drug (EP:453365 US:5142053), is the stronger anti-anginal drug of effect, and its onset is slow than pannonit, but acting duration is longer.Have the effect to antiadrenergic drug, norepinephrine and vassopressin, can reduce vascular resistance, blood flow around coronary blood flow increasing reaches promotes the generation of myocardial metabolism and cardiac energy.Can reduce simultaneously the heart working load.Reduce the consumption of myocardial consumption of oxygen and cardiac energy, thereby improve the equilibrium of supply and demand of myocardium oxygen.Stenocardia patient's controlled trial shows that trimetazidine can increase the coronary flow reserves in human body, and the myocardial ischemia that delayed motion is brought out significantly reduces anginal frequency of disease development.
The disclosed method for preparing trimetazidine has following:
1. in BSM (Special Medicament Patents), No.805M has early proposed to prepare the method for trimetazidine, with 2,3,4-trimethoxy benzyl chloride and piperazine formaldehyde are raw material, finally obtain the hydrochloride of trimetazidine by hydrolysis, acidifying, all do not obtain satisfied result but product is purity or yield.After this in the U.S. Pat 3262852, improved and planted the method for preparing trimetazidine, by 2,3, the condensation reaction of 4-trimethoxy benzyl chloride and N-formyl piperazine preparation.
2. in French Patent No:2493316, be with 2,3,4-trimethoxy benzyl chloride and 2-piperazine ketone are raw material, and resultant obtains trimetazidine with the LiAlH4 reduction again, and yield is lower, and raw material 2-piperazine ketone is difficult for preparation simultaneously.
3. in Japanese Patent JP48032889, with 2,3,4-TMB and Uricida are raw material, and single stage method has been synthesized trimetazidine, and temperature of reaction is 80-90 ℃, and the reaction times is 10-18 hour, has only 38% yield.
4. with 2,3,4-trimethoxy benzyl chloride and piperazine are raw material, generate trimetazidine, and yield is 44.2%.(Wang Wenhao, Zhang Xin, Xu Ping, Chinese pharmaceutical chemistry magazine, 2003,13,218-221)
5. in U.S. Pat 5142053, by 2,3,4-TMB and piperazine are raw material, the reductive amination process preparation of LiAlH4 or NaHB4, and yield is higher, but used dangerous higher LiAlH4 and NaHB4, be unfavorable for large-scale production.
The defective of preceding four kinds of method maximums is that yield is lower, though the 5th kind of method improved the yield of reaction, used dangerous higher LiAlH4 and NaHB4, unfavorable synthetic amplifies, the application's main purpose is that one of development is more perfect, the method for practicable production trimetazidine.
Summary of the invention
At the problems referred to above of prior art, main purpose of the present invention provides a kind of production method of trimetazidine.
The present invention with on market, can directly buy 2,3,4-TMB and piperazine are raw material, Pd/C is a catalyzer, nitrogen protection is the preparation trimetazidine down, optionally, can be made into its pharmaceutical salt form.
The beneficial effect of the invention:
At first, the present invention has adopted advanced catalytic reduction amination reaction, is catalyzer at Pd/C, and there is preparation trimetazidine down in H2, is being converted into hydrochloride then.Adopt the present invention to prepare trimetazidine, yield can reach 95-98%, greatly reduces synthetic cost.
Next avoids using dangerous higher LiAlH4 and NaHB4, has strengthened the security of experiment, helps the scale operation of trimetazidine simultaneously.
Below by specific embodiment the present invention is specifically described, but the present invention is not limited to following examples.
Embodiment
The present invention will be further described below in conjunction with the embodiment of the invention.Be necessary to be pointed out that at this following examples only are used for further instruction of the present invention; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make some nonessential improvement and adjustment to the present invention according to the foregoing invention content.
Embodiment 1
Under the nitrogen protection; 78.4g2; 3,4-TMB, 68.8g piperazine; the 400mL methyl tertiary butyl ether; 4gPd/C puts into reactor, reaction system is warming up to 50-55 ℃ rapidly, and reaction system feeds 10bar hydrogen then; continue to be warming up to 70 ℃ and kept this temperature about 2 hours then, then reaction solution is cooled to 50 ℃ of filtering catalysts.Then filtrate is cooled to 10 ℃ and filters responseless piperazine, in filtrate, add 200mL water then, with 7N hydrochloric acid filtrate PH is transferred to 7.9-8 at 13-18 ℃, and in filtrate, add 600mL water, stir separatory half an hour, organic phase abandons with 100mL toluene extracting twice, and water cools off with ice-water bath, slowly adds 42g sodium hydroxide, stir and extract three times with 120mL toluene, anhydrous magnesium sulfate drying, vacuum rotary steam gets trimetazidine, yield: 95-98%.
Embodiment 2
Under the nitrogen protection; 78.4g2; 3,4-TMB, 90.6g piperazine; 400mL ethanol; 4gPd/C puts into reactor, reaction system is warming up to 70 ℃ rapidly, and reaction system feeds 10bar hydrogen then; continue to be warming up to 70 ℃ and kept this temperature about 2 hours then, then reaction solution is cooled to 20 ℃ of filtering catalysts.Then filtrate decompression is spin-dried for, adding 200mL is cooled to-10 ℃ toluene stirring, filters out responseless piperazine, adds 200mL water then in filtrate, with concentrated hydrochloric acid filtrate PH is transferred to 6, abandon with 120mL toluene extracting twice, water cools off with ice-water bath, slowly adds 42g sodium hydroxide, stir and extract three times with 120mL toluene, anhydrous magnesium sulfate drying, vacuum rotary steam gets trimetazidine, yield: 95-98%.
