阅读说明：本技术 一种硫酸氢氯吡格雷的精制方法 (Refining method of clopidogrel hydrogen sulfate ) 是由 杨明 王俊臣 赖珅 徐文斌 武妍杰 薛娟 年蓓蕾 樊振 王文华 钱丹 殷恒亮 于 2021-09-10 设计创作，主要内容包括：本申请属于医药化工制造技术领域,具体涉及一种硫酸氢氯吡格雷的精制方法。该方法包括：物料溶解、有机萃取、去除有机相、溶解及脱色处理、结晶及制备成品等步骤。本申请的主要技术思路为：将待精制处理的硫酸氢氯吡格雷用纯化水溶剂后,在碳酸钠作用下制备出氯吡格雷游离碱,随后,游离碱在混合溶剂(丙酮、甲醇及纯化水)中与硫酸反应并进一步结晶以制备获得高纯度Ⅱ型硫酸氢氯吡格雷。本申请的精制工艺较好解决了现有工业化生产制备硫酸氢氯吡格雷中晶型不稳定、杂质高、颜色泛红的质量问题,使得相关产品质量标准能够较好满足现行药典标准,具有适于工业化应用、工艺操作简单可行的技术优点,表现出较好的实用价值和推广应用意义。(The application belongs to the technical field of pharmaceutical chemical manufacturing, and particularly relates to a refining method of clopidogrel hydrogen sulfate. The method comprises the following steps: dissolving materials, performing organic extraction, removing an organic phase, dissolving and decoloring, crystallizing, preparing a finished product and the like. The main technical thought of the application is as follows: after clopidogrel bisulfate to be refined is treated by a purified water solvent, clopidogrel free alkali is prepared under the action of sodium carbonate, and then the free alkali reacts with sulfuric acid in a mixed solvent (acetone, methanol and purified water) and is further crystallized to prepare high-purity II type clopidogrel bisulfate. The refining process disclosed by the application better solves the quality problems of unstable crystal form, high impurity content and reddish color in the existing industrial production preparation of clopidogrel hydrogen sulfate, so that the quality standard of related products can better meet the existing pharmacopoeia standard, and the refining process has the technical advantages of suitability for industrial application, simple and feasible process operation, and better practical value and popularization and application significance.)

1. A refining method of clopidogrel hydrogen sulfate is characterized by comprising the following steps:

(1) dissolution of the material

Dissolving clopidogrel bisulfate to be refined by pure water, wherein the temperature is controlled as follows in the dissolving process: 20 +/-10 ℃;

(2) organic extraction

Dropwise adding a sodium carbonate solution into the dissolved liquid in the step (1) to adjust the pH = 8-10, standing for not less than 30min, and separating liquid

Extracting the water phase with an organic extractant;

(3) removal of the organic phase

Adding a drying agent into the extraction liquid in the step (2) for drying, carrying out suction filtration, collecting filtrate, controlling the temperature below 40 ℃, and carrying out reduced pressure evaporation to remove the organic extracting agent to obtain light yellow oily liquid;

(4) dissolving and decolorizing

Adding acetone, methanol and purified water into the light yellow oily liquid obtained in the step (3) at the temperature of 10-30 ℃, and stirring until the solution is clear to ensure full dissolution; then, carrying out filter pressing to a decoloring tank, and adding a decoloring agent for decoloring;

(5) crystallization and preparation of finished products

Filter-pressing the liquid obtained after the decolorization treatment in the step (4) into a crystallizing tank, dropwise adding sulfuric acid at 40 +/-5 ℃, heating to 55-60 ℃ after completing dropwise adding, and stirring for 1-3 hours;

then, cooling to 0 +/-5 ℃, and stirring for 3-5 h;

centrifuging, and vacuum drying the precipitate at 50 deg.C or below to constant weight.

2. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein the amount of the purified water used in the step (1) is 3 to 10 times the mass of clopidogrel hydrogen sulfate.

3. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein the organic extractant in the step (2) is dichloromethane, and the amount of dichloromethane is 2 to 6 times the amount of clopidogrel hydrogen sulfate in terms of mass ratio.

