CN102924474B - Preparation method of crystal form I of clopidogrel hydrogen sulfate - Google Patents

Abstract

The invention provides a preparation method of clopidogrel bisulfate crystal form I. The preparation method comprises the following steps: (1) adding concentrated sulfuric acid or concentrated sulfuric acid 2-methyltetrahydrofuran solution dropwise to the 2-methyltetrahydrofuran solution of clopidogrel free base to obtain a mixed solution; The temperature is controlled at -10°C to 5°C; (2) The above mixed solution is heated to 10°C to 35°C, stirred and crystallized, and then the precipitated crystals are separated and dried to obtain the crystalline form of clopidogrel hydrogen sulfate I. The process of the present invention is simple and easy, has good reproducibility, and is suitable for industrial production. The prepared clopidogrel bisulfate crystal form I has high crystal form purity, high HPLC purity, cost advantage, good stability, and high solvent recovery rate. , Environmental friendliness and so on.

Description

A kind of preparation method of clopidogrel bisulfate crystal form I

technical field

The invention relates to the technical field of medicinal chemical crystallization, in particular to a preparation method of clopidogrel bisulfate crystal form I.

Background technique

Clopidogrel bisulfate is a platelet aggregation inhibitor developed by Sanofi, France. It is clinically used to prevent and treat heart, brain and other arterial circulation disorders caused by high platelet aggregation. It is suitable for patients with recent stroke, myocardial infarction and confirmed peripheral arterial disease, and can reduce the occurrence of atherosclerotic events. Compared with other antiplatelet drugs, clopidogrel bisulfate has the advantages of strong curative effect, good safety, and good tolerance, and has been ranked among the best-selling drugs in the world for many years.

The molecular structure of clopidogrel bisulfate is as follows:

EP0281459A is the first to describe clopidogrel hydrogen sulfate and its preparation, but does not mention the crystalline form. WO99065915A1 discloses two pharmaceutically acceptable crystalline forms of clopidogrel hydrogen sulfate, crystalline form I and crystalline form II. Crystal form I is a metastable crystal form with high solubility and bioavailability. Crystal form II is a thermodynamically stable crystal form, but its solubility and bioavailability are worse than those of crystal form I.

The preparation method of clopidogrel bisulfate crystal form I has been reported. The disadvantages of the process using a mixed solvent system are complex operation, high cost of solvent recovery, which is not conducive to industrial production, and the process using a single solvent also has different defects.

WO99065915A1 discloses that acetone can be used as a solvent to form crystalline form I or crystalline form II, but acetone is not suitable for industrial production, because crystalline form I is easily and irreversibly transformed into crystalline form II in acetone, a thermodynamically unstable solvent.

WO03051362A1 discloses a method for preparing crystal form I: suspending amorphous clopidogrel bisulfate in an ether for more than 1 hour, preferably a _C2-8 ether, more preferably diethyl ether or tert-butyl methyl ether. The starting material of the invention is amorphous clopidogrel hydrogen sulfate, which is obtained by dissolving clopidogrel hydrogen sulfate in methanol or ethanol, removing the solvent under reduced pressure, and collecting oil or foam. Afterwards, it is treated with ether to obtain crystalline form I or a mixture of crystalline form I and an amorphous form. The invention does not mention the purity of the obtained crystalline form I. The preparation method is complex in operation, poor in reproducibility, and difficult to control in industrialization, and both diethyl ether and tert-butyl methyl ether are volatile, flammable and toxic solvents.

WO2004020443 discloses the salt formation of clopidogrel free base and concentrated sulfuric acid in a solvent, and the isolation of clopidogrel bisulfate crystal form I, the solvent is selected from C _1-5 alcohols or their formation with C _1-4 carboxylic acids ester, the purity of the obtained crystal form I can only be controlled at 98%. WO2005100364 discloses that ether, ethyl formate, ethyl acetate, methyl acetate, isopropyl ether, and dichloromethane can be used as solvents to prepare crystal form I, and the products of ethyl formate, ethyl acetate, or isopropyl ether are used in the examples The yield is only 50% to 64%. Experiments have found that when ethyl acetate is used as a solvent, viscous substances are easily formed and adhered to the agitator during the salt formation process. The viscous substances are difficult to disperse at low temperatures, and crystal transformations are likely to occur if stirred for a long time. Butyl acetate is a volatile toxic solvent that affects the central nervous system.

