CN114369100B

CN114369100B - Preparation method of clopidogrel bisulfate spherical crystal form I

Info

Publication number: CN114369100B
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: 2023-06-20
Anticipated expiration: 2041-12-15
Also published as: CN114369100A

Abstract

The invention discloses a preparation method of clopidogrel bisulfate 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 to be 5-15 ℃, and dropwise adding concentrated sulfuric acid within 0.5-1 h; after the dripping is finished, controlling the temperature of the solution to be 10-20 ℃, and slowly dripping the mixed solvent D within 1.5-2.5 hours; (2) After the mixed solvent D is dripped, adding seed crystal, preserving heat and crystallizing for 6-8 h at 10-20 ℃, slowly cooling to below 2 ℃ after preserving heat, and controlling the total cooling time between 24-36 h; (3) Filtering at the temperature below 2 ℃, washing a filter cake with a solvent C, and drying to obtain clopidogrel bisulfate I crystal form spherical crystals. The preparation method of clopidogrel hydrogen sulfate I crystal form spherical particles has the characteristics of simplicity, high efficiency, controllability, low cost, stable crystal form and excellent quality.

Description

Preparation method of clopidogrel bisulfate spherical crystal form I

1. Technical field

The invention belongs to the field of medicine synthesis, and relates to a preparation method of clopidogrel bisulfate crystal form I spherical particles.

2. Background art

Clopidogrel bisulfate is the bisulfate of clopidogrel, and the chemical name is Clopidogrel Hydrogen Sulfate: (+) - (S) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno [3,2-c ] pyridine-5 (4H) -acetic acid methyl ester bisulfate. Clopidogrel bisulfate is a platelet inhibitor and is mainly used for preventing atherosclerosis thrombosis, thereby preventing ischemic stroke and heart attack. The product was developed by the French pharmaceutical company Sainophenanthre-Anvant, which was first marketed in the United states and British in 1998 and entered the Chinese market in 2001. Clopidogrel bisulfate is taken as a clinical oral anticoagulation first-line medicament, has little toxic and side effects, and has much higher market share than other medicaments.

The medicinal crystal forms of clopidogrel bisulfate comprise two crystal forms I and II, wherein the crystal form I is a thermodynamic metastable crystal form, and the crystal form II is a thermodynamic stable crystal form. The stability of the form I is lower than that of the form II, but the solubility and bioavailability of the form I are better than those of the form II. At present, most of clopidogrel bisulfate preparation products sold in the market are in an I crystal form, and I crystal form powder has strong electrostatic effect and is easy to absorb moisture, and sticky flushing is easy to occur 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. In the technology, a cyclohexane solution of sulfuric acid is slowly dripped into an alcohol solution of clopidogrel free alkali under a cooling condition, and the color of the cyclohexane is possibly changed due to the fact that the sulfuric acid is added into the cyclohexane, so that the color of a final product is affected.

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 water in the solvent is very easy to cause the clopidogrel bisulfate I crystal form to produce glue, is unfavorable for the synthesis of the I crystal form and has lower yield. In addition, the boiling point of water is high, and the subsequent drying requires a longer time and a higher temperature for drying.

Patent CN102432625a discloses a preparation method of clopidogrel hydrogen sulfate I crystal form spherical particles, which adopts ethyl acetate 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 process is unstable and difficult to repeat.

Therefore, searching for clopidogrel bisulfate crystal form I spherical particles which are simple, efficient, controllable, stable in crystal form and excellent in quality is still an unsolved technical problem in the prior art.

3. Summary of the invention

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

A method for preparing clopidogrel bisulfate spherical crystal form I, the method comprising the steps of:

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

the solvent A is selected from one of 1-butanol, 2-butanol and tertiary 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 the 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 the clopidogrel free alkali;

(2) After the mixed solvent D is dripped, adding seed crystal, preserving heat and crystallizing for 6-8 h at 10-20 ℃, slowly cooling to below 2 ℃ after the heat preservation is finished (preferably-5-2 ℃), and controlling the total cooling time to be 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 clopidogrel hydrogen sulfate I crystal form spherical crystals.

