Of penicillin derivatives

Solvolysis in MeOH/H20 at 21°. This method was developed for a series of penicillin derivatives where conventional cleavage methods resulted in partial /3-lactam cleavage. ... 

These processes have operated successfully for 25 years and now result in over 10x10 sales of penicillin derivatives world-wide. In many cases penicillin acylases have been developed in-house by the user companies such as SmithKline Beecham. 

The earliest reports of constrained Ugi adducts derived from bi-functional precursors appeared in the 1960s with the preparation of penicillin derivatives such as 68, involving sequential Asinger and Ugi four-component reactions (Scheme 11.13). As such, the synthesis represents the shortest preparation of a known penicillin derivative [65], The /Mactam ring is formed after isocyanide addition to the cyclic Schiff base, followed by carboxylate nitrilium ion trapping and acyl transfer to give the final penicillin core. In this example, the amine and carboxylic acid inputs may be considered tethered. 

A1C13, anisole, CH2C12, CH3N02, 0° - 25°, 5 h, 80-95% yield.10 These conditions were used to cleave the benzyl ester in a variety of penicillin derivatives. 

Serendipity occurs all the time in science. People like Fleming must be applauded. The famous discovery of penicillin by Fleming in 1928 is a well-known story. Fie noticed the effect of a mould killing bacteria. The derivatives of penicillin must be some of the greatest discoveries ever made in medical science. We now know that there are a series of penicillin derivatives based upon the structure shown in Figure 14.5. 

Since the first X-ray structure determination of benzylpenicillin potassium 42 (a penam) in 1949, the structures of a large number of -lactam antibiotics have been reported . Table 2 shows the limiting values of the -lactam ring dimensions in a range of penicillin derivatives . More recent X-ray studies on the penicillin and cephalosporin families of antibiotics have been summarized. 

Chemoselective oxidation of the ring sulfur of penicillin derivatives 100 and 101 has been reported in the presence of cobalt(lll) acetylacetonate and either isobutyraldehyde or propionaldehyde under oxygen to afford the corresponding sulfoxides 102 and 103 in excellent yields as shown in Scheme 35. Overoxidation was not observed and additional functional groups were not affected under these conditions <1996T2343>. 

Smith and Mardrall isolated and characterized polymeric materials formed in aqueous solutions of a number of penicillin derivatives The degree of polimerization ranged... 

Ushakov and Panarin synthesized polymeric salts of vinyl amine and vinyl alcohol copolymers and amides and hydrazides of penicillin derivatives. The coupled water-soluble, stable polymeric penicillin derivatives were found to have the same activity as the parent drugs. 

Penicillins and Probenecid. A number of organic acids are actively transported from the blood into the tubular urine and vice versa. In some situations, these agents interfere with each other s excretion. Probenecid (e.g., Benemid) can increase the serum concentrations and increase and prolong the activity of penicillin derivatives by blocking their tubular secretion. This is an interaction that has been used to therapeutic advantage in the treatment of certain infections. 

Eight-membered N,0,S-containing ring systems 680 have become accessible via Rh2(OAc)4-catalyzed decomposition of diazomalonic or diazo-acetoacetic esters in the presence of penicillin derivatives 681. The reaction is mediated by sulfonium ylide 682 and proceeds stereoselectively but in moderate yields. The stereochemical migration control in the ylide occurs... 

The transformation of penicillin-derived diazo ketones 696 into compounds 697a and b with the nitrogen atom in the ring fusion position on treatment by Cu(acac)2 proceeds via a sulfonium ylide with subsequent rearrangement (77T547 80TL2451 82H1647). 

Methoxylation of penicillin derivatives. Oxidation of the anhydropenicillin (I) with f-butyl hypochlorite in methanol containing sodium perborate (1, 1102) as buffer gives the 6-methoxy derivative (2) in nearly quantitative yield.5 The thiazolidine sulfur atom can be protected either as the sulfone or sulfoxide. 

The halogen-magnesium exchange of a-halo carbonyl compounds has been reported to afford magnesium enolates which react with aldehydes to yield aldol products [107, 108]. The application of this reaction to the synthesis of penicillin derivatives has been reported (Scheme 3.94) [109-111]. 

Morin and co-workers have noted rough correspondence between the frequencies of the P-lactam carbonyl absorption and the biological activities of a series of penicillin derivatives. 

The infrared spectra of penicillin analogues have been discussed. The infrared spectrum of ampicillin trihydrate was measured on a Perkin-Elmer Model 21 double-beam spectro-photometer S. Ttie infrared absorption of penicillin derivatives has been recorded and discussed. Figure 1 and Figure 2 are the spectra of the Squibb Primary Reference Substances of ampicillin trihydrate and anhydrous ampicillin recorded as mineral oil mull and potassium bromide pellets with a Perkin-Elmer Model 21 spectrophotometer. Interpretation of the spectrum of ampicillin trihydrate has been re-ported °and is given in Table 1. 

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