Cefixime

Cefixime is an antibiotic and a third generation cephalosporin antibiotic, useful for the treatment of a number of bacterial infections.

Method 1: Use 7-ACA as raw material. 7-ACA (18.7g, 67mmol) was suspended in a mixed solution of 120ml of water and 120ml of methanol, and a solution of sodium hydroxide (5.5g, 142mmo1) dissolved in 18ml of water was added dropwise at -20℃, at -10～-20℃ Stir for 25 min and neutralize with concentrated hydrochloric acid to Ph: 7.5. Salicylaldehyde (10.7 g, 87.6 mmol) was added at 15°C, and then stirred for 1 h. A solution of diphenyldiazomethane (15.7g, 80.9mmo1) in 85ml ethyl acetate was added, and stirring was continued for 1h. During the reaction, the pH value of the reaction solution was maintained at 4.0 to 4.5 with 1 mol/L hydrochloric acid. The reaction solution was extracted with 550 ml of ethyl acetate, and the extract was washed with brine and concentrated under reduced pressure. The remainder was impregnated with petroleum ether to obtain 29.6 g of compound (I) with a yield of 78.1% and a melting point of 97-98.5°C (decomposition). Compound (I) (1.01g, 2mmo1) was dissolved in 10ml of dichloromethane, and phosphorus pentachloride (0.46g, 2.2mmo1) and pyridine (0.176g, 2.2mmo1) were added at -30 to -30 Stir at ℃ for 1h. The reaction solution was poured into ice water, and the organic layer was separated, washed with brine, dried, and concentrated under reduced pressure. 0.9 g of compound (II) was obtained with a yield of 85.7% and a melting point of 180.5-182.0°C. Compound (II) (4.0 g, 7.6 mmol) was dissolved in 10 ml of dimethylformamide, and triphenylphosphine (2.2 g, 8.4 mmol) was added under cooling and stirring. After the addition, stir at room temperature for 2h. The reaction solution was poured into 250 ml of isopropyl alcohol, and the precipitate (6.7 g) was collected by filtration. The precipitate was dissolved in 10 ml of dichloromethane and 5 ml of water, and 17.4 ml of 36% aqueous formaldehyde was added. Adjust to Ph=9.0 with 10% aqueous sodium carbonate solution. After stirring at room temperature for 1 h, it was extracted with 20 ml of dichloromethane. The extract was washed with brine, dried, and concentrated under reduced pressure. 3.0 g of compound (III) was obtained with a yield of 78.9% and a melting point of 180.5-182°C (decomposition). Compound (III) (18.96g, 38.2 mmol) was dissolved in a mixture of 135ml of ethyl acetate and 34ml of ethanol, 5.7ml of concentrated hydrochloric acid was added at room temperature, and stirred for 1.5h. The precipitate was collected by filtration, washed with ethyl acetate and dried. 11.32 g of compound (IV) was obtained with a yield of 69% and a melting point of 172-173°C (decomposition). Under stirring at -5 to 0°C, to dimethylformamide (3.66g, 50.1mmo1) and 80ml of tetrahydrofuran, phosphorus oxychloride (7.7g, 50.1mmo1) was added dropwise and stirred for 30min to obtain Vismeier reagent. Under cooling in an ice bath, compound (V) (13.8 g, 41.8 mmo1) was added and stirred for another 1 h to obtain an active solution of compound (V). At -20°C, the solution was added to a solution of compound (IV) (15 g, 34.9 mmol) and N-(trimethylsilyl)acetamide (MSA) (32 g, 244mol) in 150 ml of ethyl acetate. Continue stirring for 30 min. Ethyl acetate and water were added, and the organic layer was separated, washed with 5% sodium bicarbonate solution and brine, and dried. It was concentrated under reduced pressure, and the residue was impregnated with isopropanol to obtain 23.1 g of compound (VI). The yield of compound (VI) was 97.5% (19.0 g, 28.0 mmol) was dissolved in 380 ml of methanol, and concentrated hydrochloric acid (11.6 g, 112mmo1), stirring for 1h. Neutralize with 5% aqueous sodium bicarbonate and concentrate under reduced pressure. After the residue was dissolved in ethyl acetate, it was washed with brine and dried. After concentration under reduced pressure, the residue was impregnated with isopropanol to obtain 15.3 g of compound (VII) with a yield of 84.1%. Compound (VII) (15.0 g, 23 mmol) was dissolved in 15 ml of anisole. Under ice bath cooling, 60 ml of trifluoroacetic acid was added. After the addition is complete, stir at room temperature for 80 min. With stirring, the reaction was added dropwise to 600 ml of