DEREK MARKO (HR)
LELJAK MARIJA (HR)
KIDEMET DAVOR (HR)
DEREK MARKO (HR)
LELJAK MARIJA (HR)
WO1999020639A2 | 1999-04-29 |
MORIMOO S ET AL: "Chemical modifications of erythromycins. II. Synthesis and antibacterial activity of o-alkyl derivatives of erythromycin A", JOURNAL OF ANTIBIOTICS, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. TOKYO, JP, vol. 43, 1990, pages 286 - 294, XP002093093, ISSN: 0021-8820
TECHNICAL FIELD The present invention relates to a process for selective alkylation of macrolide and azalide derivatives. Specifically the invention relates to regioselective alkylation of macrolide and azalide derivatives having vicinal diol system, using diazoalkanes in the presence of transition-metal halides and of boric acid, respectively.
BACKGROUND OF THE INVENTION A series of alkyl derivatives of macrolide and azalide antibiotics have been described in the literature. Among them O-Me derivatives of erythromycin (clarithromycin) (US Patent No. 4,331, 803) and azithromycin (US Patent No. 5,250, 518) have significant biolgical activities. The process for making this derivatives in general is a multistep procedure.
Because macrolide and azalide compounds posses a few different hydroxyl groups it is difficult to alkylate one hydroxyl group selectively in the presence of other unprotected hydroxyl groups (see e. g. J. Antibiot. 46 (1993) 647; J. Antibiot. 43 (1990) 286). Various protecting groups have been described in the literature (See e. g. J. Antibiot. 45 (1992) 527, J.
Antibiot. 37 (1984) 187, J. Antibiot. 46 (1993) 1163, US Patent Nos. 5, 872, 229; 5,719, 272; 5,929, 219). Selective synthesis of 12-OMe-azithromycin has been described in WO 99/20639.
However, the substitution at the 11-0-position with alkyl groups is not easy to accomplish and is accompanied by side reactions, by-products and low yields.
Therefore, there is considerable effort directed towards discovering more efficient and cleaner and one step method of introducing alkyl supstituents in the 11-position of macrolide and azalide derivatives that have unprotected other hydroxyl groups. The method is suitable to all macrolide and azalide compounds having vicinal diol system.
Regioselective alkylation of vicinal hydroxyl groups with diazoalkanes in the presence of transition-metal halides and of boric acid, respectively, is known in the literature. See for <BR> <BR> example, . Carbohydr. Res. 316 (1999) 187-200; Helv. Chim. Acta 79 (1996) 2114-2136; Chem. Pharm. Bull. 18 (1970) 677-686. However, there are no known reports of regioselective alkylation of 11-hydroxyl group of macrolide and azalide derivatives with diazoalkanes in the presence of transition-metal halides and of boric acid, respectively.
DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 11-0-alkyl macrolide and azalide derivatives comprising reacting an macrolide or azalide derivative with vicinal hydroxyl system with diazoalkane having the formula: R-CHN2 wherein R is a hydrogen or Cl-C3 alkyl groups in the presence of transition-metal halides and of boric acid, respectively.
Macrolide and azalide derivatives are dissolved in suitable inert organic solvent (e. g. but not limited to, lower alcohols, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, pyridine, dichloromethane, ethyl-acetate, dimethyl sulfoxide, ethers).
To reaction mixture transition-metal halide or boric acid was added and the resulting mixture is stirred at a temperature from-20°C to the reflux temperature of the solvent for 1 hour.
Then, ether solution of the coresponding diazoalkane was added dropwise. The reaction micture was stirred at said temperature until TLC analysis showed complete conversion.
Isolation by using standard methods (extraction, precipitation and like) afforded excusively desired 11-0-alkil-derivatives.
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