Cefcapene pivoxil

Off-White SolidFlomox was launched in Japan as an orally active cephalosporin for respiratory and urinary tract infections, heptatic infections, ophthalmological and otorhinolarynological infections, skinkoft tissue infections, and for use in gynacology, dentistry and oral surgery. It can be prepared by condesation of 2(Z)-(2-(t-butoxycarbonylamino) thiazol-4-yl)-2-pentenoic acid with 7-amino-3-(carbanoyloxymethyl)- 3-cephem-4-carboxylic acid pivaloyl methyl ester followed by deprotection.

Compound (II) (0.5mmo1) and triethylamine (76μl, 0.55mmo1) were dissolved in 4rnl dichloromethane, methanesulfonyl chloride (40μl, 0.52mmo1) was added, and stirred at -50°C for 4h. A solution of compound (I) (0.6 mmol) and TEA (180 μl, 1.3 mmol) in 4 ml of dichloromethane was added dropwise, and stirred at -50°C for 3 h. After adding dilute hydrochloric acid to acidify, extract with ethyl acetate. The extract was washed with brine and then with dilute sodium bicarbonate solution, dried and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-dichloromethane (1:2). Compound (III) was obtained with a yield of 86%. Compound (III) (885 mg, 1.23 mmol) was dissolved in a mixture of 3.3 ml of anisole and 8.3 ml of dichloromethane. Under ice-cooling, 1.9 ml of trifluoroacetic acid was added, and the mixture was stirred at 0°C for 2 hours. The reaction solution was concentrated, and the residue was impregnated with diethyl ether and petroleum ether to obtain 675 mg of crude product of pale brown compound (IV), which was directly used in the next reaction. Compound (Ⅳ) (3.45g, 6mmo1) and potassium carbonate (1.65g, 7.2mmo1) were suspended in 35ml of dimethylformamide, and pivaloyloxymethyl iodide (POMI) (1.15ml, 6.8) was added at -40°C mmo1), reaction 1.5h. After the reaction solution was mixed with 10% phosphoric acid, it was extracted with ethyl acetate. The extract was washed with brine, then washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with ethyl acetate-benzene (2:1). 2.05 g of colorless crystal compound (V) was obtained with a yield of 51.1%. Compound (V) (2.7 g, 4.04 mmol) was dissolved in 10 ml of dichloromethane, 30 ml of trifluoroacetic acid was added at room temperature, and reacted for 1.5 h. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate and dilute aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried and concentrated. The residue was subjected to silica gel column chromatography, eluting with ethyl acetate-dichloromethane (2:1). 1.83g of cefcarpine was obtained as a pale yellow powder, with a yield of 73%. The light yellow powder above was dissolved in ethyl acetate and mixed with a hydrogen chloride solution dissolved in ethyl acetate to precipitate a crystalline powder. Filtration and washing with ethyl acetate and methanol gave 1.4 g of cefcarpine ester hydrochloride in 53.7% yield [based on compound (V)]. The cephalosporin can start from compound (Ⅲ). Aluminum trichloride (40.2g, 0.3mol) was dissolved in 400ml of anisole, and compound (III) (43.4g, 0.06mol) was added to the solution in 210ml of dichloromethane at -30°C and stirred for 30min. /JDA 430mllmol/L hydrochloric acid, then add 210ml dichloromethane. Separate the water layer, add dilute aqueous sodium bicarbonate solution to Ph value 3.5, that is, a light brown solid precipitates. The solid was collected by filtration, and dissolved in a mixed solution of 24 g of sodium bicarbonate, 530 ml of water, 7.4 ml of acetylacetone, and 350 ml of methylene chloride, and then adjusted to Ph=7.5 with 1 mol/L hydrochloric acid. Separate the water layer and add concentrated hydrochloric acid to Ph=3.5, that is, a colorless solid precipitates. Filtration, washing with water, and drying yielded 28.5g of cefacapir, with a yield of 87.2%.

Antibacterial. Orally absorbed cephalosporin; ester prodrug of the active free acid metabolite, cefcapene