CN110713471A - Synthetic method of trimetazidine hydrochloride - Google Patents
Synthetic method of trimetazidine hydrochloride Download PDFInfo
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- CN110713471A CN110713471A CN201810767014.4A CN201810767014A CN110713471A CN 110713471 A CN110713471 A CN 110713471A CN 201810767014 A CN201810767014 A CN 201810767014A CN 110713471 A CN110713471 A CN 110713471A
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- trimetazidine
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- trimethoxybenzaldehyde
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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
Abstract
The invention provides a synthetic method of trimetazidine dihydrochloride, which takes 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine as raw materials to carry out hydroamination reaction and adopts Lindla catalyst to carry out catalysis. The trimetazidine hydrochloride produced by the method does not produce trimetazidine hydrochloride impurity B and has higher purity.
Description
Technical Field
The invention relates to a synthetic method of an anti-angina pectoris drug, in particular to a synthetic method of trimetazidine dihydrochloride.
Background
Angina pectoris is a common cardiovascular disease, is caused by coronary atherosclerosis and stenosis, resulting in insufficient blood supply to coronary arteries, transient myocardial ischemia and hypoxia, and a group of syndromes with precordial pain as the main clinical manifestation, is one of the coronary heart diseases with the highest incidence rate, and seriously threatens the health and life of human beings. It is mainly classified into stable angina pectoris and unstable angina pectoris. Angina pectoris can be onset at any time 24 hours, but with early morning to late afternoon, angina pectoris of variability is more episodic at night. Therefore, it is required that the therapeutic drug can maintain an effective therapeutic concentration for 24 hours to ensure the effectiveness, safety and stability of the treatment.
Trimetazidine hydrochloride is the first drug acting on myocardial cell metabolism and directly playing a cell protection role by rationalizing cardiac energy metabolism, so that the trimetazidine hydrochloride is widely applied to angina pectoris resistance. Trimetazidine hydrochloride is taken in European and Japanese pharmacopoeias and is a 3-ketoacyl coenzyme A thiolase inhibitor (3-KAT), and can inhibit fatty acid oxidation and stimulate glucose oxidation during myocardial ischemia, so that the metabolism tends to be balanced, and a normal metabolic pathway is maintained, thereby playing a role in protecting the myocardium; the ATP can be ensured to supply energy normally, so that the normal function of an ion pump and the normal running of a transmembrane sodium-potassium flow can be ensured, and the stability of the intracellular environment is maintained; can reduce acidosis in cells and prevent accumulation of sodium and calcium in myocardial cells; and can protect the membrane by protecting the cell contraction function and limiting cell lysis and intimal damage caused by oxygen radicals. Trimetazidine hydrochloride does not affect hemodynamics, does not reduce heart rate and blood pressure, can obviously reduce the attack frequency of angina, and has the advantages of obvious curative effect, good tolerance, small adverse reaction, low toxicity and the like, and can be used together with other medicines. In addition, the results of literature data show that trimetazidine dihydrochloride can also be used for treating stable angina, heart failure, ischemic cardiomyopathy, ischemia/reperfusion injury, coronary artery bypass grafting and percutaneous coronary artery intervention, and the curative effect is definite. Therefore, trimetazidine dihydrochloride has good clinical practical value and application prospect, and is concerned by more and more researchers.
Trimetazidine hydrochloride (Trimetazidine hydrochloride) has the chemical name: 1- [ (2, 3, 4-trimethoxyphenyl) methyl ] -piperazine hydrochloride having the following structural formula:
in the prior art, various methods for preparing trimetazidine hydrochloride have been reported, among which:
1. in French patent FR2493316, 4- (2, 3, 4-trimethoxybenzyl) -2-piperazinone is produced by reacting 2, 3, 4-trimethoxybenzyl chloride with 2-piperazinone, and then reduced to 2, 3, 4-trimethoxybenzylpiperazine (i.e. trimetazidine) using LiAlH4, with low yield.
2. In Japanese patent JP48032889, trimetazidine is synthesized in one step from 2, 3, 4-trimethoxybenzaldehyde and piperazine hexahydrate at 80-90 deg.C for 10-18 hr with a yield of only 38%.
