CN110590805A - Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate - Google Patents
Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate Download PDFInfo
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- CN110590805A CN110590805A CN201910859780.8A CN201910859780A CN110590805A CN 110590805 A CN110590805 A CN 110590805A CN 201910859780 A CN201910859780 A CN 201910859780A CN 110590805 A CN110590805 A CN 110590805A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
The invention discloses a preparation method of high-purity II crystal form clopidogrel hydrogen sulfate. The method comprises the following steps: dissolving the first clopidogrel free alkali crude product in dichloromethane, removing impurities by using a 4 wt% sodium hydroxide solution, washing an organic phase by alkali, drying, filtering, and concentrating to obtain a second clopidogrel free alkali crude product; adding ethyl acetate or a mixed solution of ethyl acetate and acetonitrile, heating to 37-39 ℃, dropwise adding concentrated sulfuric acid for crystallization, performing room-temperature crystallization, filtering, and drying a filter cake to obtain a final product II crystal form clopidogrel hydrogen sulfate. The method has mild reaction conditions, no toxic and harmful substances, reduces the use of easy-to-prepare toxic solvents, shortens the reaction time from 14-16 h to 4-6 h, reduces the energy consumption, ensures that related substances of the II crystal form clopidogrel hydrogen sulfate meet various standards at home and abroad, and avoids the generation of impurities when strong acid is dripped; the obtained II crystal form clopidogrel hydrogen sulfate has high purity and high yield.
Description
Technical Field
The invention relates to the technical field of platelet aggregation resisting medicines, in particular to a preparation method of high-purity II crystal form clopidogrel hydrogen sulfate.
Background
Clopidogrel sulfate (Clopidogrel Bisulfate) is white to off-white powder with molecular formula of C16H16O2ClNSH2SO4Molecular weight is 419.9, and the structural formula is as follows:
clopidogrel sulfate is a novel thiophene pyridine drug developed by Sanofi-Avetnis company and 1986, irreversibly inhibits platelet aggregation by selectively binding with ADP receptor coupled with platelet surface adenylate cyclase, reduces the formation of thrombus in blood vessels, and belongs to the anti-platelet aggregation drugs. CAPPIE research, CURE research and CLASSICS research show that clopidogrel has strong antiplatelet effect, excellent safety and tolerance, and particularly has good curative effect on ACS and excellent prevention effect on other ischemic events, which are highly evaluated by international clinical medicine and preventive medicine experts.
Three related impurities are mentioned in the clopidogrel hydrogen sulfate USP standard, namely impurity A, B and C, and the structural formula is as follows. Wherein the impurity A is a hydrolysis product of clopidogrel; the impurity B is clopidogrel hydrochloride raceme; the impurities A and B are easy to control in production; and the impurity C is an enantiomer of clopidogrel hydrogen sulfate, is difficult to control, and the content of the impurity C may gradually increase in the process of later storage.
The clopidogrel bisulfate has various crystal forms, the confirmed crystal forms comprise amorphous form, I form, II form and the like, and the two crystal forms, namely the I form and the II form, are mainly used for preparing the clopidogrel bisulfate at present. Of these two forms, form II is more stable than form I and also has significantly less solubility in certain solvents than form I. The crystal form II clopidogrel hydrogen sulfate has the melting point of 173-179 ℃, is easy to dissolve in methanol, is slightly soluble in dichloromethane and is insoluble in diethyl ether.
The existing preparation method of II crystal form clopidogrel hydrogen sulfate generally comprises the steps of carrying out ring closing reaction on S- (+) -methyl- (2-chlorphenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride and a formaldehyde solution to prepare clopidogrel free alkali, and then salifying to obtain the clopidogrel hydrogen sulfate crystal form II clopidogrel hydrogen sulfate.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity II crystal form clopidogrel hydrogen sulfate, which has mild reaction conditions, low energy consumption and no toxic and harmful substances in the preparation process, reduces the use of easy-to-prepare toxic solvents, can effectively remove the hydrolysate impurity A of clopidogrel, and has high purity and high yield of the obtained II crystal form clopidogrel hydrogen sulfate.
