UR-12715

Chemical Name: 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
项目整合开发状态: Preclinical
项目研究机构: Uriach (Originator)
合成路线: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).

合成路线: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.

合成路线: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).

合成路线: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.