Embodiment 3
Under the nitrogen protection; the trimetazidine 100.1g stirring and dissolving that example 1 is obtained is in the 216.0g Virahol; filtrate filtered changes the stainless steel reactor of crossing with isopropyl alcohol over to; slowly join in the 348g aqueous isopropanol that fills the 79.2g concentrated hydrochloric acid; controlled temperature is no more than 40 ℃ and stir half an hour; reaction solution normal-temperature distilled to 270g and 0 ℃ stir filtered in 2 hours the trimetazidine hydrochloride, and with Virahol drip washing twice, yield: 98%.
Claims (7)
1. the production method of trimetazidine and hydrochloride thereof.This method feature is, under the nitrogen protection, making compound (1) and compound (2) is to use the hydrogen reducing amination under the condition of catalyzer at Pd/C, and the preparation trimetazidine optionally, can be made into its pharmaceutical salt form.
Formula (1) formula (2)
2. the production method of a kind of trimetazidine as claimed in claim 1 and hydrochloride thereof is characterized in that solvent is selected from methyl tertiary butyl ether, ether, methyl alcohol, ethanol, Virahol etc.
3. the production method of a kind of trimetazidine as claimed in claim 1 and hydrochloride thereof is characterized in that, used catalyzer is 5%Pd/C.
4. the method for claim 1, the aminating temperature of hydrogen reducing is 45-75 ℃.
5. the method for claim 1, wherein the mol ratio of compound (1) and compound (2) is 1: 2 to 1: 3
6. the production method of a trimetazidine hydrochloride, it is characterized in that: the trimetazidine that makes is slowly joined in the hydrochloric acid soln that fills lower alcohol at the solution of lower alcohol, controlled temperature is no more than 40 ℃, stir half an hour, steam partial solvent, be cooled to 0 ℃ stir filtered in 2 hours the trimetazidine hydrochloride, and use Virahol drip washing, drying gets the trimetazidine hydrochloride.
7. method as claimed in claim 6, a kind of production method of trimetazidine hydrochloride is characterized in that, used solvent can be a methyl alcohol, ethanol, Virahol etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2010101062007A CN102140084A (en) | 2010-02-03 | 2010-02-03 | Trimetazidine and production method for hydrochloride of trimetazidine |
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| CN2010101062007A CN102140084A (en) | 2010-02-03 | 2010-02-03 | Trimetazidine and production method for hydrochloride of trimetazidine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850296A (en) * | 2012-09-29 | 2013-01-02 | 瑞阳制药有限公司 | Preparation method of trimetazidine |
| CN102993122A (en) * | 2012-12-24 | 2013-03-27 | 武汉武药制药有限公司 | Novel synthesis path of trimetazidine hydrochloride |
| CN103554057A (en) * | 2013-11-13 | 2014-02-05 | 武汉武药科技有限公司 | Trimetazidine derivative and preparation method thereof |
| CN110713471A (en) * | 2018-07-13 | 2020-01-21 | 北京福元医药股份有限公司沧州分公司 | Synthetic method of trimetazidine hydrochloride |
| CN116041280A (en) * | 2022-12-05 | 2023-05-02 | 三峡大学 | Preparation method of trimetazidine hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5142053A (en) * | 1990-04-20 | 1992-08-25 | Adir Et Compagnie | Process for the preparation of 1-(2,3,4-trimethoxybenzyl)piperazine by reductive animation |
| RU2234501C1 (en) * | 2002-12-25 | 2004-08-20 | Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" | Method for preparing 1-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride |
| CN1715275A (en) * | 2004-06-29 | 2006-01-04 | 北京德众万全药物技术开发有限公司 | Simple process for preparing trimetazidine and its medicinal salts |
| CN101575321A (en) * | 2009-06-18 | 2009-11-11 | 绍兴文理学院 | Trimetazidine and production method of hydrochloride thereof |
-
2010
- 2010-02-03 CN CN2010101062007A patent/CN102140084A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5142053A (en) * | 1990-04-20 | 1992-08-25 | Adir Et Compagnie | Process for the preparation of 1-(2,3,4-trimethoxybenzyl)piperazine by reductive animation |
| RU2234501C1 (en) * | 2002-12-25 | 2004-08-20 | Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" | Method for preparing 1-(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride |
| CN1715275A (en) * | 2004-06-29 | 2006-01-04 | 北京德众万全药物技术开发有限公司 | Simple process for preparing trimetazidine and its medicinal salts |
| CN101575321A (en) * | 2009-06-18 | 2009-11-11 | 绍兴文理学院 | Trimetazidine and production method of hydrochloride thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850296A (en) * | 2012-09-29 | 2013-01-02 | 瑞阳制药有限公司 | Preparation method of trimetazidine |
| CN102993122A (en) * | 2012-12-24 | 2013-03-27 | 武汉武药制药有限公司 | Novel synthesis path of trimetazidine hydrochloride |
| CN103554057A (en) * | 2013-11-13 | 2014-02-05 | 武汉武药科技有限公司 | Trimetazidine derivative and preparation method thereof |
| CN103554057B (en) * | 2013-11-13 | 2016-04-20 | 武汉武药科技有限公司 | Trimetazidine derivative and preparation method thereof |
| CN110713471A (en) * | 2018-07-13 | 2020-01-21 | 北京福元医药股份有限公司沧州分公司 | Synthetic method of trimetazidine hydrochloride |
| CN110713471B (en) * | 2018-07-13 | 2022-05-06 | 北京福元医药股份有限公司沧州分公司 | Synthetic method of trimetazidine hydrochloride |
| CN116041280A (en) * | 2022-12-05 | 2023-05-02 | 三峡大学 | Preparation method of trimetazidine hydrochloride |
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Application publication date: 20110803 |