Penam carboxylic acid

THF-Et O to give the potassium salt 163 of penam carboxylic acid (Scheme 30) (87NKK1447). Hydrogenolysis of the benzyloxycarbonyl group of 160b gave penam carboxylic acid 164 in 82% yield (87NKK1447). 

In order to obtain a sulbactam-like compound, d/-160b was oxidized with m-chloroperbenzoic acid (MCPBA) (2 mol equiv) to give d/-165, which was subjected to the usual hydrogenolysis method giving penam carboxylic acid 1,1-dioxide (d/-166) in excellent overall yield (87NKK1447) (Scheme 31). 

Penam Sulfone B-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of p-lactamase inhibitors based on the readily accessible penicillin nucleus. An early success was penicillanic acid sulfone, (2(5)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-a2abicyclo [3.2.0]heptane-2-carboxylic acid [68373-14-8] (sulbactam) (25, R = = H, R" = R" = CH ), CgH NO S. The synthesis (118), microbiology (119—121),... 

Penam p-Lactamase Inhibitors. Penam is the trivial name of 4-thia-l-azabicyclo[3.2.0]heptane. The report that 6-/3-bromopenicillanic acid, [2(5)-(2or. 5 . 6/8)]-6-bromo-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo [3.2.0]lieptane-2-carboxylic acid, (R = Br, R1 = H. R = R1 = CHi) is a potent inhibitor led to intense study both of this compound and analogues. The microbiology profile of 6-/3-bromopenicillanic acid has been reported and the compound has progressed to clinical trials. Mechanistic studies have demonstrated that the dihydrothiazine derivative is responsible for inactivation of /3-lactamases. 

The synthesis of tazobactam from 6-APA (Scheme 6.15) proceeded via the 2- -(chloromethyl)penam ester (81 a), which was first prepared by Gottstein and co-workers [47] during the synthesis of 2-/S-(chloromethyl)-2-a-methylpenam-3a-carboxylic acid 1,1-dioxide (29). 6-APA (8) was converted to 6a-bromopenicillanic acid (77) by treatment with sodium nitrite and hydrobromic acid. Oxidation with peracetic acid in the presence of benzophenone hydrazone gave benzhydryl 6a-bromopenicillanate-l-oxide (78) and reduction with zinc and acetic acid gave benzhydryl penicillanate-1-oxide (79). The unsymmetrical azetidinone disulphide (80) was obtained by heating with 2-mercaptobenzothiazole reaction with copper (II) chloride... 

Direct transformation [21] of p-lactams into the corresponding imino-p-lac-tams 19 has been effected with N-chlorosulphonylisocyanate (CSI) (Scheme 6). The reaction probably involves a [2 + 2] cycloaddition-cycloreversion sequence. The same experimental conditions applied to penam or cephem derivatives gave ring-enlarged products only [22]. Silylation of trichloroethyl 6p-phenoxyacetamido-penicillinate followed by reaction with CSI and reduction with metabisulphite yielded the bicyclic pyrimidine-2,4-dione 20a (1 1 mixture of epimers). The carboxylic acid 20b is devoid of antibiotic activity (Scheme 7). 

The thermal equilibration between penam sulfoxides and azetidinone-4-sulfenic acids 109 opens the way to a number of methodologies for obtaining azetidinone 4-thioesters. The oldest one, discovered in 1970 by Hatfield et al. [86], simply involves heating of the penam sulfoxide with a carboxylic anhydride and trimethyl phosphite thioesters 137 are obtained through a mechanism representable by the formation and collapse of penta-coordinate phosphorous intermediate 135. 

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