In the step (1), the mass of the concentrated sulfuric acid is 0.28-0.31 times of the mass 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 dosage of the crystal form is 0.01-0.05 times of the mass of clopidogrel free alkali; the slow cooling is gradient cooling, and the gradient cooling is that every 2-3 h of temperature is reduced by 1-3 ℃ until the temperature is below 2 ℃.

In the step (3), the mass of the solvent C is preferably 0.8 to 1.6 times of the mass of clopidogrel free base.

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

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

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

(2) after phase separation, washing the organic phase with water, and dehydrating the obtained organic phase by adding a decoloring agent and a drying agent;

(3) filtering, concentrating under reduced pressure to obtain clopidogrel free alkali;

in the step (1), clopidogrel salt is at least one of sulfate, hydrochloride, camphorsulfonate and benzenesulfonate. The organic solvent is at least one of dichloromethane, chloroform, cyclohexane, toluene, ethyl acetate and other organic solvents which are not mutually soluble with water. 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 decoloring agent is at least one of active carbon and adsorption resin, and the mass dosage of the decoloring agent is 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 dosage of the drying agent is preferably 0.1-0.4 times of the mass of clopidogrel salt.

The solvent according to the present invention may be any solvent of technical grade or higher.

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

(1) The solvent B and the solvent A which have better solubility to clopidogrel free alkali are added to prepare the mixed solvent, so that the solubility to clopidogrel free alkali is increased, the dosage of sec-butyl alcohol and total solvents is greatly reduced, and the use cost of the solvents is reduced; meanwhile, under the same equipment condition, the process has larger feeding quantity and higher productivity; (2) the production amount of impurities such as oxidized impurities is reduced, and a product with better quality can be obtained.

(2) In the prior art, concentrated sulfuric acid is usually diluted by organic solvents such as cyclohexane and then added into clopidogrel free alkali solution to reduce impurities, accelerate the reaction speed and make the product color better, but in the invention, concentrated sulfuric acid and the organic solvents are not required to be mixed first, concentrated sulfuric acid is directly added dropwise, then mixed solvent D with poor solubility is slowly added dropwise, so that the reaction solution gradually tends to supersaturation slowly, then seed crystal is added for slowly separating out materials, and the crystallization process is slowly carried out, thus ensuring that 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 the granularity and quality of the crystal form product are affected by the rapid material precipitation at the point that the dripped liquid drop contacts with the liquid surface of the reaction liquid when the poor solvent C is dripped independently.

4. Description of the drawings

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

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

fig. 3 is a photomicrograph (at 100 x magnification) of clopidogrel hydrogen sulfate I crystalline form sphere particles prepared in example 4.

5. Detailed description of the preferred embodiments

For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions in the embodiments of the present application will be clearly and completely described below, but the scope of protection of the present invention is not limited thereto. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

The clopidogrel salt is prepared from o-chlorophenylglycine as a raw material, and the specific preparation steps are as follows:

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

(2) Mixing tartaric acid, methanol, acetone and P1 oil at 30-50 ℃ for dissolving, cooling, slowly separating out materials to below 5 ℃, centrifuging and drying to obtain P2. The P2 can be further refined by adding methanol to obtain high-quality P2.

(3) 2-thiophenoethyl alcohol and p-toluenesulfonyl chloride, benzyl triethyl ammonium chloride or tetrabutyl ammonium bromide are dissolved in methylene dichloride or toluene, and sodium hydroxide solution with concentration of 20-50% is added dropwise at 0-20 ℃. After the dripping, the reaction is carried out for more than 5 hours at a temperature of more than 30 ℃ by adding hydrochloric acid or heating to terminate the reaction. Layering, and concentrating the organic solvent to obtain P3 oil. The P3 oil can be further refined by adding methanol to obtain high-quality P3.

(4) Dissolving the P2 in water and dichloromethane or water and toluene, and slowly adding 5-15% sodium carbonate or sodium bicarbonate solution. Layering, and concentrating the organic layer to obtain P2 oil.

