Formic Acid → Methyl Acetate

Participants

Reaction Steps

In accordance with the present invention, the crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) obtained in step (a) is subjected to conventional Eschweiler-Clarke reductive N-methylation (Eschweiler and Clarke, Org. React., 5, 290(1945)), i.e., reacted with a formic acid-aqueous formaldehyde mixture in an organic solvent which may be a halogenized solvent such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; an alcohol such as methanol, ethanol and isopropanol; a ketone such as acetone, ethylmethylketone and isobutylmethylketone; and an ester such as methyl acetate, ethyl acetate and isopropyl acetate, to give azithromycin of formula (I) in a high yield of at least 90%. The amounts of formic acid and formaldehyde used are each independently in the range of 1 to 3 mole equivalents based on the amount of the crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II), and the reaction may be performed at a temperature ranging from room temperature to the boiling point of the solvent.

Provenance & Evidence