4. The method for refining clopidogrel bisulfate according to claim 1, wherein the drying agent in the step (3) is anhydrous sodium sulfate.

5. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein in the step (4), the amount of acetone is 3 to 6 times the amount of clopidogrel hydrogen sulfate in terms of mass ratio;

the dosage of the methanol is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate;

the dosage of the purified water is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate.

6. The refining method of clopidogrel hydrogen sulfate according to claim 1, wherein in the step (4), the decoloring agent is activated carbon and/or silica gel powder, and the amount of the activated carbon is 0.05 to 0.1 times that of clopidogrel hydrogen sulfate; the silica gel powder is 300-400 meshes, and the dosage of the silica gel powder is 0.05-0.1 time of that of the clopidogrel hydrogen sulfate.

7. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein the mass concentration of the sulfuric acid is 75 to 80% and the amount of the sulfuric acid is 0.40 to 0.50 times the amount of clopidogrel hydrogen sulfate.

Technical Field

The application belongs to the technical field of pharmaceutical chemical manufacturing, and particularly relates to a refining method of clopidogrel hydrogen sulfate.

Background

The chemical name of clopidogrel hydrogen sulfate is as follows: methyl (+) - (S) -alpha-o-chlorophenyl-6, 7-dihydrothiophene [3,2-C ] pyridine-5 (4H) -acetate hydrogen sulfate, a new generation of anti-platelet aggregation agent, was first marketed in the United kingdom and the United states in 1998, and was marketed in China at 8 months in 2001.

Research has shown that clopidogrel hydrogen sulfate has various crystal forms: the crystal forms I, II, III, IV, V, VI and amorphous states, wherein only the crystal forms I and II can be used as medicines, and the other crystal forms contain a certain amount of solvent molecules, so that toxic and side effects are increased, and the crystal forms cannot be used as raw material medicines for preparation. In addition, the clopidogrel hydrogen sulfate II type is more stable than the clopidogrel hydrogen sulfate I type, and the solubility of the clopidogrel hydrogen sulfate II type in partial solution is better.

In the existing production, most of clopidogrel bisulfate is a light yellow solid and mixed crystal before refining, and according to the current pharmacopoeia standard, the main quality problems are that three unknown impurities do not meet the standard (the unknown single impurity is less than 0.1 percent), and the relative retention time is 0.90min, 0.97min and 2.17min respectively. In addition, clopidogrel hydrogen sulfate prepared by industrial production often has the problems of reddish color, unstable crystal form, high unknown single impurity and the like, so that further research is needed for a clopidogrel hydrogen sulfate refining method from the perspective of medical safety quality.

Disclosure of Invention

The application aims to provide a refining method of clopidogrel hydrogen sulfate, thereby laying a certain technical foundation for the quality stability of related yield.

The technical scheme adopted by the application is briefly described as follows.

A refining method of clopidogrel hydrogen sulfate specifically comprises the following steps:

(1) dissolution of the material

Dissolving clopidogrel bisulfate to be refined by pure water, wherein the temperature is controlled as follows in the dissolving process: 20 +/-10 ℃;

in terms of specific dosage, the dosage of the purified water is 3-10 times (preferably 4-6 times) of the mass of the clopidogrel hydrogen sulfate;

the clopidogrel hydrogen sulfate to be refined has the following specific quality standard references: maximum unknown single impurity 0.13%, impurity i: 0.01%, impurity II: 0.07 percent of total impurities, 0.4 to 0.5 percent of total impurities;

(2) organic extraction

Slowly (controlling the temperature to be 10-30 ℃) dropwise adding a sodium carbonate solution into the dissolved liquid in the step (1) to adjust the pH = 8-10 (so as to obtain clopidogrel free alkali), standing for not less than 30min, and separating liquid (separating into an organic phase and a water phase);

extracting the water phase by using an organic extractant, and further washing the extracted extract liquor by using purified water for 1-2 times;

the organic extracting agent is dichloromethane, and the dosage of the dichloromethane is 2-6 times (preferably 4-5 times) that of the clopidogrel hydrogen sulfate in terms of mass ratio; the washing water consumption is 5-10 times of the clopidogrel hydrogen sulfate consumption;

the mass concentration of the sodium carbonate solution is 6-7%;