CN1903859A uses expensive pentacarbonone or hexacarbonone as a solvent for preparing crystal form I.

WO2008093357A2 discloses an improved method for preparing crystal form I on an industrial scale. The solvent used is selected from ethyl acetoacetate, methyl acetoacetate, ethyl 4-chloroethyl acetoacetate, ethyl 3-nitropropionylacetate, and propyl lactate. Ester, Ethyl Lactate, Cyclopentyl Methyl Ether, Dipropylene Glycol Ether, Dibutyl Glycol Ether, Propyl Methyl Cellosolve, Butyl Methyl Cellosolve, Propyl Ethyl Cellosolve, Butyl Ethyl Cellosolve agent. These solvents are not commonly used, have high boiling points, and the residual solvents are not easy to remove, which affects product quality.

CN101805354A discloses a preparation method of clopidogrel bisulfate crystal form I, comprising: dissolving clopidogrel free base in tetrahydrofuran, adding concentrated sulfuric acid at -14°C~0°C; reacting the mixture for 1~2 hours , the temperature was raised to 20° C. to 40° C. to continue the reaction to fully precipitate the crystals. After obtaining the crystals, filter, wash the filter cake with tetrahydrofuran, drain, and vacuum-dry to obtain the crystal form I. The yield of this method has only 73～80%, and production cost is higher. Tetrahydrofuran has a low boiling point, low solvent recovery rate, large waste gas emission, and high cost of three waste treatment, so it is not suitable for industrial production.

Obviously, the known preparation methods of clopidogrel bisulfate crystal form I all have different defects, and cannot meet the higher requirements of obtaining high-purity and stable crystal form, simple and reliable process, cost advantage, suitable for industrial production, and environmental protection .

Contents of the invention

The purpose of the present invention is to provide a new preparation method suitable for industrialization in view of various shortcomings of the existing preparation methods of clopidogrel bisulfate crystal form I. The method is characterized by using the green and environmentally friendly 2-methyltetrahydrofuran as a solvent, and reacting clopidogrel free base with concentrated sulfuric acid to form a salt to obtain high-purity crystal form I of clopidogrel bisulfate salt. The product has less impurities and has cost advantages. , good storage stability and environmental friendliness.

After screening a large number of solvents, the present inventors found that 2-methyltetrahydrofuran is an excellent organic solvent, which is very suitable for the preparation of clopidogrel bisulfate crystal form I. 2-Methyltetrahydrofuran has good solubility to clopidogrel free base, moderate solubility to clopidogrel hydrogen sulfate, between acetone and ethyl acetate, clopidogrel hydrogen sulfate crystal form in the salt-forming reaction The precipitation speed of Ⅰ is moderate, the crystal form of the product is high in purity, and there are few impurities. It will neither make it difficult for clopidogrel hydrogen sulfate to precipitate like acetone, and the prolongation of crystallization time makes it easier for clopidogrel hydrogen sulfate to form crystal form II; Insoluble, causing salt formation and crystallization speed too fast, easy inclusion of clopidogrel free base in the formed crystal, product purity is not high, and stability is poor.

2-Methyltetrahydrofuran is a fourth-class solvent of environmental protection, its LD50 is 5720mg/kg, the LD50 of ethyl acetate is 5620mg/kg, and the LD50 of tetrahydrofuran is 1650mg/kg, so the toxicity of 2-methyltetrahydrofuran is small, Little harm to the health of operators.

The salt-forming reaction of clopidogrel bisulfate crystal form I does not consume solvent, so solvent recovery is necessary in industrial production. Compared with the boiling point of tetrahydrofuran, which is 66°C, the boiling point of 2-methyltetrahydrofuran is moderate, which is 80°C; 2-methyltetrahydrofuran is easier to recover, has a high recovery rate, less exhaust gas emission, and is more friendly to the environment.

Based on the above findings, the present inventors have accomplished the present invention.

The present invention can be realized through the following technical solutions:

A method for preparing clopidogrel bisulfate crystal form I, the preparation method comprising the following steps:

(1) Add concentrated sulfuric acid or 2-methyltetrahydrofuran solution of concentrated sulfuric acid dropwise to the 2-methyltetrahydrofuran solution of clopidogrel free base to obtain a mixed solution; the temperature of the mixed solution is controlled at -10°C~ 5°C;

(2) Heating the above mixed solution to 10°C-35°C, stirring and crystallizing, then separating the precipitated crystals and drying to obtain the crystalline form I of clopidogrel hydrogen sulfate.

In step (1), the 2-methyltetrahydrofuran solution of clopidogrel free base is obtained by dissolving clopidogrel free base in 2-methyltetrahydrofuran. For example, clopidogrel free base can be dissolved in 2-methyltetrahydrofuran with stirring at room temperature.

Preferably, in step (1), in the mixed solution, the mass percentage of the clopidogrel free base and the 2-methyltetrahydrofuran is less than or equal to 15:100. If the mass percentage of the clopidogrel free base to the 2-methyltetrahydrofuran is greater than 15:100, the precipitated clopidogrel bisulfate crystal form I is easily miscible as an oil. Further preferably, the mass percentage of the clopidogrel free base to the 2-methyltetrahydrofuran is less than or equal to 12:100; more preferably 3-10:100. When the amount of solvent used is too large, clopidogrel bisulfate is difficult to separate out, resulting in low yield, large amount of solvent, low utilization rate of equipment, and increased cost.

Preferably, in step (1), the temperature of the mixed solution is controlled at -5°C~0°C during the dropwise addition; the mass fraction of the concentrated sulfuric acid is 94%~98%; in the mixed solution, the concentrated The molar ratio of sulfuric acid to the clopidogrel free base is 0.95-1.1:1.

More preferably, in step (1), the mass fraction of the concentrated sulfuric acid is 98%; in the mixed solution, the molar ratio of the concentrated sulfuric acid to the clopidogrel free base is 0.95-1.0:1.

Preferably, the time for adding the concentrated sulfuric acid or the concentrated sulfuric acid solution in 2-methyltetrahydrofuran is 1 to 5 hours.

Preferably, concentrated sulfuric acid or 2-methyltetrahydrofuran solution of concentrated sulfuric acid is added dropwise to the 2-methyltetrahydrofuran solution of clopidogrel free base to obtain a mixed solution (dropping is completed), optionally, the mixed solution Keep warm for 0~1 hour.

Preferably, in step (2), the crystallization temperature is 15°C-25°C; the crystallization time is 5-20 hours, preferably 10-15 hours.

In step (2), the crystalline form I of clopidogrel hydrogen sulfate can be isolated by methods known in the art, such as filtration. From the perspective of industrialization, in order to prevent the crystalline form I of clopidogrel bisulfate from absorbing moisture in the air during the filtration process, causing part of the crystals to dissolve, making the surface of the filter cake sticky and affecting product quality, preferably, the separation uses nitrogen pressure Filtration is performed. More preferably, the filter cake is washed with 2-methyltetrahydrofuran for 1 to 2 times.

In step (2), the crystalline form I of clopidogrel bisulfate can be dried by methods known in the art, such as vacuum drying, specifically vacuum drying at 20-50°C for 5-24 hours.

Preferably, in step (1), the 2-methyltetrahydrofuran solution of clopidogrel free base is added with clopidogrel hydrogen sulfate crystal form I seed crystal; and the clopidogrel hydrogen sulfate salt crystal form The amount of seed crystal I used is 1.0%-2.5% of the weight of the clopidogrel free base. This step can increase the rate of crystallization. Those skilled in the art can understand that good effects can also be achieved without adding seed crystals.

