GR-63116, M-14659, -Drug Synthesis Database

【结构式】

【药物名称】GR-63116, M-14659

【化学名称】(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

【CA登记号】114627-37-1

【分子式】C₂₈H₂₀N₉Na₃O₁₁S₃

【分子量】823.6867

【开发单位】Ajinomoto (Originator), Mochida (Originator), GlaxoSmithKline (Licensee)

【药理作用】Cephalosporins

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【1】 Ohnishi, H.; Kosuzume, H.; Mizota, M.; Suzuki, Y.; Mochida, E. (Mochida Pharmaceutical Co., Ltd.); Cephalosporin derivs.. AU 8654876; AU 8655860; EP 0197409; EP 0359291; JP 1987077392; JP 1987161793; JP 1987167784; US 4840945; US 5001121; WO 8605786 .
【2】 Prous, J.; Castaner, J.; M-14659. Drugs Fut 1988, 13, 12, 1047.
【3】 Kusakabe, S.; Kosuzume, H.; Kato, K.; Shiihara, T.; Murakami, K.; Yamada, H.; Ishigura, J.; Oikawa, Y.; Mochizuki, H.; Antibacterial and pharmacokinetic properties of M1. J Antibiot 1988, 41, 3, 377.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	23001	2-[3,4-bis(acetoxy)phenyl]acetic acid		C₁₂H₁₂O₆	详情	详情
(II)	23002	2-[3,4-bis(acetoxy)phenyl]-2-bromoacetic acid		C₁₂H₁₁BrO₆	详情	详情
(III)	23003	Diphenyldiazomethane		C₁₃H₁₀N₂	详情	详情
(IV)	23004	benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-bromoacetate		C₂₅H₂₁BrO₆	详情	详情
(V)	13505	N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione	524-38-9	C₈H₅NO₃	详情	详情
(VI)	23006	benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate		C₃₃H₂₅NO₉	详情	详情
(VII)	23007	benzhydryl 2-(aminooxy)-2-[3,4-bis(acetoxy)phenyl]acetate		C₂₅H₂₃NO₇	详情	详情
(VIII)	23008	2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid		C₂₄H₁₈N₂O₃S	详情	详情
(IX)	23009	2-([2-(benzhydryloxy)-1-[3,4-bis(acetoxy)phenyl]-2-oxoethoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid		C₄₉H₃₉N₃O₉S	详情	详情

合成路线2

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.

参考文献中间体

【1】 Ohnishi, H.; Kosuzume, H.; Mizota, M.; Suzuki, Y.; Mochida, E. (Mochida Pharmaceutical Co., Ltd.); Cephalosporin derivs.. AU 8654876; AU 8655860; EP 0197409; EP 0359291; JP 1987077392; JP 1987161793; JP 1987167784; US 4840945; US 5001121; WO 8605786 .
【2】 Kusakabe, S.; Kosuzume, H.; Kato, K.; Shiihara, T.; Murakami, K.; Yamada, H.; Ishigura, J.; Oikawa, Y.; Mochizuki, H.; Antibacterial and pharmacokinetic properties of M1. J Antibiot 1988, 41, 3, 377.
【3】 Prous, J.; Castaner, J.; M-14659. Drugs Fut 1988, 13, 12, 1047.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	23009	2-([2-(benzhydryloxy)-1-[3,4-bis(acetoxy)phenyl]-2-oxoethoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid	C₄₉H₃₉N₃O₉S	详情	详情
(X)	23010	benzhydryl 7-[([(7R)-7-amino-2-[(benzhydryloxy)carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl)sulfanyl]-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate	C₄₁H₃₄N₆O₅S₂	详情	详情
(XI)	23011	benzhydryl 7-[([(7R)-7-([2-([2-(benzhydryloxy)-1-[3,4-bis(acetoxy)phenyl]-2-oxoethoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-2-[(benzhydryloxy)carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl)sulfanyl]-5-methyl[1,2,	C₉₀H₇₁N₉O₁₃S₃	详情	详情

Extended Information