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【结 构 式】

【分子编号】59470

【品名】(Z)-1-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-(4-nitrophenyl)-3-phenyl-2-propen-1-one

【CA登记号】

【 分 子 式 】C28H27N5O3

【 分 子 量 】481.55428

【元素组成】C 69.84% H 5.65% N 14.54% O 9.97%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIIIb)

Horner-Emmons condensation of 4-nitrobenzophenone (IX) with triethyl phosphonoacetate produced a 2:1 mixture of Z and E nitrophenylcinnamic esters (XI) and (X). Alternatively, the desired Z isomer was obtained in a more favorable 8:1 ratio by condensation of (IX) with ethyl (trimethylsilyl)acetate under Peterson reaction conditions. Ester hydrolysis in the mixture (X) + (XI) with K2CO3 in aqueous methanol gave the corresponding mixture of carboxylic acids (XII). Optionally, the pure Z isomer could be isolated by recrystallization from EtOAc. DCC coupling of piperidine (VIII) with either the pure Z-isomer or the Z/E-mixture of carboxylic acids (XIIa-b) gave rise to the respective Z/E isomeric amides (XIIIa-b). After catalytic hydrogenation of the nitro group of (XIII), the required Z-(4-aminophenyl)cinnamamide isomer (XIV) was isolated by column chromatography. Finally, diazotization of (XIV), followed by coupling of the resultant diazonium salt (XV) to salicylic acid, furnished the title diazo compound.

1 Ferrando, R.; Carceller, E.; Forn, J.; Ramis, J.; Escamilla, I.; Giral, M.; Merlos, M.; Salas, J.; García-Rafanell, J.; Novel azo derivatives prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity. J Med Chem 2001, 44, 18, 3001.
2 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIIa) 59467 (E)-3-(4-nitrophenyl)-3-phenyl-2-propenoic acid C15H11NO4 详情 详情
(XIIb) 59468 (Z)-3-(4-nitrophenyl)-3-phenyl-2-propenoic acid C15H11NO4 详情 详情
(XIIIa) 59469 (E)-1-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-(4-nitrophenyl)-3-phenyl-2-propen-1-one C28H27N5O3 详情 详情
(XIIIb) 59470 (Z)-1-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-(4-nitrophenyl)-3-phenyl-2-propen-1-one C28H27N5O3 详情 详情
(VIII) 59463 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine C13H18N4 详情 详情
(IX) 59464 4-Nitrobenzophenone; p-Nitrobenzophenone 1144-74-7 C13H9NO3 详情 详情
(X) 59465 ethyl (E)-3-(4-nitrophenyl)-3-phenyl-2-propenoate C17H15NO4 详情 详情
(XI) 59466 ethyl (Z)-3-(4-nitrophenyl)-3-phenyl-2-propenoate C17H15NO4 详情 详情
(XIV) 59479 (Z)-3-(4-aminophenyl)-1-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-phenyl-2-propen-1-one C28H29N5O 详情 详情
(XV) 59480 4-((Z)-3-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-oxo-1-phenyl-1-propenyl)benzenediazonium chloride C28H27ClN6O 详情 详情
(XVI) 15240 2-Hydroxybenzoic acid; Salicylic acid 69-72-7 C7H6O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIIIb)

Horner-Emmons condensation of 4-nitrobenzophenone (IX) with triethyl phosphonoacetate produced a 2:1 mixture of Z and E nitrophenylcinnamic esters (XI) and (X). Alternatively, the desired Z isomer was obtained in a more favorable 8:1 ratio by condensation of (IX) with ethyl (trimethylsilyl)acetate under Peterson reaction conditions. Ester hydrolysis in the mixture (X)+(XI) with K2CO3 in aqueous methanol gave the corresponding mixture of carboxylic acids (XII). Optionally, the pure Z isomer could be isolated by recrystallization from EtOAc. DCC coupling of piperidine (VIII) with either the pure Z-isomer or the Z/E-mixture of carboxylic acids (XII) gave rise to the respective Z/E isomeric amides (XIII). The title Z-(4-aminophenyl)cinnamamide derivative was isolated by column chromatography after catalytic hydrogenation of the nitro group.

1 Ferrando, R.; Carceller, E.; Forn, J.; Ramis, J.; Escamilla, I.; Giral, M.; Merlos, M.; Salas, J.; García-Rafanell, J.; Novel azo derivatives prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity. J Med Chem 2001, 44, 18, 3001.
2 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIIa) 59467 (E)-3-(4-nitrophenyl)-3-phenyl-2-propenoic acid C15H11NO4 详情 详情
(XIIb) 59468 (Z)-3-(4-nitrophenyl)-3-phenyl-2-propenoic acid C15H11NO4 详情 详情
(XIIIa) 59469 (E)-1-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-(4-nitrophenyl)-3-phenyl-2-propen-1-one C28H27N5O3 详情 详情
(XIIIb) 59470 (Z)-1-{4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinyl}-3-(4-nitrophenyl)-3-phenyl-2-propen-1-one C28H27N5O3 详情 详情
(VIII) 59463 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine C13H18N4 详情 详情
(IX) 59464 4-Nitrobenzophenone; p-Nitrobenzophenone 1144-74-7 C13H9NO3 详情 详情
(X) 59465 ethyl (E)-3-(4-nitrophenyl)-3-phenyl-2-propenoate C17H15NO4 详情 详情
(XI) 59466 ethyl (Z)-3-(4-nitrophenyl)-3-phenyl-2-propenoate C17H15NO4 详情 详情
Extended Information