Carumonam

ChEBI: An N-sulfonated monobactam antibiotic.

Method 1: The racemic compound (I) (50.2g, 171mmol) and bis(p-toluoyl)-D-tartaric acid (34.5g, 86.lmmol) were dissolved in 128ml of hot acetonitrile. Filter, and place the filtrate overnight at room temperature. The precipitated crystals were collected by filtration, washed with cold acetonitrile, and recrystallized with acetonitrile to obtain the optically active compound (3S, 4S -I) and the salt of tartaric acid (1:1), which were colorless crystals, 40.6g, yield 70%, melting point 166～169℃, [α] D26+70.1°(C=0.9, methanol). The salt (17.8g, 26.2mmol) was suspended in a mixture of 100ml of water and 200ml of tetrahydrofuran, and while stirring in an ice bath, sodium bicarbonate (6.6g, 78.6mmo1) and benzyl chloroformate (5.4g) were added. , 3l.6mmo1). Stir under ice cooling for 1 h, and then at room temperature for 1 h. After the reaction solution was concentrated under reduced pressure, it was diluted with 200 ml of water and 400 ml of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 200 ml of ethyl acetate. The extract and the organic layer were combined, washed successively with 5% sodium bicarbonate aqueous solution, brine, 1mol/L hydrochloric acid and brine, and dried. After evaporation to dryness, the solid residue was washed with ether and recrystallized with ethyl acetate-hexane (1:1). The compound (II) was obtained as colorless crystals, the yield was 47%, the melting point was 120-121°C, and [α]D23+24.7°(C=1, chloroform). Compound (II) (12.0g, 30rnmol) was dissolved in 500ml of tetrahydrofuran, and under cooling and stirring in an ice bath, a solution of sodium borohydride (2.65g, 70mmol) in 250ml of water was added. After the addition, stir at room temperature for 5h. The tetrahydrofuran was evaporated under reduced pressure, and the concentrated solution was diluted with water. The resulting precipitate was collected by filtration, washed with water, and recrystallized with ethyl acetate. Compound (III) was obtained with a yield of 76%, a melting point of 137-138°C, and [α]D23+40.1. (C=1, methanol). Compound (III) (400 mg, 1 mmol) was dissolved in 8 ml of dichloromethane, and under ice cooling and stirring, chlorosulfonyl isocyanate (0.09 ml, 1 mmol) was added and stirred for 30 min. Then add 0.09ml of chlorosulfonyl isocyanate and stir for another 10min. Add a solution of 280 mg of sodium sulfite in 6 ml of water, and stir at room temperature for 1 h. Dilute with dichloromethane, separate the organic layer, wash with brine and dry. It was concentrated under reduced pressure, the residue was impregnated with ether, and the crystals were collected by filtration. The compound (IV) is obtained and used directly in the next reaction. Add compound (IV) (1.0mmo1), potassium peroxodisulfate (1.4～4.0mmo1) and potassium monohydrogen phosphate (1.3～2.0mmo1) into a mixture of acetonitrile and water (2:1, 30m1), in an oil bath (80～95℃) Heat and stir for 1～3h. Acetonitrile was evaporated under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The extract was washed successively with aqueous sodium bicarbonate solution and brine, and dried. Concentrate under reduced pressure, and purify the residue by column chromatography or recrystallization. The compound (V) was obtained as colorless needle crystals, the yield was 74%, the melting point was 19l～192°C, [α]D23+60.6°(C=1, methanol). Compound (V) (293 mg, 1 mmol) was dissolved in 10 ml of dioxane, and sulfur trioxide-pyridine complex (477 mg, 3 mmol) was added with stirring, and stirred at room temperature for 14 hours. The solvent was evaporated, 20ml water and 20ml [Dowex 50W (Na+ type) were added, and the mixture was stirred at room temperature for 1 h. The resin was removed by filtration, and the filtrate was concentrated under reduced pressure. The concentrated solution was chromatographed with 20ml Amberlite XAD-2 and eluted with an aqueous ethanol solution (1%-10%) with a slowly changing ratio. After the eluate was lyophilized, 270 mg of compound (VI) was obtained as a colorless powder, with a yield of 64%, [α]D23+29.4° (C=0.7, water). Compound (VI) (422 mg, 1 mmol) and 422 mg of 10% palladium-carbon catalyst were suspended in 10 ml of water and 10 ml of tetrahydrofuran, and hydrogenated under normal pressure at room temperature for 1 h. The catalyst was filtered off, the filtrate was cooled in an ice bath, and sodium bicarbonate (202 mg, 2.4 mmol) and 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-(4-nitro) were added with stirring. Benzyloxycarbonylmethoxyimino)acetyl chloride hydrochloride (614mg, 1.2mmol), stirred for 30min. Adjust the Ph value to 5 with 1mol/L hydrochloric acid. Concentrate under reduced pressure to about 30ml, then add 10ml of tetrahydrofuran to dilute, then add 194mg of sodium N-methyldithiocarbamate, and stir at room temperature for 1h. Then add 194 mg of sodium N-methyldithiocarbamate, and stir for another 1 h at room temperature. The tetrahydrofuran was evaporated, and the remaining solution was washed with ether and concentrated under reduced pressure. 200m1 for the remainder. Amberlite XAD-2 chromatography, eluted with ethanol aqueous solution (0-20%) with a gradually changing ratio. The eluate was lyophilized to obtain 500 mg of compound (VII) as a pale yellow powder, with a yield of 76%, [α]D26+10.1° (C=1, water). Compound (VII) (500mg, 0.75mmol), sodium bicarbonate (71.4mg) and 10% palladium-carbon catalyst (300mg) were suspended in a mixture of 20ml water and 21ml tetrahydrofuran, and hydrogenated under normal pressure at room temperature for 1.5h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure, and then treated with 3mol/L hydrochloric acid (0.83ml). Then it was chromatographed with 140ml Amberlite XAD-2, and eluted with an aqueous ethanol solution (0-5%) with a gradually changing ratio. After the eluate was lyophilized, a colorless powder was obtained. The powder was suspended in 4.5 ml of water and left overnight at 5°C. The crystals were collected by filtration and washed with cold water to obtain 280 mg of colorless crystals of carummonam with a yield of 75%, [α]D264-46.3° (C=1, dimethyl sulfoxide). Method 2: Take the following compounds as raw materials and obtain them through the following reactions.

Monocyclic β-lactam antibiotics. The antibacterial spectrum is similar to that of ammonia, and it has a high bacteriostatic activity against Gram-negative bacteria. The effect of anti-Pseudomonas aeruginosa is slightly worse than ammonia and ceftazidime but better than other antibiotics, and it is highly effective against pneumoniae. It is also effective against bacteria resistant to gentamicin and third and fourth generation cephalosporins. It is very stable to the lactamase produced by various bacteria, and is stable to the chromosome or plasmid-mediated β-lactamase. Used for sepsis caused by sensitive bacteria, chronic respiratory infection, cholangitis, peritonitis, chronic bronchitis, cystitis, etc.