CN103554057B - Trimetazidine derivative and preparation method thereof - Google Patents

Trimetazidine derivative and preparation method thereof Download PDF

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Publication number
CN103554057B
CN103554057B CN201310567723.5A CN201310567723A CN103554057B CN 103554057 B CN103554057 B CN 103554057B CN 201310567723 A CN201310567723 A CN 201310567723A CN 103554057 B CN103554057 B CN 103554057B
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preparation
trimetazidine
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CN103554057A (en
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杨波
郭亚兵
朱墨
陈国华
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WUHAN WUYAO TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/36—Control of physical parameters of the fluid carrier in high pressure liquid systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to medicinal chemistry art, the invention discloses a kind of trimetazidine derivative I, be i.e. N, N-[(2,3,4-2,4,5-trimethoxyphenyl) dimethyl] piperazine, and preparation method thereof; The invention solves structural identification and the synthetic method of impurity in Trimetazidine Hydrochloride medicine and preparation thereof, and the impurity reference substance of preparation is used for the purposes in Trimetazidine Hydrochloride and quality of the pharmaceutical preparations control thereof.

Description

Trimetazidine derivative and preparation method thereof
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of trimetazidine derivative I, be i.e. N, N-[(2,3,4-2,4,5-trimethoxyphenyl) dimethyl] piperazine, and preparation method thereof, and purposes.
Background technology
Trimetazidine, by ensureing the energy metabolism in the myocardial cell of hypoxic-ischemic, prevents intracellular ATP levels from declining, is maintaining the function guaranteeing ionic pump while intracellular environment, improves to receive-potassium pump normal transport with cross-film.Experimentation on animals shows, and trimetazidine contributes to the energy metabolism maintained in the myocardial cell of hypoxic-ischemic, can also reduce the scope of real myocardial infarction, and can not produce any direct blood flow kinetic effect.The controlled trial display of Patients With Angina Pectoris, can increase coronary flow reserve, treat the myocardial ischemia brought out by delayed motion in human body, and can limit rapid blood pressure fluctuation and not cause heart rate noticeable change, significantly reduces angina pectoris attacks frequency.Trimetazidine has good security and reliable curative effect, is applied to clinical just more and more widely.
The chemistry of trimetazidine derivative I is called: N, N-[(2,3,4-2,4,5-trimethoxyphenyl) dimethyl] piperazine, and structure is as follows:
Carrying out finding in the detection of Trimetazidine Hydrochloride drug quality, Compound I is present in Trimetazidine Hydrochloride and preparation thereof as impurity.
Through the impurity that structural confirmation and mass analysis checking Compound I are side reaction generation in Trimetazidine Hydrochloride building-up process.
Carrying out in drug quality testing process, needing highly purified impurity and be used as reference substance, for controlling the quality that may contain the medicine of this impurity.Therefore, highly purified known impurities compound must be synthesized.Compound I and synthetic method thereof, have no report.
Therefore, the present invention mainly solves the associated problem of trimetazidine derivative I synthesis.
Summary of the invention
We are in the quality examination process of carrying out Trimetazidine Hydrochloride bulk drug and preparation, find that determine through carefully studying, surprised this impurity of discovery is compound shown in formula I containing 1 impurity in Trimetazidine Hydrochloride raw material.
The invention provides the synthetic method of Compound I.Compound I can be obtained by reacting by piperazine and 2,3,4-TMB, and synthetic route is as follows:
The preparation method of Compound I is:
(1) in autoclave pressure, throw 2,3,4-TMB, piperazine, solvent and catalyzer, in airtight eliminating still after air, logical hydrogen, stirs, reacts under certain temperature and pressure, the preferred 50-60 DEG C of temperature, the preferred 0.3-1MPa of pressure.
(2) reacted, filtered, removing catalyzer, is concentrated into dry by filtrate, adds water and hydrochloric acid conciliation pH to 1-2;
(3) filter, the derivative I that dry purity is higher.
In above-mentioned preparation method, solvent is methyl alcohol, ethanol, Virahol, n-propyl alcohol, tetrahydrofuran (THF) etc., preferred alcohol.
Purification process can simple recrystallization, also can use column chromatography, or adopt liquid phase separation preparation.Recrystallization solvent can use methyl alcohol, ethanol, Virahol etc.Also can adopt column chromatography or liquid phase separation preparation, its moving phase is methanol-water or acetonitrile water or degree or the gradient elution such as methyl alcohol, acetonitrile water, accepts product flow point, is concentrated into dry product.We show in research, can obtain purity more than 99% product, can be used to do quality approach completely.Can be used for the contamination levels product in Control of drug quality or impurity reference substance.
