Synthesis and .beta.-lactamase inhibitory properties of 2.beta.-(chloromethyl)-2.alpha.-methylpenam-3.alpha.-carboxylic acid 1,1-dioxide

Gottstein, W. J.; Crast, L. B.; Graham, R.L.; Haynes, U. J.; Mcgregor, D. N.

doi:10.1021/jm00144a034

Cited by 24 publications

(7 citation statements)

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“…The reaction of para-substituted imines 8 with homophthalic anhydride (5) was performed in three different solvents, and the influence of the substituents on the ratios of isomers trans-9 and cis-9 formed was estimated by ' Figure 1. Hammett plots of the data listed in Table II.…”

Section: Resultsmentioning

confidence: 99%

“…good as can be expected given the limitations of NMR integrations, which are only accurate within a few percent, and the values of the Hammett + constants, which are themselves subject to experimental error.10 A separate series of reactions involved competition experiments in which imine 8c was allowed to compete with imines lOa-c for reaction with homophthalic anhydride f, R=CH(CH3)2 (5) according to the general equation 5 + 8 equiv of imine 8c + 8 equiv of imines lOa-c -* products A steric effect of considerable magnitude was realized in the observation that 9c was the exclusive reaction product of all competition experiments involving imine 8c. A further result regarding electronic effects was obtained when it was found that the bulky fert-butylimine 10b reacted preferentially over the less hindered, but also less nucleophilic .…”

Section: Resultsmentioning

confidence: 99%

“…R1=H Discussion Three mechanisms have been considered in an attempt to rationalize the correlation of the stereochemical outcome of the condensation of Schiff bases with homophthalic anhydride (5). The first of these invokes an imino Diels-Alder reaction between the Schiff base 21 and the dienol tautomer 22 of homophthalic anhydride, which has been previously proposed as a reactant in the condensation of homophthalic anhydride and a variety of dienophiles11 (Scheme I).…”

Section: Resultsmentioning

confidence: 99%

“…Since the discovery of the condensation of benzylidenemethylamine (1) with succinic anhydride (2) to form substituted 2-pyrrolidinones 3,1 the reaction has been extended to glutaric2 and homophthalic anhydrides (4,5),…”

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A study and mechanistic interpretation of the electronic and steric effects that determine the stereochemical outcome of the reaction of Schiff bases with homophthalic anhydride and 3-phenylsuccinic anhydride

Cushman¹,

Madaj²

1987

J. Org. Chem.

113

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A study and mechanistic interpretation of the electronic and steric effects that determine the stereochemical outcome of the reaction of Schiff bases with homophthalic anhydride and 3-phenylsuccinic anhydride

Cushman¹,

Madaj²

1987

J. Org. Chem.

113

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“…To prepare benzyl 6,6-dibromo-2-chloromethyl-2-methylpenicillanate, (1) (Gottstein et al, 1981;Zhang et al, 2006), a solution of (4) (6.1 g) in anhydrous dioxane (15 ml) was heated at reflux under nitrogen for 4 h with quinoline (1.8 g) and fresh benzoyl chloride (1.7 g). After the reaction was complete, the solvent was concentrated under reduced pressure and then diluted with excess water.…”

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Benzyl 6,6-dibromo-2β-chloromethyl-2α-methylpenicillanate

et al. 2007

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β‐Lactamase Inhibitors

Stam

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The antibacterial effectiveness of penicillins, cephalosporins, and other β‐lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β‐lactam antibiotics often produce enzymes called β‐lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β‐lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β‐lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β‐lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β‐lactamases to inhibit clinically are the gram‐positive penases, the gram‐negative TEM, which are Richmond‐Sykes type III, and the gram‐negative chromosomal cephalosporinases–cephases which are Richmond‐Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β‐lactamases are serine proteases that form an acyl enzyme intermediate with β‐lactam substrates and β‐lactam‐derived β‐lactamase inhibitors. A number of β‐lactamase‐resistant penicillins and cephalosporins were found to be β‐lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β‐lactamases, including penases and Richmond‐Sykes types II, III, IV, V, VI ( Bacteroides ). Carbapenems are another class of natural product β‐lactamase inhibitors. Many penem β‐lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2( S )‐ cis )‐3,3‐dimethyl‐7‐oxo‐4,4‐dioxide‐4‐thia‐1‐azabicyclo [3.2.0]heptane‐2‐carboxylic acid (sulbactam) ( , ), C 8 H 11 NO 5 S, is a weak antibacterial, but is a potent irreversible inactivator of many β‐lactamases, including penases and Richmond‐Sykes type II, III, IV, V, and VI ( Bacteroides ) β‐lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β‐lactamase inhibitors. Among penam β‐lactamase inhibitors, of 6‐β‐bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β‐lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C 15 H 16 N 2 O 6 S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β‐lactam antibiotic as Betamaze.

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Synthesis and .beta.-lactamase inhibitory properties of 2.beta.-(chloromethyl)-2.alpha.-methylpenam-3.alpha.-carboxylic acid 1,1-dioxide

Cited by 24 publications

References 1 publication

A study and mechanistic interpretation of the electronic and steric effects that determine the stereochemical outcome of the reaction of Schiff bases with homophthalic anhydride and 3-phenylsuccinic anhydride

A study and mechanistic interpretation of the electronic and steric effects that determine the stereochemical outcome of the reaction of Schiff bases with homophthalic anhydride and 3-phenylsuccinic anhydride

Benzyl 6,6-dibromo-2β-chloromethyl-2α-methylpenicillanate

β‐Lactamase Inhibitors

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