Cephem 2-thia

To a suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (11.25 g), 2-(aminothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid S-mercaptobenzothiazole ester (23.88 g) in ethylacetate (266 ml) and water (9 ml) at 2°C is added triethylamine. After completion of the reaction, water is added and pH is adjusted to 2.1 with diluted sulfuric acid. The phases are separated and the aqueous phase is extracted with ethylacetate. The organic extracts are combined and concentrated to a volume of 120 ml, then acetonitrile (100 ml) and formic acid (22 ml) are added. The mixture is stirred at 30-35°C for 1 hour. The mixture is cooled to 2°C, the precipitate is filtered, washed with acetonitrile and dried to obtain 20.86 g of 5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2-amino-4-thiazolyl)(carboxymethoxy)imino)acetylamino)-3-ethenyl-8-oxo-, (6R,7R)-(Cefixime). 

Fig. 1 Chemical structure of 7-aminocephalosporanic acid [3-(acetyloxy-methyl)-7-amino-8-oxo-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid or briefly 7-ACA] and cephem ring system.

ChemicalAbstracts indexes cephalosporins as 5-thia-l-azabicydo[4.2.0]oct-2-enes. Using this system then, cephalosporin C [61 -24-5]> C1(5H21N3OgS, (2) is 3-[(acetyloxy)methyl]-7- [(5-amino-5-carboxy-l-oxopentyl)amino]-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid Such names are too cumbersome for general use. One simplification defines the ring system of the cephalosporins as cepham (3) (1). Hence cephalosporins become 3-acetoxymethyl-7-acylamino-3-cephem-4-carboxylic acids. In this widely used nomenclature system, the numbering, as shown in structure (3), differs from that used by Chemical Abstracts shown in structure (2). In both systems, however, the important C-7, C-6, and C-3 positions remain unchanged. The cephem numbering system (3) is used herein. 

Cephalosporin C 1 was first synthesized by Woodward s group at Harvard in 1966 and, the chiral pool starting material for this synthesis was L-(-i-)-cysteine. The approach is noted below in abbreviated form to the A cephem nucleus 5 via the key 4-thia-2,6-diazabicyclo[3.2.0]heptane nucleus, 6, Scheme 11.1. Nucleus 5 contains the same stereochemistry at C-6 and C-7 as natural cephalosporin C. 

Cefminox. [6R-[6a,7thio]methyl]S-oxo-S-thia-I-azabicyc (o-[4.2.0]oct-2-ene-2-carboxytic add 7,5-t2-1 -amino -2-ea rb-oxyethy]thioacetamido)-7 -methoxy-3-[[(l -methyl-12f-tetrazol 5-yl)thio]methyl]-3-cephem -4 -carboxylic acid. C)6HnN707S3 mol wt 519.57. C 36.99%, H 4.07%, N 18.87%, O 21.56%, S 18.51 %. Semisynthetic broad spectrum cephamycin antibiotic. Prepn Belg. pat. 880,686, K. 

Cefroxadiite. 7-[(Amino-l,4 cyciohexadien-l-yl-acetyl)amino]-3 methoxy 8-oxo-5-thia-l,azabicyclo[4.2.0]-oct-2-ene 2-carboxylic acid 7-[d-2-ami no-2-(1,4-cyclohex-adienyl)acetamidej -3 -methoxy -3 -cephem -4-carboxylic acid CGP-9000 Oraspor. Cl(iH1(NjOsS mol wt 365,41, C 52.59%. H 5.24%, N 11.50%, O 21.89%, S 8.77%. Orally active cephalosporin deriv. Prepn R. Scartazzini, H. 

Cephaloglycin. 3-[(Acetyloxy>methyl]-7-[carboxylic acid 7-(2-amino-2-phenylacetamido)-3-[Pg.304]

In an attempted ring-enlargement reaction, surprisingly, anhydropenicillin G (16) was obtained instead of 3-cephems [149]. In this reaction participation of a 1-thia-2-azaoctam derivative (214) was proposed, but this compound was not... 

Yields of the reaction (224)- (225) are almost quantitative, and further steps lead to 3-cephems in a high overall yield. 5-Thia-7-azaoct-6-em derivatives (228) also give 3-cephems upon treatment with HgO/I [176]. 

Fluorophenylureido)-3-(2-methyl-1,3,4>thia-diazol 5-ylthiomethyl)-3-cephem-4 arboxylicacid A B 0.29... 

Several new methods for cephem ring construction have appeared and suitably substituted thioazetidinones figure prominently among the various schemes. In an extension of some earlier work Foglio and co-workers have shown that the adduct (166) obtained from dimethyl azodicarboxylate and an azetidinone thiol may be cyclized upon treatment with base. Alternatively the ring system may be set up by selective reduction of readily available 6/f-l,3-thiazines, affording a synthesis of 3-acetyl-7,7-dimethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]2-octene... 

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