We show in research, and in Trimetazidine Hydrochloride bulk drug, impurity HPLC peak position is consistent with our synthetic compound I liquid phase retention time, and liquid matter molecular weight is consistent, and its Compound I nuclear magnetic data ownership rationally.Therefore illustrate that synthetic compound I is the impurity in Trimetazidine Hydrochloride bulk drug, determine through LC-MS, both molecular weight are consistent.
Compound I hydrogen nuclear magnetic resonance modal data: 1hNMR(DMSO): δ 2.40-2.50 (8H ,-CH2-), δ 3.60-3.65 (4H ,-CH2-), δ 3.68-3.75 (18H ,-CH3), δ 6.10-6.50 (4H ,-CH-).
Embodiment
Embodiment 1: the preparation method 1 of Compound I
In 1L autoclave pressure, add 19.6g(0.1mol) 2,3,4-TMB, 3.6g(0.05mol) piperazine, ethanol 600ml, catalyzer 10% palladium carbon 1g.Closed reactor, vacuumizes, air in logical nitrogen row still.Vacuumize, logical hydrogen, in bat still after nitrogen.Logical hydrogen, to 0.5MPa, stirs, is heated to 50-60 DEG C, reacts constant to pressure.React complete, filter, filtrate is concentrated into dry, add water 100ml, dispersed with stirring, water layer hydrochloric acid neutralization value pH=1-2, filter, drying obtains crude product, then carries out recrystallization with methyl alcohol, naturally be chilled to room temperature, separate out a large amount of solid, suction filtration, dry off-white color solid 14.5g, be Compound I, yield 67.4%, HPLC areas of peak normalization method content 98.4%.
Embodiment 2: the preparation method 2 of Compound I
In 2L autoclave pressure, add 29.4g(0.15mol) 2,3,4-TMB, 3.6g(0.05mol) piperazine, n-propyl alcohol 1200ml, catalyzer 10% palladium carbon 3g.Closed reactor, vacuumizes, air in logical nitrogen row still.Vacuumize, logical hydrogen, in bat still after nitrogen.Logical hydrogen, to 0.5MPa, stirs, is heated to 50-60 DEG C, reacts constant to pressure.React complete, filter, filtrate is concentrated into dry, add water 100ml, dispersed with stirring, water layer hydrochloric acid neutralization value pH=1-2, filter, drying obtains crude product, then carries out recrystallization 3 times with ethanol, naturally be chilled to room temperature, separate out a large amount of solid, suction filtration, dry off-white color solid 12.5g, be Compound I, yield 38.5%, HPLC areas of peak normalization method content 96.5%.
Embodiment 3: the preparation method 3 of Compound I
In 2L autoclave pressure, add 39.2g(0.20mol) 2,3,4-TMB, 3.6g(0.05mol) piperazine, tetrahydrofuran (THF) 1500ml, catalyzer 10% palladium carbon 3g.Closed reactor, vacuumizes, air in logical nitrogen row still.Vacuumize, logical hydrogen, in bat still after nitrogen.Logical hydrogen, to 0.6MPa, stirs, is heated to 50-60 DEG C, reacts constant to pressure.React complete, filter, filtrate is concentrated into dry, add water 100ml, dispersed with stirring, water layer hydrochloric acid neutralization value pH=1-2, filter, drying obtains crude product, then carries out recrystallization 3 times with methyl alcohol, naturally be chilled to room temperature, separate out a large amount of solid, suction filtration, dry off-white color solid 13.4g, be Compound I, yield 31.1%, HPLC areas of peak normalization method content 95.5%.
Embodiment 4: the preparation method 4 of Compound I
In 2L autoclave pressure, add 39.2g(0.20mol) 2,3,4-TMB, 14.4g(0.20mol) piperazine, methyl alcohol 1500ml, catalyzer 10% palladium carbon 3g.Closed reactor, vacuumizes, air in logical nitrogen row still.Vacuumize, logical hydrogen, in bat still after nitrogen.Logical hydrogen, to 0.6MPa, stirs, is heated to 50-60 DEG C, reacts constant to pressure.React complete, filter, filtrate is concentrated into dry, add water 100ml, dispersed with stirring, water layer hydrochloric acid neutralization value pH=1-2, filter, drying obtains crude product, then carries out recrystallization 2 times and refining methanol 3 times with ethanol, naturally be chilled to room temperature, separate out a large amount of solid, suction filtration, dry off-white color solid 8.9, be Compound I, yield 20.7%, HPLC areas of peak normalization method content 93.5%.
Embodiment 5: the application of Compound I in the HPLC of Trimetazidine Hydrochloride detects:
The HPLC detection method of Trimetazidine Hydrochloride:
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; Be moving phase with water-methanol-acetonitrile-heptane sulfonic acid sodium salt (get sodium heptanesulfonate 5.5g, add phosphoric acid 3ml, be diluted with water to 100ml, shake up, to obtain final product) (55:45:10:3); Determined wavelength is 210nm; Number of theoretical plate calculates should be not less than 4000 by Trimetazidine Hydrochloride peak; The resolution of Trimetazidine Hydrochloride peak and adjacent peak should conform with the regulations.
Assay method gets this product 10mg, accurately weighed, puts in 50ml measuring bottle, adds moving phase and dissolves and be diluted to scale, shake up, as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, adds moving phase and is diluted to scale, shake up, in contrast solution; Separately get impurity reference substance 2,3,4 trimethoxybenzoic acid, 2,3,4-TMB and 2,3,4-trimethoxybenzyl alcohol, N, N-[(2,3,4-2,4,5-trimethoxyphenyl) dimethyl] each 10mg of piperazine, accurately weighed, put in same measuring bottle, dissolve by moving phase and dilute the solution made containing each 1 μ g of above impurity reference substance in every 1ml, product solution in contrast.Get contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be more than 10% of full range; Get each 20 μ l of moving phase, contrast solution, reference substance solution and need testing solution injection liquid chromatography respectively again, record color atlas is to 4 times of principal constituent peak retention time.

Claims (1)

1. a preparation method for trimetazidine derivative I, I is as shown in the formula shown in I:
The preparation method of described derivative I is: in 1L autoclave pressure, add 19.6g2,3,4-TMB, 3.6g piperazine, ethanol 600ml, catalyzer 10% palladium carbon 1g; Closed reactor, vacuumizes, air in logical nitrogen row still; Vacuumize, logical hydrogen, in row's still after nitrogen, logical hydrogen, to 0.5MPa, stirs, is heated to 50-60 DEG C, reacts constant to pressure;
React complete, filter, filtrate be concentrated into dry, add water 100ml, dispersed with stirring, water layer hydrochloric acid is neutralized to pH=1-2, and filter, drying obtains crude product, then carries out recrystallization with methyl alcohol, is naturally chilled to room temperature, separate out a large amount of solid, suction filtration, dry off-white color solid, is Compound I.
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Publication number Priority date Publication date Assignee Title
CN109307725B (en) * 2018-10-31 2021-08-17 远大医药（中国）有限公司 Analysis method of trimetazidine hydrochloride
CN109734683B (en) * 2018-12-14 2020-12-18 北京嘉林药业股份有限公司 Method for converting trimetazidine production waste into useful substances

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1303080A (en) * 1961-07-25 1962-09-07 Science Union Et Compagnie Soc Disubstituted piperazines
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
CN102010386A (en) * 2010-11-10 2011-04-13 武汉武药科技有限公司 Method for preparing trimetazidine hydrochloride
CN102140084A (en) * 2010-02-03 2011-08-03 辽宁本源制药有限公司 Trimetazidine and production method for hydrochloride of trimetazidine
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2681324B1 (en) * 1991-09-18 1993-10-29 Adir Cie NOVEL TRIMETAZIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1303080A (en) * 1961-07-25 1962-09-07 Science Union Et Compagnie Soc Disubstituted piperazines
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
CN102140084A (en) * 2010-02-03 2011-08-03 辽宁本源制药有限公司 Trimetazidine and production method for hydrochloride of trimetazidine
CN102010386A (en) * 2010-11-10 2011-04-13 武汉武药科技有限公司 Method for preparing trimetazidine hydrochloride
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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Synthesis of trimetazidine hydrochloride impurity B by conventional method;Swapnali S. Patil 等;《Journal of Chemical and Pharmaceutical Research》;20121231;第4卷(第6期);2888-2894 *
六甲氧苄嗪对缺血再灌注损伤离体兔心的保护作用;徐礼鲜 等;《中国药理学与毒理学杂志》;19930831;第7卷(第3期);166-169 *
曲美他嗪合成方法的改进;王文浩 等;《中国药物化学杂志》;20030831;第13卷(第4期);219-221 *

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