The Research On The Synthesis Of Chiral Zwitterion Of The Carumonam

In 1981 the first N-sulfonated monocyclic beta-lactam antibiotic, sulfazecin, was discovered by Takeda Chemical Industries. The chemical modification of this molecule led to carumonam(Ro 17-2301, AMA-1080) (fig1), a potent antibacterial compound which shows high resistance to hydrolysis by both chromosomal and plasmid-mediated beta-lactamases.Carumonam is the second monobactam after aztreonam. It was first introduced into Japan in 1988 as a compound active against gram-negative bactaeria with similar activity with aztreonam. So far, it has not been produced in China and has good commercial value.Sodium(3 S,4S)-3-amino-4-[(carbamoyloxy)methyl]-2-ox-Oazetidine-1 -sulfonate is its key intermediate, a chiral zwitterion. It was synthesized by 14 steps reaction, using calcium L-threonate as a convenient and inexpensive chiral starting material and its many steps were investigated and improved. The reaction of calcium L-threonate with hydrogen bromide in acetic acid readily yields (2S, 3S)-2, 4 -dibromo-3 -hydroxy butanoic acid which was further converted into methyl (2s, 3S)-2,4-dibromo-3-hydroxybutanoate by treatment of methanol. Methyl (2S,3S)-4-Acetoxy-2,3-epoxybutanoate was prepared from it by treatment of potassium acetate in dimethylfonnamide. Thus, regiospecific opening of the epoxide, derived from Methyl (2S,3S)-4-Acetoxy-2,3-epoxybutanoate with ammonia,followed by protection of the amino group as the (benzyloxy)carbonyl derivatives, gave 6. The primary alcohol hydroxy group was selectively protected by reaction with chloroacetyl chloride in N,N-dimethylacetamide. Subsequent mesylation with methanesulfonyl chloride and triethylamine in dimethoxyethane gave 9 which was further converted to 10 by sulfonation with 2-picoline · SO3 complex and treatment with tetrabutylannonium hydrogen sulfate. Stereospecific beta-lactam formation proceed at reflux in a two-phase system consisting of 1.2-dichloroethane and aqueous potassium bicarbonate with concomitant hydrolysis of the chloroacetyl protecting group giving rise to 12. Introduction of the urethane function in 26 was then achieved by reaction with dichlorophosphoryl isocyanate, chloroacetyl isocyanate or chlorosulfonyl isocyanate. The dichlorophosphoryl group, chloroacetyl group or the chlorosulfonyl group could be removed with sodium bicarbonate, sodium N-methyldithiocarbamate or sodium sulfite, respectively. The synthesis of the chiral zwitterion was completely by catalytic hydrogenation to remove the carbobenzoxy group from 14.