(3) removal of the organic phase

Adding a drying agent into the extract liquor obtained in the step (2) for drying (anhydrous sodium sulfate is used as the drying agent, and the anhydrous sodium sulfate is added for drying treatment for 1-3 h), carrying out suction filtration, collecting filtrate, controlling the temperature below 40 ℃, and carrying out reduced pressure evaporation to remove dichloromethane to obtain light yellow oily liquid;

in terms of the dosage of the drying agent, the dosage of the anhydrous sodium sulfate is referred to be 0.3-0.5 time of the dosage of the clopidogrel hydrogen sulfate;

(4) dissolving and decolorizing

Adding acetone, methanol and purified water into the light yellow oily liquid obtained in the step (3) at the temperature of 10-30 ℃, and stirring until the solution is clear to ensure full dissolution; then, carrying out filter pressing to a decoloring tank, and adding a decoloring agent for decoloring;

in terms of the specific dosage, the dosage of the acetone is 3-6 times of the dosage of the clopidogrel hydrogen sulfate in terms of mass ratio;

the dosage of the methanol is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate;

the dosage of the purified water is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate;

the decolorizing agent is activated carbon and/or silica gel powder, and the dosage of the activated carbon is 0.05-0.1 time of that of clopidogrel hydrogen sulfate; the silica gel powder is 300-400 meshes, and the dosage of the silica gel powder is 0.05-0.1 time of that of the clopidogrel hydrogen sulfate;

(5) crystallization and preparation of finished products

Filter-pressing the liquid obtained after the decolorization treatment in the step (4) into a crystallizing tank, dropwise adding sulfuric acid at 40 +/-5 ℃, slowly heating to 55-60 ℃ after completing dropwise adding, and stirring for 1-3 hours;

then, cooling to 0 +/-5 ℃, and stirring for 3-5 h;

centrifuging (in a manner of throwing filtration), and drying the precipitate in vacuum at the temperature of below 50 ℃ to constant weight to obtain II-type clopidogrel hydrogen sulfate;

in the process, the mass concentration of the sulfuric acid is 75-80%, and the dosage of the sulfuric acid is 0.40-0.50 time of that of clopidogrel hydrogen sulfate.

The main technical thought of the application is as follows: after clopidogrel bisulfate to be refined is treated by a purified water solvent, clopidogrel free alkali is prepared under the action of sodium carbonate, and then the free alkali reacts with sulfuric acid in a mixed solvent (acetone, methanol and purified water) and is further crystallized to prepare high-purity II type clopidogrel bisulfate.

In general, preliminary experiment results show that the refining process of the application better solves the quality problems of unstable crystal form, high impurity content and reddish color in the existing industrial production of clopidogrel hydrogen sulfate, so that the quality standard of related products can better meet the standard of the existing pharmacopoeia, and the refining process has the technical advantages of suitability for industrial application, simple and feasible process operation, and shows better practical value and popularization and application significance.

Detailed Description

The present application is further illustrated by the following examples.

Example 1

The brief introduction of the specific operation steps of the method for refining clopidogrel bisulfate provided in the embodiment is as follows.

(1) Dissolution of the material

In a 200L glass lining reaction tank, 35Kg of purified water and 10Kg of unqualified clopidogrel hydrogen sulfate to be refined are added (slowly added),

the clopidogrel hydrogen sulfate to be refined has the following specific quality standards: maximum unknown single impurity 0.13%, impurity i: 0.01%, impurity II: 0.07 percent of the total impurities and 0.4 to 0.5 percent of the total impurities.

(2) Organic extraction

Slowly (controlling the temperature to be about 15 ℃) dropwise adding a sodium carbonate solution into the dissolved liquid in the step (1) to adjust the pH =9.5, standing for not less than 30min, and separating liquid;

the mass concentration of the sodium carbonate solution is 6.5 percent;

the aqueous phase is extracted with 30Kg of the organic extractant dichloromethane and the extract is washed 2 times with 50Kg of purified water.

