CN114369100A

CN114369100A - Preparation method of clopidogrel hydrogen sulfate spherical crystal form I

Info

Publication number: CN114369100A
Application number: CN202111584817.4A
Authority: CN
Inventors: 蒲通; 陈恬; 王乃星; 盛志红; 卢王杰; 郑利平; 王意中
Original assignee: Zhejiang Charioteer Pharmaceutical CO Ltd
Current assignee: Zhejiang Charioteer Pharmaceutical CO Ltd
Priority date: 2021-12-15
Filing date: 2021-12-15
Publication date: 2022-04-19
Anticipated expiration: 2041-12-15
Also published as: CN114369100B

Abstract

The invention discloses a preparation method of a clopidogrel hydrogen sulfate spherical crystal form I, which comprises the following steps: (1) dissolving clopidogrel free alkali in a solvent A, adding a solvent B, stirring, controlling the temperature of the solution at 5-15 ℃, and dropwise adding concentrated sulfuric acid within 0.5-1 h; after the dropwise addition, controlling the temperature of the solution at 10-20 ℃, and then slowly dropwise adding the mixed solvent D within 1.5-2.5 h; (2) adding seed crystals after the dripping of the mixed solvent D is finished, carrying out heat preservation crystallization at 10-20 ℃ for 6-8 h, slowly cooling to below 2 ℃ after the heat preservation is finished, and controlling the total cooling time to be 24-36 h; (3) filtering at the temperature below 2 ℃, washing a filter cake by using a solvent C, and drying to obtain the clopidogrel hydrogen sulfate I crystal form spherical crystal. The preparation method of the clopidogrel hydrogen sulfate I crystal form spherical particles has the characteristics of simplicity, high efficiency, controllability, low cost, stable crystal form and high quality.

Description

Preparation method of clopidogrel hydrogen sulfate spherical crystal form I

One, the technical field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of clopidogrel hydrogen sulfate crystal form I spherical particles.

Second, background Art

Clopidogrel bisulfate, which is the bisulfate of Clopidogrel, is known as Clopidogrel Hydrogen Sulfate and has the chemical name: (+) - (S) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) -acetic acid methyl ester hydrogen sulfate salt. Clopidogrel hydrogen sulfate is a platelet inhibitor and is mainly used for preventing atherothrombosis and further preventing ischemic stroke and heart attack. The product was developed by the French pharmaceutical corporation Sonofield-Anvant, first marketed in the United states and United kingdom in 1998, and entered the Chinese market in 2001. Clopidogrel hydrogen sulfate is taken as a clinical oral anticoagulant first-line medicament, has little toxic and side effect and has far higher market share than other medicaments.

The medicinal crystal forms of the clopidogrel bisulfate include a crystal form I and a crystal form II, wherein the crystal form I is a thermodynamically metastable crystal form, and the crystal form II is a thermodynamically stable crystal form. The stability of the crystal form I is lower than that of the crystal form II, but the solubility and bioavailability of the crystal form I are better than those of the crystal form II. Most of the currently marketed clopidogrel bisulfate preparation products are I crystal forms, and I crystal form powder has strong electrostatic effect and is easy to absorb moisture, and sticking easily occurs in the direct-pressing process of the preparation powder, so that the clopidogrel bisulfate preparation products can be prepared into spherical crystals with good fluidity to solve the problems.

Patent CN201180072203.6 discloses a preparation method of clopidogrel hydrogen sulfate I crystal form spherical particles, which adopts a mixed solvent system of 2-butanol and cyclohexane to prepare the I crystal form spherical particles. According to the technology, a cyclohexane solution of sulfuric acid is slowly dripped into an alcoholic solution of clopidogrel free alkali under a cooling condition, and the color of cyclohexane is possibly changed due to the fact that the sulfuric acid needs to be added into the cyclohexane, so that the color of a final product is influenced.

Patent WO2011083955 discloses a preparation method of clopidogrel hydrogen sulfate I crystal form spherical particles, which uses a mixed solvent system of 2-butanol and water to prepare the I crystal form spherical particles. Experiments prove that the clopidogrel hydrogen sulfate I crystal form is easy to glue due to water contained in the solvent, the synthesis of the I crystal form is not facilitated, and the yield is low. In addition, the boiling point of water is high, and the subsequent drying requires a long time and a high temperature for drying.

