Process for etherifying β-lactam antibiotics

Claim 1

A process for preparing a substituted β-lactam compound of the formula ##SPC11## which compries a) reacting in an inert, anhydrous solvent at a temperature between -90 and -15° C. a β-lactam of the formula ##SPC12## with between 2 and 6 equivalents per 1 equivalent of β-lactam of an alkali metal salt of the formula M.sup.+O.sup.- -R.sub.2, wherein m + is an alkali metal cation, in the presence of an excess of the corresponding alcohol of the formula HOR 2 ; b) adding between 1 and 5 equivalents of a positive halogenating agent selected from a t-butyl hypohalite, an N-haloamide, an N-haloimide, an N-halosulfonamide, an N-halohydantoin, and an N-halotriazine, wherein halo is chloro or bromo; c) acidifying said mixture; and d) recovering the substituted β-lactam from the reaction mixture; where in the preceding formula R is hydrogen, C 1 -C 6 alkyl, 4-amino-4-carboxybutyl, phenyl, substituted phenyl, wherein the substituent is chloro, bromo, fluoro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, amino, or carboxy; or a group of the formula ##EQU1## wherein P is phenyl, C 1 -C 4 lower alkylphenyl, halophenyl, hydroxyphenyl, C 1 -C 4 lower alkoxyphenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, or 1-tetrazyl; Z is an oxygen atom, or a sulfur atom; n is 0 or 1; a is hydrogen or C 1 -C 3 lower alkyl; b is hydrogen, C 1 -C 3 lower alkyl, protected hydroxy, wherein the protecting group is benzyl, benzhydryl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, or 1-ethoxyethyl; amino, or protected amino; and when n is 1, P is phenyl, C 1 -C 4 lower alkylphenyl, halophenyl, hydroxyphenyl, C 1 -C 4 lower alkoxyphenyl, and b is hydrogen or C 1 -C 3 lower alkyl; R 9 is hydrogen, an alkali metal cation, acetoxymethyl or a readily removable ester forming moiety; R 2 is C 1 -C 4 lower alkyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl; Y is a substituted three-carbon fragment of the formula ##EQU2## wherein R 3 is hydrogen, C 2 -C 4 alkanoyloxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, ##SPC13## wherein R 4 , R 5 and R 6 are hydrogen, C 1 -C 4 lower alkyl, phenyl, C 1 -C 4 lower alkylphenyl; C 1 -C 4 lower alkoxyphenyl, halophenyl or hydroxyphenyl; or a carbamoyloxy group of the formula ##EQU3## wherein R 7 and R 8 are the same or different and are hydrogen or C 1 -C 4 lower alkyl.