(3) Removal of the organic phase

And (3) adding 5.0Kg of anhydrous sodium sulfate into the extract liquid obtained in the step (2) for drying (about 2 hours of drying treatment), carrying out suction filtration, collecting filtrate, controlling the temperature to be about 40 ℃, and carrying out reduced pressure evaporation to remove dichloromethane to obtain light yellow oily liquid.

(4) Dissolving and decolorizing

When the temperature of the yellowish oily liquid in the step (3) is reduced to 30 ℃, adding acetone, methanol and purified water, and stirring until the solution is clear to ensure full dissolution; then, carrying out filter pressing to a decoloring tank, and adding a decoloring agent for decoloring;

in terms of the specific dosage, the dosage of the acetone is 60Kg in terms of mass ratio;

the dosage of the methanol is 1 Kg;

the amount of purified water is 0.5 Kg;

the decolorizing agent is active carbon and silica gel powder, and the dosage of the active carbon is 0.5 Kg; the silica gel powder is 400 meshes, and the dosage of the silica gel powder is 1 Kg;

(5) crystallization and preparation of finished products

Filter-pressing the liquid obtained after the decolorization treatment in the step (4) into a crystallizing tank, dropwise adding sulfuric acid at 40 ℃, slowly heating to 60 ℃ after dropwise adding, and stirring for 1 h;

then, cooling to 4 ℃ and stirring for 5 hours;

centrifuging (in a manner of throwing filtration), and drying the precipitate in vacuum at the temperature of below 50 ℃ to constant weight to obtain II-type clopidogrel hydrogen sulfate;

in the process, the mass concentration of the sulfuric acid is 75 percent, and the dosage of the sulfuric acid is 4 Kg.

After weighing, 9.0Kg of clopidogrel bisulfate is finally obtained. After detection according to pharmacopeia standards, the prepared clopidogrel hydrogen sulfate is type II, the maximum unknown single impurity is 0 percent, and the impurity I: 0%, impurity II: 0.07 percent and total impurities 0.07 percent.

Example 2

The refining method of clopidogrel bisulfate provided by the embodiment is generally the same as the operation of the embodiment 1, and only part of process parameters are adjusted as follows:

in the step (1), 40Kg of purified water and 10Kg of unqualified clopidogrel hydrogen sulfate to be refined (the raw materials are the same as those in the example 1);

in step (2), pH =10.0 was adjusted (other parameters were the same as in example 1);

in the step (3), the operation was the same as in example 1;

in the step (4), the dosage of acetone is 58 Kg; the dosage of the methanol is 0.8 Kg; the amount of purified water was 0.5Kg (other parameters were the same as in example 1);

in the step (5), the mass concentration of the sulfuric acid is 80 percent, and the dosage of the sulfuric acid is 4.1 Kg.

9.1Kg of clopidogrel bisulfate is finally prepared. After detection according to pharmacopeia standards, the prepared clopidogrel hydrogen sulfate is type II, the maximum unknown single impurity is 0 percent, and the impurity I: not detected, impurity ii: 0.07 percent and total impurities 0.07 percent.

Example 3

The refining method of clopidogrel bisulfate provided by the embodiment is generally the same as the operation of the embodiment 1, and only part of process parameters are adjusted as follows:

in the step (1), 50Kg of purified water and 10Kg of unqualified clopidogrel hydrogen sulfate to be refined (the raw materials are the same as those in the example 1);

in step (2), pH =8.3 was adjusted (other parameters were the same as in example 1);

in the step (3), the operation was the same as in example 1;

in the step (4), the dosage of acetone is 60 Kg; the dosage of the methanol is 1.0 Kg; the amount of purified water was 0.6Kg (other parameters were the same as those in example 1);

in the step (5), the mass concentration of the sulfuric acid is 80 percent, and the dosage of the sulfuric acid is 4.3 Kg.

9.2Kg of clopidogrel bisulfate is finally prepared. After detection according to pharmacopeia standards, the prepared clopidogrel hydrogen sulfate is type II, the maximum unknown single impurity is 0 percent, and the impurity I: not detected, impurity ii: 0.06 percent and total impurities 0.06 percent.