SI8910310B - Process for obtaining 4-demethoxy-daunomycinone, the aglycone of 4- demethoxy-daunorubicine - Google Patents

Claims (10)

A process for the preparation of N-demethoxy-davnomycinone of formula (I); (a) protecting the 13-keto group of the 4-demethyldaunomycinone of formula (2): 2 by treatment with ethylene glycol; (b) reacting the resulting 4-demethyl-13-dioxolanyl-davnomycinone with formula (3): 1 with a sulphonyl chloride of formula II: R-SO2Cl (II) wherein R represents an alkyl group of 1 to 10 carbon atoms (optionally substituted with one or more halogen atoms) or an aryl group optionally substituted L - 16 - with halogen, alkyl, alkoxy or nitro ^ in the presence of N, N-diisopropylethylamine and a catalytic amount of 4-dimethylamino-pyridine; (c) reacting the resulting sulfonated N-demethyl-13-dioxolanyl-davnomycinone with formula (4): wherein R 1 is as defined above, with an amine of formula III: r 1 (r 2) CH-NH 2 (III) 1 2 wherein each of R and R independently represents a hydrogen atom or a phenyl group bearing one or more alkoxy groups; (d) removing the amino protecting group from the resulting M-demethyl-4- (protected amino) -13-dioxolanyl-davnomycinone of formula (5): 1 2 wherein R and R are as defined above; 2 (e) diazotizing the 4-amino group of the resulting U-demethoxy-N-amino-daunomycinone of formula (6): 17 - and (f) reducing the resulting diazo derivative of formula (7): under mild conditions to give 4-demethoxy-davnomycinone of formula I. Process according to Claim 1, characterized in that 4-demethyl-davnomycinone of formula (2) is prepared by demethylation of davnomycinone of formula (1): Process according to Claim 2, characterized in that the demethylation is carried out at reflux with aluminum chloride in an inert organic solvent. Process according to any one of the preceding claims, characterized in that step (a) is carried out by treatment with ethylene glycol in the presence of p-toluenesulphonic acid at reflux temperature. 18 Process according to any one of the preceding claims, characterized in that the sulfonyl chloride of formula (II) in step (b) is p-toluenesulfonyl chloride or 4-fluorophenylsulfonyl chloride. Process according to any one of the preceding claims, characterized in that the amine of formula (III) in step (c) is 4-methoxybenzylamine or 3,4-dimethoxybenzylamine. Process according to any one of the preceding claims, characterized in that step (d) is carried out by reaction with trifluoroacetic acid. Process according to any one of the preceding claims, characterized in that step (e) is carried out using sodium nitrite. Process according to any one of the preceding claims, characterized in that step (f) is carried out using hypophosphoric acid. A process for the preparation of 4-demethoxy-davnorubicin of formula IV or a pharmaceutically acceptable salt thereof, characterized in that it comprises reacting 4-demethoxy-davnomycinone of formula I, prepared by a process according to any one of the preceding claims, with a sugar derivative of formula V: 19 Hal In which Hal represents a halogen atom, R4 represents a protected hydroxyl group and R5 represents a protected amino group, and to remove the protecting groups after reaction with 4-demethoxy-davnomycinone, and, if desired, the metabolism of the thus obtained 4-demethoxy-davnorubicin in a pharmaceutically acceptable salt thereof