(2-Amino-4-thiazolyl) amino] -2-carboxy-8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl]
English Synonyms: caz; Ceptaz; Fortum; gr20263; hy; innersalt, (6-alpha, 7- beta- (z))) - droxid; 4-thiazolyl (1-carboxy-1-methylethoxy) imino) acety; sn401
CAS number: 72558-82-8
Molecular formula: C22H22N6O7S2
Molecular weight: 546.58
EINECS No. 276-715-9
Related Categories: Chiral Reagents; Heterocycles; Intermediates & Fine Chemicals; Pharmaceuticals; Sulfur & Selenium Compounds; β-Lactam Antibiotics; Antibiotics; Drugs; Other Reagents; RELPAX; Pharmaceutical Intermediates; Antibiotics; Pharmaceutical Raw Materials; Inhibitors; pharmaceutical raw materials
Mol File: 72558-82-8.mol
Ceftazidime
Ceftazidime nature
Merck 14,1946
Stability Stable, but keep refrigerated. Incompatible with strong oxidizing agents, nitric acid, permanganates, peroxides.
Ceftazidime use and synthesis method
Chemical properties colorless crystal or white powder.
Pentahydrate: C22H22N6O7S2 5H2O. [78439-06-2]. Crystalline solid. UV maximum absorption (Ph = 6): 257 nm (E1 cm1% 348).
Use The third generation of broad-spectrum cephalosporins, a variety of β-lactamase stability, against Gram-positive bacteria and negative bacteria and anaerobic strains have a strong bactericidal effect on Pseudomonas aeruginosa has high efficiency, is the only One can replace the aminoglycosides cephalosporins, which was called the fourth generation cephalosporins. Clinically for the general-sensitive infections caused by sensitive bacteria (such as sepsis, meningitis, bacteremia, etc.), respiratory infections (such as pneumonia, bronchitis, etc.), ENT infections, skin and soft tissue infections, urinary tract infections, stomach Intestinal, gall and abdominal infections, bone and joint infections.
Use semi-synthetic broad-spectrum cephalosporins, mainly for respiratory infections caused by sensitive bacteria, urinary system, soft tissue infections
Production Method Method 1: 572 mg of (Z) -2- (2-tert-butoxycarbonylpropan-2-yloxyimino) -2- (2-tritylaminothiazol-4-yl) -acetyloxymethyl-7-aminocephellen-3-em-4-carboxylate was dissolved in 10 ml of dimethylformamide, cooled to 0 ° C, 150 mg of 1-hydroxybenzotriazole and 225 mg DCC (dicyclohexylcarbodiimide). Heat to room temperature and allow to stir overnight at room temperature for 5h. Filter, white cake washed with a small amount of ether. The washings were combined with the filtrate, diluted with 50 ml of water and extracted with ethyl acetate. The extract was continuously washed with water, 2 mol / L hydrochloric acid, water, sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was subjected to column chromatography (silica gel-diethyl ether). A solution of 3-acetoxymethyl-7 - [(Z) -2- (2-tert- butoxycarbonylpropan-2-oxyimino) -2- (2-tritylaminothiazole-4- Acetamido] ceph-3-em-4-carboxylate, and concentrated to give 533 mg of product. Some products can be recrystallized with diisopropyl ether, the melting point of 103 ~ 113 ° C (decomposition), [α] D20 + 8.5 ° (C = 1.0, dimethyl sulfoxide).
2.4 g of the product obtained above was dissolved in 18 ml of anisole, 18 ml of trifluoroacetic acid were added at 0 ° C, then stirred at room temperature for 2 h and concentrated. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The pH of the extract was adjusted to 6, then ethyl acetate was added and the aqueous layer was acidified to pH 1.5 and saturated with sodium chloride and then extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried and concentrated. The residue is dissolved in 20 ml of hot 50% aqueous formic acid and left for 2 h. Dilute with 50 ml water and filter. The filtrate was concentrated, the residue redissolved in 50 ml of water and filtered. The crude product was freed from the cold to give 920 mg of 3-acetyloxymethyl-7 - [(Z) -2- (2aminothiazol-4-yl) -2- ] Ceph-3-em-4-carboxylic acid, [α] D 20 + 20.0 ° (c = 1.0, dimethyl sulfoxide).
1.8 g of the product obtained above, together with 2 ml of pyridine, is added with stirring at 80 ° C to a solution of 7.12 g of sodium iodide in 2.2 ml of water. The reaction at 80 ℃ 1h, cooled, with. 100ml water dilution. The pH of the reaction was adjusted to 6.0 with 2 mol / L sodium hydroxide and concentrated to remove pyridine. The remaining aqueous solution was diluted with 100 ml of water and two drops of methyl isobutyl ketone were added, followed by 2 mol / k. Hydrochloric acid is acidified to pH = 1. Filter, filter cake washed with 1L. The filtrate and washings were combined, washed with ethyl acetate and then adjusted to pH = 6.0 with 2 mol / L sodium hydroxide. After concentrating to 50 ml, column chromatography was performed using 500 g of Amberlite: XAD-2 resin, and then a 20% ethanol aqueous solution was used as a developing solution. The effluent containing ceftazidime was collected, concentrated, and frozen under reduced pressure to give 0.56 g of product. Method 2: The side chain (I) is reacted with phosphorus pentachloride to form the corresponding acid chloride (II). Without isolation, the acylation of 7-aminocephalosporanic acid tert- . Followed by treatment with a mixture of formic acid and hydrochloric acid to remove all three protecting groups to give cephem compound (V). In the presence of sodium iodide, the acetoxy group is reacted with pyridine to give an amorphous solid ceftazidime.
Method 3: It is best to use cefotaxime as a starting material, because ceftazidime already has 3-pyridyl methyl. After silylation with trimethylsilyl chloride and then phosphorus pentachloride followed by reaction at low temperature, a lower alcohol or diol is added to give an amorphous solid which is then treated with a suitable solvent such as hydrochloric acid in acetonitrile or isopropanol To give pure crystalline compound (VI). Followed by reaction with the compound (II) in dichloromethane. After the reaction solution is washed with water and the methylene chloride is distilled off, dimethylformamide is added to obtain a pure compound (VII) containing 2.5 molecules of dimethylformamide. The basic No impurities. To a solution of the compound (VII) in dimethylformamide, a mixed solution of formic acid and hydrochloric acid is added to the mixture to remove the precipitate by filtration, followed by addition of acetone or methanol to obtain a very pure compound (VIII). The compound (VIII) is dissolved in water, the pH is adjusted to the isoelectric point, and the precipitated ceftazidime pentahydrate crystallizes with high yield and the product is pure and stable.
The side chain compound (I) used can be synthesized by the following method.