(6R,7R)-7-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Off-White Solid

Into a 1000ml four-necked flask was added 132ml (141.1g, 1.57mol) dimethyl carbonate, 162g boron trifluoride-dimethyl carbonate complex, was added at 10-12 deg. C 21.5g (0.185mol) 1-methyl-5-mercaptotetrazole, after stirring for 10min was added 50g (0.184mol) 7-aminocephalosporanic acid (7-ACA), reacted at 25 deg. C, after 45min, cooled to 0 deg. C, was added dropwise 32g (0.283mol) of chloroacetyl chloride in 37ml N'N- dimethylformamide solution, the reaction was kept for 45min, the reaction mixture was added with 300ml of water and 300ml of dimethyl carbonate then stirred, separated and the aqueous layer was extracted with 400ml of dimethyl carbonate, dimethyl carbonate layers combined, added 5g active carbon for 30min, a solution of triethylamine in dimethyl carbonate was added dropwise, adjusted to pH 6.8 at 0 -5 deg. C crystallization for 2h, filtration, the filter cake was dried in vacuo at 45 deg. C, to obtain 67g (0.180mol) 7-aminocephalosporanic triazine (7-ACT), a yield of 98percent.5-Mercapto-1-methyl-1H-tetrazole (6.32 g, 54.48 mmol) and7-ACA (4, 14.8 g, 54.41 mmol) were successively added toa stirred solution of BF3·Et2O (23.6 g) in anhydrous acetonitrile(75 mL). The resulting solution was allowed to reactat 50 °C for 2.5 h. After cooling in an ice-bath, the reactionsolution was diluted with H2O (75 mL) and adjusted to pH4.0 by the addition of 28 percent NH4OH. Crystals that precipitatedwere collected by filtration, and washed with waterand then acetone, to give 5 (16.3 g, 91.3 percent) as earth-yellowsolid. m.p.: 207–209 °C [lit. [37, 38]: 224–226 °C (dec.)].IR (KBr): 3423, 3170, 1803, 1735, 1618, 1542, 1411, 1342, 1084 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.56 (d, 2J = −18 Hz, 1H, H-4), 3.73 (d, 2J = −18 Hz, 1H, H-4), 3.93 (s, 3H, CH3), 4.20 (d, 2J = −13.6 Hz, 1H, CH2), 4.36(d, 2J = −13.6 Hz, 1H, CH2), 4.78 (d, 3J = 5.2 Hz, 1H, H-6), 4.96 (d, 3J = 5.2 Hz, 1H, H-7).1) 7-TMCA (II): A mixture of 7-ACA (14.8g, 54.41mmol), mercapto tetrazole (6.32g, 54.48mmol) and BF(1) 1.5 L of acetonitrile, 300 g of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2-carboxylic acid, 1.5 kg of 5-Mercapto-1- methyltetrazole, 1.4 L of Borontrifluoride / acetonitrile complex were mixed, then heated to 40 ° C, and rapidly stirred for 1 h. after completion of reaction, it was cooled to 2 ° C. The reaction solution was mixed with 2.25 L of purified water pre-cooled to 5 ° C and slowly stirred until the crystal was precipitated, then stir again for 30 min, add 10percent ammonia to adjust the pH to 3.4, control the temperature to 0 ~ 5 ° C, and raise the crystal for 3h. Filtration carried out, then washed twice with 1.5L of acetone, and vacuum drying to obtain white crystalline powder (6R, 7R) -7-amino-3 [(Z) -2- (4- methylthiazole) -5- yl] Vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 324g(1) 1L acetonitrile, 200 g of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2-carboxylic acid, 1kg of formazane tetrazolium, 900ml of boron trifluoride/acetonitrile complex, Raise the temperature to 30°C and stir the reaction rapidly for 2h.After the reaction was completed, the temperature was lowered to 0° C., and the reaction solution was mixed with 1.5 L of purified water pre-cooled to 0° C.Slowly stir until crystals precipitate, stir for an additional 30 min, add 10percent ammonia to adjust the pH to 3.0, Control temperature 0 ~ 5 °C, crystal growth 2h, filtration, 1L of acetone was washed twice.Vacuum dryingThe white crystalline powder (6R, 7R)-7amino-3[(Z)-2-(4-methylthiazole)-5-yl]vinyl-8-oxo-5-thia-1-aza was obtained as a white crystalline powder. Bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (223.5 g);Into 1000 ml reaction flask was sequentially added 30g of 7-TMCA, according to the mass ratio of 95:5 proportion add 340 ml post-purification treated dichloromethane-chloroform mixed solvent and 20 ml hexamethyldisilazane. At temperature of 15 C, reflux reaction 1.5h to system become clear, and lowering the temperature to -5 C, get the reaction liquid 1;At room temperature, three bottles of 60.0g 3-TZ were added to 200ml of tetrahydrofuran and stirred well.Cool to 0C, add basic catalyst triethylamine andHexamethylsilazane, The silanization protects the carboxyl and amino groups and heats up to 30C.Reaction 2h.After the reaction is completed, concentrate under reduced pressure to remove tetrahydrofuran, add 1000 ml of chloroform, and stir well.Cool down to -30C, add 30% sodium methoxide solution 80g, control temperature below -30C when adding dropwise, After the temperature was increased to -20C, the reaction was carried out for 0.5 h to obtain a methylation reaction solution.The methylation reaction solution was added with 50 ml of triethylamine and the temperature was lowered to -20C.Cyanomethylmercapto acetyl chloride36.5g, Then warmed to -10 C, incubated 0.5h.Add 550g of hydrochloric acid to water, warm up to 15C, keep the reaction for 0.5h, stand still, keep the organic phase, In the organic phase, 10% sodium bicarbonate was added dropwise to adjust the pH to 6.5-7.0. The liquid was separated, the aqueous phase was taken, and the active carbon 10 g was decolorized for 1 h.After filtration, the temperature was kept at 30C, ph=2.6-2.7 was adjusted with a 5% phosphoric acid solution, and the crystal was grown for 1 h. The temperature was lowered to 0C.Crystal growth 1h, suction filtration, Cefopermapic acid 60 g was obtained after drying, the yield was 100%, and HPLC purity was 99%.

7-Amino-3-(1-methyl-5-tetrazolylthio)methyl-3-cephem-4-carboxylic Acid is a cephalosporin derivative with antibacterial activity. 7-Amino-3-(1-methyl-5-tetrazolylthio)methyl-3-cephem-4-carboxylic Acid is an intermediate in the preparation of Cefmetazole (C242850) and other semi-synthetic antibiotics.

Molecular Weight:328.4
XLogP3:-3.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:4
Exact Mass:328.04123061
Monoisotopic Mass:328.04123061
Topological Polar Surface Area:178
Heavy Atom Count:21
Complexity:515
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes