Process for the synthesis of penems and carbapenems
AssigneeSchering Corporation
InventorsAdriano Afonso, Frank Hon
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Abstract
Described is a novel process for the preparation of penems and carbapenems useful as antibacterial agents which comprises the reaction of an appropriate 4-substituted-azetidine-2-one with an acid halide in the presence of a tertiary amine and an alkaline earth metal carbonate, followed by reaction of the thereby formed 1-imido-4-substituted-azetidine-2-one with a trialkyl phosphite. Also described are novel penems useful as antibacterials which are prepared by the described process.
Claims16
The process for the preparation of a compound of Formula I:
- ##STR15## wherein R.sub.1 is hydrogen, lower alkyl, acylamino or ##STR16## wherein R.sub.4 is hydrogen, lower alkyl, aryl, heteroaryl and R.sub.5 is an O-protecting group:
- R.sub.2 is lower alkyl, aryl, alkylaryl, an N-protected amino-lower alkyl, an O-protected hydroxyalkyl, thioalkyl, thioaryl, thioheteroaryl, an .alpha.-(N-protected) amino acid ester or an alkylcarboxylic acid ester;
- R.sub.3 is nitrile, tetrazole, or --COOR.sub.6 wherein R.sub.6 is lower alkyl, lower alkylthihalogenomethykl, aryl, allyl, or a metabolisable ester:
- X and Z are independently sulfur, oxygen, -NR.sub.7 wherein R.sub.7 is acyl, alkyl, aryl, or an N-protecting group;
- or --(CH.sub.2).sub.n --wherein n is 1 or 2;
- which comprises the reaction of an azetidinone of Formula A:
- ##STR17## wherein R.sub.1, R.sub.2, X and Z are as hereinabove defined, with an acid halide of Formula B:
- ##STR18## wherein in R.sub.3 is as hereinabove defined, in an inert solvent in the presence of a tertiary amine and an alkaline earth metal carbonate;
- followed by reaction of the thereby produced imido derivative of Formula C:
- ##STR19## wherein in R.sub.1, R.sub.2, R.sub.3, X and Z are as hereinabove defined:
- with a trialkyl phosphite, said reaction being carried out at temperatures in the range of from about 20.degree. to about 80.degree. C.
The process for the preparation of a compound represented by formula I:
- ##STR22## wherein R.sub.1 is hydrogen, lower alkyl, acylamino or ##STR23## wherein R.sub.4 is hydrogen, lower alkyl, aryl or heteroaryl and R.sub.5 is an O-protecting group:
- R.sub.2 is lower alkyl, aryl, alkylaryl, an N-protected amino-lower alkyl, an O-protected hydroxyalkyl, thioalkyl, thioaryl, thioheteroaryl, an .alpha.-(N-protected) amino acid ester or an alkylcarboxylic acid esters
- R.sub.3 is nitrile, tetrazole, or --COOR.sub.6 wherein R.sub.6 is lower alkyl, lower alkyltrihalogenomethyl, aryl, allyl, or a metabolisable ester;
- X and Z are independently sulfur, oxygen, --NR.sub.7 --wherein R.sub.7 is acyl, alkyl, aryl, or an N-protecting group;
- or 13 (CH.sub.2).sub.n --wherein n is 1 or 2;
- which comprises the reaction of an imido derivative of formual C:
- ##STR24## wherein R.sub.1, R.sub.2, R.sub.3, X and Z are as hereinabove defined;
- with a trialkyl phosphite, said reaction being carried out at temperatures in the range of from about 20.degree. C. to about 80.degree. C.
The process of claim 10 wherein the compound represented by Formula C is prepared by the reaction of an azetidinone represented by Formula A:
- ##STR25## wherein R.sub.1, R.sub.2, X and Z are as defined in claim 13, with an acid halide represented by Formula B:
- ##STR26## wherein R.sub.3 is as defined in claim 13;
- in an inert solvent in the presence of a tertiary amine and alkaline earth metal carbonate.
Dependencies are inferred from the claim text.