6- Bromopenicillanic acid

Bromopenicillanic acid (24) was originally obtained as a mixture with its inactive 6a-bromo epimer (36), either by aqueous equilibration of the latter at pH 9.1 and 30°C for 3 to 4 days, or by selective reduction of... 

The selectivity in addition reactions of cyclobutyl radicals to alkenes has been investigated in reactions of /1-lactam derivatives31-33. 6-Bromopenicillanic acid esters were used as precursors in reductive addition reactions with alkenes31,32 or with allylstannanes30,31. Addition to the intermediate penicillanic acid-6-yl radical occurred exclusively from the a-face of the /1-lactam ring. 

Tabic 1. Allylation of 6-Bromopenicillanic Acid Derivatives with Tributyl(2-propenyl)stannane... 

Penicillanic acid sulphone (Tig. 5.6D) protects ampicillin flom hydrolysis by staphylococcal Alactamase and some, but not all, of the Mactamases produced by Gram-negative bacteria, but is less potent than clavulanic acid. /3-bromopenicillanic acid (Tig. 5.6E) inhibits some types of Alactamases. 

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 discovery in 1978 that 6-y5-bromopenicillanic acid is a potent inhibitor of bacterial yS-lactamases [41] prompted a thorough investigation of the chemistry and biology of 6-y8-halopenicillanic acids and their derivatives. 

Table 6.8. SYNERGISTIC EFFECT OF 6- 8-BROMOPENICILLANIC ACID (24) AND 6-)8-IODOPENICILLANlC ACID (25) IN COMBINATION WITH AMPICILLIN...

Both 6-yS-bromopenicillanic acid (24) and 6-y5-iodopenicillanic acid (25) were as potent as clavulanic acid and inhibited the same range of /S-lactamase enzymes Table 6.7) [18, 43, 66], They acted synergistically with ampicillin and cefazolin to inhibit yS-lactamase containing S. aureus, those members of the Enterobacteriaceae which contain plasmid yS-lactamases such as the TEM enzyme, and a Klebsiella spp. which contains a chromosomal yS-lactamase. They did not however inhibit most of the yff-lactamases of organisms such as Enterobacter spp. Providencia spp., P. aeruginosa, or Serratia spp. Table 6.8) [66]. 

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... 

Aminopenicillanic acid (8) was converted to 6(5)-bromopenicillanic acid by trapping of the diazo-intermediate with hydrogen bromide. Esterification of the dicyclohexylamine salt (93) with p-methoxybenzyl bromide, followed by oxidation, afforded the sulphoxide (94) in 60% yield from 6-APA. Elaboration of this sulphoxide to the disulphide (96) was effected by the procedure established by Kamiya et al. [98] the sulphenic acid (95), formed by heating the sulphoxide to reflux in toluene, was intercepted by reaction with 2-mercaptobenzothiazole to yield the disulphide (96). The latter was transformed by base-catalysed double bond isomerization to the conjugated ester disulphide (97) [95% yield from (94)]. Reductive formylation of disulphide (97) then provided the formylthio-derivative (98). Cyclization of the oxalimide (99), obtained by ozonolysis of... 

Fig. 10.6 A, Nocardicin A B, 3-aminomonobactamic acid (3-AMA) C, aztreonam D, penicillanicacid sulphone (sodium salt) E, 3-bromopenicillanic acid (sodium salt) F, tazobactam G, sulbactam.

Chemists from the Sankyo Co. reported the use of 6-bromopenicillanate 28, easily obtained from 6-aminopenicillanic acid, in a multistep synthesis of (3RAR)-4-acetoxy-3- (R)- -((/-hutyldimethylsilyl)oxy)ethyl]-2-azctidinonc (31)97, a pivotal intermediate for the synthesis of 1-/9-methyl carbapenem antibiotics (equation 23)98. After cleavage of the thiazolidine ring of 28 with trimethyloxonium tetralluoroborate, the intermediate 29 was subjected to a Reformatsky condensation with acetaldehyde, catalysed by diethyla-luminium chloride. The 8-(S) stereocentre in 30, formed in 50% d.e., was inverted under Mitsunobo conditions to approach the target molecule 31. 

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