A preparation method of high-purity trimetazidine hydrochloride

Abstract

The present invention provides a preparation method of high-purity trimetazidine hydrochloride, and the steps include: S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to an ionic liquid, adding an asymmetric catalyst, and performing microwave radiation heating to obtain a mixed solution; S2, the mixed solution is subjected to supercritical fluid extraction, cooled to room temperature, and an extract is obtained; S3, the extract is added to an organic solvent, hydrochloric acid is added and mixed evenly, the temperature is lowered and crystallized, suction filtration is washed, and dried, crushed and sieved to obtain high-purity trimetazidine hydrochloride. The preparation process of the present invention adopts microwave radiation technology and supercritical fluid extraction technology to improve the yield and purity of trimetazidine hydrochloride, and the obtained trimetazidine hydrochloride yield is as high as 95%, the purity is as high as 99.95%, the production efficiency is high, the cost is low, the product quality is stable, and it has a good market prospect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing high-purity trimetazidine hydrochloride. Background Art

[0002] Trimetazidine hydrochloride is an important vasodilator and antiplatelet aggregation drug, which is widely used in the treatment of cardiovascular diseases. The traditional synthesis methods of trimetazidine hydrochloride mainly include: benzoic acid method: trimetazidine base and benzoic acid are refluxed in toluene to obtain trimetazidine benzoate, which is then hydrolyzed with hydrochloric acid to obtain trimetazidine hydrochloride. Acetic acid method: trimetazidine base and acetic anhydride are reacted in pyridine to obtain trimetazidine acetate, which is then hydrolyzed with hydrochloric acid to obtain trimetazidine hydrochloride. Phosgene method: trimetazidine base and phosgene are reacted in dichloromethane to obtain trimetazidine chloroformate, which is then hydrolyzed with hydrochloric acid to obtain trimetazidine hydrochloride. Problems of traditional methods: ① Harsh reaction conditions: Traditional methods usually require reactions under high temperature and high pressure conditions, with long reaction times and low yields. ② Low product purity: Impurities are easily generated during the reaction of traditional methods, and the purity of the obtained products is low, requiring multiple crystallization purifications. ③ Environmental pollution: Traditional methods use toxic solvents and catalysts, which pollute the environment.

[0003] At present, impurity B of trimetazidine hydrochloride is the most easily produced impurity in the synthesis of trimetazidine hydrochloride, and its structural formula is as follows:

[0004]

[0005] Therefore, it is of great significance to find a preparation process to ensure the high purity and high yield of trimetazidine hydrochloride. Summary of the invention

[0006] In view of this, the present invention proposes a method for preparing high-purity trimetazidine hydrochloride. The technical solution of the present invention is achieved as follows:

[0007] A method for preparing high-purity trimetazidine hydrochloride, the specific steps comprising:

[0008] S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine into an ionic liquid, adding an asymmetric catalyst, and heating by microwave radiation to obtain a mixed liquid;

[0009] S2, subjecting the mixed solution to supercritical CO2 fluid extraction, cooling it to room temperature, and obtaining an extract;

[0010] S3. Add the extract to an organic solvent, add hydrochloric acid and mix evenly, cool and crystallize, filter and wash, dry, crush and sieve to obtain high-purity trimetazidine hydrochloride.

[0011] Furthermore, in step S1, the ionic liquid is any one of 1-hexyl-3-methylimidazolium dicyanamide, 1-n-butylpyridinium tetrafluoroborate and 1-n-butyl-3-methylimidazolium chloride.

[0012] Furthermore, in step S1, the asymmetric catalyst is any one of (R)-2,2'-dimethoxy-1,1'-binaphthyl, 2,2-bis(diphenylphosphino)-1,1-binaphthyl or 1,2-bis(diphenylphosphino)ethane.

[0013] Furthermore, in step S1, the molar ratio of the 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and ionic liquid is 1:1-3:2-4; and the molar ratio of the asymmetric catalyst to 2,3,4-trimethoxybenzaldehyde is 0.05-0.08:1.