Preferably, the method of the present invention further comprises: beating the crystalline form I of clopidogrel bisulfate obtained in step (2) in acetone at -15°C~-5°C, and the beating time is 20~60 minutes; the acetone The weight ratio of the volume of the clopidogrel hydrogen sulfate to the crystalline form I of clopidogrel hydrogen sulfate is 5-10ml:1g; then it is separated and dried. The separation and drying after beating are the same as those in step (2). The beating step does not affect the crystal form of the product, and can further remove residual 2-methyltetrahydrofuran and sulfuric acid, so that the storage stability of the product is further improved.

More preferably, the preparation method of clopidogrel bisulfate crystal form I of the present invention is specifically:

(1) Dissolving the clopidogrel free base in the 2-methyltetrahydrofuran solution with stirring at room temperature according to the mass percentage of the clopidogrel free base and the 2-methyltetrahydrofuran at a ratio of 3 to 10:100, and lowering the system temperature to drop to -5°C~0°C; then dropwise add concentrated sulfuric acid with a mass fraction of 98% to obtain a mixed solution; the molar ratio of the concentrated sulfuric acid to the clopidogrel free base is 0.95~1.0:1;

(2) Heat the above mixed solution to 15°C~25°C, stir and crystallize for 10~15 hours, then separate the precipitated crystals by nitrogen pressure filtration and wash the filter cake with 2-methyltetrahydrofuran for 1~2 times, 20~ Vacuum drying at 50°C for 5-24 hours to obtain clopidogrel hydrogen sulfate crystal form I; the clopidogrel hydrogen sulfate salt crystal form I was beaten in acetone at -15°C~-5°C, and the beating time was 20~ 60 minutes; the weight ratio of the volume of acetone to the crystalline form I of clopidogrel hydrogen sulfate is 5-10ml:1g; then separate and dry to obtain the crystalline form I of clopidogrel hydrogen sulfate.

Those skilled in the art can understand that the above-mentioned steps of the present invention are all carried out under sufficient stirring conditions.

Compared with the prior art, the preparation method of clopidogrel bisulfate crystal form I of the present invention has the following advantages:

The clopidogrel bisulfate crystal form I prepared by the preparation method of the present invention has an HPLC purity of more than 99.5%, high crystal form purity, no trace of crystal form II, and good product stability. The yield is more than 93%, which has a cost advantage. The process is simple and easy to implement, has good reproducibility and is suitable for industrial production. 2-Methyltetrahydrofuran, which is green, environmentally friendly and low-toxic, is used as the solvent, which has little harm to the health of personnel, high solvent recovery rate, and is environmentally friendly.

Description of drawings

Figure 1 is the X-ray powder diffraction pattern (XRD) of the crystalline form I of clopidogrel bisulfate prepared in Example 8 measured by detection method 1.

Fig. 2 is the X-ray powder diffraction pattern (XRD) of clopidogrel bisulfate crystal form I prepared in Example 8 measured by detection method 2.

Fig. 3 is the differential scanning calorimetry (DSC) curve of clopidogrel bisulfate crystal form I prepared in Example 8.

Detailed ways

The following examples will help to further understand the present invention, but are not intended to limit the content of the present invention.

The raw materials and reagents in the examples of the present invention are all commercially available products.

The relevant detection of product of the present invention is as follows:

Related substances detection

Detection instrument: Agilent 1260 high performance liquid chromatograph

Detection method: the quality standard of clopidogrel bisulfate recorded in European Pharmacopoeia 7.2 edition.

X-ray powder diffraction pattern determination:

Testing instrument: Bruker D8Advance XRD

Detection method 1: Cu-Kα radiation is used, the scanning angle is 3.0°～40.0°, the scanning step is 0.02°, and the scanning speed is 0.5 seconds/step.

Detection method 2: Cu-Kα radiation is used, the scanning angle is 11.0°-14.0°, the scanning step is 0.02°, and the scanning speed is 35 seconds/step.

