Process for the preparation of 4'-epidaunorubicin, 3',4'-diepidaunorubicin, their doxorubicin analogs, and intermediates used in said process

Claim 1

A process for preparing 4'-epi-daunorubicin.HCl (VII) and 3',4'-di-epidaunorubicin.HCl (VIII): ##STR3## said process comprising subjecting N-trifluoroacetyl daunrorubicin (I): ##STR4## by treatment with dimethylsulfoxide activated by trifluoroacetic anhydride, to oxidation at the C-4' hydroxyl group at a temperature of about -65° to -60° C., followed by basification thereof with 1,5-diazobicyclo (4.3.0)-non-5-ene to form 4'-keto-N-trifluoroacetyl daunorubicin (III a): ##STR5## subjecting said 4'-keto-N-trifluoroacetyl daunorubicin (IIIa) to selective stereospecific reduction with sodium borohydride at a temperature of about -10° C. to obtain 4'-epi-N-trifluoroacetyl daunorubicin Va: ##STR6## converting said 4'-epi-N-trifluoroacetyl daunorubicin (Va) to 4'-epi-daunorubicin base (VII) by treatment with a mild alkali to remove the N-trifluoroacetyl group and isolating said 4'-epi-daunorubicin as its hydrochloride or alternatively, subjecting said 4'-keto-N-trifluoroacetyl daunorubicin (IIIa) to epimerization by filtering a solution thereof through a column of silica gel buffered at pH 7 with M/15 phosphate buffer to give a 1:1 epimeric mixture of said (IIIa) and 3'-epi-4'-keto-N-trifluoroacetyl daunorubicin (IV a): ##STR7## stereospecifically reducing said epimeric mixture with sodium borohydride as hereinabove described to obtain a 1:1 mixture of 4'-epi-N-trifluoroacetyl daunorubicin (Va) and 3'-4'-diepi-N trifluoroacetyl daunorubicin VI a: ##STR8## separating pure (VIa) from said mixture by chromatography on a column of silica gel buffered at pH 7 with M/15 phosphate buffer, removing the N-trifluoroacetyl group therefrom to obtain free 3',4'-diepi-daunorubicin base (VIII) and isolating same as the hydrochloride.