Process for preparing monohydrate and crystal modifications of fluconazole

A process for the synthesis of monohydrate and crystal modifications of fluconazole of formula (I)

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• comprising the steps of:
• a.) hydrolyzing a silyl ether derivative of formula (II)
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• wherein the meaning of R2 is hydrogen, or a C1-C10 alkyl or phenyl group, R3 and R4 independently of each other are a C1-C10 alkyl or phenyl group—at a pH preferably either below 3 or above 8 in an aqueous solution,
• then cooling the obtained reaction mixture containing the fluconazole of formula (I) and isolating the precipitated fluconazole monohydrate and optionally
• dissolving the fluconazole monohydrate obtained from the hydrolysis of silyl-fluconazole in a C1-C4 straight or branched chain alcohol at boiling temperature and cooling the solution with a speed of 5-15° C./h to obtain the crystal modification II of fluconazole, or
• b.) dissolving anhydrous fluconazole or monohydrate of it in a C1-C4 straight or branched chain alcohol at boiling temperature and cooling the solution with a speed of 5-15° C./h to obtain the crystal modification II of fluconazole, or
• c.) drying slowly fluconazole monohydrate after seeding preferably with seeding crystals of crystal modification II at 30-70° C., preferably in vacuum to obtain the crystal modification II of fluconazole, or
• d.) drying fast fluconazole monohydrate after seeding preferably with seeding crystals of crystal modification I at 80° C., to obtain the crystal modification I of fluconazole.