Patent CN102432625A discloses a preparation method of clopidogrel hydrogen sulfate I crystal form spherical particles, wherein ethyl acetate is used as a solvent to prepare the I crystal form spherical particles, and the crystallization time is long. When ethyl acetate is used as a crystallization solvent, the solvent amount is large, the crystallization time is long, and the production cost is high; and the oil is easy to agglomerate in production to form viscous yellow oily matter, and the process is unstable and difficult to repeat.

Therefore, the finding of the clopidogrel hydrogen sulfate crystal form I sphere particles which are simple, efficient, controllable, stable in crystal form and excellent in quality is still an unsolved technical problem in the prior art.

Third, the invention

The invention aims to provide a preparation method of clopidogrel hydrogen sulfate I crystal form spherical particles with low cost and excellent product quality.

A process for the preparation of clopidogrel hydrogen sulfate in the form of spherical crystal I, said process comprising the steps of:

(1) dissolving clopidogrel free alkali in a solvent A, adding a solvent B, stirring, controlling the temperature of the solution at 5-15 ℃, and dropwise adding concentrated sulfuric acid within 0.5-1 h; after the dropwise addition, controlling the temperature of the solution at 10-20 ℃, and slowly dropwise adding the mixed solvent D within 1.5-2.5 h;

the solvent A is selected from one of 1-butanol, 2-butanol and tert-butanol, and the mass ratio of the solvent A to clopidogrel free alkali is 7.7-8.3 times; the solvent B is selected from one of formic acid and acetic acid, and the mass ratio of the solvent B to clopidogrel free alkali is 0.9-1.3 times; the mixed solvent D is a mixed solution of a solvent B and a solvent C, wherein the solvent C is selected from one of normal hexane and cyclohexane, the mass of the solvent B contained in the mixed solvent D is 0.05-0.2 times of the mass of clopidogrel free alkali, and the mass of the solvent C contained in the mixed solvent D is 0.85-1.2 times of the mass of clopidogrel free alkali;

(2) adding seed crystals after the dripping of the mixed solvent D is finished, carrying out heat preservation crystallization at 10-20 ℃ for 6-8 h, slowly cooling to below 2 ℃ (preferably-5-2 ℃) after the heat preservation is finished, and controlling the total cooling time for 24-36 h;

(3) filtering at the temperature below 2 ℃ (preferably-5-2 ℃), washing a filter cake with a solvent C, and drying to obtain the clopidogrel hydrogen sulfate I crystal form spherical crystal.

In the step (1), the mass of the concentrated sulfuric acid is 0.28-0.31 time of that of clopidogrel free alkali.

In the step (1), the solvent A is preferably 2-butanol.

In the step (1), the solvent B is preferably acetic acid.

In the step (1), the solvent C is preferably cyclohexane.

In the step (1), the mixed solvent D is preferably cyclohexane and acetic acid.

In the step (1), it is particularly preferable that: the solvent A is 2-butanol, the solvent B is acetic acid, the solvent C is cyclohexane, and the mixed solvent D is cyclohexane and acetic acid.

In the step (2), the seed crystal is selected from clopidogrel hydrogen sulfate I type seed crystal, and the mass consumption of the crystal form is 0.01-0.05 times of that of clopidogrel free alkali; the slow cooling is gradient cooling, and the gradient cooling is that the temperature is reduced by 1-3 ℃ every 2-3 hours until the temperature is below 2 ℃.

In the step (3), the mass of the solvent C is preferably 0.8-1.6 times of that of clopidogrel free alkali.

In the step (3), the drying temperature is 55-75 ℃, the vacuum degree is-0.07-0.10 Mpa, and the time is 6-10 h.