Differential Scanning Calorimetry (DSC) Analysis:

Testing instrument: TA Q200DSC

Detection method: heating rate 10°C/min, heating up to 200°C

Example 1

Add 32.1g (0.10 mol) of clopidogrel free base and 214g of 2-methyltetrahydrofuran into a 1000mL four-neck flask, stir and dissolve at room temperature, cool the system to -10°C, add 9.5g of 98% concentrated sulfuric acid (0.095 mol) dropwise, and then The system was heated up to 10°C, kept stirring and crystallized for 20 hours, filtered under nitrogen pressure, and the filter cake was vacuum-dried at room temperature for 3 hours, then heated to 45°C and vacuum-dried for 10 hours to obtain 39.3g of clopidogrel bisulfate crystal form I , the molar yield is 93.8%, the HPLC content is 99.6%, and the HPLC content of all single heterogeneous compounds is less than 0.1%.

Example 2

Add 32.1g (0.10 mol) of clopidogrel free base and 270g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at -5°C, add 9.8g of 98% concentrated sulfuric acid (0.098 mol) dropwise, and the addition is complete Afterwards, the system was heated up to 20°C, kept stirring and crystallized for 12 hours, filtered under nitrogen pressure, washed the filter cake with 100mL 2-methyltetrahydrofuran, filtered under nitrogen pressure, and dried under vacuum at 40°C for 10 hours to obtain 39.9g of clopidogrel sulfate Hydrogen salt crystal form I, molar yield 95.0%, HPLC content 99.8%, all single hetero HPLC content less than 0.1%.

Example 3

Add 32.1g (0.10mol) of clopidogrel free base and 321g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at 0°C, add 9.8g of 98% concentrated sulfuric acid (0.098mol) dropwise, after the addition is complete The system was heated up to 25°C, kept stirring and crystallized for 10 hours, filtered under nitrogen pressure, and the filter cake was vacuum-dried at 40°C for 10 hours to obtain 40.6g of clopidogrel bisulfate crystal form I, with a molar yield of 96.7% and an HPLC content of 99.8 %, all simple HPLC content is less than 0.1%.

Example 4

Add 32.1g (0.10 moles) of clopidogrel free base and 1070g of 2-methyltetrahydrofuran into a 2000mL four-neck flask, stir and dissolve, control the temperature of the system at 0°C, add 0.64g of clopidogrel bisulfate crystal form I seed crystals, and then Add 9.8g of 98% concentrated sulfuric acid (0.098 mol) dropwise for 1 hour. After the dropwise addition, raise the temperature of the system to 25°C, keep stirring and crystallize for 10 hours, filter under nitrogen pressure, and dry the filter cake in vacuum at 40°C for 10 hours. 40.3 g of clopidogrel hydrogen sulfate crystal form I were obtained, the molar yield after deducting the seed crystal was 94.7%, the HPLC purity was 99.8%, and all single heterogeneous HPLC was less than 0.1%. Add 340mL of acetone to a 500mL four-neck flask, cool to -10°C, add 40.3g of clopidogrel bisulfate crystal form I prepared above, start stirring and beating for 30 minutes, nitrogen pressure filter, filter cake at 45°C under vacuum After drying for 10 hours, 39.2 g of clopidogrel hydrogensulfate crystalline form I were obtained, with an HPLC content of 99.8%, and the HPLC content of all single heteros was less than 0.1%.

Example 5

Add 32.1g (0.10 moles) of clopidogrel free base and 430g of 2-methyltetrahydrofuran into a 1000mL four-neck flask, stir to dissolve, cool the system to 5°C, add 0.32g of clopidogrel bisulfate crystal form I seed crystals, and then Add 10g of 98% concentrated sulfuric acid (0.10 mol) dropwise, then raise the temperature of the system to 15°C, keep stirring and crystallize for 15 hours, filter, wash the filter cake with 100mL of 2-methyltetrahydrofuran, drain it, and dry the filter cake in vacuum at room temperature for 1 hour. Then the temperature was raised to 40°C and vacuum dried for 15 hours to obtain 39.9 g of clopidogrel bisulfate crystal form I, with a molar yield of 94.3% after deducting the seed crystals, an HPLC content of 99.7%, and all simple HPLC content of less than 0.1%.

