US 6,437,106 B1 · Process for preparing 6-o-substituted erythromycin derivatives

Process for preparing 6-o-substituted erythromycin derivatives

AssigneeAbbott Laboratories

InventorsEric J. Stoner, Matthew J. Peterson, Yi-Yin Ku, Russell D. Cink, Arthur J. Cooper, Mahendra N. Deshpande, Tim Grieme, Anthony R. Haight, David R. Hill, Margaret Chi-Ping Hsu, Steven A. King, Marvin Robert Leanna, Elaine C. Lee, Maureen A. McLaughlin, Howard E. Morton, James J. Napier, Daniel J. Plata, Prasad S. Raje, Michael Rasmussen, David Riley, Jien-Heh J. Tien, Steven J. Wittenberger

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Abstract

In one aspect, the invention relates to a process for preparing 6-O-substituted erythromycin derivatives comprising reacting 2′-substituted and optionally 4″-substituted 9-oxime erythromycin derivatives with an alkylating agent in the presence of a palladium catalyst and phosphine. In another aspect, the invention relates to processes for preparing 6-O-substituted erythromycin ketolides using the palladium-catalyzed alkylation reaction.

Claims30

Dependent claims

A process for preparing 6-O-substituted erythromycin derivatives comprising reacting an erythromycin derivative with an alkylating agent having the formula:

wherein:
R is independently selected from the group consisting of:
hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl,
heteroaryl and substituted heteroaryl;
R1 is an alkyl group of one to ten carbon atoms, and
X is O or NR′, wherein R′ is alkyl or aryl, or R1 and R′ taken together form an aromatic or non-aromatic ring;
in the presence of palladium catalyst and a phosphine.

4 more elements

A process for preparing a compound represented by formula:

or pharmaceutically acceptable salt, ester or prodrug thereof, wherein
Ra is represented by the formula:
wherein:
R is independently selected from the group consisting of:
hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence;
the process comprising the steps of:
(a) reacting an erythromycin derivative with an alkylating agent having the formula:
wherein
R is as defined above;
R1 is an alkyl group of one to ten carbon atoms, and
X is O or NR′, wherein R′ is alkyl or aryl, or R1 and R′ taken together form an aromatic or non-aromatic ring;
in the presence of palladium catalyst and a phosphine;
(b) optionally deprotecting and deoximating the 6-O substituted erythromycin of step (a) to obtain the compound of formula:
wherein Z is hydroxyl or protected hydroxyl group and Ra and Rp are as defined above;
(c) reacting the compound from step (b) with 1,1′-carbonyldiimidazole in the presence of an amine base or an amine base catalyst followed by a reaction with ammonia or ammonium hydroxide optionally carried out in the presence of a strong base to afford a compound having the formula:
(d) removing the cladinose moiety from the compound obtained in step (c) by hydrolysis with acid to give a compound having the formula
(e) oxidizing the 3-hydroxyl group, and optionally deprotecting and isolating the resulting compound.

14 more elements

A process for preparing a compound of formula:

or pharmaceutically acceptable salt, ester or prodrug thereof, wherein
Ra is represented by the formula:
wherein R is independently selected from the group consisting of:
hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl,
heteroaryl and substituted heteroaryl;
the process comprising the steps of:
(a) removing the cladinose moiety from an erythromycin derivative by hydrolysis with an acid to give a compound having the formula
(b) protecting the hydroxyl groups to obtain a compound of the formula
wherein Z is hydroxyl or protected hydroxyl group;
(c) treating the compound from step (b) with an alkylating agent having the formula:
wherein R is as defined above;
R1 is an alkyl group of one to ten carbon atoms, and
X is O or NR′, wherein R′ is an alkyl or an aryl;
or R1 and R′ taken together form an aromatic or non-aromatic ring;
in the presence of palladium catalyst and a phosphine to obtain a compound of the formula:
(d) deprotecting and deoximating the compound from step (c) to obtain a compound of formula:
(e) optionally protecting the 2′- and 3- hydroxyl groups and reacting the compound from step (d) with 1,1′-carbonyldiimidazole, in the presence of an amine base or an amine base catalyst followed by reaction with ammonium hydroxide optionally carried out in the presence of a strong base to obtain a compound having the formula:
(f) optionally deprotecting the 3-hydroxyl group and oxidizing the 3-hydroxyl group;
and
(g) optionally deprotecting the hydroxyl-protecting groups.

17 more elements

Dependencies are inferred from the claim text.