Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-09-18
1999-08-31
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
552201, C07C 49423, C07H 1708
Patent
active
059455187
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of anthracycline antibiotics.
FIELD OF THE INVENTION
Epirubicin (epidoxorubicin) and epidaunomycin are antibiotics belonging to the anthracycline class having antitumoral activity.
These compounds differ from the antitumorals doxorubicin and daunorubicin in the configuration of the hydroxy group at the C-4' position of the glycosidic moiety of the molecule, which configuration is respectively axial in doxo- and daunorubicin and equatorial in epirubicin and epidaunorubicin.
BACKGROUND OF THE PRIOR ART
Doxorubicin has been used for a long time in the antineoplastic treatment, for a review see Arcamone, ed. "Doxorubicin", Acad. Press, New York 1981. A serious side-effect of doxorubicin is the onset of often irreversible myocardiopathies.
Epirubicin was found to have advantageous pharmacological properties compared with its analogue, showing an equivalent antitumoral activity but less side-effects (R. B. Weiss et al., Cancer Chemother. Pharmacol. 18, 185-97 (1986)).
The starting synthesis of epirubicin involved the condensation between daunorubicin aglycone of formula (B) ##STR2## and the 1-chloro-derivative of acosamine protected as trifluoroacetamide (Arcamone, F. et al., J. Med. Chem., 18, 7, 703-707, (1975)), subsequent deprotection and working up of the side chain with a method well known in literature, already used for the transformation of daunorubicin into doxorubicin (E. M. Acton, J. Med. Chem., 17,65 (1974); DE 1917874).
Trifluoroacetylacosaminyl chloride N,O derivative was obtained by synthetic transformation of various natural sugars with a number of rather complex, expensive processes.
Italian Patent 1,163,001 and, subsequently, G. Bonadonna in "Advances in Anthracycline Chemotherapy Epirubicin", Masson Ed., Milan, Italy, 1984, disclose a synthesis process carried out on the whole N-trifluoroacetyldaunorubicin glycoside. This process comprises the oxidation of the hydroxy group at C-4' to keto group, then its stereoselective reduction to hydroxy group by means of sodium borohydride. The oxidation reaction has to be performed at exceedingly low temperatures (-70.degree. C.). The keto derivative is very delicate and unstable. Moreover, the reduction with sodium borohydride must be carried out at a low temperature to minimize the competitive reduction of the aglycone carbonyl group. Although not stated, the maximum isomerization yields which can deduced from said patent are of about 48%.
Another method for the epimerization of C-4' is described by B. Barbieri et al. Cancer Research, 47, 4001 (1987). This method aims at obtaining 4'-halogen-daunorubicin, then effects the epimerization from the equatorial configuration to the axial one, i.e. in a direction opposite to that desired in the present invention. The epimerization reaction is carried out by nucleophilic substitution of the triflate group (equatorial) with a tetrabutylammonium halide.
SUMMARY OF THE INVENTION
Now a novel method has been found for the isomerization of the 4' hydroxy group of the daunosamine residue on the whole anthracycline antibiotic molecule, reaction conditions which can be regulated more easily, particularly with respect to the reaction temperature, and with easier purification procedures.
According to this method, the epimerization of the 4' hydroxy group from the axial configuration to the equatorial one of the daunosamine residue, which is suitably protected at the amino group, is obtained by introducing a strong leaving group and subsequently substituting it with a carboxylate group, with inversion of the configuration of the 4' carbon atom, subsequently hydrolysing the carboxylic ester, restoring the hydroxy group, removing the amino-protective group.
During the study of the epimerization reaction, the yields in the desired epimer were found to be not very high, due to a side product formed in competition with the substitution reaction of the triflate leaving group.
Surprisingly, the protection of the hydroxy groups of the aglycone moiety, particu
REFERENCES:
patent: 4537882 (1985-08-01), Horton et al.
patent: 4749693 (1988-06-01), Angelucci et al.
patent: 5015745 (1991-05-01), De Bernardinis et al.
patent: 5037970 (1991-08-01), Angelucci et al.
Bianchi Francesco
Bigatti Ettore
Covington Raymond
Kight John
Sicor Societa' Italiana Corticosteroida S.p.A.
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