Process for etherifying .beta.-lactam antibiotics
AssigneeEli Lilly and Company
InventorGary A. Koppel
Life of this patent
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Abstract
6-Alkoxylated-6-acylamidopenicillanic acids and 7-alkoxylated-7-acylamidocephalosporin acids and esters thereof, are provided by reacting a 6-acylamidopenicillanic acid ester or a 7-acylamidocephalosporin ester under anhydrous conditions at -90.degree. C. to -15.degree. C. with an alkali metal salt of a lower alkyl alcohol in the presence of an excess of the corresponding alcohol to produce, in situ, the anionic form of the antibiotic which on halogenation with a positive halogen compound, e.g. t-butyl hypochlorite, yields the compound of the invention. Compounds of the invention, e.g. 6-methoxy-6-phenoxyacetamidopenicillanic acid and 7-methoxy-7-[2-(2-thienyl)acetamido]cephalosporanic acid are useful antibiotics.
Claims5
A process for preparing a substituted .beta.-lactam compound of the formula ##SPC11##
- which compries a) reacting in an inert, anhydrous solvent at a temperature between -90 and -15.degree. C. a .beta.-lactam of the formula ##SPC12##
- with between 2 and 6 equivalents per 1 equivalent of .beta.-lactam of an alkali metal salt of the formula
- M.sup.+O.sup.- -R.sub.2,
- wherein m.sup.+ is an alkali metal cation, in the presence of an excess of the corresponding alcohol of the formula HOR.sub.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 .beta.-lactam from the reaction mixture;
- where in the preceding formula R is hydrogen, C.sub.1 -C.sub.6 alkyl,
- 4-amino-4-carboxybutyl, phenyl, substituted phenyl, wherein the substituent is chloro, bromo, fluoro, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, nitro, amino, or carboxy;
- or a group of the formula ##EQU1## wherein P is phenyl, C.sub.1 -C.sub.4 lower alkylphenyl, halophenyl, hydroxyphenyl, C.sub.1 -C.sub.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.sub.1 -C.sub.3 lower alkyl;
- b is hydrogen, C.sub.1 -C.sub.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.sub.1 -C.sub.4 lower alkylphenyl, halophenyl, hydroxyphenyl, C.sub.1 -C.sub.4 lower alkoxyphenyl, and b is hydrogen or C.sub.1 -C.sub.3 lower alkyl;
- R.sub.9 is hydrogen, an alkali metal cation, acetoxymethyl or a readily removable ester forming moiety;
- R.sub.2 is C.sub.1 -C.sub.4 lower alkyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl;
- Y is a substituted three-carbon fragment of the formula ##EQU2## wherein R.sub.3 is hydrogen, C.sub.2 -C.sub.4 alkanoyloxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, ##SPC13##
- wherein R.sub.4, R.sub.5 and R.sub.6 are hydrogen, C.sub.1 -C.sub.4 lower alkyl, phenyl, C.sub.1 -C.sub.4 lower alkylphenyl;
- C.sub.1 -C.sub.4 lower alkoxyphenyl, halophenyl or hydroxyphenyl;
- or a carbamoyloxy group of the formula ##EQU3## wherein R.sub.7 and R.sub.8 are the same or different and are hydrogen or C.sub.1 -C.sub.4 lower alkyl.
Dependencies are inferred from the claim text.