GR-63116, M-14659
Chemical Name: (7R,8R)-7beta-[2-(2-Aminothiazol-4-yl)-2-[(S)-carboxy-(3,4-dihydroxyphenyl)methoxyimino)acetamido]-3-(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl)-3-cephem-4-carboxylic acid trisodium salt; (6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamido]-3-[(2-carboxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trisodium salt
CAS No. 114627-37-1
项目整合开发状态: Phase I
项目研究机构: Ajinomoto (Originator), Mochida (Originator), GlaxoSmithKline (Licensee)
合成路线:The bromination of 3,4-diacetoxyphenylacetic acid with N-bromosuccinimide (NBS) and SOCl2 gives the corresponding bromoacetic acid (II),which is esterified with diphenyldiazomethane (III) in acetone affording the diphenylmethyl ester (IV).The reaction of (IV) with N-hydroxyphthalimide (V) by means of triethylamine in acetonitrile yields diphenylmethyl-2-phthalimidooxy-2-(3,4-diacetoxy phenyl)acetate (VI),which is treated witb methyl hydrazine in dichloromethane to give diphenylmethyl-2-aminooxy-2-(3,4-diacetoxyphenyl)acetate (VII).The condensation of (VII) with (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (VIII) in methanol affords 2-(2-triphenylmethylamino-4-thiazolyl)-2-[(Z)-(diphenyl)methoxyimino]acetic acid (IX),which is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI).Finally,this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
合成路线:2-[1(S)-(3,4-dihydroxyphenyl)-1-(diphenylmethoxycarbonyl)methoxyimino]-2-[2-(triphenylmethylamino)thiazol-4-yl]-acetic acid (IX) is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI).Finally,this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
📌 参考资料/链接：
参考文献标题:Cephalosporin derivs.
文献作者:Ohnishi,H.; Kosuzume,H.; Mizota,M.; Suzuki,Y.; Mochida,E.(Mochida Pharmaceutical Co.,Ltd.)
参考来源:AU 8654876; AU 8655860; EP 0197409; EP 0359291; JP 1987077392; JP 1987161793; JP 1987167784; US 4840945; US 5001121; WO 8605786
📄 详细内容
合成路线:The bromination of 3,4-diacetoxyphenylacetic acid with N-bromosuccinimide (NBS) and SOCl2 gives the corresponding bromoacetic acid (II),which is esterified with diphenyldiazomethane (III) in acetone affording the diphenylmethyl ester (IV).The reaction of (IV) with N-hydroxyphthalimide (V) by means of triethylamine in acetonitrile yields diphenylmethyl-2-phthalimidooxy-2-(3,4-diacetoxy phenyl)acetate (VI),which is treated witb methyl hydrazine in dichloromethane to give diphenylmethyl-2-aminooxy-2-(3,4-diacetoxyphenyl)acetate (VII).The condensation of (VII) with (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (VIII) in methanol affords 2-(2-triphenylmethylamino-4-thiazolyl)-2-[(Z)-(diphenyl)methoxyimino]acetic acid (IX),which is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI).Finally,this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
合成路线:2-[1(S)-(3,4-dihydroxyphenyl)-1-(diphenylmethoxycarbonyl)methoxyimino]-2-[2-(triphenylmethylamino)thiazol-4-yl]-acetic acid (IX) is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI).Finally,this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
参考文献标题:M-14659
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1988,13(12),1047
合成路线:The bromination of 3,4-diacetoxyphenylacetic acid with N-bromosuccinimide (NBS) and SOCl2 gives the corresponding bromoacetic acid (II),which is esterified with diphenyldiazomethane (III) in acetone affording the diphenylmethyl ester (IV).The reaction of (IV) with N-hydroxyphthalimide (V) by means of triethylamine in acetonitrile yields diphenylmethyl-2-phthalimidooxy-2-(3,4-diacetoxy phenyl)acetate (VI),which is treated witb methyl hydrazine in dichloromethane to give diphenylmethyl-2-aminooxy-2-(3,4-diacetoxyphenyl)acetate (VII).The condensation of (VII) with (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (VIII) in methanol affords 2-(2-triphenylmethylamino-4-thiazolyl)-2-[(Z)-(diphenyl)methoxyimino]acetic acid (IX),which is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI).Finally,this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
合成路线:2-[1(S)-(3,4-dihydroxyphenyl)-1-(diphenylmethoxycarbonyl)methoxyimino]-2-[2-(triphenylmethylamino)thiazol-4-yl]-acetic acid (IX) is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI).Finally,this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
参考文献标题:Antibacterial and pharmacokinetic properties of M1
文献作者:Mochizuki,H.; Oikawa,Y.; Yamada,H.; Kusakabe,S.; Shiihara,T.; Murakami,K.; Kato,K.; Ishigura,J.; Kosuzume,H.
参考来源:J Antibiot 1988,41(3),377