Loracarbef monohydrate

ChEBI: The monohydrated form of loracarbef.Loracarbef is a new orally active, broad-spectrum cephalosporin suitable for twice a day dosing. It is approved for use in both adults and children for the treatment of upper and lower respiratory tract infections, urinary tract and skin infections.

Loracarbef is a semi-synthetic, broad-spectrum, beta-lactamase resistant, second-generation cephalosporin antibiotic derived from cephasporium. The bactericidal activity of loracarbef results from the inhibition of bacterial cell wall synthesis through interference with the cross-linking of peptidoglycan units. This results in a reduction of cell wall stability and causes cell lysis. Loracarbef is more active against a variety of gram-negative organisms but less active against gram-positive pathogens compared to first-generation agents.

Method 1: 528 mg of compound (I) was dissolved in 15 ml of anhydrous benzene, 0.2 rnl of thiophenol and 0.2 ml of piperidine were added, and the mixture was stirred at room temperature for 2 hours. It was washed with 10% citric acid aqueous solution and saturated brine, dried, and concentrated under reduced pressure. The oily residue was chromatographed on a silica gel column and eluted with hexane-ethyl acetate (4:1) to obtain 720 mg of compound (II) with a yield of 96.3% and a melting point of 77.5-78°C. 480 mg of compound (II) was dissolved in 50 ml of distilled chloroform, and 240 mg of m-chloroperbenzoic acid (m-CPBA) was added under ice cooling. After stirring for 30 min at 0°C, the reaction solution was washed with saturated sodium bicarbonate solution and saturated brine, dried, and concentrated to obtain 500 mg of compound (III) with a yield of 99.9% and a melting point of 95.5-96.5°C. 109 mg of compound (III) and 23.5 mg of calcium oxide were suspended in 1 ml of dichloromethane, and 27 μl of sulfuryl chloride was added at 0°C. And stirred at 0°C for 1h. The reaction solution was washed successively with 10% citric acid solution, saturated sodium bicarbonate and saturated brine, dried and concentrated. The residue was chromatographed on a silica gel column and eluted with hexane-ethyl acetate (5:1) to obtain 66.5 mg of oily compound (IV), with a yield of 56.1%. 1.3g compound (IV) was dissolved in 100ml carbon tetrachloride and refluxed for 6h. After cooling, the reaction solution was concentrated. The residue was chromatographed on silica gel column and eluted with n-hexane-ethyl acetate (5:1) to obtain 596 mg of compound (V) with a yield of 65.2% and a melting point of 96.0-97.0°C. 350mg compound (V) and 70mg 10% palladium-carbon catalyst were suspended in 100ml ethanol and 1.2ml 1mol/L hydrochloric acid, hydrogenated at room temperature and normal pressure for 3h, the catalyst was filtered off and washed with a small amount of ethanol. The filtrate and washing liquid were combined and concentrated. The remaining solid was dissolved in water and washed with ether. After adjusting the Ph value of the water layer to 8 with sodium bicarbonate, it was extracted with ethyl acetate. The extract was washed with saturated brine, dried, and concentrated to obtain 218 mg of compound (VI) as a colorless powder with a yield of 68.4%. 102 mg of compound (VI) and 1 ml of trifluoroacetic acid were reacted at room temperature for 30 minutes. After concentration, the residue was impregnated with ether to obtain 75.5 mg of yellow powdery compound (VII) with a yield of 75.5%. The porous ceramic column with a diameter of about 1mm is treated with γ-aminopropyltriethoxysilane and then treated with glutamine. The crude enzyme (Kluyvera citrophila KY-7844 extract) is reacted with the porous ceramic treated above to obtain the immobilized enzyme. 9.73g compound (VII) was dissolved in 580ml phosphate buffer solution (Ph=6.75), and 51g phenylglycine methyl ester was added. The mixed solution was passed through the column containing the immobilized enzyme (185ml) prepared above, the internal temperature of the column was kept at 20°C, and it was circulated three times for about 8.5h. Can get 6.15g chlorocarbocephalosporin, the yield is 78.2%, the melting point is 205～215℃ (decomposition). Method 2: 9.20g compound (VIII) was dissolved in 100ml chloroform, 2.83ml thiophenol and 0.5ml piperazine were added, and stirred for 3h. After concentration, the residue was chromatographed on silica gel column and eluted with n-hexane-ethyl acetate (2:1). 9.26 g of colorless compound (IX) crystals were obtained, and the yield was 77.5%. 4.78g compound (IX) was dissolved in 100ml chloroform, 2.37g chloroperoxybenzoic acid was added at 0°C, after stirring for 30min, 1ml 10% sodium thiosulfate solution was added. The organic layer was separated, washed with saturated sodium bicarbonate and saturated brine, dried, and concentrated. The remaining white solid was dissolved in 50 ml of dichloromethane, and 1.45 ml of sulfuryl chloride was added under ice cooling, and the mixture was stirred at 0°C for 1 hour. After diluting with 50ml of dichloromethane, wash with 10% citric acid solution, sodium bicarbonate solution and saturated brine successively, dry and concentrate. The colorless powder obtained was dissolved in 80 ml of toluene, refluxed for 2 hours and then concentrated. The residue was chromatographed on silica gel and eluted with n-hexane-ethyl acetate (1:1) to obtain 3.50 g of colorless crystals of compound (X) with a yield of 87% and a melting point of 177.6°C. 1.7g of compound (X) and 8ml of trifluoroacetic acid were stirred at 0°C for 1h. After concentration under reduced pressure, a brown oil was obtained. After being impregnated with ether, 1.1 g of compound (XI) was obtained, with a yield of 71.8%. 10.96g compound (XI) is dissolved in 150ml water, treated with 1.85 times hydrazine hydrate, and adjusted to Ph=7.5～7.7 with 0.2mol/L sodium hydroxide. After stirring for 3 hours at 5°C, the temperature was raised to 35°C, acidified with 1mol/L hydrochloric acid to Ph=0.8, and left for 4 hours. The precipitate was removed by filtration, and the filtrate was concentrated to 93 ml and left at room temperature overnight. The precipitated precipitate was collected by filtration, and after drying, 5.54 g of the crude product of compound (VII) was obtained with a purity of 83.5% and a yield of 70.6%. After purification by chromatography, colorless crystals of compound (VII) can be obtained. Compound (VII) can be obtained according to Method 1 to obtain chlorocarbef.

Its antibacterial activity is similar to cefaclor and cefuroxime axetil. It is used for pneumonia, pharyngitis, chronic bronchitis, mild to moderate acute bronchitis secondary bacterial infections, tonsillitis, etc. caused by sensitive bacteria.

Molecular Weight:367.78
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:4
Exact Mass:367.0934984
Monoisotopic Mass:367.0934984
Topological Polar Surface Area:114
Heavy Atom Count:25
Complexity:600
Defined Atom Stereocenter Count:3
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes