Process for preparing epirubicin or acid addition salts thereof

Details Process for preparing epirubicin or acid addition salts thereof Process for preparing epirubicin or acid addition salts thereof

1997-12-04

1999-02-23

Peselev, Elli

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 185, 536 186, C07H 100, C07H 1524

Patent

active

058745505

ABSTRACT:
This invention relates to a novel method for the chemical preparation of epirubicin or acid addition salts thereof, in particular the HCl salt, from daunorubicin. This process avoids the disadvantages of the prior art. First daunorubicin is methanolized to obtain daunomycinone and daunosamine methyl ether in very high yields. Daunomycinone is converted to 14-acetoxy daunomycinone by bromination and acetoxylation, while daunosamine methyl ether is converted into an N-protected 4'-epi daunosamine. The choice of the protecting group of the amino group of the daunosamine methyl ether is important because it has to be removed after coupling the sugar with the aglycone without causing side reactions of the aglycone. Two protecting groups were selected: the trifluoroacetyl group and the allyloxycarbonyl group. After coupling the 14-acetoxy daunomycinone with the N-protected 4'-epi daunosamine, the obtained compound was converted to epirubicin; for the latter conversion two routes were developed, depending on the amino-protecting group.

REFERENCES:
patent: 4946831 (1990-08-01), Gatti et al.
Carbohydrate Research, vol. 184, 1988, Amsterdam, NL, pp. 231-235, XP000644752. Horton, D. et al., "Preparative procedures for conversion of daunorubicin into doxorubicin (adriamycin) and 14-0-acetyldoxorubicin by way of 14-bromodaunorubicin."
Heterocycles, vol. 26, No. 1, 1987, pp. 341-345, XP000618500. T.Van, H.D. et al., "Chiral pool synthesis of 8-hydroxymethyl-'9-oxa'-anthracyclinones."
Bulletin of the Chemical Society of Japan, vol. 59, 1986, Tokyo, JP., pp. 423-431, XP000644326. Kimura, Y. et al., "Novel glycosidation of 4-demethoxyanthracyclinones by use of trimethylsilyl triflate. Synthesis of optically active 40-demethoxydaunorubicin and 4-demethoxyadriamycin."

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