Flomoxef

Flomoxef is a oxacephem group antibiotic, with excellent activity against various Gram-positive bacteria[1][2].

Flomoxef is a second-generation oxacephem antibiotic in which the oxazine ring is substituted at C-3 with a hydroxyethyl-substituted tetrazolylthiomethyl group and the azetidinone ring carries 7alpha-methoxy and 7beta-{2-[(difluoromethyl)thiomethyl]acetamido} substituents. It has a role as an antibacterial drug. It is a N-acyl-amino acid, an oxacephem and an organonitrogen heterocyclic antibiotic.|Flomoxef has been used in trials studying the treatment of Urinary Tract Infection.|Flomoxef is a cephamycin antibiotic with a difluoromethylthio-acetamido group at the 7-beta position of the cephem nucleus, commonly used for postoperative prophylaxis. Flomoxef has activity against epidermides, streptococci, propionibacteria, and both methicillin-resistant and -susceptible Staphylococcus aureus.

Add 109.6 ml of ethyl mercaptoacetate to the sodium ethoxide solution prepared from 25.3 g of sodium and 700 rnl of absolute ethanol. Quickly pass Freon 22 at room temperature for bubbling. When the temperature rises to 60°C, slowly pass Speed, and continue to pass at 40 ℃ for 2h. The reaction solution was neutralized with concentrated hydrochloric acid (9 ml), and ethanol was distilled off under reduced pressure. To the residue, add 1000 ml of ethyl acetate, 50 ml of 1 mol/L sodium hydroxide and ice water. The separated aqueous layer was extracted with 500 ml of ethyl acetate. The extract and organic layer were combined, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and vacuum distillation yielded 119.8 g of compound (I) with a yield of 70.5% and a boiling point of 46-48.5°C (400 Pa). 381.4g of compound (I) and 491ml of 25% potassium hydroxide aqueous solution were stirred vigorously under ice bath cooling for 2h, and a homogeneous solution was slowly formed. The reaction solution was mixed with 300 ml of ethyl acetate and 100 ml of saturated aqueous sodium chloride solution. The organic layer was separated and washed with 100 ml of water, and the aqueous layer was extracted with 300 ml of ethyl acetate. All aqueous layers were combined, mixed with 1.6 L of ethyl acetate, acidified with 255 ml of concentrated hydrochloric acid, and then saturated with 270 g of sodium chloride. The organic layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to obtain 309.3g of compound (II) with a yield of 97.1%. Without purification, it can be directly used in the subsequent reaction. 30.54g of ethanolamine was dissolved in 370ml of ethanol and 30ml of water, and 60.6g of triethylamine and 45g of carbon disulfide were added at 15°C. After stirring for 1 h, 80 g of methyl iodide was added at 15°C. After stirring for 30 min, the reaction solution was concentrated under reduced pressure, diluted with 350 ml of water and hexane, and left to separate. The aqueous layer was separated and acidified with 1.5 ml of phosphoric acid. After extraction with ethyl acetate, the extract was concentrated to obtain 81.7 g of compound (III) containing a small amount of solvent, which was directly used in the next reaction without purification. The compound (III) obtained above was dissolved in 300 ml of dichloromethane, 54 g of dihydropyran and 1.0 g of p-toluenesulfonic acid monohydrate were added, and stirred for 1 h. The reaction solution was washed with aqueous sodium bicarbonate solution and concentrated to obtain 129 g of crude compound (IV). 