Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I
A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in the field of production and preparation of major cardiovascular and cerebrovascular drugs, and can solve problems such as difficulty in judging products
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Embodiment 1
[0060] Embodiment 1 Preparation of clopidogrel bisulfate crystal form I
[0061] Replace the air in the crystallizer with nitrogen; add a solution of clopidogrel free base in anisole (6ml, concentration 100mg / ml) and sulfuric acid in methyl isobutyl ketone (2.4ml, concentration 77.1mg / ml) in parallel with a pump , about 1.0eq), added within 0.5 hours; added 0.1g clopidogrel bisulfate crystal form I as a seed crystal; cooled the system to -10°C; stirred at -10°C for 0.25 hours; at -10°C Next, a solution of clopidogrel free base in anisole (24ml, concentration 100mg / ml) and sulfuric acid in methyl isobutyl ketone (9.6ml, 1.0eq, concentration 77.1mg / ml) were added in parallel by pump for 5 hours Add 0.1g clopidogrel bisulfate crystal form I as a seed crystal; raise the temperature to 40°C (0.3°C / min); keep the temperature at 40°C for 1 hour; cool down to 5°C, and hold the temperature for 3 hours, A solid-liquid slurry was obtained; the resulting solid-liquid slurry was filtered ...
Embodiment 2
[0063] Example 2 Preparation of Clopidogrel Hydrogen Sulfate Form I
[0064] Replace the air in the crystallizer with nitrogen; add anisole solution of clopidogrel free base (5ml, concentration 50mg / ml) and sulfuric acid solution in tetrahydrofuran (2ml, about 1.0eq, concentration 38.6mg / ml) in parallel with a pump, Add within 5 minutes; add 0.02g of clopidogrel bisulfate crystal form I as a seed crystal; cool down the system to -15°C; stir at -15°C for 1 hour; at -15°C, add in parallel with a pump Anisole solution of clopidogrel free base (25ml, concentration 50mg / ml) and sulfuric acid solution in tetrahydrofuran (10ml, about 1.0eq, concentration 38.6mg / ml), within 5 hours; add 0.1g clopidogrel Bisulfate crystal form I is used as a seed crystal; the temperature is raised to 40°C; the temperature is kept at 40°C for 2 hours; the temperature is lowered to 5°C and the temperature is kept for 10 hours; the filter cake is filtered under reduced pressure; the filter cake is washed ...
Embodiment 3
[0065] Example 3 Preparation of Clopidogrel Hydrogen Sulfate Form I
[0066] Replace the air in the crystallizer with nitrogen; add 13.5ml anisole and 5.8ml tetrahydrofuran to the crystallizer; add 0.1g clopidogrel bisulfate crystal form I as crystal seed to the crystallizer; cool the system to 5 ℃, and stirred for 0.25 hours; at 5 ℃, the anisole solution of clopidogrel free base (15ml, concentration 200mg / ml) and tetrahydrofuran solution of sulfuric acid (5.64ml, 164.8mg / ml) were added in parallel with a pump, Added within 16 hours; add 0.1g clopidogrel bisulfate crystal form I as a seed crystal; raise the temperature of the system to 35°C (0.3°C / min); keep at 35°C for 0.5 hours, take a sample to measure XRPD, confirm that it is pure Crystal form I; lower the temperature to 5°C (2°C / min), and stir at constant temperature for 0.5 hours; filter under reduced pressure; wash the filter cake with ethyl acetate three times, each time using 10ml ethyl acetate, take samples for XRPD ...
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