In the industrial production process, the clopidogrel free base in the technical scheme can be prepared from a corresponding clopidogrel salt, and the steps are as follows:

firstly, adding clopidogrel salt (preferably with the HPLC purity of more than 99 percent) into an organic solvent, and adding 5 to 15 percent of inorganic alkali aqueous solution;

after phase separation, washing an organic phase with water, and adding a decolorizing agent and a drying agent into the obtained organic phase to carry out dehydration and dehydration;

filtering, decompressing and concentrating to obtain clopidogrel free alkali;

in the step I, the clopidogrel salt is at least one of sulfate, hydrochloride, camphorsulfonate and benzene sulfonate. The organic solvent is at least one of dichloromethane, trichloromethane, cyclohexane, toluene, ethyl acetate and other water-immiscible organic solvents. The inorganic base is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate and disodium hydrogen phosphate; the mass ratio of the clopidogrel salt to the inorganic base is 1: 0.15-1: 0.45. The decolorizing agent is at least one of active carbon and adsorption resin, and the mass and the dosage of the decolorizing agent are preferably 0.01-0.04 times of the mass of clopidogrel salt. The drying agent is at least one of magnesium sulfate, sodium sulfate, calcium sulfate and calcium chloride, and the mass and the dosage of the drying agent are preferably 0.1-0.4 times of the mass of the clopidogrel salt.

The solvent of the present invention may be a solvent of industrial grade or higher.

Compared with the prior art, the invention has the beneficial effects that:

(1) the solvent B with better solubility to the clopidogrel free alkali and the solvent A are added to prepare the mixed solvent, so that the solubility to the clopidogrel free alkali is increased, the consumption of sec-butyl alcohol and the total solvent is greatly reduced, and the use cost of the solvent is reduced; meanwhile, under the same equipment condition, the process has larger feeding amount and higher productivity; secondly, the generation amount of impurities such as oxidation impurities is reduced, and products with better quality can be obtained.

(2) In the prior art, concentrated sulfuric acid is diluted by organic solvents such as cyclohexane and the like and then added into clopidogrel free alkali solution to reduce impurities, accelerate reaction speed and improve product color, but in the invention, the concentrated sulfuric acid and the organic solvents are not required to be mixed firstly, but the concentrated sulfuric acid is directly dripped, and then a mixed solvent D with poor solubility is slowly dripped to ensure that reaction liquid gradually and slowly tends to supersaturation, then seed crystals are added for slow precipitation, so that the crystallization process is slowly carried out, and the obtained crystal form product is spherical particles and has good granularity and quality. The existence of the solvent B in the mixed solvent D avoids the problem that when the poor solvent C is singly dripped, the dripped liquid drop is quickly separated from the contact point of the liquid surface of the reaction liquid, thereby influencing the granularity and the quality of the crystal form product.

Description of the drawings

FIG. 1 is an XRD pattern of clopidogrel hydrogen sulfate form I spherical particles prepared in example 3;

FIG. 2 is an electron micrograph of clopidogrel hydrogen sulfate I crystal form spherical particles prepared in example 3;

fig. 3 is a microphotograph (magnification 100 times) of clopidogrel hydrogen sulfate I crystal form spherical particles prepared in example 4.

Fifth, detailed description of the invention

In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be clearly and completely described below, but the scope of the present invention is not limited thereto. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The clopidogrel salt is prepared by taking o-chlorophenylglycine as a raw material, and specifically comprises the following steps:

mixing o-chlorophenylglycine, methanol and concentrated sulfuric acid, heating to reflux, reacting for at least 3h, distilling the methanol under reduced pressure until the reaction liquid is thick, adding water and dichloromethane or toluene, stirring, dissolving, layering, and concentrating the organic layer to obtain P1 oil.

② mixing tartaric acid, methanol, acetone and P1 oil at 30-50 ℃, cooling, slowly precipitating to below 5 ℃, centrifuging and drying to obtain P2. The P2 can be further refined with methanol to obtain high-quality P2.

Dissolving 2-thiopheneethanol, p-toluenesulfonyl chloride, benzyltriethylammonium chloride or tetrabutylammonium bromide in dichloromethane or toluene, and dropwise adding a sodium hydroxide solution with the concentration of 20-50% at the temperature of 0-20 ℃. After dripping, the reaction is carried out for more than 5h, and then hydrochloric acid is added or the temperature is raised to more than 30 ℃ to terminate the reaction. Separating the layers, and concentrating the organic solvent to obtain the P3 oil. The P3 oil can be further refined with methanol to obtain high-quality P3.

