Total synthesis of 7-oxo-4-thia-1-azabicyclo-[3,2,0]-heptane-2-carboxyl derivatives useful as β-lactamase inhibitors and antibacterial agents

Claim 1

A process for the preparation of compounds of formula I: ##STR32## wherein R is hydrogen, lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, or a --CH(CH 3 ) OCOOEt group; R 1 is --CH 2 OH, --CHO, --CH 3 SH, --CH 2 NH 2 , --CH 2 OCOR 2 , --COOR 2 , --CH 2 NHCOR 2 , or --CH 2 OR 3 , where R 2 is a lower alkyl, and R 3 is a lower alkyl, benzyl, or trityl, which comprises reacting a 4-acetoxy azitidinone of formula II: ##STR33## dissolved in a solvent selected from the group consisting of acetone, tetrahydrofuran, dimethylformamide, water, and mixtures thereof, at room temperature and in the presence of a base selected from the group consisting of NaHCO 3 , KOH, K 2 CO 3 , and Et 3 N, with a β-thioketoester of formula: ##STR34## where R 1 has the meanings given above, to obtain a mixture of diastereoisomeric products of formula III; ##STR35## where R 1 is as above defined, which mixture is successively condensed, dissolved in anhydrous acetone and in the presence of a base selected from the group consisting of pyridine and triethylamine, at room temperature, with a glyoxylic ester of formula: ##STR36## where R has the meanings given above, to give a mixture of diastereoisomeric substituted carbinols of formula IV: ##STR37## where R and R 1 are as above defined, reacting that mixture with thionyl chloride, at a temperature ranging from -78° C. to 0° C. and in the presence of pyridine, to afford the corresponding chlorides of formula V: ##STR38## which are transformed by means of triphenylphosphine and a base selected from the group consisting of pyridine and 2,6-lutidine, at a temperature of 25°-50° C., into their respective phosphorous ylids of formula VI: ##STR39## ozonolysing the compounds of formula VI in the presence of trifluoroacetic acid, to obtain the corresponding phosphoranes of formula VII: ##STR40## and successively heating the so-obtained phosphoranes of formula VII at a temperature ranging from 30° to 140° C., in an inert solvent selected from the group consisting of benzene, toluene, and xylene, to obtain the desired compounds of formula I.