Process for preparing a crystalline form of halobetasol propionate
a technology of halobetasol propionate and crystalline form, which is applied in the directions of steroid, medical preparations, organic chemistry, etc., can solve the problems of toxic five (5) solvent systems and methylene chloride in solvent systems, and achieve the effect of high yield
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example 1
Synthesis of Crude Halobetasol Propionate
[0155] Diflorasone 17-propionate 21-mesylate (1.65 kg) and lithium chloride (1.67 kg) were added to N,N-dimethylacetamide (16 L) in a 100-L reaction vessel. The resulting mixture was stirred under nitrogen at about 80° C. for 3 hours.
[0156] The mixture was then cooled to about 20° C. Water (45 L) was added over the course of 50 minutes to the cooled mixture. The resulting mixture was then stirred for about 1 hour at about 20° C. The resulting precipitate was filtered and washed with water (20 L) to provide a wet crude halobetasol propionate (2.84 kg; approximately 1.25 kg on a dry basis).
example 2
Crystallization of Crude Halobetasol Propionate to Provide a Commercial Scale Composition of a Crystalline Form of Halobetasol Propionate
[0157] The wet crude halobetasol propionate prepared in Example 1 (2.84 kg) was added to ethanol (14 L) in a 100-L reaction vessel. The resulting mixture was heated at reflux (about 78° C.) for 30 minutes.
[0158] The mixture was then cooled to about 70° C. A suspension of activated carbon (0.14 kg) in ethanol (1 L) and a suspension of CELITE 545® (manufactured by Eagle-Picher Minerals Europe (Germany), active ingredient=siliceous earth) (0.14 kg) in ethanol (1 L) were added to the cooled mixture. The resulting mixture was heated at reflux (about 78° C.) for 30 minutes, and then hot filtered.
[0159] Water (16 L) was added to the resulting filtrate over the course of 55 minutes at about 70° C. The resulting mixture was stirred at this temperature for 30 minutes. The mixture was cooled to about 25° C., and then stirred for 1 hour at 19-25° C. The resu...
example 3
Recrystallization of Halobetasol Propionate to Provide a Commercial Scale Composition of a Crystalline Form of Halobetasol Propionate
[0160] The crystalline form of halobetasol propionate prepared in Example 2 (1.49 kg) was added to ethanol (15 L) in a 150-L reaction vessel. The resulting mixture was heated at reflux (about 78° C.) for 30 minutes, and then transferred to a 100-L reactor.
[0161] Water (7.5 L) was added to the mixture over the course of 30 minutes at a temperature of about 71-73° C. The resulting mixture was stirred at 70-71° C. for 30 minutes. The mixture was cooled to 25° C., and then stirred for 1 hour at 20-25° C. The resulting precipitate was filtered and washed with a mixture (3 L) of ethanol and water (v / v=67:33), to provide a crystalline form of halobetasol propionate as wet crystals (1.33 kg).
[0162] The wet crystalline form of halobetasol propionate was dried for 12 hours at 70° C. under vacuum (80 mbar) to provide a crystalline form of halobetasol propionate...
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