Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same

A method of converting a protected silylated clarithromycin oxime to clarithromycin comprising

• a) reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to obtain a solution,
• b) refluxing the solution obtained by step a),
• c) cooling the solution obtained after step b) to about 15° C. to about 25° C., and
• d) adding NaOH.

A method of converting protected silylated clarithromycin oxime to clarithromycin including

• reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture;
• cooling the reaction mixture to about 15° C. to about 25° C.;
• and
• adding sodium hydroxide solution to the reaction mixture;
• wherein essentially no additional water to process clarithromycin.

Clarithromycin formed by a process comprising

• converting erythromycin A to 2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime;
• reacting 2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with methylating agent while stirring in the presence of at least one solvent and a base, wherein the at least one solvent comprises methyl tertbutyl ether, to form 6-O-methyl-2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime;
• and
• reacting the 6-O-methyl-2′, 4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime with an acid and a deoximating agent in the presence of aqueous ethanol to form clarithromycin.

Clarithromycin formed by a process comprising

• converting erythromycin A to protected silylated clarithromycin oxime;
• reacting the protected silylated clarithromycin oxime with acid and deoximating agent in the presence of ethanol and water at an ethanol to water ratio of about 1:1 to form a reaction mixture;
• cooling the reaction mixture to about 15° C. to about 25° C.;
• and
• adding sodium hydroxide solution to the reaction mixture.

A method of converting erythromycin A to clarithromycin comprising

• converting erythromycin A to protected silylated clarithromycin oxime;
• reacting protected silylated clarithromycin oxime with methylating agent while stirring in the presence of at least one solvent, wherein the at least one solvent comprises methyl tertbutyl ether, and a base to form 6-O-methyl protected silylated clarithromycin oxime;
• and
• reacting the 6-O-methyl-protected silylated clarithromycin oxime with acid and a deoximating agent in the presence of aqueous ethanol to form clarithromycin.