FIELD: drugs.
SUBSTANCE: invention relates to a one-pot method for producing amorphous form 4-[4- [4- [4 - [[(3R, 5R)-5- (2,4-difluorophenyl) tetrahydro-5 (1H-1,2,4-triazole- 1-ylmethyl) -3-furanyl] methoxy] phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1, 2,4-triazol-3-one of formula (IV) (posaconazole), which includes a) treatment of 4-(4- (4- (4 - (((3R, 5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl) methoxy) phenyl) piperazin-1-yl)phenyl)-1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazole-5(4H)-one
of formula (III) with concentrated hydrochloric acid and stirring the reaction mixture at a temperature55-70°C, b) cooling the reaction mixture and introducing a halogenated hydrocarbon solvent, c) separation of layers, d) introducing a halogenated hydrocarbon solvent into the aqueous layer and adjusting the pH to 8-12, e) partial concentration of the organic layer and the possible introduction into the reaction mixture of a solvent - aliphatic ketone, f) mixing the reaction mixture of Stage e) and an aliphatic hydrocarbon solvent at a temperature 10-25°C and g) filtration and optional washing with an aliphatic hydrocarbon solvent to obtain an amorphous compound of formula IV, wherein 4-(4-(4-(4-(((3R, 5R)-5-((1H-1,2,4-triazole-1-yl)methyl)-5- (2,4-difluorophenyl) tetrahydrofuran-3-yl) methoxy) phenyl) piperazin-1yl) phenyl)-1- ((2S, 3S) -2- (benzyloxy) pentan-3-yl )-1H-1,2,4-triazol-5 (4H)-one of formula (III) is crystalline B-3 form, which is characterized by the X-ray diffractogram shown in Fig. 3. The invention also relates to crystalline form B-3 4-(4-(4-(4-(((3R, 5R)-5-((1H-1,2,4-triazol-1-yl) methyl)-5- (2,4-difluorophenyl) tetrahydrofuran-3-yl) methoxy) phenyl) piperazin-1-yl) phenyl)-1-((2S, 3S)-2-(benzyloxy) pentan-3-yl)-1H-1, 2,4-triazol-5 (4H)-one of formula (III), which is an intermediate for the preparation of amorphous posaconazole, and a method for its preparation.
EFFECT: effective method for amorphous posaconazole preparation.
5 cl, 3 tbl, 7 dwg, 9 ex
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