[0014] Furthermore, in step S1, the microwave radiation has a power of 100-300 W, a temperature of 80-120° C., and a time of 2-4 h.

[0015] Furthermore, in step S2, the supercritical CO2 fluid extraction temperature is 40-60°C, the pressure is 10-30MPa, the time is 1-3h, and the flow rate is 4-6mL / min.

[0016] Furthermore, in step S3, the organic solvent is ethanol or isopropanol.

[0017] Furthermore, in step S3, the solid-liquid ratio of the extract to the organic solvent is 1:5-10 g / mL.

[0018] Furthermore, in step S3, the concentration of the hydrochloric acid is 1-3 moL / L; and the volume ratio of the hydrochloric acid to the extract is 1-2:1.

[0019] Furthermore, in step S3, the crystallization temperature is 10-20°C.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. The preparation process of the present invention has high production efficiency and low cost. The yield of trimetazidine hydrochloride obtained is as high as 95%, the purity is as high as 99.95%, the impurity B of trimetazidine hydrochloride is not detected, and the product quality is stable.

[0022] 2. The present invention adopts microwave radiation heating to achieve uniform heating, shorten the reaction time, and improve the yield of trimetazidine hydrochloride. The present invention selects a specific asymmetric catalyst with high selectivity, avoids subsequent splitting and purification steps, improves the purity of trimetazidine hydrochloride, and the asymmetric catalyst can be reused to reduce production costs. The present invention uses supercritical fluid extraction, mild conditions, effective impurity removal, helps to improve the purity of trimetazidine hydrochloride, and is more environmentally friendly. DETAILED DESCRIPTION

[0023] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0024] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0025] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0026] Example 1

[0027] S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to 1-hexyl-3-methylimidazole dicyanamide, the molar ratio of 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and 1-hexyl-3-methylimidazole dicyanamide is 1:2:3, adding (R)-2,2'-dimethoxy-1,1'-binaphthyl, the molar ratio of (R)-2,2'-dimethoxy-1,1'-binaphthyl to 2,3,4-trimethoxybenzaldehyde is 0.07:1, and heating under microwave radiation for 3h at a power of 200W and a temperature of 100°C to obtain a mixed solution;

[0028] S2, subjecting the mixed solution to supercritical CO2 fluid extraction for 2 h at a temperature of 50°C, a pressure of 20 MPa, and a CO2 flow rate of 5 mL / min, and cooling to room temperature to obtain an extract;

[0029] S3, the extract was added to ethanol, the solid-liquid ratio of the extract to ethanol was 1:8g / mL, 2moL / L hydrochloric acid was added and mixed evenly, the volume ratio of hydrochloric acid to the extract was 1.5:1, the temperature was lowered to 15°C for crystallization, suction filtered and washed, dried, crushed and sieved to obtain trimetazidine hydrochloride. The yield of trimetazidine hydrochloride was 95%, the purity was 99.95%, and the trimetazidine hydrochloride impurity B was not detected.

[0030] Example 2

[0031] S1. Adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to 1-hexyl-3-methylimidazole dicyanamide, the molar ratio of 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and 1-hexyl-3-methylimidazole dicyanamide is 1:1:2, adding (R)-2,2'-dimethoxy-1,1'-binaphthyl, the molar ratio of (R)-2,2'-dimethoxy-1,1'-binaphthyl to 2,3,4-trimethoxybenzaldehyde is 0.05:1, and heating by microwave radiation for 2 h at a power of 100 W and a temperature of 80° C. to obtain a mixed solution;

[0032] S2, subjecting the mixed solution to supercritical CO2 fluid extraction for 1 h at a temperature of 40°C, a pressure of 10 MPa, a CO2 flow rate of 4 mL / min, and cooling to room temperature to obtain an extract;

[0033] S3. The extract was added to ethanol, the solid-liquid ratio of the extract to ethanol was 1:5 g / mL, 1 mol / L hydrochloric acid was added and mixed evenly, the volume ratio of hydrochloric acid to the extract was 1:1, the temperature was lowered to 10°C for crystallization, suction filtered and washed, dried, crushed and sieved to obtain trimetazidine hydrochloride. The yield of trimetazidine hydrochloride was 93%, the purity was 99.93%, and the impurity B of trimetazidine hydrochloride was not detected.