11.8 g of compound (IV) was dissolved in 40 ml of ethanol, 20 ml of an aqueous solution containing 3.40 g of sodium azide was added, and refluxed for 2.5 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, extracted with ethyl acetate, acidified with phosphoric acid, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain 10.4 g of solid. This solid is pyrrole ether of compound (V). The solid was dissolved in an acetone aqueous solution, acidified with concentrated hydrochloric acid to Ph=2, and left at room temperature for 2h. Concentrate and extract with ethyl acetate. The extract was dried and concentrated. The residue was recrystallized with a mixed solvent of ethyl acetate and hexane to obtain 6.2 g of compound (V), with a yield of 85% and a melting point of 135 to 137°C. 977 mg of compound (V) was dissolved in 5 ml of dimethylformamide, and 1.3 ml of a 5.2 mol/L sodium methoxide methanol solution was added at -20*°C. At -20°C, this solution was added to a solution of 2.80 g of compound (VI) (see Yoshioka M, et al. Tetrahedron Lett, 1980, 21: 351 354 for its preparation) in 19 ml of dimethylformamide. After the addition, stir for 2h. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was chromatographed on silica gel to obtain 3.7 g of compound (VII) containing a small amount of solvent. The yield was almost quantitative. 3.38 g of compound (VII) and 3.6 ml of pyridine were dissolved in 3 ml of dichloromethane, a solution of 3.4 g of benzyl p-methylchloroformate in 2 ml of dichloromethane was added at 20° C., and stirred for 5 h. The reaction solution was poured into cold water, and after conventional treatment, it was chromatographed on silica gel to obtain 3.2 g of compound (VIII) with a yield of 82.6% (based on compound (V)). 1.0 g of compound (V1) was dissolved in 10 ml of dichloromethane, cooled to -55°C, and sequentially reacted with 192 μl of tert-butyl hypochlorite and 0.92 ml of a 2 mol/L lithium methoxide methanol solution. After the resulting solution was stirred for 15 min, 0.8 ml of acetic acid was added to stop the reaction. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was treated with silica gel after routine treatment to obtain 770 mg of compound (IX) in 74% yield. 500 mg of compound (IX) was dissolved in 10 ml of dichloromethane, and 112 μl of pyridine and 263 mg of phosphorus pentachloride were sequentially added under cooling in an ice bath. After the addition, the reaction solution was warmed to room temperature and stirred for 2.5h. Cool to -20°C and add 5ml of methanol. Stir for another 3h at 2～3℃. The reaction solution was poured into a cold sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The extract was treated normally to obtain 326 mg of compound (X) crystals, with a yield of 75% and a melting point of 135 to 138.5°C. The compound is slightly sensitive to air. 1.0 g of compound (X) was suspended in dichloromethane, and 0.52 g of pyridine and 0.17 g of compound (II) were added under cooling in an ice bath. Cool to -15°C and slowly add 0.25g of phosphorus oxychloride. After the resulting solution was stirred at -17 to -15°C for 20 min, it was poured into ice water and extracted with dichloromethane. The extract was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After the residue was impregnated with ethyl acetate, 935 mg of crystals of compound (XI) were obtained, the yield was 83%, and the melting point was 80-82°C. 405rng compound (XI), 2.5 ml of dichloromethane and 0.5 ml of nitromethane were mixed, and a solution of 0.11 ml of anisole and 0.17 ml of tin tetrachloride in 2 ml of dichloromethane was added at -30°C. In the stirred 3.5h, slowly warm up to -10 ℃, poured into a mixture of 1mol/L hydrochloric acid, ethyl acetate and methyl ethyl ketone. The separated organic layer was mixed with an aqueous solution of sodium bicarbonate, the aqueous layer was acidified with concentrated hydrochloric acid, and extracted with a mixed solution of ethyl acetate and methyl ethyl ketone. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized with acetone and dichloromethane to obtain 260 mg of crystalline cephalosporin with a yield of 100% and a melting point of 82.5-87.5°C.

Flomoxef is an oxacephem derived beta-lactam antibiotic that is particularly effective against gram-positive bacteria.

Molecular Weight:496.5
XLogP3:-1.3
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:14
Rotatable Bond Count:11
Exact Mass:496.06464561
Monoisotopic Mass:496.06464561
Topological Polar Surface Area:220
Heavy Atom Count:32
Complexity:793
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes