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Patent / 2002

Process for the preparation of flumethasone and its 17-carboxyl-androstene analog

Hovione Limited

Authors:
  • Ivan Villax
Source:
WO 2002100878
A process was disclosed for prepg. Flumethasone, Flumethasone 21-acetate, or its 17-carboxyl-androstene analog via fluorination of I (X = H) with electrophilic fluorination agent to form intermediate I (X = F). Thus, (9b,11b,16b)-21-(acetyloxy)-9,11-epoxy-17-hydroxy-16-methylpregna-1,4-diene-3,20-dione was reacted with benzoyl chloride by heating at 80-85 pyridine and N,N-dimethylacetamide (DMA) to form benzoate I (X = H) situ which was fluorinated situ using Selectfluor to form the unisolated intermediate I (X = F) which was subsequently treated with sodium metabisulfite and ammonia CH2Cl2 to give II (RR1 = 9b,11b-epoxide, R2 = CH2OAc). The epoxide thus formed was converted to Flumethasone 21-acetate II (R = OH, R1 = a-F, R2 = CH2OAc) using HF DMF which was turn hydrolyzed using KOH/MeOH to give Flumethasone II (R = OH, R1 = a-F, R2 = CH2OH). Flumethasone 21-acetate was alconverted to its 17b-carboxy analog II (R = OH, R1 = a-F, R2 = OH) with 91.3% yield by treatment with KOH/MeOH followed with aq. H2O2.