Fourthly, the P2 is taken and dissolved in water and dichloromethane or water and toluene, and then sodium carbonate or sodium bicarbonate solution with the concentration of 5 percent to 15 percent and the equivalent weight is slowly added. The layers were separated and the organic layer was concentrated to give P2 oil.

Adding the P3 and P2 oil, benzyltriethylammonium chloride or tetrabutylammonium bromide, sodium carbonate or dipotassium hydrogen phosphate into acetonitrile or toluene, reacting at 80-120 ℃ for more than 20h, evaporating to remove the organic solvent, adding water and dichloromethane or water and toluene, stirring to dissolve, extracting and layering to obtain an organic layer. Adding appropriate amount of ethyl acetate and methanol, dripping hydrochloric acid below 40 deg.C, cooling to below 10 deg.C, filtering, and oven drying to obtain P4.

Fifthly, adding P4 into the formaldehyde aqueous solution, reacting for 25-35 h at 20-30 ℃, adding cyclohexane or toluene for reaction, adding sodium carbonate solution, extracting for layering, and concentrating the organic solvent to dryness to obtain oil. Then adding acetone, adding sulfuric acid or camphorsulfonic acid or benzenesulfonic acid or hydrochloric acid at the temperature below 10 ℃ to form salt, stirring and separating the material for more than 5 hours, and filtering to obtain the clopidogrel salt.

Example 1:

mixing 200g of o-chlorophenylglycine, 400g of methanol and 180g of concentrated sulfuric acid, heating to reflux, reacting for 4 hours, distilling the methanol under reduced pressure until the reaction solution is thick, adding 200g of water and 200g of dichloromethane, stirring, dissolving, layering, and concentrating the organic layer to obtain 200g P1 oil.

② 160g of tartaric acid, 1000g of methanol, 300g of acetone and 200g of P1 oil are mixed and dissolved at 40 ℃, then cooled, slowly separated to below 5 ℃, filtered and dried to obtain 300g P2. 300g P2 adding 800g methanol, maintaining the temperature at 30 deg.C, refining, and cooling to below 5 deg.C to obtain 260g P2.

③ 100g of 2-thiopheneethanol, 200g of paratoluensulfonyl chloride and 15g of benzyltriethylammonium chloride are dissolved in 700g of dichloromethane, and 300g of 30 percent sodium hydroxide solution is dripped at 10 ℃. After dropping, the reaction was kept for 6 hours, and 5kg of hydrochloric acid was added to terminate the reaction. The layers are separated, and the organic solvent is concentrated to obtain 250g P3 oil. Adding 250g of methanol into P3 oil, cooling to below 5 ℃, separating out materials, and filtering to obtain 220g P3.

(iv) the above synthesized P2200 g was dissolved in 500g of water and 600g of methylene chloride, and 800g of a 10% sodium carbonate solution was slowly added thereto. Layering, concentrating the organic layer to obtain P2 oil, adding 200g P3 g benzyltriethylammonium chloride, 10g sodium carbonate and 120g acetonitrile, reacting at 90 deg.C for 30h, evaporating to remove organic solvent, adding 500g water and 500g dichloromethane, stirring, removing solvent, extracting, layering to obtain organic layer, and concentrating to dryness. Then 450g of ethyl acetate and 100g of methanol are added, 70g of hydrochloric acid is dripped at the temperature of 40 ℃, the temperature is reduced to 10 ℃ after dripping, and 150g P4 is obtained after filtration and drying.

Fifthly, adding 150g P4 into 900g of 37 percent formaldehyde water solution, reacting for 33 hours at 25 ℃, then adding 500g of cyclohexane, adding 250g of 10 percent sodium carbonate solution, extracting and layering, and concentrating the organic solvent to dryness to obtain oil. Then adding 500g of acetone, adding 39g of concentrated sulfuric acid at 5 ℃ to form salt, stirring and separating the materials for 6 hours, and filtering to obtain 135g of clopidogrel salt with the HPLC purity of more than 99.0%.

Example 2:

mixing 200g of o-chlorophenylglycine, 400g of methanol and 180g of concentrated sulfuric acid, heating to reflux, reacting for 4 hours, distilling the methanol under reduced pressure until the reaction solution is thick, adding 200g of water and 200g of toluene, stirring, dissolving, layering, and concentrating the organic layer to obtain 200g P1 oil.

