METHYLENE-6 TETRACYCLINES

摘要

1370318 Preparation of 6-methylenetetracyclines RACHELLE LABORATORIES ITALIA SpA 21 Dec 1971 [28 Dec 1970 26 Oct 1971] 59247/71 Heading C2A A process for the preparation of a 6-methylenetetracycline comprises halogenating a tetracycline base or an acid salt thereof in solution at sub-ambient temperatures while maintaining the pH of the reaction mixture at from 3À0 to 5À0 to spontaneously crystallize the 11a-halo-6,12- hemiketal substantially entirely in the enolic form. Then the 11a-halo-6,12-hemiketal base is converted to the corresponding acid salt, e.g. the perchlorate, this salt is dehydrated to the corresponding 11a-halo-6-methylene tetracycline and this is dehalogenated to provide the desired 6-methylene tetracycline. The hemiketal base may be treated with acid at a temperature from -10‹ C. to 20‹ C. in order to convert it to the corresponding acid salt. The 6-methylene tetracyclines which may be prepared include 6- methylene-5-oxytetracycline, for which the initial tetracycline reactant is 5-oxytetracycline. The 11a-halo-6-methylenetetracycline may be dehalogenated to form an acid salt of the 6- methylene tetracycline and the acid salt converted to the free base of the desired 6-methylenetetracycline by neutralizing it at a temperature of from 50‹ C. to 90‹ C. in an aqueous solution maintained at a pH of from 6À5 to 7À5. The 11a-halo-6,12-hemiketal base may be formed by halogenating the tetracycline base or acid salt thereof in solution at a temperature below 0‹ C. and at a pH of from 3À5 to 5À0.