Example 6

Add 32.1g (0.10 mol) of clopidogrel free base and 250g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, cool the system down to -10°C, add 11g of 98% concentrated sulfuric acid (0.11 mol) dropwise, and then raise the temperature of the system Heat to 35°C, keep stirring and crystallize for 5 hours, filter, wash the filter cake with 100mL 2-methyltetrahydrofuran, drain it, dry the filter cake in vacuum at room temperature for 3 hours, then raise the temperature to 45°C and dry in vacuum for 10 hours to obtain 39.1g chlorine Pidogrel bisulfate crystal form I, molar yield 93.1%, HPLC content 99.6%, all single hetero HPLC content less than 0.1%.

Example 7

Add 32.1g (0.10 moles) of clopidogrel free base and 340g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at -5°C, add 0.8g of clopidogrel bisulfate crystal form I seed crystals, Then 10g of 94% concentrated sulfuric acid (0.096 mol) was added dropwise. After the dropwise addition, the system was heated up to 20°C, kept stirring and crystallized for 12 hours, filtered under nitrogen pressure, and the filter cake was washed with 100mL of 2-methyltetrahydrofuran and drained. After vacuum drying at 40°C for 10 hours, 40.6 g of clopidogrel bisulfate crystal form I was obtained, with a molar yield of 95.0% after deducting the seed crystals, an HPLC content of 99.8%, and all simple HPLC content of less than 0.1%.

Example 8

Add 32.1g (0.10mol) of clopidogrel free base and 340g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at -5°C, add dropwise 10g of 98% concentrated sulfuric acid (0.10mol) to dilute in 40g of 2-methanol After the dropwise addition, the system was heated up to 20°C, kept stirring and crystallized for 12 hours, filtered under nitrogen pressure, the filter cake was washed with 100mL 2-methyltetrahydrofuran, filtered under nitrogen pressure, and dried under vacuum at 40°C for 10 hours , to obtain 40.7g of clopidogrel bisulfate crystal form I, the molar yield was 96.9%, the HPLC content was 99.8%, and the HPLC content of all single heteros was less than 0.1%. The X-ray powder diffraction pattern (XRD) determined by detection method 1 is shown in Figure 1. The X-ray powder diffraction pattern (XRD) determined by detection method 2 is shown in Figure 2. The differential scanning calorimetry (DSC) curve is shown in Figure 3.

Example 9

Add 32.1g (0.10 mole) of clopidogrel free base and 340g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at -5°C, add 0.5g of clopidogrel hydrogen sulfate crystal form I seed crystal, Then add dropwise a solution of 10g 98% concentrated sulfuric acid (0.10 mol) diluted in 40g 2-methyltetrahydrofuran. After the dropwise addition, raise the temperature of the system to 15°C, keep stirring and crystallize for 15 hours, filter the filter cake with 100mL 2-methyltetrahydrofuran Tetrahydrofuran was washed, nitrogen pressure was filtered, and the filter cake was vacuum-dried at 40°C for 10 hours to obtain 41.2 g of clopidogrel bisulfate crystal form I, with a molar yield of 96.9% after deducting the seed crystals. HPLC purity 99.8%, all single heterogeneous HPLC is less than 0.1%. Add 300mL of acetone to a 500mL four-neck flask, cool to -5°C, add 40.7g of clopidogrel bisulfate crystal form I prepared above, start stirring and beating for 20 minutes, nitrogen pressure filter, filter cake at 45°C under vacuum After drying for 10 hours, 39.1 g of clopidogrel bisulfate crystalline form I was obtained, with an HPLC content of 99.8%, and the HPLC content of all single heteros was less than 0.1%.

Example 10

Add 3.21kg (10 moles) of clopidogrel free base and 34kg 2-methyltetrahydrofuran into a 100L reaction kettle, stir and dissolve, control the temperature of the system at 0°C, add 1kg of 98% concentrated sulfuric acid (10 moles) dropwise, and dissolve the system Heat up to 20°C, keep stirring and crystallize for 12 hours, filter under nitrogen pressure, and vacuum-dry the filter cake at 40°C for 10 hours to obtain 4.07kg of clopidogrel bisulfate crystal form I, with a molar yield of 96.9% and an HPLC content of 99.7%. All simple HPLC content is less than 0.1%.

