7- -3-cephem-4-carboxylic

Isomerization of 3-cephems (27) to 2-cephems (28) takes place in the presence of organic bases (e.g. pyridine) and is most facile when the carboxyl is esterified. Normally an equilibrium mixture of 3 7 (3-cephem/2-cephem) is reached. Since the 2-cephem isomers are not active as antibacterial agents, the rearrangement proved to be an undesirable side reaction that complicated acylation of the C-7 amine under certain conditions. A method for converting such mixtures to the desired 3-cephem isomer involves oxidation with concomitant rearrangement to the 3-cephem sulfoxide followed by reduction. Additions... 

Application of the Curtius reaction to the 3-carboxyl of a penicillin has provided intermediates which have been used for the construction of cephem derivatives. As can be seen in Scheme 23, this route allows the selective cleavage of the C(3)—N(4) bond of the thiazolidine ring, thereby allowing a reconstruction of that ring in a different form (72HCA388 and the following three papers). The preparation of a related intermediate is shown in Scheme 24 (76HCA2298). 

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). ... 

Chemical Name 7-(D-0 -Phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid Common Name —... 

Preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid To a solution of 750 mg (1 55 mmol) of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride in 20 ml of tetrahydrofuran and 40 ml of methanol was added a suspension of 750 mg of prereduced 5% palladium on carbon catalyst in 20 ml of ethanol and the suspension was hydrogenated under 50 psi of hydrogen at room temperature for 45 minutes. The catalyst was filtered and washed with THF and water. The filtrate and catalyst washes were combined and evaporated to dryness. The residue was dissolved in a water-ethyl acetate mixture and the pH adjusted to pH 3. The insoluble product was filtered and triturated with acetone. The product was then dried to yield 115 mg of 7-amlno-3-chloro-3-cephem-4-carboxylic acid. 

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. 

The mixture was stirred at ice bath temperature for 2 hours, 1 ml of methanol was added and the mixture was filtered to remove insoluble impurities. Two milliliters of water were added to the filtrate and the pH was adjusted momentarily to pH 1.5, to effect removal of theenamine block, and then to pH 4.5 with triethylamine. After stirring for an additional hour at ice bath temperature the reaction product,7-(D-0 -phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid (zwitterion) precipitated from the reaction mixture as a crystalline solid. 

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. 

Chemical Name Sodium 7-(D-2-formyloxy-2-phenylacetamldo)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate... 

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 product was dissolved in 5 of acetone and the solution was mixed with a solution of 430 g (2.59 mols) of sodium 2-ethylhexanoate in 5.4 of acetone. The combined solutions were seeded and stirred in an ice bath for 1.5 hours. The crystalline precipitate of sodium 7-(D-2-formyloxy-2-phenylacetamido)-3-(1 -methyl-1 H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate was filtered and washed with 5 of acetone. The crystalline salt was dried overnight in a vacuum oven at 40°C to yield 1,060 g (80%) of product, melting at 182°C to 184°C. 

A suspension of 37.3 g (0.1 mol) of 7/3-amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride dioxanate in 500 ml methylene chloride is stirred for 15 minutes at room temperature under an argon atmosphere and treated with 57.2 ml (0.23 mol) of bis-(trimethylsilyl)-acetamide. After 45 minutes the faintly yellow slightly turbid solution is cooled to 0°C and treated within 10 minutes with 31.2 g (0.15 mol) of D-Ct-amino-Ct-d, 4-cyclohexadienyl (acetyl chloride hydrochloride. Thirty minutes thereafter 15 ml (about 0.21 mol) of propylene oxide is added and the mixture is further stirred for 1 hour at 0°C. A cooled mixture of 20 ml of absolute methanol in 200 ml of methylene chloride is added within 30 minutes, after another 30 minutes the precipitate is filtered off under exclusion of moisture, washed with methylene chloride and dried under reduced pressure at room temperature. The obtained hygroscopic crystals of the hydrochloride of 7j3-[D-a-(1,4-cyclohexadienyl)acetylamino] -... 

Diphenylmethyl 7j3-amino-7a-methoxy-3-(1 -methyltetrazol-B-yD-thiomethyl-l -oxa-dethia-3-cephem-4-carboxylate Aluminum chloride Sodium-2-ethylhexanoate... 

C1H9NO 156-87-6) see Acamprosate calcium Cyclophosphamide Dexpanthenol Domperidone Gusperimus trihydrochloride Mefenorex Urapidil 7-amino-3-[(Z)-l-propenyl]-3-cephem-4-carboxylic acid (CiqHi2N203S 106447-44-3) see ci s-Cefprozil 3-aminopropionaIdehyde diethyl acetal (C7H,7N02 41365-75-7) see Atorvastatin calcium P-aminopropionic acid phosphite (C3H, N0 P) see Pamidronic acid... 

C2,H2oCl2N20,S 107837-26-3) see t/.t-Cefprozil diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate monohydrochloride (C2,H2oCl2N20,S 79349-53-4) see Cefixime diphenylmethyl 7-amino-7-methoxycephalosporanatc (C24H24N20 S 35565-04-9) see Cefoxitin diphenylmethyl 7(R)-7-amino-7-methoxy-3-(l-methyl-tetrazol-5-ylthiomethyl)-l-oxa-l-dethia-3-cephem-4-carb-oxylate... 

C24H24NSO5S 66510-99-4) see Latamoxef diphenylmethyl 7(/f)-amino-3-(l-methyl-lH-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (C23H22N6O3S2 53090-86-1) see Cefbuperazone diphenylmethyl 7-amino-3-[(Z)-f -propenyl]-3-cephem-4-carboxylate... 

C23H22N2O3S 106447-41-0) see ci.t-Cefprozil diphenylmethyl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride... 

C28H23CIN2O5 68314-04-5) see Flomoxef Latamoxef diphenylmethyl 7-[5-benzamido-S-(diphenylmethoxy-carbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate... 

C24H23N3OHS) see Ceftizoxime 4-nitrobenzyl 7(i )-amino-3-cephcm-4-carboxylate (Ci4H] 3N303S 68780-69- ) see Ceftizoxime 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4>carboxylate hydrochloride... 

J. Nishikawa, K. Tori, 3-Substituent Effect and 3-Methylene Substituent Effect on the Structure-Reactivity Relationship of 7 beta-(Acylamino)-3-cephem-4-carboxylic Acid Derivatives Studied by Carbon-13 and IR Spectroscopies , J. Med. Chem. 1984, 27, 1657-1663. 

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