② 160g of tartaric acid, 1000g of methanol, 300g of acetone and 200g of P1 oil are mixed and dissolved at 35 ℃ and then cooled, the mixture is slowly precipitated to below 5 ℃, filtered and dried to obtain 300g P2. 300g P2 adding 800g methanol, maintaining the temperature at 30 deg.C, refining, and cooling to below 5 deg.C to obtain 260g P2.

③ 100g of 2-thiopheneethanol, 200g of paratoluensulfonyl chloride and 15g of tetrabutyl ammonium bromide are dissolved in 700g of dimethylbenzene, and 300g of 30 percent sodium hydroxide solution is dripped at 10 ℃. After dropping, the temperature is kept for reaction for 6h, and then the temperature is increased to 35 ℃ to terminate the reaction. The layers are separated, and the organic solvent is concentrated to obtain 250g P3 oil. Adding 250g of methanol into P3 oil, cooling to below 5 ℃, separating out materials, and filtering to obtain 220g P3.

(iv) the synthesized P2200 g was dissolved in 500g of water and 600g of toluene, and 800g of a 10% sodium hydrogen carbonate solution was slowly added thereto. Layering, concentrating the organic layer to obtain P2 oil, adding 200g P3 g tetrabutylammonium bromide, 120g dipotassium hydrogen phosphate and 120g toluene, reacting at 110 ℃ for 35 hours, adding 100g methanol after the reaction is finished, dropwise adding 70g hydrochloric acid at 40 ℃, cooling to 10 ℃ after dropwise adding, filtering and drying to obtain 150g P4.

Fifthly, adding 150g P4 into 900g of 37% concentration formaldehyde water solution, reacting for 27h at 30 ℃, adding 500g of toluene for reaction, adding 250g of 10% sodium carbonate solution, extracting and layering, and concentrating the organic solvent to be dry to obtain oil. Then adding 500g of acetone, adding 90g of camphorsulfonic acid at the temperature below 3 ℃ to form salt, stirring and separating the materials for 6.5h, and filtering to obtain 175g of clopidogrel salt with the HPLC purity of more than 99.0 percent.

Example 3:

1. 55g of sodium carbonate is taken, 1045g of water is added, and stirring is carried out to prepare a 5% sodium carbonate solution.

2. 210g of clopidogrel bisulfate prepared according to the step of example 1 is taken, 900g of dichloromethane is added, and the 5% sodium carbonate solution is added until the pH value of an aqueous layer is 7-9. Standing for layering, washing the organic layer with water for 2 times, adding 6g of activated carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the quality of clopidogrel free alkali is not changed any more, wherein the mass of clopidogrel free alkali is 160 g.

3. Adding 1300g of 2-butanol into the clopidogrel free alkali, stirring for dissolving, adding 180g of acetic acid, stirring for cooling to 15 ℃, dropwise adding 48.5g of concentrated sulfuric acid, and finishing dripping after 50 min. After the dripping is finished, the temperature is controlled to be 20 ℃, and then 220g of the mixed solvent (30 g of acetic acid and 190g of cyclohexane) is dripped, and the dripping is finished for 2 h.

4. After the dropwise addition, 8g of clopidogrel hydrogen sulfate crystal form I seed crystal is added, the temperature is kept at 20 ℃ for 6h, then the temperature is reduced by 2 ℃ every 3h, when the temperature is 0 ℃, the filtration is carried out, a filter cake is leached by 200g of cyclohexane, and the vacuum drying is carried out for 6h at 75 ℃ and the vacuum degree of-0.08 Mpa, so that 159g of clopidogrel hydrogen sulfate crystal form I spherical particles are obtained. The XRD spectrum and the electron micrograph of the clopidogrel hydrogen sulfate I crystal form sphere particles prepared in example 3 are shown in fig. 1 and 2, respectively.

Example 4:

1. a sodium hydrogencarbonate solution (about 6%) was prepared by adding 375g of water to 25g of sodium hydrogencarbonate and stirring.

