Method of preparation of 3-methylenecephams
AssigneeEli Lilly and Company
InventorStjepan Kukolja
Life of this patent
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Abstract
Penicillin sulfoxide derived azetidinone sulfinyl chlorides and related sulfinic acid derivatives are cyclized to 3-methylenecephams by reaction with Friedel-Crafts catalysts or metathetic cation forming agents.
Claims35
The process for preparing a 3-methylenecepham sulfoxide of the formula ##STR58## by reacting a compound of the formula ##STR59## with a Lewis acid type Friedel-Crafts catalyst, a Bronsted proton acid type Friedel-Crafts catalyst or a metathetic cation-forming agent in a dry inert organic solvent, or dissolving such compound in a Bronsted acid selected from the group consisting of methanesulfonic acid, trifluoromethanesulfonic acid, trilfuoroacetic acid, trichloroacetic acid, or dichloroacetic acid;
- wherein in the above formulae
- R is a carboxylic acid protecting group;
- R' is R or hydrogen;
- R.sub.1 is (1) an imido group of the formula ##STR60## wherein R.sub.2 is C.sub.2 -C.sub.4 alkenylene, C.sub.2 -C.sub.4 alkylene, 1,2-phenylene, 1,2-cyclohexenylene;
- or
- 2.
an amido group of the formula ##STR61## wherein R.sub.3 is a. hydrogen, C.sub.1 -C.sub.3 alkyl, halomethyl, cyanomethyl or 3-(2-chlorophenyl)-5-methylisoxazol-4-yl;
- b. benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, tert-butoxy, or 4-methoxybenzyloxy;
- c. the group R" wherein R" is 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.4 alkoxy;
- d. an arylalkyl group of the formula
- R.sup.o -- (Q).sub.m --CH.sub.2 --
- wherein R.sup.o is R" as defined above, 2-thienyl, 3-thienyl or 1,4-cyclohexadienyl, m is 0 or 1, and Q is O or S subject to the limitation that when m is 1, R.sup.o is R";
- e. a substituted arylalkyl group of the formula ##STR62## wherein R.sup.o is as defined above and W is protected hydroxy or protected amino;
- 3.
an imido group of the formula ##STR63## wherein R.sup.o and m are as defined hereinabove and R.sub.2 ' is C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.6 haloalkyl, C.sub.1 -C.sub.3 alkoxy or trichloroethoxy;
- or R.sub.1 is
- 4.
Dependencies are inferred from the claim text.