7- 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). ... 

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. 

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. 

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] -... 

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... 

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. 

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... 

The cycloaddition of DMAD and EP to 7-acylamino-3-azidomethyl-3-cephem-4-carboxylic acid derivatives (88) gave the expected 1,2,3-triazole derivatives 89 and 90.813 A similar addition of MP to the diazo compound 91 gave 92,814 and the nitrone 93 gave 94 with DMAD, a rearrangement having taken place.815... 

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. 

A total 6.5 g (1 1.55 mmol) of7-[D-a-t-butoxycarbonylamino-a-(p-hydroxyphenyl)acetamido]-3-(l,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was dissolved in 175 ml (98 to 100% formic acid under anhydrous conditions. The mixture was stirred at room temperature for 2.5 hours. Part of the solution, 125 ml, was evaporated under reduced pressure to an amber oil. The oil was then azeotroped 3 times with 70 ml of toluene under reduced pressure. The residue was suspended in an 80 20 H20-CH30H solution (700 ml) and stirred for 0.5 hour until most of the solid dissolved, then filtered. The filtration was treated with 1.59 of (Darko) charcoal for about 20 minutes. The charcoal was filtered off through a Celite pad. The solution was then freeze-dried in 9 separate 100 ml round bottom flasks. The freeze-dried material weighed 2.415 g. It was recrystallized in batches of 0.200 g as described above to yield a total of 0.923 g 7-[D-a-amino-a-(p-hydroxyphenyl) acetamidol-3-(l,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. NMR was consistent, indicating the presence of 0.33 mol of CH3OH. 

Synthesis of 7(3-[2-(2-aminothiazol-4-yl)-2-(Z)-(trytiloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid x p-toluenesulfonic acid x 2 N,N-dimethylacetamide (the precursor of Cefdinir) was described in Patent US 6,093,814. 

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

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). 

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