[0034] Example 3

[0035] S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to 1-hexyl-3-methylimidazole dicyanamide, the molar ratio of 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and 1-hexyl-3-methylimidazole dicyanamide is 1:3:4, adding (R)-2,2'-dimethoxy-1,1'-binaphthyl, the molar ratio of (R)-2,2'-dimethoxy-1,1'-binaphthyl to 2,3,4-trimethoxybenzaldehyde is 0.08:1, and heating by microwave radiation for 4 hours at a power of 300 W and a temperature of 120° C. to obtain a mixed solution;

[0036] S2, subjecting the mixed solution to supercritical CO2 fluid extraction for 3 h at a temperature of 60° C., a pressure of 30 MPa, and a CO2 flow rate of 6 mL / min, and cooling to room temperature to obtain an extract;

[0037] S3. Add the extract to ethanol, the solid-liquid ratio of the extract to ethanol is 1:10 g / mL, add 3 mol / L hydrochloric acid and mix evenly, the volume ratio of hydrochloric acid to the extract is 2:1, cool to 20°C for crystallization, filter and wash, dry, crush and sieve to obtain trimetazidine hydrochloride. The yield of trimetazidine hydrochloride is 94%, the purity is 99.94%, and the trimetazidine hydrochloride impurity B is not detected.

[0038] Comparative Example 1

[0039] The difference from Example 1 is that step S1 lacks microwave radiation heating; the rest is consistent with Example 1.

[0040] S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to 1-hexyl-3-methylimidazole dicyanamide, the molar ratio of 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and 1-hexyl-3-methylimidazole dicyanamide is 1:2:3, adding (R)-2,2'-dimethoxy-1,1'-binaphthyl, the molar ratio of (R)-2,2'-dimethoxy-1,1'-binaphthyl to 2,3,4-trimethoxybenzaldehyde is 0.07:1, heating at a temperature of 100° C. for 3 hours to obtain a mixed solution;

[0041] S2, subjecting the mixed solution to supercritical CO2 fluid extraction for 2 h at a temperature of 50°C, a pressure of 20 MPa, and a CO2 flow rate of 5 mL / min, and cooling to room temperature to obtain an extract;

[0042] S3, the extract was added to ethanol, the solid-liquid ratio of the extract to ethanol was 1:8g / mL, 2moL / L hydrochloric acid was added and mixed evenly, the volume ratio of hydrochloric acid to the extract was 1.5:1, the temperature was lowered to 15°C for crystallization, suction filtered and washed, dried, crushed and sieved to obtain trimetazidine hydrochloride. The yield of trimetazidine hydrochloride was 75%, the purity was 99.90%, and the content of impurity B in trimetazidine hydrochloride was detected to be 0.08%.

[0043] Comparative Example 2

[0044] The difference from Example 1 is that step S1 lacks an asymmetric catalyst and uses a conventional Pd / C catalyst; the rest is consistent with Example 1.