3. 2, 3, 4-trimethoxybenzaldehyde and piperazine are used as raw materials to generate trimetazidine with the yield of 44.2%. (Wangwnhao Zhang Xin xu Pinna, China journal of pharmaceutical chemistry 2003, 13, 218-supplement 221)
4. In US5142053, the preparation by reductive amination of LiAlH4 or NaBH4 from 2, 3, 4-trimethoxybenzaldehyde and piperazine is carried out in high yield, but the use of LiAlH4 and NaBH4, which are dangerous, is not suitable for large-scale production.
5. In the patent of CN102140084A, 2, 3, 4-trimethoxybenzaldehyde and piperazine are used as raw materials, and Pd/C is used as a catalyst to prepare trimetazidine by reductive amination with hydrogen, and then the trimetazidine is further converted into a hydrochloride form.
Disclosure of Invention
The invention provides a synthetic method of trimetazidine dihydrochloride, which takes 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine as raw materials, obtains trimetazidine through hydrogenation reductive amination reaction carried out by a Lindla catalyst, and then obtains trimetazidine dihydrochloride through acidification reaction. According to the invention, a Lindla catalyst is selected for catalytic reaction, so that the production of trimetazidine hydrochloride impurities can be effectively controlled, the yield and the purity of trimetazidine hydrochloride are improved, the total yield of the prepared trimetazidine hydrochloride is up to more than 90%, the purity of the prepared crude trimetazidine hydrochloride is up to more than 99%, and refining steps such as further purification and filtration are not needed; and after the reaction is finished, the used Lindla catalyst is easy to recycle, the production cost can be reduced, and the method is suitable for industrial large-scale production.
The inventor researches the existing synthetic method of trimetazidine dihydrochloride, and finds that trimetazidine dihydrochloride impurity B is the most easily generated impurity in the synthetic trimetazidine dihydrochloride bulk drug, and the specific structural formula is as follows:
the inventor finds that in the process of synthesizing trimetazidine by using 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine as raw materials, when the catalytic activity of a catalyst used for the reaction of the 2, 3, 4-trimethoxybenzaldehyde and the anhydrous piperazine is too active, the trimetazidine hydrochloride impurity B is very easy to generate. In order to control the production of trimetazidine dihydrochloride impurity B, the inventor researches the existing catalyst, and finds that the catalytic activity of the commonly used palladium-carbon or raney-nickel is too high, the reaction speed is too high, the LiAlH4 and NaBH4 produced by trimetazidine dihydrochloride impurity B cannot be controlled to be high in danger when the catalyst is used, and the safe production cannot be guaranteed.
The inventor carries out intensive research on how to effectively control trimetazidine hydrochloride impurities in the process of synthesizing trimetazidine hydrochloride raw material medicines, particularly on trimetazidine hydrochloride impurity B which is easy to generate, and finally the inventor finds that the generation of trimetazidine hydrochloride impurities can be controlled by using a Lindera reagent as a catalyst for hydrogenation, reduction and amination reaction of 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine. Lindla reagent is prepared by adsorbing palladium on carrier (calcium carbonate or barium sulfate) and adding small amount of inhibitor (lead acetate or quinoline). Wherein the content of palladium is 3-10%. Conventional Lindla catalysts can be used in the present invention, and specific examples thereof include Pd-CaCO3-PbO, Pd-CaCO3-PbAc2, Pd-BaSO 4-quinoline, etc. According to the invention, the properties of the Lindla catalyst are well utilized, and PbO, PbAc2 or quinoline and other substances added into the catalyst are taken as inhibitors, so that palladium adsorbed on a carrier can be poisoned, and the catalytic activity of the palladium is further inhibited. Therefore, the Lindera catalyst can ensure that the 2, 3, 4-trimethoxybenzaldehyde and the anhydrous piperazine react at a moderate reaction speed with proper catalytic activity, and the bimolecular impurity trimetazidine hydrochloride impurity B generated by the excessively violent reaction of the 2, 3, 4-trimethoxybenzaldehyde and the anhydrous piperazine is avoided.
The invention provides a synthetic method of trimetazidine dihydrochloride, which takes 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine as raw materials and adopts Lindera catalyst to synthesize trimetazidine dihydrochloride. The specific reaction steps are as follows:
(1) adding 2, 3, 4-trimethoxybenzaldehyde, anhydrous piperazine, a Lindla catalyst and a solvent A into a hydrogenation reaction kettle;
(2) introducing hydrogen into the hydrogenation reaction kettle, and stirring until the reaction is complete;
(3) and (3) decompressing and concentrating the reaction product, adding the solvent B, stirring, adding concentrated hydrochloric acid, and crystallizing to obtain trimetazidine hydrochloride.
