Synthesis of sulfazecin-type 2-azetidinones with a carbon substituent at the 4-position.

Sir: As reported in our previous paper,1) chemical modification of sulfazecin2) at the 3-position significantly enhanced its antibacterial activity; however, further improvement was desired especially in regard to the stability to some p-lactamases. We focused our attention on modifying the unexplored 4-position, and cis-1-(2,4dimethoxybenzyl)4methoxycarbonyl3 -phthalimido-2-azetidinone (1a) was selected as a starting material, since the methoxycarbonyl group can be convertible into various kinds of other 4substituents.3) Compound 1a, first synthesized by GLEASON et al.,3) was obtained in 72 % yield as colorless needles, mp 172~175'C, by a slightly modified cycloaddition reaction in which the amount of triethylamme was increased to 1.2 molar equivalents. Epimerization4) of la with 1,8-diazabicyclo[5.4.0]-7-undecene in benzene gave the trans isomer (1b), and both 1a and 1b were converted into 3-acylamino-l-sulfo derivatives (6a,b) (Chart 1). Since the antibacterial activity of the 3,4-cis compound (6a) was higher than that of the trans isomer (6b), and 6a was very active against Escherichia coli T-7, a producer of TEM-1 p-lactamase, we decided to explore further modification of the cis series. Treatment of 4a with 25~28 % ammonia water or 40 % aqueous methylamine in tetrahydrofuran (THF) gave 4-carbamoyland 4-methylcarbamoyl-2-azetidinones (7a,b) respectively. Hydrolysis of 4a with K2CO3 afforded the 4-carboxy compound (7c), which was then converted into 4-dimethylcarbamoyl and 4-methoxycarbamoyl derivatives (7d,e). Reduction5) of 3a and 4a with sodium borohydride in THE water gave alcohols (8a,b), from which various 3-amino-4substituted 2-azetidinones (9) were prepared by the conventional methods. For example, compound 9a was obtained by treating 8a with chlorosulfonyl isocyanate followed by deprotection (Chart 2). Among the 3-acylamino-l-sulfo derivatives derived from these intermediates in a procedure similar to that of Chart 1, 4-carbamoyl and 4-carbamoyloxymethyl compounds (11 and 12) were found to be highly active against Gramnegative bacteria including Pseudomonas aeruginosa and some p-lactamase producing strains. Since ceftazidime has unique antibacterial