2. 150g of clopidogrel camphorsulfonate prepared in example 2 was taken, 600g of dichloromethane was added, and the above 6% sodium bicarbonate solution was added until the pH of the aqueous layer was 7 to 9. Standing for layering, washing the organic layer with water for 2 times, adding 3g of active carbon and 25g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the quality of clopidogrel free alkali is not changed any more, wherein the mass of clopidogrel free alkali is 85 g.

3. Adding 700g of 2-butanol into the clopidogrel free alkali, stirring for dissolving, adding 90g of acetic acid, stirring for cooling to 15 ℃, dropwise adding 25g of concentrated sulfuric acid, and finishing dripping after 32 min. After the dripping is finished, the temperature is controlled to be 20 ℃, and then 100g of the mixed solvent (7 g of acetic acid and 93g of cyclohexane) is dripped, and the dripping is finished for 1.5 h.

4. After the dropwise addition, 3g of clopidogrel hydrogen sulfate I crystal seed crystal is added, and after the temperature is kept at 20 ℃ for 6 hours, the temperature is reduced by 2.5 ℃ every 3 hours. And when the temperature is-1 ℃, filtering, leaching a filter cake by using 120g of cyclohexane, and drying for 6 hours in vacuum at 75 ℃ and the vacuum degree of-0.09 Mpa to obtain 85g of clopidogrel hydrogen sulfate I crystal form spherical particles. A photomicrograph (at 100 x magnification) of the clopidogrel hydrogen sulfate crystalline form I spherical particles prepared in example 4 is shown in fig. 3.

Example 5:

1. 55g of sodium carbonate is taken, 312g of water is added, and stirring is carried out to prepare 15 percent sodium carbonate solution.

2. 210g of clopidogrel bisulfate prepared according to the step of example 1 is taken, 1000g of dichloromethane is added, and the sodium carbonate solution with the concentration of 15% is added until the pH value of an aqueous layer is 7-9. Standing for layering, washing an organic layer for 2 times, adding 3g of active carbon and 25g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the quality of clopidogrel free alkali is not changed any more, wherein the mass of the clopidogrel free alkali is 158 g.

3. 1200g of 2-butanol is added into the clopidogrel free alkali, stirred and dissolved, 160g of acetic acid is added, stirred and cooled to 5 ℃, 46.5g of concentrated sulfuric acid is added dropwise, and the addition is finished after 53 min. After the dripping is finished, the temperature is controlled to be 10 ℃, and then 220g of the mixed solvent (30 g of acetic acid and 190g of cyclohexane) is dripped, and the dripping is finished for 2.2 h.

4. After the dropwise addition, 5g of clopidogrel hydrogen sulfate I crystal seed crystal is added, and the temperature is kept at 10 ℃ for 8 hours and then is reduced by 1 ℃ every 3 hours. And when the temperature is 0 ℃, filtering, leaching a filter cake by using 150g of cyclohexane, and drying for 9 hours in vacuum at 55 ℃ and under the vacuum degree of-0.10 Mpa to obtain 152g of clopidogrel hydrogen sulfate I crystal form spherical particles.

Example 6:

1. 85g of sodium bicarbonate was taken, and 800g of water was added thereto, followed by stirring to prepare a sodium bicarbonate solution having a concentration of about 10%.

2. 210g of clopidogrel bisulfate prepared according to the step of example 1 is taken, 900g of toluene is added, and the 10% sodium carbonate solution is added until the pH value of an aqueous layer is 7-9. Standing for layering, washing the organic layer with water for 2 times, adding 6g of activated carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the quality of clopidogrel free alkali is not changed any more, wherein the mass of clopidogrel free alkali is 158 g.

3. Adding 1300g of 1-butanol into the clopidogrel free alkali, stirring for dissolving, adding 150g of formic acid, stirring for cooling to 10 ℃, dropwise adding 48g of concentrated sulfuric acid, and finishing dripping after 52 min. After the dripping is finished, the temperature is controlled to be 15 ℃, and then 200g of the mixed solvent (25 g of formic acid and 175g of n-hexane) is dripped, and the dripping is finished for 2 h.