In order to achieve the aim, the invention provides a preparation method of high-purity II crystal form clopidogrel hydrogen sulfate, which comprises the following steps: (1) dissolving the first clopidogrel free alkali crude product in dichloromethane, removing impurities by using a 4 wt% sodium hydroxide solution, washing an organic phase by alkali, and then drying, filtering and concentrating to obtain a second clopidogrel free alkali crude product; (2) and adding ethyl acetate or a mixed solution of ethyl acetate and acetonitrile into the obtained second clopidogrel free alkali crude product for dissolving, heating to 37-39 ℃, dropwise adding concentrated sulfuric acid for crystallization, cooling to room temperature for crystallization, filtering to obtain a wet product of the II crystal form clopidogrel hydrogen sulfate, and drying a filter cake to obtain a final product of the II crystal form clopidogrel hydrogen sulfate.
In a preferred embodiment, in step (1), the preparation method of the first crude clopidogrel free base comprises the following steps: (1) adding S- (+) -methyl- (2-chlorphenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride into methanol in a closed system, then adding formaldehyde, carrying out ring closing reaction for 4-6 h at the temperature of 40-45 ℃ to obtain an amine intermediate, and (2) adding water and dichloromethane into the obtained amine intermediate for quenching reaction, then adding a sodium bicarbonate solution to adjust the pH value to 6-7, extracting twice by using dichloromethane, and then drying, filtering and concentrating to obtain a first clopidogrel free alkali crude product.
In a preferred embodiment, in step (1), the organic phase is further washed with an alkali solution after the concentration; preferably, the alkali solution is 1 wt% sodium hydroxide. The organic phase is dried, concentrated and then dissolved, and the organic phase is washed by alkali solution, so that the treatment aims are as follows: to remove impurities from the free base and to reduce the production of impurities.
In a preferred embodiment, in step (1), the temperature during concentration is not higher than 40 ℃.
In a preferred embodiment, in step (2), the volume ratio of acetonitrile to ethyl acetate is 1: 5 to 15, preferably 1: 9.
In a preferred embodiment, in the step (2), the crystallization time with concentrated sulfuric acid is 4 h; and/or the crystallization time is 4h when the temperature is reduced to room temperature.
In a preferred embodiment, in the step (2), the drying time is 2-3 h when the filter cake is dried; and/or, the temperature of drying is not higher than 45 ℃.
In a preferred embodiment, in step (1), the mass ratio of the hydrochloride salt of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate to methanol is 1: 1 to 4, preferably 1: 2.
In a preferred embodiment, in step (1), the mass ratio of the hydrochloride salt of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate to formaldehyde is 1: 4 to 10, preferably 1: 6.5.
In a preferred embodiment, in step (1), the sodium bicarbonate solution is a saturated sodium bicarbonate solution.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention adopts a methanol system as a reaction solvent for preparing the first clopidogrel free alkali crude product, and the reaction system is changed into a balloon sealing system, thereby reducing formaldehyde volatilization.
(2) According to the invention, the reaction temperature in the preparation process of the amine intermediate is increased from about 37 ℃ to 40-45 ℃, the reaction time is shortened from 14-16 h to 4-6 h, the process flow is greatly shortened, and the energy consumption is reduced.
(3) The clopidogrel free alkali crude product is dried and concentrated twice and washed with alkali to remove impurities, so that related substances of the clopidogrel hydrogen sulfate in the II crystal form meet various standards at home and abroad.
(4) The mixed solvent of ethyl acetate and acetonitrile is used as the crystallization solution of the second clopidogrel free alkali crude product, so that the generation of impurities is avoided when strong acid is dripped.
(5) Removing impurities, namely, replacing water with a sodium hydroxide solution to more effectively remove impurity A of a clopidogrel hydrolysate; thereby meeting the quality requirement without further impurity removal.
