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【结 构 式】 
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【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% |
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 |