US 6,642,364 B2Granted

Process to obtain clarithromycin

AssigneeErcros Industrial, S.A.

InventorsRamón Asensio Dominguez, Maria del Carmen Cruzado Rodriguez, Luis Ángel Diaz Tejo, Rosa Nomen Ribé, Julià Sempere Cebrián, José Ignacio Borrell Bilbao

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Abstract

This process is intended to obtain clarithromycin. According to the process, it starts from the erythromycin A 9-oxime hydrochloride, which is transformed into clarithromycin by means of a synthetic sequence in which an acetal of the 9-oxime is initially formed. The use of the oxime hydrochloride permits that only the use of catalytic amounts of pyridine salts are necessary to favor the reaction. Next, the hydroxyls in positions 2′ and 4″ are protected with a silylating agent and the hydroxyl in position 6 is methylated; all this without the isolation of any reaction intermediate being necessary. Finally, the acetal and 2′ and 4″ silanes unprotection, followed by the deoximation yields clarithromycin with a high yield and a form which is easily applicable industrially.

Claims4

Dependent claims

A process for producing clarithromycin comprising the steps of:

(a) reacting erythromycin A 9-oxime hydrochloride with 1,1-diisopropoxycyclohexane in the presence of a catalytic amount of a pyridine salt, in methylene chloride as a solvent, so as to obtain a mixed acetal;
(b) reacting hexamethyldisilazane and imidazole in the presence of sulfuric acid, and thereafter adding chlorotrimethysilane in methylene chloride as a solvent, so as to obtain a silylation agent;
(c) reacting the resulting mixed acetal of step (a) with the resulting silylation agent of step (b) in methylene chloride as a solvent, so as to obtain erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime;
(d) reacting the resulting erythromycin A 2′,4″-bis(trimethylsilyl)-9-[O-isopropoxycyclohexyl]oxime of step (c) with methyl iodide and potassium hydroxide in methylene chloride and dimethylsulfoxide as solvents, so as to obtain erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime;
(e) deprotecting the resulting erythromycin A 2′,4″-bis(trimethylsilyl)-6-O-methyl-9-[O-isopropoxycyclohexyl]oxime obtained in step (d) in a solution of methanol, water and 85% formic acid, so as to obtain clarithromycin oxime;
and
(f) deoximating the resulting clarithromycin oxime of step (e) with aqueous sodium metabisulfite so as to obtain clarithromycin.

4 more elements

Dependencies are inferred from the claim text.