(6) The II crystal form clopidogrel hydrogen sulfate prepared by the method has high purity, high yield and low energy consumption; the reaction conditions in the preparation process are mild, no toxic or harmful substances are generated, the use of solvents which are easy to prepare the toxic substances is reduced, and the method is a process method suitable for industrial production.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Example 1: preparation method of II crystal form clopidogrel hydrogen sulfate
The preparation method comprises the following steps:
adding 34.6g of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride into a 500ml three-neck flask filled with 70ml of methanol solution, then adding 200ml of formaldehyde solution, heating to 40 ℃, stirring and reacting for 6h to obtain an amine intermediate, wherein the reaction system is in a closed state by a balloon or a plug;
to the resulting amine intermediate, 50ml of water and 100ml of dichloromethane were sequentially added to carry out quenching reaction, then saturated sodium bicarbonate solution was added to adjust the weak acid to pH 6-7, and extraction was carried out twice with dichloromethane (100ml × 2), and the organic phases were combined; drying for 2h by using anhydrous sodium sulfate; performing suction filtration and concentration at the temperature below 40 ℃ to obtain a first clopidogrel free alkali crude product of oily liquid;
dissolving the obtained first clopidogrel free alkali crude product by using 200ml of dichloromethane, washing twice by using 4 wt% of sodium hydroxide solution (50ml multiplied by 2), removing impurities, drying an organic phase for 2 hours by using anhydrous sodium sulfate, and performing suction filtration and concentration to obtain a second clopidogrel free alkali crude product;
dissolving the obtained second clopidogrel free alkali crude product in 180ml of a mixed solvent of acetonitrile and ethyl acetate (V: V is 1: 9), heating to 37 ℃, slowly dripping 10.0g of concentrated sulfuric acid into the solution, stirring to form salt and crystallize for 4 hours, cooling to room temperature, and continuously stirring to crystallize for 4 hours; and (3) carrying out forced air drying for 2h at the temperature of 40 ℃ to obtain the white II crystal form clopidogrel hydrogen sulfate.
The yield by weight of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride is 96%, in the related substance items calculated by High Performance Liquid Chromatography (HPLC) measurement according to an external standard method, the impurity A is approximately equal to 0.15%, the impurity B is approximately equal to 0.19%, the impurity C is approximately equal to 0.4%, other unknown impurities are all less than 0.1%, and the total impurity is approximately equal to 0.9%.
Example 2: preparation method of II crystal form clopidogrel hydrogen sulfate
The preparation method comprises the following steps:
adding 34.6g of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride into a 500ml three-neck flask filled with 70ml of methanol solution, then adding 200ml of formaldehyde solution, heating to 42 ℃, stirring and reacting for 5h to obtain an amine intermediate, wherein the reaction system is in a closed state by a balloon or a plug;
to the resulting amine intermediate, 50ml of water and 100ml of dichloromethane were sequentially added to carry out quenching reaction, then saturated sodium bicarbonate solution was added to adjust the weak acid to pH 6-7, and extraction was carried out twice with dichloromethane (100ml × 2), and the organic phases were combined; drying for 2h by using anhydrous sodium sulfate; performing suction filtration and concentration at the temperature below 40 ℃ to obtain a first clopidogrel free alkali crude product of oily liquid;
dissolving the obtained first clopidogrel free alkali crude product by using 200ml of dichloromethane, washing twice by using 4 wt% of sodium hydroxide solution (50ml multiplied by 2), removing impurities, drying an organic phase for 2 hours by using anhydrous sodium sulfate, and performing suction filtration and concentration to obtain a second clopidogrel free alkali crude product;
dissolving the obtained second clopidogrel free alkali crude product in 180ml of a mixed solvent of acetonitrile and ethyl acetate (V: V is 1: 9), heating to 38 ℃, slowly dripping 10.0g of concentrated sulfuric acid into the solution, stirring to form salt and crystallize for 4 hours, cooling to room temperature, and continuously stirring to crystallize for 4 hours; and (3) carrying out forced air drying at the temperature of 43 ℃ for 3h to obtain the white II crystal form clopidogrel hydrogen sulfate.