Adding the P3 and P2 oil, benzyl triethyl ammonium chloride or tetrabutyl ammonium bromide, sodium carbonate or dipotassium hydrogen phosphate into acetonitrile or toluene, reacting for more than 20 hours at 80-120 ℃, evaporating to remove the organic solvent, adding water and dichloromethane or water and toluene, stirring and dissolving, and extracting and layering to obtain an organic layer. Adding proper amount of ethyl acetate and methanol, dropwise adding hydrochloric acid below 40 ℃, cooling to below 10 ℃, filtering and drying to obtain P4.

(5) Adding P4 into formaldehyde aqueous solution, reacting at 20-30 ℃ for 25-35 h, adding cyclohexane or toluene, adding sodium carbonate solution, extracting and layering, and concentrating the organic solvent until the organic solvent is dry to obtain the oil. Then adding acetone, adding sulfuric acid or camphorsulfonic acid or benzenesulfonic acid or hydrochloric acid below 10deg.C to form salt, stirring and separating material for more than 5 hr, and filtering to obtain clopidogrel salt.

Example 1:

(1) mixing 200g of o-chlorobenzeneglycine, 400g of methanol and 180g of concentrated sulfuric acid, heating to reflux, reacting for 4 hours, decompressing and distilling the methanol until the reaction liquid is thick, adding 200g of water and 200g of dichloromethane, stirring, dissolving, layering, and concentrating an organic layer to obtain 200g of P1 oil.

(2) 160g of tartaric acid, 1000g of methanol, 300g of acetone and 200g of P1 oil are mixed and dissolved at 40 ℃, cooled, slowly separated to below 5 ℃, filtered and dried to obtain 300g of P2. 300g of P2 is added with 800g of methanol, the temperature is kept at 30 ℃ for refining, and the temperature is reduced to below 5 ℃ to obtain 260g of P2.

(3) 100g of 2-thiopheneethanol, 200g of p-toluenesulfonyl chloride, 15g of benzyltriethylammonium chloride were dissolved in 700g of methylene chloride, and 300g of a 30% strength sodium hydroxide solution was added dropwise at 10 ℃. After the dripping, the reaction is carried out for 6 hours at a constant temperature, and then 5kg of hydrochloric acid is added to terminate the reaction. Layering, and concentrating the organic solvent to obtain 250g of P3 oil. Adding 250g of methanol into P3 oil, cooling to below 5 ℃ for separating out materials, and filtering to obtain 220g of P3.

(4) 200g of the synthesized P2 was dissolved in 500g of water and 600g of methylene chloride, and 800g of a 10% strength sodium carbonate solution was slowly added thereto. Layering, concentrating the organic layer to obtain P2 oil, adding 200g of P3, 10g of benzyl triethyl ammonium chloride, 120g of sodium carbonate and 120g of acetonitrile, reacting at 90 ℃ for 30 hours, evaporating the organic solvent, adding 500g of water and 500g of dichloromethane, stirring for dissolving, extracting and layering to obtain the organic layer, and concentrating to dryness. Then 450g of ethyl acetate and 100g of methanol are added, 70g of hydrochloric acid is added dropwise at 40 ℃, the temperature is reduced to 10 ℃ after the dripping, and 150g of P4 is obtained after filtering and drying.

(5) 150g of P4 are added into 900g of 37% formaldehyde aqueous solution, reacted for 33 hours at 25 ℃, 500g of cyclohexane are added, 250g of 10% sodium carbonate solution are added, the layers are extracted and separated, and the organic solvent is concentrated to dryness to obtain oil. Then adding 500g of acetone, adding 39g of concentrated sulfuric acid at 5 ℃ to form salt, stirring and separating out the material for 6 hours, and filtering to obtain 135g of clopidogrel salt with the HPLC purity of more than 99.0 percent.

Example 2:

(1) mixing 200g of o-chlorobenzeneglycine, 400g of methanol and 180g of concentrated sulfuric acid, heating to reflux, reacting for 4 hours, decompressing and distilling the methanol until the reaction liquid is thick, adding 200g of water and 200g of toluene, stirring, dissolving, layering, and concentrating an organic layer to obtain 200g of P1 oil.