The inventor researches the dosage of 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine, when the dosage of 2, 3, 4-trimethoxybenzaldehyde is excessive relative to the anhydrous piperazine, trimetazidine hydrochloride impurity B can be generated, and in order to avoid the generation of trimetazidine hydrochloride impurity B, the molar ratio of 2, 3, 4-trimethoxybenzaldehyde to anhydrous piperazine is selected to be 1: 2-6.
The inventor researches the dosage of the Lindla catalyst, and the dosage of the Lindla catalyst is limited to be 1-5% of the mass dosage of the 2, 3, 4-trimethoxybenzaldehyde.
The solvent A in the step (1) is one or more of methanol, ethanol, isopropanol or toluene; preferably, solvent a is methanol.
The reaction temperature in the step (2) is 20-70 ℃; the hydrogen pressure is 0.5-3 MPa.
The crystallization temperature in the step (3) is 0-40 ℃.
The solvent B in the step (3) is a crystallization solvent of trimetazidine dihydrochloride, the selected solvent B only needs to be capable of dissolving the reaction product in the step (3) in the solvent B, and concentrated hydrochloric acid is added to enable trimetazidine to be in hydrochloride form and then crystallization can be carried out, and the solvent B is selected from one or more of acetone, ethyl acetate, diethyl ether and normal hexane but not limited.
Drawings
FIG. 1: HPLC chromatogram of trimetazidine dihydrochloride related substance obtained in example 1
FIG. 2: HPLC chromatogram of trimetazidine dihydrochloride related substance obtained in comparative example 1
FIG. 3: HPLC chromatogram of trimetazidine dihydrochloride related substance obtained in comparative example 2
FIG. 4: HPLC chromatogram of trimetazidine dihydrochloride related substance obtained in comparative example 3
Fig. 1 is an HPLC chromatogram for trimetazidine dihydrochloride detection obtained by using a lindlar catalyst in example 1 of the present invention, and impurity B is not detected in the obtained trimetazidine dihydrochloride; FIG. 2 is an HPLC chromatogram of trimetazidine dihydrochloride detection obtained by using a palladium-carbon catalyst in comparative example 1, and the trimetazidine dihydrochloride is detected to contain impurity B, wherein the content of the impurity B is 0.08%; fig. 3 is an HPLC chromatogram of trimetazidine hydrochloride detection obtained by using a raney nickel catalyst in comparative example 2, and it is detected that trimetazidine hydrochloride contains impurity B, the content of impurity B is 0.09%; fig. 4 is an HPLC chromatogram of trimetazidine hydrochloride obtained by referring to the preparation method of CN102140084A patent in comparative example 3, and it is detected that trimetazidine hydrochloride contains impurity B, the content of impurity B is 0.09%. As can be seen from the figures 1-4, the invention adopts the Lindla catalyst to synthesize trimetazidine dihydrochloride, which can effectively avoid the generation of impurity B.
Detailed Description
The analytical detection method of the trimetazidine dihydrochloride liquid chromatography is used for detecting according to the method of European pharmacopoeia with the reference number of 1741, pages 3843-3845.
Example 1
To a 2000L hydrogenation reactor, 500kg of ethanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 150kg of anhydrous piperazine, 2kg of Lindla catalyst (Pd-CaCO3-PbO containing 10% of palladium) were sequentially added. Pressurizing with 2.0MPa hydrogen, heating to 60 deg.c, maintaining and stirring for 16 hr while controlling the hydrogen pressure at 2.0MPa to complete the reaction. And cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of acetone, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 10 ℃, crystallizing, stirring for 5 hours, and centrifuging to obtain 191.3kg of trimetazidine hydrochloride, wherein the yield is 92.5%, the purity is 100%, and trimetazidine hydrochloride impurity B is not detected.
Example 2
To a 2000L hydrogenation reactor, 450kg of methanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 210kg of anhydrous piperazine, 2.4kg of Lindla catalyst (Pd-CaCO3-PbAc2 containing 5% of palladium) were sequentially added. Pressurizing with hydrogen at 2.0MPa, heating to 65 deg.c, maintaining and stirring for 16 hr while controlling the hydrogen pressure at 1.0MPa to complete the reaction. And cooling the reaction solution to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of acetone, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 20 ℃, crystallizing, stirring for 5 hours, and centrifuging to obtain 189.6kg of trimetazidine hydrochloride, wherein the yield is 91.7%, the purity is 99.9%, and the trimetazidine hydrochloride impurity B is not detected.
