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【结 构 式】

【药物名称】UR-12715

【化学名称】3-(4-Aminophenyl)-1-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-ylmethyl)piperidin-1-yl]-3-phenyl-2(Z)-propen-1-one

【CA登记号】

【 分 子 式 】C28H29N5O

【 分 子 量 】451.57623

【开发单位】Uriach (Originator)

【药理作用】GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, Platelet-Activating Factor (PAF) Antagonists

合成路线1

4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI), to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).

1 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
(I) 19349 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine 7144-05-0 C6H14N2 详情 详情
(II) 19352 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate 144222-22-0 C11H22N2O2 详情 详情
(III) 29971 4-chloro-3-nitropyridine C5H3ClN2O2 详情 详情
(IV) 59460 tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate C16H24N4O4 详情 详情
(V) 59461 tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate C16H26N4O2 详情 详情
(VI) 12831 ethyl ethanimidoate 1000-84-6 C4H9NO 详情 详情
(VII) 59462 tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate C18H26N4O2 详情 详情
(VIII) 59463 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine C13H18N4 详情 详情

合成路线2

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