Process for preparation of 7-alkoxy-3-bromomethylcephems
AssigneeEli Lilly and Company
InventorGary A. Koppel
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Abstract
7-Alkoxy-3-bromomethyl-3-cephems are provided by reacting a 3-methylenecepham with an alkali metal salt of a lower primary alcohol in the presence of a positive brominating agent at a temperature ranging from about -80.degree. to about 0.degree. C. The 3-bromomethylcephems provided by this invention are useful intermediates for the preparation of known cephalosporin antibiotics.
Claims12
A process for preparing a 3-bromomethylcephem compound of the formula ##STR16## which comprises reacting a compound of the formula ##STR17## with from about 4 to about 8 equivalents of an alkali metal salt of a C.sub.1 -C.sub.7 primary alcohol of the formula R.sub.1 'OH in the presence of about 4 to about 8 equivalents of a positive brominating agent selected from the group consisting of bromine, DBU hydrobromide perbromide, iodine monobromide and tert-butyl hypobromite in an inert organic solvent at a temperature of -80.degree. to about -20.degree. C. wherein in the above formulae
- q is 1 or 0;
- R is a carboxylic acid protecting group;
- R.sub.1 ' is primary C.sub.1 -C.sub.6 alkyl or benzyl;
- and
- R.sub.2 is an amido group of the formula ##STR18## wherein R.sub.3 is a. hydrogen, C.sub.1 -C.sub.3 alkyl, halomethyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl or 4-protected amino-4-protected carboxybutyl;
- b. benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, or 4-methoxybenzyloxy;
- c. the group --R" wherein R" is 1,4-cyclohexadienyl, phenyl or phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halo, protected hydroxy, nitro, cyano, trifluoromethyl, C.sub.1 -C.sub.3 alkyl, and C.sub.1 -C.sub.7 alkoxy;
- d. an arylalkyl group of the formula
- R" --(O).sub.m --CH.sub.2 --
- wherein R" is as defined above, and m is 0 or 1;
- e. a substituted arylalkyl group of the formula ##STR19## wherein R'" is R" as defined above, 2-thienyl or 3-thienyl, and W is protected hydroxy or protected amino;
- or
- f. a heteroarylmethyl group of the formula
- R""--CH.sub.2 --
- wherein R"" is 2-thienyl, 3-thienyl, 2-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl, or 4-isoxazolyl;
- with the limitation that when R'" or R""is 2thienyl, 3-thienyl or 2-furyl the reaction is carried out at a temperature below about -40.degree. C. and a halogen quenching agent is added before the mixture is allowed to warm above about 0.degree. C.
Dependencies are inferred from the claim text.