4. After the dropwise addition, 5g of clopidogrel hydrogen sulfate I crystal seed crystal is added, and the temperature is kept at 15 ℃ for 7 hours and then is reduced by 1.5 ℃ every 3 hours. And when the temperature is up to-2 ℃, filtering, leaching a filter cake by using 150g of normal hexane, and drying for 8 hours in vacuum at 65 ℃ and under the vacuum degree of-0.08 Mpa to obtain 149g of clopidogrel hydrogen sulfate I crystal form spherical particles.

Comparative example 1: example 2 of CN2020105148000

(1) Obtaining clopidogrel base according to the operation steps of the embodiment 3, dissolving the clopidogrel base in a mixed solvent of butyl acetate and n-butyl alcohol, wherein the molar ratio of the butyl acetate to the n-butyl alcohol is 5:1, obtaining a free alkali solution with the concentration of 0.01g/ml, dissolving concentrated sulfuric acid in the same mixed solvent of the butyl acetate and the n-butyl alcohol at the temperature of 30 ℃ to obtain a sulfuric acid solution with the concentration of 0.3g/ml, mixing the two solutions, and ensuring that the molar ratio of the mixed sulfuric acid to the clopidogrel free base is 1.4: 1;

(2) adjusting the temperature to 35 ℃, adding clopidogrel hydrogen sulfate I crystal form seed crystal, wherein the mass of the seed crystal is 0.1 percent of that of clopidogrel free alkali, reducing the temperature to 0 ℃ at the rate of 0.5 ℃/min, and then keeping the temperature and stirring for 40 min;

(3) filtering, washing and drying to obtain the clopidogrel hydrogen sulfate I crystal form spherical crystal.

Comparative example 2: example 1 of CN201410847832

760g (purity greater than 99.0%) of clopidogrel hydrogensulfate prepared in example 1 was dispersed in a mixture of 10L of dichloromethane and 5L of water, and solid sodium bicarbonate was added to bring the aqueous phase to a pH > 7. The mixture was allowed to stand for liquid separation, the organic phase was taken and washed with water (1L. times.2), and anhydrous magnesium sulfate was removed to remove water until the solution was clear.

Filtering the organic phase, vacuum evaporating until the quality is not changed, dissolving the remainder in 10.5L 2-butanol, and keeping the temperature of the solution at 25 ℃. 100ml of concentrated sulfuric acid (181g) is dispersed in 2.5L of 2-butanol and added into the system within 10 minutes, and crystal seeds of 10g I are dispersed in 1L of 2-butanol and poured together. Keeping the temperature at 25 ℃ for 2.5h, cooling to 15 ℃, keeping the temperature for 3h, performing suction filtration, washing a filter cake with ethyl acetate, and performing vacuum drying at 40 ℃ for 1.0h to obtain 610g of a product.

Comparative example 3:

2. 210g of clopidogrel bisulfate prepared according to the step of example 1 is taken, 900g of dichloromethane is added, and the 5% sodium carbonate solution is added until the pH value of an aqueous layer is 7-9. Standing for layering, washing the organic layer with water for 2 times, adding 6g of activated carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the quality of clopidogrel free alkali is not changed any more, wherein the mass of clopidogrel free alkali is 158 g.

3. Adding 1300g of 2-butanol into the clopidogrel free alkali, stirring for dissolving, adding 180g of acetic acid, stirring for cooling to 15 ℃, dropwise adding 48.5g of concentrated sulfuric acid, and finishing dripping after 50 min. And controlling the temperature to be 20 ℃ after dripping, dripping 190g of cyclohexane, wherein the contact point of the dripped cyclohexane and the reaction liquid level becomes white and separates during dripping, and then the solution quickly disappears after dripping for 1.8 h.

4. After the dropwise addition, 8g of clopidogrel hydrogen sulfate I crystal form crystal seeds are added, the temperature is kept at 20 ℃ for 6 hours, then the temperature is reduced by 2 ℃ every 3 hours, when the temperature is 0 ℃, the filtration is carried out (the slow filtration is found at the moment, the filtrate is difficult to carry out the suction filtration, the whole suction filtration time is prolonged by about one time, the phenomenon is mainly caused by the small granularity of the batch), the filter cake is leached by 200g of cyclohexane, and the vacuum drying is carried out for 6 hours at 75 ℃ and under the vacuum degree of-0.08 Mpa, so that 166g of clopidogrel hydrogen sulfate I crystal form spherical particles are obtained.