[0045] S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to 1-hexyl-3-methylimidazole dicyanamide, the molar ratio of 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and 1-hexyl-3-methylimidazole dicyanamide is 1:2:3, adding Pd / C catalyst, the molar ratio of Pd / C catalyst to 2,3,4-trimethoxybenzaldehyde is 0.07:1, and heating by microwave radiation for 3h, the power is 200W, the temperature is 100°C, and a mixed solution is obtained;

[0046] S2, subjecting the mixed solution to supercritical CO2 fluid extraction for 2 h at a temperature of 50°C, a pressure of 20 MPa, and a CO2 flow rate of 5 mL / min, and cooling to room temperature to obtain an extract;

[0047] S3, the extract was added to ethanol, the solid-liquid ratio of the extract to ethanol was 1:8g / mL, 2moL / L hydrochloric acid was added and mixed evenly, the volume ratio of hydrochloric acid to the extract was 1.5:1, the temperature was lowered to 15°C for crystallization, suction filtered and washed, dried, crushed and sieved to obtain trimetazidine hydrochloride. The yield of trimetazidine hydrochloride was 89%, the purity was 98.55%, and the content of impurity B in trimetazidine hydrochloride was detected to be 0.09%.

[0048] Comparative Example 3

[0049] The difference from Example 1 is that step S2 lacks supercritical fluid extraction and uses filtration to remove impurities; the rest is consistent with Example 1.

[0050] S1. Adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to 1-hexyl-3-methylimidazole dicyanamide, the molar ratio of 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and 1-hexyl-3-methylimidazole dicyanamide is 1:2:3, adding (R)-2,2'-dimethoxy-1,1'-binaphthyl, the molar ratio of (R)-2,2'-dimethoxy-1,1'-binaphthyl to 2,3,4-trimethoxybenzaldehyde is 0.07:1, heating under microwave radiation for 3h, the power is 200W, the temperature is 100°C, cooling to room temperature, filtering, and obtaining a material;

[0051] S2. Add the material to ethanol, the solid-liquid ratio of the material to ethanol is 1:8g / mL, add 2moL / L hydrochloric acid and mix evenly, the volume ratio of hydrochloric acid to the material is 1.5:1, cool to 15°C for crystallization, filter and wash, dry, crush and screen to obtain trimetazidine hydrochloride. The yield of trimetazidine hydrochloride is 88%, the purity is 98.00%, and the content of impurity B in trimetazidine hydrochloride is detected to be 0.10%.

[0052] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing high-purity trimetazidine hydrochloride, characterized in that: The specific steps include: S1, adding raw materials 2,3,4-trimethoxybenzaldehyde and anhydrous piperazine to ionic liquid 1-hexyl-3-methylimidazole dicyanamide, adding an asymmetric catalyst (R)-2,2'-dimethoxy-1,1'-binaphthyl, and heating by microwave radiation to obtain a mixed solution; The molar ratio of the 2,3,4-trimethoxybenzaldehyde, anhydrous piperazine and ionic liquid 1-hexyl-3-methylimidazole dicyanamide is 1:1-3:2-4; the molar ratio of the asymmetric catalyst (R)-2,2'-dimethoxy-1,1'-binaphthyl to 2,3,4-trimethoxybenzaldehyde is 0.05-0.08:1; The microwave radiation has a power of 100-300W, a temperature of 80-120°C, and a time of 2-4h; S2, subjecting the mixed solution to supercritical CO2 fluid extraction, cooling it to room temperature, and obtaining an extract; The supercritical CO2 fluid extraction temperature is 40-60°C, the pressure is 10-30MPa, the time is 1-3h, and the flow rate is 4-6mL / min; S3. Add the extract to the organic solvent ethanol, add hydrochloric acid and mix evenly, cool and crystallize, filter and wash, dry, crush and sieve to obtain high-purity trimetazidine hydrochloride.

2. The method for preparing high-purity trimetazidine hydrochloride according to claim 1, characterized in that: In step S3, the solid-to-liquid ratio of the extract to the organic solvent ethanol is 1:5-10 g / mL.

3. The method for preparing high-purity trimetazidine hydrochloride according to claim 1, characterized in that: In step S3, the concentration of the hydrochloric acid is 1-3 moL / L; the volume ratio of the hydrochloric acid to the extract is 1-2:

1.

4. The method for preparing high-purity trimetazidine hydrochloride according to claim 1, characterized in that: In step S3, the crystallization temperature is 10-20°C.

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