3-Chloromethyl cephalosporin

The 3-chloromethyl cephalosporin 41 has been used for the preparation of nitrocefin 42 via Finkelstein and Wittig reactions <05JOC367>. The bicyclic P-lactam 43, a simple C3 homologue of sulbactam, has been prepared and evaluated as an improved inhibitor of class C P-lactamases <05JOC4510>. 

Another application of the electrolytic ene-type chlorination is a straightforward synthesis on-chloromethyl-dc/f -cephems 10 from azetidinone 8 derived from natural penicillins, 0). 3-Chloromethyl-substituted cephalosporin antibiotics. They have been prepared by displacement of the acetoxyl group of 3-acetoxymethylcephalosporins with a chlorine atom n). The conversion of 8 to 10 comprises the electrolytic ene-type chlorination 12) of 8 and the ring closure of 9 with base (Scheme 2-3). Apparently, the arenesulfonyl... 

Methylation of halothiophenes 166 and 168 was accomplished via the Stille reaction with tetramethyltin to give methylated thieno[3,2-/)]pyran 167 [112] and thienyldeoxyuridine 169 [113], respectively. Analogously, the coupling of an allyl chloride, chloromethyl-cephem 170 and 2-tri-n-butylstaimylthiophene furnished 171, an intermediate for a C(3) thiophene analog of cephalosporin [114],... 

The majority of the semisynthetic cephalosporins are not effective when administered orally. The main exceptions are cephalexin and cephradine, and recently reported compounds such as cefaclor, cefadroxyl and cefatrizine. In view of the fact that oral activity is observed primarily in derivatives of a-amino aryl acetic acids, we designed our synthetic course on the basis of modification of the aryl part of a readily available a-amino acid, in such a way that initial functionalization of the aromatic ring would provide a "handle , which could in turn be easily converted into a variety of functional groups. The second in5)ortant criterion was the necessary optical activity of the amino acids. In order to avoid the resolution of each individual compound thus obtained, it was deemed important to start with an optically active amino acid whose modification would proceed without racemization. These two requirements were fulfilled upon chloromethylation of D-a-amino-4-hydroxyphenyl acetic acid 1. ... 

Cleavage of the 1,2-bond has also been achieved by chlorination or bromin-ation of penicillin sulphoxides. The resulting sulphinyl bromide (103 y) or chloride (104 t) cyclizes readily to the A -cephalosporin sulphoxide (2 X = H). The reaction of (103 t) with diazomethane, however, gives a mixture of three novel cepham sulphoxides (105 t), (106 t), and (107 t) as well as the chloromethyl sulphoxide (109 t). These products are believed to result from a diazo-sul-phoxide (108 t), which undergoes a rapid intramolecular cyclization, via either the sulphoxocarbene (110) or the pyrazoline (111). Cephalosporins (112) and (113), derived from these sulphoxides, exhibited weak antibacterial activity. 

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