(2) 160g of tartaric acid, 1000g of methanol, 300g of acetone and 200g of P1 oil are mixed and dissolved at 35 ℃, cooled, slowly separated to below 5 ℃, filtered and dried to obtain 300g of P2. 300g of P2 is added with 800g of methanol, the temperature is kept at 30 ℃ for refining, and the temperature is reduced to below 5 ℃ to obtain 260g of P2.

(3) 100g of 2-thiopheneethanol, 200g of p-toluenesulfonyl chloride, 15g of tetrabutylammonium bromide were dissolved in 700g of xylene, and 300g of a 30% strength sodium hydroxide solution was added dropwise at 10 ℃. After the dripping, the reaction is carried out for 6 hours at a temperature of 35 ℃ after the dripping, and then the reaction is terminated after the dripping is added. Layering, and concentrating the organic solvent to obtain 250g of P3 oil. Adding 250g of methanol into P3 oil, cooling to below 5 ℃ for separating out materials, and filtering to obtain 220g of P3.

(4) 200g of the synthesized P2 was dissolved in 500g of water and 600g of toluene, and 800g of 10% strength sodium hydrogencarbonate solution was slowly added thereto. Layering, concentrating an organic layer to obtain P2 oil, adding 200g of P3, 10g of tetrabutylammonium bromide, 120g of dipotassium hydrogen phosphate and 120g of toluene, reacting at 110 ℃ for 35 hours, adding 100g of methanol after the reaction is finished, dropwise adding 70g of hydrochloric acid at 40 ℃, cooling to 10 ℃ after the dropwise adding, filtering and drying to obtain 150g of P4.

(5) 150g of P4 are added into 900g of 37% formaldehyde aqueous solution, reacted for 27h at 30 ℃, 500g of toluene is added, 250g of 10% sodium carbonate solution is added, the mixture is extracted and layered, and the organic solvent is concentrated to dryness to obtain oil. Then adding 500g of acetone, adding 90g of camphorsulfonic acid below 3 ℃ to form salt, stirring and separating out the material for 6.5h, and filtering to obtain 175g of clopidogrel salt, wherein the HPLC purity is above 99.0%.

Example 3:

1. 55g of sodium carbonate was taken, 1045g of water was added thereto, and stirred to prepare a 5% sodium carbonate solution.

2. 210g of clopidogrel bisulfate prepared in accordance with the procedure of example 1 was taken, 900g of methylene chloride was added, and the above 5% strength sodium carbonate 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 6g of active carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the mass of clopidogrel free alkali is not changed, wherein the mass of clopidogrel free alkali is 160g.

3. 1300g of 2-butanol is added into the clopidogrel free alkali, the solution is stirred and cleared, 180g of acetic acid is added, the temperature is reduced to 15 ℃ by stirring, 48.5g of concentrated sulfuric acid is added dropwise, and the dripping is completed after 50 minutes. The temperature is controlled at 20 ℃ after the dripping, 220g of mixed solvent (30 g of acetic acid and 190g of cyclohexane) is added dropwise, and the dripping is completed for 2 hours.

4. After the dripping is finished, 8g of clopidogrel hydrogen sulfate I crystal form seed crystal is added, after the temperature is kept at 20 ℃ for 6 hours, the temperature is reduced by 2 ℃ every 3 hours, when the temperature is 0 ℃, the filtration is carried out, 200g of cyclohexane is used for leaching a filter cake, and 159g of clopidogrel hydrogen sulfate I crystal form spherical particles are obtained after the leaching is carried out on the filter cake, and the vacuum drying is carried out for 6 hours under the vacuum degree of 75 ℃ and the vacuum degree of-0.08 Mpa. XRD patterns and electron micrographs of clopidogrel hydrogen sulfate I crystal form spherical particles prepared in example 3 are shown in fig. 1 and 2 respectively.

