Ceftizoxime

Ceftizoxime is a bacterial inhibitor which acts by interfering with bacterial cell wall synthesis and inhibiting cross-linking of the peptidoglycan.

A semisynthetic cephalosporin antibiotic which can be administered intravenously or by suppository. The drug is highly resistant to a broad spectrum of beta-lactamases and is active against a wide range of both aerobic and anaerobic gram-positive and gram-negative organisms. It has few side effects and is reported to be safe and effective in aged patients and in patients with hematologic disorders.

Method 1: To a solution of dimethylformamide (4.0g, 54.8mmo1) and 200ml tetrahydrofuran, add phosphorus oxychloride (8.4g, 54.8mmo1) dropwise at -5～5℃ and stirring, and stir for 10min, Get Vilsmeier reagent. Under ice-cooling, add (2-formamido-4-thiazolyl) glyoxylic acid (5.35 g, 26.7 mmol) and stir for 30 min to form an active acid solution. Add compound (I) (9.0g, 24.3mmo1) and 20ml O, N-bis(trimethylsilyl)acetamide (BSA) in 100ml ethyl acetate solution at -15℃, at 15～0℃ Stir for 30min. 50ml of water was added, the resulting precipitate was collected by filtration, washed with water, and dried on phosphorus pentoxide to obtain 7.12g of compound (II) with a yield of 57.0%. The organic layer in the filtrate was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain another 1.03 g of compound (II) with a yield of 8.2%. Compound (II) (3.0g, 5.82mmol) and 1.5g of 10% palladium-carbon catalyst were suspended in a mixture of 70ml methanol, 30ml tetrahydrofuran and 10ml acetic acid, and hydrogenated at room temperature and atmospheric pressure for 4h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in aqueous sodium bicarbonate solution, washed with ethyl acetate, and adjusted to Ph=2.0 with 10% hydrochloric acid. The resulting precipitate is collected by filtration, washed with water, and dried in the presence of phosphorus pentoxide. 1.57 g of compound (111) was obtained with a yield of 71.0%. Compound (III) (2.44g, 6.41mm01) was dissolved in 20rnl methanol, 5ml concentrated hydrochloric acid was added at room temperature and stirred for 5h. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in aqueous sodium bicarbonate solution, washed with ethyl acetate, and adjusted to Ph=3.5 with 10% hydrochloric acid. The resulting precipitate is collected by filtration, washed with water, and dried in the presence of phosphorus pentoxide. 0.49 g of compound (1V) was obtained with a yield of 21.796. The filtrate and washing liquid were combined, and chromatographed with HP-20 resin column, eluting with 15% isopropanol aqueous solution. The eluate was concentrated under reduced pressure, and the residue was lyophilized to obtain 1.56 g of compound (IV) with a yield of 69.0%. Compound (IV) (1.78g, 4.58mmol), methanolamine hydrochloride (1.37g, 16.4mmol) and sodium acetate (0.38g, 4.58mmol) were suspended in 100ml of water and adjusted to Ph=7.0 with aqueous sodium bicarbonate. Stir at 48°C for 1 hour, and use sodium bicarbonate to dissolve in water to maintain the pH value of the reaction solution from 7.0 to 7.3. After the reaction solution was washed once with ethyl acetate, it was adjusted to Ph=3.5 with 10% hydrochloric acid under cooling in an ice bath. The precipitate is collected by filtration, washed with water, and dried in the presence of phosphorus pentoxide. 0.12 g of ceftizoxime was obtained, and the yield was 6.8%. The filtrate was chromatographed with HP-20 resin column and eluted with 40% acetone aqueous solution. The eluate was evaporated under reduced pressure to remove acetone and then lyophilized to obtain 0.95 g of ceftizoxime, with a yield of 54.0%. Method 2: Suspend 2g of 2-methoxyimino-2-(2-amino-1, 3-thiazol-4-yl)acetic acid (V) in 20ml of anhydrous ethyl acetate solution at 5～10℃ Adding 2.0 g of phosphorus oxychloride at one time, stirring at 7-10°C for 20 min, adding 0.4 g of bis(trimethylsilyl)acetamide. After stirring for 10 min at 7-10°C, 2.0 g of phosphorus oxychloride was added dropwise. After stirring for another 10 min at 7-10°C, 0.8 g of dry dimethylformamide was added dropwise. After stirring for 30 min at 7-10°C, a clear solution was obtained, which was the acid chloride compound (VI). In addition, 2.45 g of 7-aminocephalosporanic acid was suspended in 8 ml of dry ethyl acetate solution, and 7.35 g of trimethylsilylacetamide was added. After the addition, stir at 40°C to obtain a clear solution. At -15°C, add the above-prepared acid chloride (VI) solution to the clear solution, and continue stirring for 1 hour at a temperature of 10 to -15°C. After cooling to -30°C, add 80ml of water. The aqueous layer was separated and adjusted to a Ph value of 4.5 with sodium bicarbonate. Column chromatography was performed on Diaion HP-20 resin (Mitsuishi Chemical Industries Ltd.), using 25% isopropanol aqueous solution as the eluent. The effluent was concentrated under reduced pressure and lyophilized to obtain 1.8 g of ceftizoxime with a melting point of 227°C (decomposition).

Mainly used to treat respiratory system, urinary system, bone and joint infections

Molecular Weight:383.4
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:5
Exact Mass:383.03581088
Monoisotopic Mass:383.03581088
Topological Polar Surface Area:201
Heavy Atom Count:25
Complexity:669
Undefined Atom Stereocenter Count:2
Undefined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes