Sultamicillin

Sultamicillin is an orally active double prodrug of Ampicillin/Sulbactan. Sulbactam is a semisynthetic beta-lactamase inhibitor which, in combination with Ampicillin, extends the antibacterial activity of the latter to include some beta-lactamase-producing strains of bacteria that would otherwise be resistant[1].

Sultamicillin is a penicillanic acid ester. It derives from an ampicillin and a sulbactam.|Sultamicillin has been used in trials studying the prevention and treatment of Ventilator Associated Pneumonia and Chronic Obstructive Pulmonary Disease (COPD).|Sultamicillin is a combination formulation of the sodium salts of the antibiotic ampicillin and the beta-lactamase inhibitor sulbactam with antibacterial activity. Ampicillin, a broad-spectrum, semisynthetic penicillin, binds to and inactivates penicillin-binding proteins (PBP) located on the inner membrane of the bacterial cell wall, thereby interfering with the cross-linking of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. As a result, the cell wall is weakened and the cell lyses. The sulbactam component irreversibly binds to bacterial beta-lactamase at or near its active site, thereby interfering with substrate binding and inhibiting bacterial metabolism of penicillin and cephalosporin beta-lactam antibiotics, effectively extending their antibiotic spectrum to include many beta-lactam-resistant bacteria.

Starting from penicillanoic acid. Potassium penicillanoate (I) (23.8g, 0.1mol), potassium bicarbonate (30g, 0.3mol) and tetrabutylammonium hydrogen sulfate (3.4g, 0.01mol) dissolved in 200ml of dichloromethane-water (1: In the mixed solution of 1), add dropwise a solution of chloromethyl chlorosulfonate (11.5ml, 0.115mol) in 40ml dichloromethane, and control the dropping rate to keep the reaction below 30°C. After the addition, stir at room temperature for 30 min. The organic layer was separated, and the aqueous layer was extracted with 50 ml of dichloromethane. The extract and the organic layer were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remainder is dissolved in 150ml of ether, with the help of filter aid, filtered to remove insolubles. The filtrate was concentrated under reduced pressure to obtain 22.5 g of compound (II) as a colorless oil with a yield of 90%. Compound (II) (20g, 0.08mol) was dissolved. 100ml isopropanol, add 20ml 30% hydrogen peroxide under stirring, and then add 5ml 0.5mol/L sodium tungstate aqueous solution. After a few minutes, the temperature of the reaction solution rose to about 60°C and then slowly decreased. Leave at room temperature overnight. Cool to 0-5°C, filter the precipitated crystalline precipitate, wash with isopropanol (2×20m1), and dry to obtain 172 g of compound (Ⅲ), the yield is 76.3%, and the melting point is 96-97°C. After the filtrate was concentrated under reduced pressure, the residue was chromatographed on a silica gel column to obtain 2.0 g of compound (III) with a yield of 8.9% and a melting point of 95-96°C. In addition, starting from penicillanoic acid 1, 1-dioxide. Dissolve penicillanic acid 1, 1-dioxide (46.6g, 0.2mol), sodium bicarbonate (63.8g, 0.76mol) and tetrabutylammonium hydrogen sulfate (6.8g, 0.02mol) in 400ml of dichloromethane -In the water (1:1) mixture, add dropwise chloromethyl chlorosulfonate (23ml, 0.23mol) in a solution of 50ml dichloromethane, and control the dropping rate to keep the reaction temperature below 30°C. After the addition, stir another 30 mino at room temperature to separate the organic layer, dry with anhydrous magnesium sulfate, concentrate to about 80 ml, and then add 300 ml of isopropanol to dilute. Scrape to produce crystals, and evaporate methylene chloride under reduced pressure. Place in the refrigerator overnight. The crystals were collected by filtration, washed with isopropanol (6×20ml), and then washed with ether (2×25ml), and dried to obtain 43.1g of compound (Ⅲ), the yield was 76.5%, and the melting point was 95-97°C. Potassium carbonate (76.0g, 0.55mol) was suspended in 625ml of dimethylformamide solution, and methyl acetoacetate (108ml, 1.0mol) and ampicillin trihydrate (201.5g, 0.5mol) were added, and stirred at room temperature. 2h, then stir at 0～5℃ for 4h. Add 2.5L diethyl ether, stir for another 5min, and then place it at 0～5℃ for 30min to let the solvent settle. The residue thus obtained was settled twice with 1L ether according to the above operation, and finally dissolved in 1.25L acetone. The insoluble matter was removed by filtration, and the filtrate was diluted with 1.25 L of isopropanol and inoculated. Dilute with 2L isopropanol, then concentrate under reduced pressure to about 2L. To produce colorless crystals. Placed overnight at 0-5°C, filtered and collected the crystals, washed with isopropanol (2×150m1), then washed with ether (2×250m1), and dried to obtain 219.1g of compound (IV) with a yield of 90.0%. Compound (HI) (56.4g, 0.2mol) and sodium iodide (45g, 0.3mol) were dissolved in 150ml of acetone, and stirred at room temperature for 18h. The resulting suspension is cooled to 0-5°C, and the Ph value is adjusted from 3.0 to 7.2 with saturated carbon such as sodium hydrogen while stirring. Drop 0.5mol/L sodium thiosulfate solution to decolorize, and then stir, drop 150ml of water to precipitate colorless crystals. The crystals were collected by filtration, washed successively with acetone-water (1:1) (2×20ml), ether (2×20ml), and dried to obtain 62.8g of compound (V), the yield was 84.2%, and the melting point was 100-102°C. Compound (IV) (276.8g, 0.57mol) was dissolved in 1L of dimethylformamide, and compound (V) (186.6g, 0.5mol) was added with stirring at 5°C, and stirred at 5-10°C for 15min. Under stirring, the reaction solution was poured into a mixture of 4L ethyl acetate and 2L saturated aqueous calcium chloride solution cooled with ice. Separate the organic layer, wash with saturated calcium chloride (2×500ml), and filter. The filtrate was concentrated under reduced pressure to about 1L. The solution contains compound (VI), without separation, add 500ml water and 500ml n-butanol. Under stirring, 4mol/L hydrochloric acid was added dropwise to Ph=2.5 to remove the protective group of the amino group in compound (VI). Under stirring, add 1L ether and 500ral water. Separate the water layer, and extract the organic layer with 800 ral water. The extract and the aqueous layer were combined, washed with 1L of ether, and then added 640g of sodium chloride and 2L of dichloromethane, and stirred for 15min. The organic layer was separated, and the aqueous layer was extracted with 1 L of dichloromethane. The extract and the organic layer were combined and dried with anhydrous magnesium sulfate. Concentrate under reduced pressure to about 600ml, add 200ml 2-butanone, and place in the refrigerator overnight. Filter and collect the resulting crystals: wash with 2-butanone (2×100ml), then with ether (2×200ml), and dry to obtain 250.2g of sultamicillin hydrochloride, yield 79.2%, melting point 150～170℃ (decomposition) .

Anti-infectives.

Molecular Weight:594.7
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:9
Exact Mass:594.14542089
Monoisotopic Mass:594.14542089
Topological Polar Surface Area:216
Heavy Atom Count:40
Complexity:1240
Defined Atom Stereocenter Count:6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes