Dersalazine, UR-12746S(sodium salt), UR-12746, -Drug Synthesis Database

【结构式】

【药物名称】Dersalazine, UR-12746S(sodium salt), UR-12746

【化学名称】2-Hydroxy-5-[4-[3-[4-(2-methylimidazo[4,5-c]pyridin-1-ylmethyl)piperidin-1-yl]-3-oxo-1-phenyl-1(Z)-propenyl]phenylazo]benzoic acid

【CA登记号】188913-58-8

【分子式】C₃₅H₃₂N₆O₄

【分子量】600.68309

【开发单位】Uriach (Originator), Indevus (Licensee)

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

合成路线1 合成路线2

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).

参考文献中间体

【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 (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.

参考文献中间体

【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

Extended Information