Example 3
To a 2000L hydrogenation reactor, 550kg of isopropanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 184kg of anhydrous piperazine, and 3.6kg of Lindla catalyst (Pd-CaCO3-PbO containing 7% palladium) were sequentially added. Pressurizing with 2.0MPa hydrogen, heating to 50 deg.c, maintaining and stirring for 17 hr while controlling the hydrogen pressure at 2.5MPa to complete the reaction. And cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of ethyl acetate, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 15 ℃, crystallizing, stirring for 5 hours, and centrifuging to obtain 190.5kg of trimetazidine hydrochloride, wherein the yield is 92.1%, the purity is 99.8%, and the trimetazidine hydrochloride impurity B is not detected.
Example 4
400kg of methanol, 200kg of ethanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 263kg of anhydrous piperazine and 4.2kg of Lindla catalyst (Pd-CaCO3-PbAc 23 percent containing palladium) were sequentially added into a 2000L hydrogenation reactor. Pressurizing with hydrogen at 2.0MPa, heating to 70 deg.c, maintaining the temperature and stirring for 16 hr while controlling the hydrogen pressure at 3.0MPa to complete the reaction. And cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 500kg of acetone and 400kg of n-hexane, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 0 ℃, crystallizing, stirring for 5 hours, and centrifuging to obtain 188.0kg of trimetazidine hydrochloride, wherein the yield is 90.9%, the purity is 99.9%, and the trimetazidine hydrochloride impurity B is not detected.
Example 5
To a 2000L hydrogenation reactor, 600kg of toluene, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 105kg of anhydrous piperazine, 1.2kg of Lindla catalyst (Pd-BaSO 4-quinoline contains 6% of palladium), and the addition was completed. Pressurizing with hydrogen at 2.0MPa, heating to 20 deg.c, maintaining and stirring for 22 hr while controlling the hydrogen pressure at 0.5MPa to complete the reaction. And cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of diethyl ether, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 40 ℃, crystallizing, stirring for 5 hours, and centrifuging to obtain 189.2kg of trimetazidine hydrochloride, wherein the yield is 91.5%, the purity is 99.8%, and the trimetazidine hydrochloride impurity B is not detected.
Example 6
To a 2000L hydrogenation reactor, 550kg of methanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 315kg of anhydrous piperazine, 6kg of Lindla catalyst (Pd-BaSO 4-quinoline contains 5% of palladium) were sequentially added. Pressurizing with 2.0MPa hydrogen, heating to 30 deg.c, maintaining and stirring for 20 hr while controlling the hydrogen pressure at 2.0MPa to complete the reaction. And cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of acetone, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 35 ℃, crystallizing, stirring for 5 hours, and centrifuging to obtain 188.8kg of trimetazidine hydrochloride, wherein the yield is 91.3%, the purity is 99.9%, and the trimetazidine hydrochloride impurity B is not detected.
Comparative example 1
To a 2000L hydrogenation reactor, 500kg of ethanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 150kg of anhydrous piperazine, 3kg of palladium on carbon (containing 10% palladium) were sequentially added. Pressurizing with 2.0MPa hydrogen, heating to 60 deg.c, maintaining and stirring for 16 hr while controlling the hydrogen pressure at 2.0MPa to complete the reaction. Cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of acetone, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 10 ℃ for crystallization, stirring for 5 hours, centrifuging to obtain 162.3kg of trimetazidine hydrochloride, wherein the yield is 78.5%, the purity is 99.91%, and the content of trimetazidine hydrochloride impurity B is detected to be 0.08%.
Comparative example 2
500kg of ethanol, 120kg of 2, 3, 4-trimethoxybenzaldehyde, 150kg of anhydrous piperazine and 10kg of Raney nickel are sequentially added into a 2000L hydrogenation reaction kettle. Pressurizing with 2.0MPa hydrogen, heating to 60 deg.c, maintaining and stirring for 16 hr while controlling the hydrogen pressure at 2.0MPa to complete the reaction. Cooling the reaction liquid to room temperature, filtering to remove the Lindla catalyst, concentrating under reduced pressure at 30-40 ℃ until no fraction is produced, adding 1000kg of acetone, stirring for 10 minutes, adding 125kg of concentrated hydrochloric acid, cooling to 10 ℃ for crystallization, stirring for 5 hours, centrifuging to obtain 156.1kg of trimetazidine hydrochloride, wherein the yield is 75.5%, the purity is 99.89%, and the content of trimetazidine hydrochloride impurity B is detected to be 0.09%.