Comparative example 4:

2. 210g of clopidogrel bisulfate prepared according to the step of example 1 is taken, 900g of dichloromethane is added, and the 5% sodium carbonate solution is added until the pH value of an aqueous layer is 7-9. Standing for layering, washing the organic layer with water for 2 times, adding 6g of activated carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the quality of clopidogrel free alkali is not changed any more, wherein the mass of clopidogrel free alkali is 157 g.

3. 1300g of 2-butanol is added into the clopidogrel free alkali, the temperature is reduced to 15 ℃ by stirring, 48.5g of concentrated sulfuric acid is dripped, and after dripping is finished for 50min, the inner wall of the reaction bottle and the oil on the stirring paddle are separated out and attached. The temperature is controlled at 20 ℃, and 220g of mixed solvent (30 g of acetic acid and 190g of cyclohexane) is added dropwise after 2 h. After the dripping is finished, the oily matter is partially dissolved, and a small part of the oily matter is still attached to the inner wall of the reaction bottle and the stirring paddle.

4. After the dropwise addition, 8g of clopidogrel hydrogen sulfate crystal form I seed crystal is added, the temperature is kept at 20 ℃ for 6h, then the temperature is reduced by 2 ℃ every 3h, when the temperature is 0 ℃, the filtration is carried out, a filter cake is leached by 200g of cyclohexane, and the vacuum drying is carried out for 6h at 75 ℃ and the vacuum degree of-0.08 Mpa, so as to obtain 185g of clopidogrel hydrogen sulfate, which is detected as mixed crystal.

The quality of the products prepared in examples 3-6 and comparative examples 1-4 was determined according to the method of clopidogrel bisulfate in the pharmacopoeia 2020 edition of China, and the results are shown in Table 1:

TABLE 1 quality comparison

The quality detection of the obtained comparative example and the embodiment is as above, and it can be seen that the embodiment 3-6 can ensure that all impurities are less than 0.05%, and the obtained product has better quality.

Claims

1. A process for the preparation of clopidogrel hydrogen sulfate in the form of spherical crystal I, said process comprising the steps of:

(1) dissolving clopidogrel free alkali in a solvent A, adding a solvent B, stirring, controlling the temperature of the solution at 5-15 ℃, and dropwise adding concentrated sulfuric acid within 0.5-1 h; after the dropwise addition, controlling the temperature of the solution at 10-20 ℃, and then slowly dropwise adding the mixed solvent D within 1.5-2.5 h;

(2) adding seed crystals after the dripping of the mixed solvent D is finished, carrying out heat preservation crystallization at 10-20 ℃ for 6-8 h, slowly cooling to below 2 ℃ after the heat preservation is finished, and controlling the total cooling time to be 24-36 h;

(3) filtering at the temperature below 2 ℃, washing a filter cake by using a solvent C, and drying to obtain the clopidogrel hydrogen sulfate I crystal form spherical crystal.

2. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (1), the mass of the concentrated sulfuric acid is 0.28-0.31 time of that of clopidogrel free alkali.

3. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (1), the solvent A is 2-butanol.

4. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (1), the solvent B is acetic acid.

5. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (1), the solvent C is cyclohexane.

6. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (1), the mixed solvent D is cyclohexane and acetic acid.

7. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (2), the seed crystal is selected from clopidogrel hydrogen sulfate I type seed crystal, and the mass consumption of the crystal form is 0.01-0.05 times of that of clopidogrel free alkali; the slow cooling is gradient cooling, and the gradient cooling is that the temperature is reduced by 1-3 ℃ every 2-3 hours until the temperature is below 2 ℃.

8. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (2), after the heat preservation is finished, slowly cooling to-5-2 ℃; in the step (3), filtering is carried out at a temperature of-5 to 2 ℃.

9. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (3), the mass of the solvent C is 0.8-1.6 times of that of clopidogrel free alkali.

10. The process for the preparation of clopidogrel bisulfate spherical crystalline form I according to claim 1, characterized in that: in the step (3), the drying temperature is 55-75 ℃, the vacuum degree is-0.07-0.10 Mpa, and the time is 6-10 h.