Example 4:

1. 25g of sodium bicarbonate was taken, 375g of water was added thereto, and the mixture was stirred to prepare an approximately 6% sodium bicarbonate solution.

2. 150g of clopidogrel camphorsulfonate prepared in example 2 was taken, 600g of methylene chloride was added, and the above 6% strength 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 mass of clopidogrel free alkali is not changed, wherein the mass of clopidogrel free alkali is 85g.

3. 700g of 2-butanol is added into the clopidogrel free alkali, the solution is stirred and cleared, 90g of acetic acid is added, the temperature is reduced to 15 ℃ by stirring, 25g of concentrated sulfuric acid is added dropwise, and the dripping is completed after 32 min. The temperature is controlled at 20 ℃ after the dripping, 100g of mixed solvent (7 g of acetic acid and 93g of cyclohexane) is added dropwise, and the dripping is completed for 1.5 hours.

4. After the dripping is finished, 3g of clopidogrel bisulfate I crystal form 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. When the temperature is minus 1 ℃, filtering, leaching the filter cake by using 120g cyclohexane, and vacuum drying for 6 hours at 75 ℃ and the vacuum degree of minus 0.09Mpa, thus obtaining 85g clopidogrel hydrogen sulfate I crystal form sphere particles. A photomicrograph (at 100 x magnification) of clopidogrel hydrogen sulfate I crystalline form sphere particles prepared in example 4 is shown in fig. 3.

Example 5:

1. 55g of sodium carbonate was taken, 312g of water was added thereto, and the mixture was stirred to prepare a 15% sodium carbonate solution.

2. 210g of clopidogrel bisulfate prepared in accordance with the procedure of example 1 was taken, 1000g of methylene chloride was added, and the above 15% strength sodium carbonate 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 mass of clopidogrel free alkali is not changed, wherein the mass of clopidogrel free alkali is 158g.

3. Adding 1200g of 2-butanol into the clopidogrel free alkali, stirring to dissolve, adding 160g of acetic acid, stirring and cooling to 5 ℃, and then dropwise adding 46.5g of concentrated sulfuric acid for 53 min. The temperature is controlled at 10 ℃ after the dripping, 220g of mixed solvent (30 g of acetic acid and 190g of cyclohexane) is added dropwise, and the dripping is completed for 2.2 hours.

4. After the dripping is finished, 5g of clopidogrel bisulfate I crystal form seed crystal is added, and after the temperature is kept at 10 ℃ for 8 hours, the temperature is reduced by 1 ℃ every 3 hours. When the temperature is 0 ℃, filtering, leaching the filter cake by using 150g cyclohexane, and vacuum drying for 9 hours at 55 ℃ and the vacuum degree of-0.10 Mpa to obtain 152g clopidogrel hydrogen sulfate I crystal form sphere particles.

Example 6:

1. 85g of sodium bicarbonate was taken, 800g of water was added thereto, and the mixture was stirred to prepare about 10% sodium bicarbonate solution.

2. 210g of clopidogrel bisulfate prepared in accordance with the procedure of example 1 was taken, 900g of toluene was added, and the above 10% strength sodium carbonate 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 6g of active carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the mass of clopidogrel free alkali is not changed, wherein the mass of clopidogrel free alkali is 158g.

3. 1300g of 1-butanol is added into the clopidogrel free alkali, stirring is carried out to dissolve, 150g of formic acid is added, stirring is carried out to reduce the temperature to 10 ℃, 48g of concentrated sulfuric acid is added dropwise, and the dripping is finished after 52 minutes. The temperature is controlled at 15 ℃ after the dripping, 200g of mixed solvent (25 g of formic acid and 175g of n-hexane) is added dropwise, and the dripping is completed for 2 hours.

4. After the dripping is finished, 5g of clopidogrel bisulfate I crystal form seed crystal is added, and after the temperature is kept at 15 ℃ for 7 hours, the temperature is reduced by 1.5 ℃ every 3 hours. When the temperature is between minus 2 ℃, filtering, leaching the filter cake by using 150g of normal hexane, and vacuum drying for 8 hours at 65 ℃ and the vacuum degree of minus 0.08Mpa to obtain 149g of clopidogrel bisulfate I crystal form sphere particles.