COMPARATIVE EXAMPLE 3 (see CN102140084A patent)
Under the protection of nitrogen, 78.4g of 2, 3, 4-trimethoxybenzaldehyde, 68.8g of piperazine, 400mL of methyl tert-butyl ether and 4g of Pd/C are placed in a reactor, the reaction system is rapidly heated to 50-55 ℃, then 10bar of hydrogen is introduced into the reaction system, then the temperature is continuously raised to 70 ℃ and is kept at the temperature for about 2 hours, and then the reaction liquid is cooled to 50 ℃ to filter the catalyst. Then cooling the filtrate to 10 ℃, filtering the unreacted piperazine, then adding 200mL of water into the filtrate, adjusting the pH of the filtrate to 7.9-8 by using 7N hydrochloric acid at 13-18 ℃, adding 600mL of water into the filtrate, stirring for half an hour for separating liquid, extracting the organic phase twice by using 100mL of toluene and discarding, cooling the aqueous phase by using an ice water bath, slowly adding 42g of sodium hydroxide, stirring and extracting three times by using 120mL of toluene, drying by anhydrous magnesium sulfate, and carrying out decompression rotary evaporation to obtain the trimetazidine. Dissolving the obtained trimetazidine in 216.0g of isopropanol by stirring, transferring the filtered filtrate into a stainless steel reactor rinsed by the isopropanol, slowly adding the filtrate into 348g of isopropanol solution containing 79.2g of concentrated hydrochloric acid, controlling the temperature not to exceed 40 ℃, stirring for half an hour, distilling the reaction liquid to 270g at normal temperature, stirring for 2 hours at 0 ℃ and filtering to obtain trimetazidine hydrochloride, leaching twice by the isopropanol to obtain 122.0g of trimetazidine hydrochloride, and obtaining the yield: 90.0 percent and the purity is 99.85 percent, and the content of trimetazidine dihydrochloride impurity B is detected to be 0.09 percent.
Claims (10)
1. A synthetic method of trimetazidine dihydrochloride takes 2, 3, 4-trimethoxybenzaldehyde and anhydrous piperazine as raw materials to carry out hydroamination reaction, and is characterized in that a Lindla catalyst is adopted in the reaction.
2. The method for synthesizing trimetazidine dihydrochloride according to claim 1, characterized in that the reaction steps are as follows:
(1) adding 2, 3, 4-trimethoxybenzaldehyde, anhydrous piperazine, a Lindla catalyst and a solvent A into a hydrogenation reaction kettle;
(2) introducing hydrogen into the hydrogenation reaction kettle, and stirring until the reaction is complete;
(3) and (3) decompressing and concentrating the reaction product, adding the solvent B, stirring, adding concentrated hydrochloric acid, and crystallizing to obtain trimetazidine hydrochloride.
3. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the molar ratio of 2, 3, 4-trimethoxybenzaldehyde to anhydrous piperazine is 1: 2-6.
4. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the amount of the lindlar catalyst is 1-5% by mass of the amount of 2, 3, 4-trimethoxybenzaldehyde.
5. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the solvent A in step (1) is one or more of methanol, ethanol, isopropanol or toluene.
6. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the solvent A in step (1) is methanol.
7. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the reaction temperature in step (2) is 20-70 ℃.
8. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the hydrogen pressure in step (2) is 0.5-3 MPa.
9. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the crystallization temperature in step (3) is 0-40 ℃.
10. The method for synthesizing trimetazidine dihydrochloride according to claim 2, wherein the solvent B in the step (3) is one or more of acetone, ethyl acetate, diethyl ether and n-hexane.
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| 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 |
| CN106397357A (en) * | 2016-09-16 | 2017-02-15 | 苏州敬业医药化工有限公司 | Method for preparing trimetazidine dihydrochloride |
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| 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 |
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| CN116041280A (en) * | 2022-12-05 | 2023-05-02 | 三峡大学 | Preparation method of trimetazidine hydrochloride |
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