7- 3-methyl-3-cephem-4-carboxylic acid

Cefazaflur (58) stands out among this group of analogues because it lacks an arylamide C-7 side chain (see cephacetri 1 e for another example).Cefazaflur (58) is synthesized by reaction of 3-(1-methyl-lB[-tetrazol-5-ylthiomethylene)-7-amino-cephem-4-carboxylic acid (56) with trifluoromethylthioacetyl chloride (57). ... 

Preparation of 7-(D-0t-phenyigiycyiamido)-3-chioro-3-cephem-4-carboxyiic acid To a suspension of 280 mg (1.2 mmol) of 7-amino-3-chloro-3-cephem-4-carboxylic acid in 14 ml of acetonitrile was added with stirring at room temperature 0.5 ml of N, 0-bis-(trimethylsilyl)acetamide to form the soluble disilylmethyl derivative thereof. The solution was cooled to 0°C and was slowly added to a solution of the mixed anhydride formed by reacting 408 mg (1.5 mmol) of methyl-3-a-carboxybenzylaminocrotonate sodium salt with 161 mg (1.7 mmol) of methyl chloroformate in the presence to 2 drops of N, N-dimethylbenzyl amine in 7 ml of acetonitrile. 

Amino-3-methyl-3-cephem-4-carboxylic acid Manufacturing Process... 

On the other hand, 1 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methanol, and 1.4 g of triethylamine was added thereto to be dissolved, and 0,4 ml of acetic acid was further added thereto. This solution was cooled to -20°C and the mixed acid anhydride prepared previously was added thereto. After the mixture was reacted at -20°C for 1 hour, the temperature of the reaction mixture was raised to 0°C over a period of 1 hour, and the mixture was reacted for 3 hours at the same temperature. 

Amino-3-(1 -methyl-1 H-tetrazol-5-yI-thiomethyI)-3-cephem-4-carboxylic acid... 

To 13 of ethyl acetate were added 85.1 g (2.59 mols) of 7-emino-3-(1 -methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1,361 g (10.37 mols) of monotrimethylsilyl acetamide, and the mixture was stirred at 50°C until a clear solution was obtained. The solution was cooled to 20°C and 514 g (2.59 mols) of 0-formyl mandeloyl chloride was added at a rate such that the temperature of the reaction solution was maintained between about 20°C to 25°C with ice-cooling. 

The polarographic reductions of cephaloridine, cephalothin, and cephalosporin C each yield one wave that is both pH and concentration dependent [126]. The reduction of these compounds and a related derivative, 3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-7-[2-(3-sydnone)acetamido]-3-cephem-4-carboxylic acid-sodium salt [I], have been described [127]. The reduction of I yields two waves. The first is believed to be the two-electron reductive elimination of the... 

After the reaction, 1 ml of water was added to the reaction mixture, and the mixture was adjusted to a pH of 1.0 with concentrated hydrochloric acid while being cooled, and then stirred for 30 minutes, The insoluble matters were filtered off, and the filtrate was adjusted to a pH of 5.5 with triethylamine. This solution was concentrated under reduced pressure, and the residue was diluted with 20 ml of acetone to precipitate white crystals. The crystals were collected by filtration and washed with ethanol to obtain 1.46 g of white crystals of 7-[D(-)-a-amino-(4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid having a decomposition point of 197°C. 

The reaction mixture was stirred for 1.5 hours at about room temperature after the addition of the mandeloyl chloride was completed. Five liters of water were then added to the reaction mixture and the diluted mixture was stirred for about 10 minutes. The organic layer was separated and was washed twice with water. The combined washes are extracted with 1.5 I of ethyl acetate and the extract is combined with the washed organic layer. The whole was dried over magnesium sulfate, filtered and evaporated in vacuo on a 25°C water bath to yield 1,460 g of product, 7-(D-2-formyloxy-2-phenylacetamido)-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, as a yellow foam. 

Amino-3-[(Z)-2-(methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid Triethylamine... 

Chemical Name 7-[D-(-)-a-(4-Ethyl-2,3-dioxo-l-piperazinecarboxamido)-a-(4-hydroxyphenyl)acetamido]-3-[( 1-methyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid... 

D-(-)-a-Amino-p-hydroxyphenylacetamido]-3-[5-(l-methyl-l,2,3,4-tetrazolyl)-thiomethyl]-8(3)-cephem-4-carboxylic acid 4-Ethyl-2,3-dioxo-l-piperazinocarbonyl chloride... 

To a suspension of 3.0 g of 7-[D-(-)-a-amino-p-hydroxyphenylacetamido]-3-[5-(l-methyl-l,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-l-piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone... 

To a solution of 7p(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyl-tetrazol-5-yl)thiomethyll-oxadethia-3-cephem-4-carboxylic acid (359 mg) in methanol (7 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mols/liter 1.73 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate, and dried to give disodium salt of 7P(a-p-hydroxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(l-methyl-tetrazol-5-yl)thiomethyll-oxadethia-3-cephem-4-carboxylic acid (342 mg). Yield 888%. Colorless powder. MP decomposition from 170°C. 

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. 

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. 

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

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