Comparative example 1: example 2 of CN2020105148000

(1) Clopidogrel base is obtained according to the operation procedure of example 3, clopidogrel base is dissolved in a mixed solvent of butyl acetate and n-butyl alcohol, the molar ratio of butyl acetate to n-butyl alcohol is 5:1, a free alkali solution with the concentration of 0.01g/ml is obtained, concentrated sulfuric acid is dissolved in the same mixed solvent of butyl acetate and n-butyl alcohol at the temperature of 30 ℃ to obtain a sulfuric acid solution with the concentration of 0.3g/ml, the two solutions are mixed, and the molar ratio of the mixed sulfuric acid to clopidogrel free base is 1.4:1;

(2) Adjusting the temperature to 35 ℃, adding clopidogrel bisulfate I crystal form seed crystal with the mass of 0.1% of clopidogrel free alkali, cooling to 0 ℃ at the cooling rate of 0.5 ℃/min, and then keeping the temperature and stirring for 40min;

(3) Filtering, washing and drying to obtain clopidogrel bisulfate I crystal form spherical crystals.

Comparative example 2: example 1 of CN201410847832

(1) 760g (purity greater than 99.0%) of clopidogrel hydrogensulfate prepared in example 1 was dispersed in a mixture of 10L of methylene chloride and 5L of water, and solid sodium bicarbonate was added to a pH of the aqueous phase of >7. The solution was separated by standing, the organic phase was taken and washed with water (1 L.times.2), and anhydrous magnesium sulfate was removed to clarify the solution.

(2) The organic phase was filtered, distilled in vacuo until the mass was no longer changed, the residue was dissolved in 10.5L of 2-butanol and the solution was incubated at 25 ℃. 100ml of concentrated sulfuric acid (181 g) was dispersed in 2.5L of 2-butanol, and the mixture was added to the system over 10 minutes, and 10g I crystalline form seed crystals were dispersed in 1L of 2-butanol and poured together. Preserving heat for 2.5h at 25 ℃, cooling to 15 ℃, preserving heat for 3h continuously, carrying out suction filtration, washing a filter cake with ethyl acetate, and carrying out vacuum drying at 40 ℃ for 1.0h to obtain 610g of product.

Comparative example 3:

2. 210g of clopidogrel bisulfate prepared in accordance with the procedure of example 1 was taken, 900g of methylene chloride was added, and the above 5% strength sodium carbonate 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 6g of active carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the mass of clopidogrel free alkali is not changed, wherein the mass of clopidogrel free alkali is 158g.

3. 1300g of 2-butanol is added into the clopidogrel free alkali, the solution is stirred and cleared, 180g of acetic acid is added, the temperature is reduced to 15 ℃ by stirring, 48.5g of concentrated sulfuric acid is added dropwise, and the dripping is completed after 50 minutes. And after the dripping, controlling the temperature at 20 ℃, dripping 190g of cyclohexane, and in the dripping process, whitening and separating materials at the contact point of the cyclohexane and the reaction liquid surface, and then quickly dissolving and clearing the materials, wherein the dripping is finished for 1.8 hours.

4. After the dripping is finished, 8g of clopidogrel hydrogen sulfate I crystal form seed crystal is added, after the temperature is kept for 6 hours at 20 ℃, the temperature is reduced by 2 ℃ every 3 hours, when the temperature is 0 ℃, the filtering is carried out (the filtering is found to be slow, the filtering liquid is difficult to carry out pumping filtration, the whole pumping filtration time is prolonged by about one time, the phenomenon is mainly caused by the small granularity of the batch), 200g of cyclohexane is used for leaching a filter cake, and the clopidogrel hydrogen sulfate I crystal form ball particles are obtained after the filter cake is dried for 6 hours under the vacuum degree of 75 ℃ and the vacuum degree of-0.08 Mpa.