isopropanol. The resulting precipitate was collected by filtration, dissolved in 5% aqueous sodium bicarbonate solution, and washed with ethyl acetate. The aqueous solution was adjusted to Ph=6.0 with 5% hydrochloric acid, column chromatography with a macroporous non-ionic absorption resin (Diaion HP-20), and elution with water. Under cooling, the effluent was acidified to Ph=2.3 with 10% hydrochloric acid. The precipitate was collected by filtration and dried to obtain 3.55 g of cefixime with a yield of 34.1%. Method 2: Use deacetylated cephalosporin C as raw material. Deacetylcephalosporin C sodium salt (118.6g, 0.3mo1) was dissolved in 1.0L water and 0.6L acetone, and benzoyl chloride (42.1g, 0.3mo1) was added at 10-15°C. During the addition process, use 20 The% sodium carbonate solution keeps the Ph value of the reaction solution at 6.5-7.5. After the addition is complete, stir at 10-15°C for 1 h. Acetone was distilled off under reduced pressure, and the remaining aqueous solution was washed with ethyl acetate. 300ml of ethyl acetate was added to the aqueous solution, and a solution of diazodiphenylmethane (135.8g, 0.75mol) in 1.0L of ethyl acetate was added. After adjusting to Ph=3.5 with concentrated hydrochloric acid, stir at room temperature for 1.5h. After adjusting the reaction solution to Ph=2.5 with concentrated hydrochloric acid, the organic layer was separated, washed with brine, dried, and concentrated under reduced pressure. The residue was dissolved in 400 ml of acetone, and 4.0 L of isopropyl ether was added. The precipitate was collected to obtain 224.8 g of compound (VIII) with a yield of 92.5%. Compound (VIII) (100g, 0.123mol) was dissolved in 600ml of dichloromethane, phosphorus pentachloride (25.6g, 0.123mol) was added at -30°C, and pyridine (9.8g, 0.123mol) was added. After stirring at -20 to 10°C for 1 h, the reaction solution was poured into a mixed solution of 500 ml of dichloromethane and 300 ml of water. The methylene chloride layer was separated, washed with brine, dried, and concentrated under reduced pressure. The residue was impregnated with isopropyl ether to obtain 114.5 g of powdered compound (IX) with a yield of 98%. Compound (IX) (102g, 0.123mol) was dissolved in 300ml of dimethylformamide, sodium iodide (18.4g, 0.123mol) was added at 35°C, and stirred for 30min. Add triphenylphosphine (48.5g, 0.185mol) and stir at 35-38°C for 1h. After concentration under reduced pressure to 2/3 volume remaining, it was added dropwise to 5.0 L of isopropanol. The precipitate was collected by filtration, washed with isopropyl ether and dried. After concentration under reduced pressure, the remaining solid about 123.5g was dissolved in 1.0L of dichloromethane, 300ml of 36% formaldehyde was added at 25°C, stirred for 2h, and the Ph value was maintained at 9.0 with 20% sodium carbonate. After the reaction was completed, it was adjusted to Ph=5.0 with 10% hydrochloric acid. The organic layer was separated, washed with brine, and evaporated under reduced pressure. The residue was impregnated with ethyl acetate to obtain 63.5 g of powdered compound (X) in a yield of 75.8%. To a solution of phosphorus pentachloride (15.5g, 74.4mmo1) in 200ml of dichloromethane at 5°C, pyridine (5.9g, 74.4mmo1) was added and stirred for 20min. Compound (X) was added at 5°C, stirred for 2 h, cooled to -40°C, and 120 ml of methanol, which was also cooled to -40°C, was added at once. The reaction solution slowly rose to 20°C within 1 h. The reaction solution was concentrated under reduced pressure, and the residue was impregnated with 300 ml of ethyl acetate and 50 ml of water. The precipitate was collected by filtration, washed twice with 50 ml of isopropyl alcohol and then with 50 ml of isopropyl ether. 8.4 g of crystalline compound (IV) was obtained with a yield of 79.0%. Compound (IV) is then reacted in the same way as Method 1 to obtain cefixime.

Orally active, third generation cephalosporin antibiotic

Molecular Weight:453.5
XLogP3:-0.7
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:12
Rotatable Bond Count:8
Exact Mass:453.04129018
Monoisotopic Mass:453.04129018
Topological Polar Surface Area:238
Heavy Atom Count:30
Complexity:861
Undefined Atom Stereocenter Count:2
Undefined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes