CN105712951A - Trimetazidine hydrochloride industrial preparation method - Google Patents
Trimetazidine hydrochloride industrial preparation method Download PDFInfo
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- CN105712951A CN105712951A CN201410722190.8A CN201410722190A CN105712951A CN 105712951 A CN105712951 A CN 105712951A CN 201410722190 A CN201410722190 A CN 201410722190A CN 105712951 A CN105712951 A CN 105712951A
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Abstract
The present invention provides a new synthetic route of trimetazidine hydrochloride, methyl piperazine is dissolved in an organic solvent, a catalyst is added, an elemental halogen is in batches added, and after stirring for 1-3h, the mixture is filtered and concentrated; low reaction temperature is controlled, 1,2,3-trimethoxybenzene is added into an obtained concentrated solution, a catalyst is added in batches, and after full reaction, crude trimetazidine is obtained by filtration, reflux and refiltration; the crude trimetazidine is recrystallized by an organic solvent, an obtained pure product is dissolved in an alkali liquid, after heating, hydrochloric acid is added for refining, pH is adjusted to acidic, and a trimetazidine hydrochloride finished product is obtained by cooling, mixing, filtering, washing and drying. The organic solvent and the alkali liquid can be recycled and re-used, and the method has the characteristics of being simple in operation, green, easy in control of reaction process.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to the industrial preparative method of a kind of antianginal drug Trimetazidine Hydrochloride.
Background technology
Optimize energy metabolism of myocardial, strengthen myocardial glucose metabolism, be conducive to alleviating the tissue injury that myocardial ischemia causes, improve myocardial function.Trimetazidine can suppress fatty acids metabolism, fatty acids metabolism is made to reduce, so that cardiac muscle is with glucose metabolism for the raw energy of main product, when at coronary artery pathological changes, myocardial oxygen delivery is restricted, improve the availability of oxygen, produce more energy-rich phosphate bond, to alleviate myocardial ischemia symptom, and maintain the survival of cardiac muscle and the function of heart.
Trimetazidine can reduce vascular resistance, increases coronary flow and surrounding loop blood flow, promotes the generation of myocardial metabolism and cardiac energy；Heart working load can be lowered, reduce the consumption of myocardial oxygen consumption and cardiac energy, thus improving the equilibrium of supply and demand of cardiac muscle oxygen.Still can increase the toleration to cardiotonic glycoside.Clinical in arteria coronaria functional defect, angina pectoris, old myocardial infarction etc..
Trimetazidine is provided that metabolic myocardial cell protection effect, improves myocardial contraction；Suppress the reduction of intracellular ph value and ATP；Reduce neutrophil accumulation, it is suppressed that the infringement of radical pair myocardial cell, increase the myocardial cell tolerance to hypoxia stress.Trimetazidine also has the mitochondrial normal function of maintenance, make in myocardial cell oxygen-derived free radicals produce to reduce, suppress in cardiac muscular tissue the effects such as neutrophil infiltration, all that its function of resisting myocardial ischemia is favourable.
Summary of the invention
It is an object of the invention to provide a kind of simple and convenient synthetic method being suitable for industrial trimetazidine.
Trimetazidine Hydrochloride, chemical name 1-(2,3,4-trimethoxybenzyl group) piperazine dihydrochloride.
The synthetic route of the compounds of this invention (I) is as follows:
(1) by methyl piperazine organic solvent dissolution, adding catalyst, add halogen simple substance in batches, stirring 1-3h filters, concentration；
(2) control low-temp reaction temperature, the concentrated solution obtained adds 1,2,3-trimethoxy-benzene, then be dividedly in some parts catalyst in (1), after reaction fully, filter, backflow, refilter, obtain thick trimetazidine；
(3) with organic solvent to crude product recrystallization；
(4) being dissolved by the sterling alkali liquor obtained, addition salt acid treating after intensification, regulating pH is acidity, and cooling, stirring, filtration, washing dry, and obtain Trimetazidine Hydrochloride finished product；
Wherein organic solvent described in step (1) is ether, dichloromethane, oxolane, pyridine, one or more of toluene, it is preferred to ether.
Wherein in step (1), halogen simple substance is elemental chlorine, bromine simple substance, elemental iodine, it is preferred to elemental chlorine, and mixing time is 1-5 hour, it is preferable that 2.5 hours.
Wherein in step (2) low temperature control between-5-5 DEG C, it is preferable that 0 DEG C.
Wherein in step (2), catalyst is lewis acid, zinc chloride, stannic chloride, one or more of aluminum chloride, it is preferable that zinc chloride.Response time is 5-48 hour, it is preferable that 12 hours.
Wherein in step (3), organic solvent is ethanol, methanol, DMF, dichloromethane, pyridine, one or more of DMSO.
Wherein in step (4), alkali liquor is sodium hydroxide, potassium hydroxide, Lithium hydrate, ammonia, it is preferable that sodium hydroxide.
Wherein in step (4), the mass concentration of hydrochloric acid solution is 5%-30%, it is preferable that 20%.