Example 11

Add 3.21kg (10 moles) of clopidogrel free base and 34kg of 2-methyltetrahydrofuran into a 100L reactor, stir to dissolve, control the temperature of the system at 0°C, add 1kg of 98% concentrated sulfuric acid (10 moles) dropwise, and add it for 2 hours. After the dropwise addition, the system was heated up to 20°C, kept stirring and crystallized for 12 hours, nitrogen pressure filtration, the filter cake was washed with 10L 2-methyltetrahydrofuran, nitrogen pressure filtration, and the filter cake was vacuum-dried at 40°C for 12 hours to obtain 4.04kg chlorine Pidogrel bisulfate crystal form I, the molar yield is 96.2%, the HPLC purity is 99.7%, and all simple heterogeneous HPLC is less than 0.1%. Then add 40L of acetone to the 100L reaction kettle, cool to -15°C, add 4.04kg of clopidogrel bisulfate crystal form I prepared above, start stirring and beating for 1 hour, press nitrogen filter, and vacuum the filter cake at 45°C After drying for 10 hours, 3.92 kg of clopidogrel bisulfate crystalline form I was obtained, with an HPLC content of 99.8%, and the HPLC content of all simple heterogeneous compounds was less than 0.1%.

Example 12

Add 19.3kg (60 moles) of clopidogrel free base and 215kg of 2-methyltetrahydrofuran into a 500L reactor, stir to dissolve, control the temperature of the system at 0°C, add 6.0kg of 98% concentrated sulfuric acid (60 moles) dropwise, and add dropwise for 4 hours , after the dropwise addition, the system was heated up to 20°C, kept stirring and crystallized for 15 hours, filtered under nitrogen pressure, and the filter cake was vacuum-dried at 40°C for 10 hours to obtain 24.3kg of clopidogrel hydrogen sulfate crystal form I, with a molar yield of 96.4 %, HPLC content is 99.8%, and all single heterogeneous HPLC content is less than 0.1%.

The samples prepared in other examples above have the same or similar X-ray powder diffraction patterns and differential scanning calorimetry curves (not shown) as in Example 8. It shows that what is prepared in these examples is the same substance as in Example 8, which are all clopidogrel bisulfate crystal form I.

Related substances (Related substances) test results: the HPLC content of the clopidogrel bisulfate crystalline form I prepared in all the examples of the present invention reaches more than 99.5%, and the HPLC content of all simple complexes is less than 0.1%.

Detection results of X-ray powder diffraction pattern: The result of detection method 1 shows that the clopidogrel hydrogen sulfate prepared in all the examples of the present invention has obvious characteristic peaks of crystal form I, which is the crystal form I of clopidogrel hydrogen sulfate. Detection method 2 further conducts a fine scan in the range of 2θ=11~14°. According to the detection of the 12.8° characteristic peak of crystal form II and the detection of 11.5° and 13.8° characteristic peaks of crystal form I, it can be judged whether the sample contains crystal Form II, so as to judge the crystal purity of Form I. The result of detection method 2 shows that all the samples in the examples are not detected as crystal form II, but are all crystal form I, indicating that the present invention has obtained high-purity crystal form I of clopidogrel hydrogen sulfate.

Differential Scanning Calorimetry (DSC) detection results: the samples prepared in all embodiments of the present invention have an endothermic peak at about 184°C between 170°C and 190°C.

Those skilled in the art can understand that some modifications or changes can be made to the present invention under the teaching of this specification. These modifications and changes should also be within the scope defined by the claims of the present invention.

