超大现代农业股吧:盐酸头孢甲肟 [CAS:75738-58-8]合成路线图解??有机化学网

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Chemical Name： 7beta-[2-(2-Aminothiazol-4-yl)-(Z)-2-(methoxyiminoacetamido)]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid hemihydrochloride;7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]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 hemihydrochloride Generic Name： 盐酸头孢甲肟;Cefmenoxime hydrochloride Other Names： Cefmenoxime hydrochloride;SCE-1365(free acid);Bestron;Cemix;Tacef;Bestcall CAS： 75738-58-8 Formula： C₁₆H₁₈ClN₉O₅S₃ Mole Weight： 548.02416 structure： Company： Senju (Originator), Takeda (Originator), Grelan (Marketer), Kyorin (Comarketer) Usage： Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins Route 1 The methylation of ethyl 3-oxo-2-hydroxyiminobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 3-oxo-2-methoxyiminobutyrate (II), which is brominated with Br2 in CHCl3 to afford ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate (III). The cyclization of (III) with thiourea (A) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (IV), which is acylated with chloroacetyl chloride in dimethylacetamide to yield ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (V). The hydrolysis of (V) with KOH in ethanol-water gives the corresponding free acid (VI), which is treated with PCl5 in methylene chloride to obtain the acyl chloride (VII). The condensation of tert-butyl 7-aminocephalosporanate (VIII) with (VII) by means of pyridine in methylene chloride gives tert-butyl 7-[alpha-methoxyimino-(2-chloroacetamidothiazol-4-yl)acetamido]cephalosporanate (IX), which is desacylated with thiourea and triethylbenzylammonium bromide in THF-ethanol yielding tert-butyl 7-[alpha-methoxyimino-alpha-(2-aminothiazol-4-yl)acetamido]cephalosporanate (X), which is hydrolyzed with trifluoroacetic acid to afford the free cephalosporanic acid (Xl). Finally, this compound is condensed with 1-methyl-5-mercaptotetrazol (XII) by means of NaHCO3 and triethylbenzylammoniurn bromide in water. Intermediates: Serial No. methyl (1S,3aS,4S,5S,7aS)-4-(cyanomethyl)-7a-methyl-5-[(1R,3R,6R)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1H-indene-1-carboxylate (A) methyl (1S,3aS,4S,5S,7aS)-4-(cyanomethyl)-7a-methyl-5-[(1R)-1-methyl-2,4-dioxocyclohexyl]octahydro-1H-indene-1-carboxylate (III) methyl (1S,3aS,4S,5S,7aS)-4-(2-amino-2-oxoethyl)-5-[(1R)-2-methoxy-1-methyl-4-oxo-2-cyclohexen-1-yl]-7a-methyloctahydro-1H-indene-1-carboxylate (IV) [2-[2-(chloromethyl)-1H-imidazol-1-yl]-5-nitrophenyl](2-chlorophenyl)methanone (I) (7S,11S,12S,13S,14R,15R,16R,17S,18S)-26-formyl-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.1(4,7).0(5,28)]triaconta-1(28),1(29),2,4,9,19,21,25,27-nonaen-13-yl acetate; 3-Formyirifamycin SV (II) 2-Bromo-4-(2-chlorophenyl)-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine (V) 4-[5-bromo-3-[bromo(2-chlorophenyl)methyl]-2-thienyl]-3-(chloromethyl)-5-methyl-4H-1,2,4-triazole (VI) tert-butyl (1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate (XII) methyl (2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-hydroxytetrahydro-2H-pyran-2-carboxylate (XI) (VII) (VIII) (IX) (X) Reference 1:     Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17. Reference 2:     Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 . Reference 3:     Ochiai, M.; et al. (Takeda Chemical Industries, Ltd.); Thiazolylacetamido cephasloporin type compounds. DE 2556736; ES 464772; FR 2294690; GB 1536283; NL 7514811; US 4098888 . Reference 4:     Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146.
Route 2 The condensation of (VII) or the free acid (VI) by means of pyridine or isobutyl chloroformate, respectively, with 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIII) gives 7-[alpha-(2-chloroacetylamidothiazol-4-yl)-alpha-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIV), which is finally desacylated with thiourea (A) and benzyltriethylammonium bromide as before. Intermediates: Serial No. methyl (1S,3aS,4S,5S,7aS)-4-(cyanomethyl)-7a-methyl-5-[(1R,3R,6R)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1H-indene-1-carboxylate (A) 4-[5-bromo-3-[bromo(2-chlorophenyl)methyl]-2-thienyl]-3-(chloromethyl)-5-methyl-4H-1,2,4-triazole (VI) (VII) (XIII) (XIV) Reference 1:     Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17. Reference 2:     Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 . Reference 3:     Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146.