The weight yield of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride is 98%, in the related substance items calculated by High Performance Liquid Chromatography (HPLC) determination according to an external standard method, the impurity A is approximately equal to 0.13%, the impurity B is approximately equal to 0.14%, the impurity C is approximately equal to 0.2%, other unknown impurities are all less than 0.1%, and the total impurity is approximately equal to 0.7%.
Example 3: preparation method of II crystal form clopidogrel hydrogen sulfate
The preparation method comprises the following steps:
adding 34.6g of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride into a 500ml three-neck flask filled with 70ml of methanol solution, then adding 200ml of formaldehyde solution, heating to 45 ℃, and stirring for reacting for 4h to obtain an amine intermediate, wherein the reaction system is in a closed state by a balloon or a plug;
to the resulting amine intermediate, 50ml of water and 100ml of dichloromethane were sequentially added to carry out quenching reaction, then saturated sodium bicarbonate solution was added to adjust the weak acid to pH 6-7, and extraction was carried out twice with dichloromethane (100ml × 2), and the organic phases were combined; drying for 2h by using anhydrous sodium sulfate; performing suction filtration and concentration at the temperature below 40 ℃ to obtain a first clopidogrel free alkali crude product of oily liquid;
dissolving the obtained first clopidogrel free alkali crude product by using 200ml of dichloromethane, washing twice by using 4 wt% of sodium hydroxide solution (50ml multiplied by 2), removing impurities, drying an organic phase for 3 hours by using anhydrous sodium sulfate, and performing suction filtration and concentration to obtain a second clopidogrel free alkali crude product;
dissolving the obtained second clopidogrel free alkali crude product in 160ml of ethyl acetate mixed solvent, heating to 39 ℃, slowly dripping 10.0g of concentrated sulfuric acid into the solution, stirring to form salt and crystallize for 4 hours, then cooling to room temperature, and continuously stirring and crystallizing for 4 hours; and (3) carrying out forced air drying for 2h at the temperature of 45 ℃ to obtain the white II crystal form clopidogrel hydrogen sulfate.
The yield by weight of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride is 97%, in the related substance items calculated by High Performance Liquid Chromatography (HPLC) measurement according to an external standard method, the impurity A is approximately equal to 0.14%, the impurity B is approximately equal to 0.10%, the impurity C is approximately equal to 0.23%, other unknown impurities are all less than 0.1%, and the total impurity is approximately equal to 0.8%.
Example 4: preparation method of II crystal form clopidogrel hydrogen sulfate
The preparation method comprises the following steps:
adding 34.6g of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride into a 500ml three-neck flask filled with 70ml of methanol solution, then adding 200ml of formaldehyde solution, heating to 43 ℃, stirring and reacting for 5h to obtain an amine intermediate, wherein the reaction system is in a closed state by a balloon or a plug;
to the resulting amine intermediate, 50ml of water and 100ml of dichloromethane were sequentially added to carry out quenching reaction, then saturated sodium bicarbonate solution was added to adjust the weak acid to pH 6-7, and extraction was carried out twice with dichloromethane (100ml × 2), and the organic phases were combined; drying for 2h by using anhydrous sodium sulfate; performing suction filtration and concentration at the temperature below 40 ℃ to obtain a first clopidogrel free alkali crude product of oily liquid;
dissolving the obtained first clopidogrel free alkali crude product with 200ml of dichloromethane, washing twice with 4 wt% of sodium hydroxide solution (50ml multiplied by 2), removing impurities, drying an organic phase for 2.5 hours by using anhydrous sodium sulfate, and carrying out suction filtration and concentration to obtain a second clopidogrel free alkali crude product;
dissolving the obtained second clopidogrel free alkali crude product in 180ml of a mixed solvent of acetonitrile and ethyl acetate (V: V is 1: 9), heating to 38 ℃, slowly dripping 10.0g of concentrated sulfuric acid into the solution, stirring to form salt and crystallize for 4 hours, cooling to room temperature, and continuously stirring to crystallize for 4 hours; and (3) carrying out forced air drying at the temperature of 43 ℃ for 3h to obtain the white II crystal form clopidogrel hydrogen sulfate.
The weight yield of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride is 100%, in the related substance items calculated by High Performance Liquid Chromatography (HPLC) determination according to an external standard method, the impurity A is approximately equal to 0.10%, the impurity B is approximately equal to 0.13%, the impurity C is approximately equal to 0.15%, other unknown impurities are all less than 0.1%, and the total impurity is approximately equal to 0.7%.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (10)
1. A preparation method of high-purity II crystal form clopidogrel hydrogen sulfate is characterized by comprising the following steps:
(1) dissolving the first clopidogrel free alkali crude product in dichloromethane, removing impurities by using a 4 wt% sodium hydroxide solution, washing an organic phase by alkali, and then drying, filtering and concentrating to obtain a second clopidogrel free alkali crude product;
(2) and adding ethyl acetate or a mixed solution of ethyl acetate and acetonitrile into the obtained second clopidogrel free alkali crude product for dissolving, heating to 37-39 ℃, dropwise adding concentrated sulfuric acid for crystallization, cooling to room temperature for crystallization, filtering to obtain a wet product of the II crystal form clopidogrel hydrogen sulfate, and drying a filter cake to obtain a final product of the II crystal form clopidogrel hydrogen sulfate.
2. The process according to claim 1, wherein in step (1), the process for preparing the first crude clopidogrel free base comprises the steps of:
(1) in a closed system, adding S- (+) -methyl- (2-chlorphenyl) [ (2- (2-thienyl) aminoethyl ] acetate hydrochloride into methanol, then adding formaldehyde, and carrying out ring closing reaction for 4-6 h at the temperature of 40-45 ℃ to obtain an amine intermediate;
(2) and adding water and dichloromethane into the obtained amine intermediate to carry out quenching reaction, then adding a sodium bicarbonate solution to adjust the pH value to 6-7, extracting twice by using dichloromethane, and then drying, filtering and concentrating to obtain a first clopidogrel free alkali crude product.
3. The process according to claim 1, wherein in the step (1), the organic phase is further washed with an alkali solution after the concentration; the preferred base solution is a 1 wt% sodium hydroxide solution.
4. The method according to claim 1, wherein in the step (1), the temperature at the time of the concentration is not higher than 40 ℃.
5. The method according to claim 1, wherein in the step (2), the volume ratio of acetonitrile to ethyl acetate is 1: 5 to 15, preferably 1: 9.
6. The preparation method according to claim 1, wherein in the step (2), the crystallization time with concentrated sulfuric acid is 4 h; and/or the crystallization time is 4h when the temperature is reduced to room temperature.
7. The preparation method according to claim 1, wherein in the step (2), the drying time is 2-3 h when the filter cake is dried; and/or, the temperature of drying is not higher than 45 ℃.
8. The process according to claim 2, wherein in the step (1), the mass ratio of the hydrochloride salt of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate to methanol is 1: 1 to 4, preferably 1: 2.
9. The process according to claim 2, wherein in the step (1), the mass ratio of the hydrochloride salt of S- (+) -methyl- (2-chlorophenyl) [ (2- (2-thienyl) aminoethyl ] acetate to formaldehyde is 1: 4-10, preferably 1: 6.5.
10. The method according to claim 1, wherein in the step (1), the sodium bicarbonate solution is a saturated sodium bicarbonate solution.
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| CN113735877A (en) * | 2021-09-10 | 2021-12-03 | 天方药业有限公司 | Refining method of clopidogrel hydrogen sulfate |
| CN113880858A (en) * | 2021-11-08 | 2022-01-04 | 成都化润药业有限公司 | Clopidogrel hydrogen sulfate impurity A and preparation method thereof |
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Application publication date: 20191220 |