Wherein in step (4), temperature controls between 30-80 DEG C, it is preferable that 60 DEG C, pH controls between 1-6, it is preferable that pH=3,
Organic solvent and alkali liquor in the present invention can reclaim re-using.
The present invention has simple to operate, green, the feature that course of reaction is easily controllable.
It should be appreciated that, in the claim limited range of the present invention, various conversion and change can be carried out.
The substantial feature of the present invention can emerge from from following embodiment.
Detailed description of the invention
Embodiment 1: the preparation of intermediate 1 chloromethyl piperazine:
1kg methyl piperazine is dissolved in the diethyl ether solution of 30L, under room temperature, stirs, in batches the three batches of halogen simple substance adding 1.8kg, the every batch of interval 20 minutes.After reacting 2.5 hours, by reacting liquid filtering, concentration, obtain the crude intermediate 1 of 1.3kg.
Embodiment 2: the preparation of intermediate 2:
Controlling low-temp reaction temperature is 0 DEG C, is dissolved into by the concentrated solution obtained in the 20L ether dried, adds 1 in (1), 2,3-trimethoxy-benzene 1.5kg, stir, then criticize addition zinc chloride catalyst 0.5kg altogether in two batches, after reaction 12h, filter, filter cake is leached, add 30L water, 100 DEG C of backflow 3h, quickly cool down, refilter, obtain crude product trimetazidine 1.2kg.
Embodiment 3: refining of intermediate 2:
By in the 1.2kg trimetazidine dissolving crude product that obtains to 15L dichloromethane, add appropriate DMF solution, after being completely dissolved, add pure trimetazidine seed, cooling, precipitate out crystal 1.1kg.
Embodiment 4: the preparation of Trimetazidine Hydrochloride I:
The 1.1kg sterling trimetazidine 30L10% sodium hydroxide solution obtained is slowly ramped to 60 DEG C of dissolvings, rear addition mass concentration is the salt acid treating of 20%, regulating pH is 3, it is stirred for, slowly lowers the temperature, precipitating out Trimetazidine Hydrochloride, filter, being washed with water to pH is 5, dry, obtain Trimetazidine Hydrochloride finished product 0.9kg.
Claims (8)
1. a preparation method for Trimetazidine Hydrochloride, rises and is characterised by, be described below:
(1) by methyl piperazine organic solvent dissolution, adding catalyst, add halogen simple substance in batches, stirring 1-3h filters, concentration；
(2) control low-temp reaction temperature, the concentrated solution obtained adds 1,2,3-trimethoxy-benzene, then be dividedly in some parts catalyst in (1), after reaction fully, filter, backflow, refilter, obtain thick trimetazidine；
(3) with organic solvent to crude product recrystallization；
(4) being dissolved by the sterling alkali liquor obtained, addition salt acid treating after intensification, regulating pH is acidity, and cooling, stirring, filtration, washing dry, and obtain Trimetazidine Hydrochloride finished product.
2. organic solvent according to claim 1 is ether, dichloromethane, oxolane, pyridine, one or more of toluene, it is preferred to ether.
3. being elemental chlorine according to halogen simple substance in claim 1, bromine simple substance, elemental iodine, it is preferred to elemental chlorine, mixing time is 1-5 hour, it is preferable that 2.5 hours.
4. according to temperature control low in claim 1 between-5-8 DEG C, it is preferable that 0-3 DEG C.
5. it is lewis acid according to catalyst in claim 1, zinc chloride, stannic chloride, one or more of aluminum chloride, it is preferable that zinc chloride.
6. the response time is 5-50 hour, it is preferable that 12-24 hour.
7. it is sodium hydroxide according to alkali liquor in claim 1, potassium hydroxide, Lithium hydrate, ammonia, it is preferable that sodium hydroxide.
8. it is 5%-30% according to the mass concentration of hydrochloric acid solution in claim 1, it is preferable that 20%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410722190.8A CN105712951A (en) | 2014-12-03 | 2014-12-03 | Trimetazidine hydrochloride industrial preparation method |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410722190.8A CN105712951A (en) | 2014-12-03 | 2014-12-03 | Trimetazidine hydrochloride industrial preparation method |
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| CN105712951A true CN105712951A (en) | 2016-06-29 |
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| CN201410722190.8A Pending CN105712951A (en) | 2014-12-03 | 2014-12-03 | Trimetazidine hydrochloride industrial preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054599A (en) * | 2019-05-14 | 2019-07-26 | 中南民族大学 | A kind of Trimetazidine oxalates and its preparation method and application |
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2014
- 2014-12-03 CN CN201410722190.8A patent/CN105712951A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054599A (en) * | 2019-05-14 | 2019-07-26 | 中南民族大学 | A kind of Trimetazidine oxalates and its preparation method and application |
| CN110054599B (en) * | 2019-05-14 | 2021-05-07 | 中南民族大学 | Trimetazidine oxalate and preparation method and application thereof |
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Application publication date: 20160629 |