Claims (12)

1. a preparation method for crystal form I of clopidogrel hydrogen sulfate, is characterized in that, described preparation method comprises the following steps:

(1) the 2-methyltetrahydrofuran solution dripping the vitriol oil or the vitriol oil in the 2-methyltetrahydrofuran solution of clopidogrel free alkali obtains mixing solutions; During dropping, the temperature of described mixing solutions controls at-10 DEG C ~ 5 DEG C;

(2) above-mentioned mixing solutions is warming up to 10 DEG C ~ 35 DEG C, stirring and crystallizing, the crystal separation then will separated out, dry, obtain described crystal form I of clopidogrel hydrogen sulfate.

2. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 1, it is characterized in that, in step (1), in described mixing solutions, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 15:100.

3. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 2, is characterized in that, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 12:100.

4. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 3, is characterized in that, the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran is less than or equal to 3 ~ 10:100.

5. the preparation method of the crystal form I of clopidogrel hydrogen sulfate according to any one of Claims 1 to 4, is characterized in that, in step (1), during dropping, the temperature of described mixing solutions controls at-5 DEG C ~ 0 DEG C; The massfraction of the described vitriol oil is 94% ~ 98%; In described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.1:1.

6. want the preparation method of the crystal form I of clopidogrel hydrogen sulfate described in 5 according to right, it is characterized in that, in step (1), the massfraction of the described vitriol oil is 98%; In described mixing solutions, the mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1.

7. the preparation method of the crystal form I of clopidogrel hydrogen sulfate according to any one of Claims 1 to 4, is characterized in that, in step (2), described recrystallization temperature is 15 DEG C ~ 25 DEG C; The described crystallization time is 5 ~ 20 hours.

8. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 7, is characterized in that, the described crystallization time is 10 ~ 15 hours.

9. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 7, is characterized in that, described separation adopts nitrogen press filtration to carry out.

10. the preparation method of crystal form I of clopidogrel hydrogen sulfate according to claim 9, it is characterized in that, in step (1), in the 2-methyltetrahydrofuran solution of described clopidogrel free alkali, be added with the crystal seed of crystal form I of clopidogrel hydrogen sulfate; And the consumption of the crystal seed of described crystal form I of clopidogrel hydrogen sulfate is 1.0% ~ 2.5% of described clopidogrel free alkali weight.

The preparation method of 11. crystal form I of clopidogrel hydrogen sulfate according to any one of Claims 1 to 4, it is characterized in that, comprise further: the crystal form I of clopidogrel hydrogen sulfate that step (2) obtains pulled an oar in acetone in-15 DEG C ~-5 DEG C, beating time is 20 ~ 60 minutes; The volume of described acetone and the weight ratio of described crystal form I of clopidogrel hydrogen sulfate are 5 ~ 10ml:1g; Then carry out being separated and drying.

The preparation method of 12. 1 kinds of crystal form I of clopidogrel hydrogen sulfate, is characterized in that, described preparation method is:

(1) be that clopidogrel free alkali is dissolved in 2-methyltetrahydrofuran solution in stirring at room temperature by 3 ~ 10:100 according to the mass percent of described clopidogrel free alkali and described 2-methyltetrahydrofuran, system temperature be down to-5 DEG C ~ 0 DEG C; Then drip massfraction be 98% the vitriol oil obtain mixing solutions; The mol ratio of the described vitriol oil and described clopidogrel free alkali is 0.95 ~ 1.0:1;

(2) above-mentioned mixing solutions is warming up to 15 DEG C ~ 25 DEG C, stirring and crystallizing 10 ~ 15 hours, then nitrogen press filtration is adopted to carry out being separated and use 2-methyltetrahydrofuran washing leaching cake 1 ~ 2 time in the crystal of precipitation, at 20 ~ 50 DEG C, vacuum-drying 5 ~ 24 hours, obtains crystal form I of clopidogrel hydrogen sulfate; This crystal form I of clopidogrel hydrogen sulfate pulled an oar in acetone in-15 DEG C ~-5 DEG C, beating time is 20 ~ 60 minutes; The volume of described acetone and the weight ratio of described crystal form I of clopidogrel hydrogen sulfate are 5 ~ 10ml:1g; Then be separated and drying, obtain described crystal form I of clopidogrel hydrogen sulfate.