Comparative example 4:

2. 210g of clopidogrel bisulfate prepared in accordance with the procedure of example 1 was taken, 900g of methylene chloride was added, and the above 5% strength sodium carbonate 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 6g of active carbon and 50g of magnesium sulfate, stirring, filtering, and vacuum concentrating until the mass of clopidogrel free alkali is unchanged, wherein the mass of clopidogrel free alkali is 157g.

3. 1300g of 2-butanol is added into the clopidogrel free alkali, the temperature of the stirred solution is reduced to 15 ℃, 48.5g of concentrated sulfuric acid is added dropwise, the dripping is completed for 50 minutes, and the oily substances on the inner wall of a reaction bottle and a stirring paddle are separated and attached. The temperature is controlled at 20 ℃, 220g of mixed solvent (30 g of acetic acid and 190g of cyclohexane) is added dropwise, and the dropping is completed after 2 hours. After dripping, the oily matter is found to be dissolved partially, and the inner wall of the reaction bottle and the stirring paddle are still attached partially.

4. After the dripping is finished, 8g of clopidogrel bisulfate crystal form I seed crystal is added, after the temperature is kept for 6 hours at 20 ℃, the temperature is reduced by 2 ℃ every 3 hours, when the temperature is 0 ℃, the filtration is carried out, 200g of cyclohexane is used for leaching a filter cake, the vacuum drying is carried out for 6 hours at 75 ℃ under the vacuum degree of-0.08 Mpa, 185g of clopidogrel bisulfate is obtained, and the mixed crystal is detected.

The quality of the products prepared in examples 3-6 and comparative examples 1-4 were examined according to the method of clopidogrel bisulfate in the 2020 edition of the chinese pharmacopoeia, and the results are shown in table 1:

table 1 quality comparison

The quality of the obtained comparative examples and examples are detected as above, and it can be seen that examples 3 to 6 can ensure that all impurities are less than 0.05%, and the quality of the obtained products is better.

Claims

1. A method for preparing clopidogrel bisulfate spherical crystal form I, the method comprising the steps of:

(1) Dissolving clopidogrel free alkali in a solvent A, adding a solvent B, stirring, controlling the temperature of the solution to be 5-15 ℃, and dropwise adding concentrated sulfuric acid within 0.5-1 h, wherein the mass of the concentrated sulfuric acid is 0.28-0.31 times of that of the clopidogrel free alkali; after the dripping is finished, controlling the temperature of the solution to be 10-20 ℃, and slowly dripping the mixed solvent D within 1.5-2.5 hours;

the solvent A is selected from one of 1-butanol and 2-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 the 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 the clopidogrel free alkali;

(2) After the mixed solvent D is dripped, adding seed crystal, preserving heat and crystallizing for 6-8 h at 10-20 ℃, slowly cooling to below 2 ℃ after preserving heat, and controlling the total cooling time between 24-36 h;

(3) Filtering at the temperature below 2 ℃, washing a filter cake with a solvent C, and drying to obtain clopidogrel bisulfate I crystal form spherical crystals.

2. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (1), the solvent A is 2-butanol.

3. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (1), the solvent B is acetic acid.

4. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (1), the solvent C is cyclohexane.

5. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (1), the mixed solvent D is cyclohexane and acetic acid.

6. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (2), the seed crystal is selected from clopidogrel hydrogen sulfate I-type seed crystal, and the mass dosage of the crystal form is 0.01-0.05 times of the mass of clopidogrel free alkali; the slow cooling is gradient cooling, and the gradient cooling is that every 2-3 h of temperature is reduced by 1-3 ℃ until the temperature is below 2 ℃.

7. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (2), after the heat preservation is finished, slowly cooling to-5-2 ℃; in the step (3), filtration is carried out at-5 to 2 ℃.

8. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (3), the mass of the solvent C is 0.8-1.6 times of the mass of clopidogrel free alkali.

9. The preparation method of clopidogrel bisulfate spherical crystal form I as defined in claim 1, which is characterized in that: in the step (3), the drying temperature is 55-75 ℃, the vacuum degree is-0.07 to-0.10 Mpa, and the time is 6-10 h.