PNTI
Chemical Name: N-(Cyclopropylmethyl)-4,5alpha-epoxy-7'-(3,4-diformylbenzamido)-6,7-didehydroindolo[2',3':6,7]morphinan-3,14beta-diol
项目整合开发状态: Preclinical
项目研究机构: University of Minnesota (Originator)
合成路线:Treatment of naltrexone hydrochloride (I) with 2-nitrophenylhydrazine (II) under Fischer conditions in HCl:HOAc provides nitroindole derivative (III),which is reduced by means of hydrazine and Ni Raney in EtOH to afford amine (IV).Separately,3,4-dimethylbenzoic acid (V) is brominated with NBS and benzoyl peroxide in refluxing CCl4 to furnish tetrabromo derivative (VI),which is then hydrolyzed with Na2CO3 in H2O to yield 3,4-diformylbenzoic acid (VII).Bis acetalization of (VII) with ethylene glycol (VIII) in benzene in the presence of p-TsOH affords carboxylic acid (IX),which is then coupled with intermediate (IV) by means of DCC and HOBt in DMF to give the corresponding amido ester derivative (X).Selective saponification of (X) with K2CO3 in MeOH affords amide (XI),which is finally converted into the target compound by hydrolysis with HCl in acetone.
📌 参考资料/链接：
参考文献标题:Reporter affinity labels: An o-phthalaldehyde derivative of beta-naltrexamide as a fluorogenic ligand for opioid receptors
文献作者:Le Bourdonnec,B.; El Kouhen,R.; Lunzer,M.M.; Law,P.Y.; Loh,H.H.; Portoghese,P.S.
参考来源:J Med Chem 2000,43(13),2489
📄 详细内容
合成路线:Treatment of naltrexone hydrochloride (I) with 2-nitrophenylhydrazine (II) under Fischer conditions in HCl:HOAc provides nitroindole derivative (III),which is reduced by means of hydrazine and Ni Raney in EtOH to afford amine (IV).Separately,3,4-dimethylbenzoic acid (V) is brominated with NBS and benzoyl peroxide in refluxing CCl4 to furnish tetrabromo derivative (VI),which is then hydrolyzed with Na2CO3 in H2O to yield 3,4-diformylbenzoic acid (VII).Bis acetalization of (VII) with ethylene glycol (VIII) in benzene in the presence of p-TsOH affords carboxylic acid (IX),which is then coupled with intermediate (IV) by means of DCC and HOBt in DMF to give the corresponding amido ester derivative (X).Selective saponification of (X) with K2CO3 in MeOH affords amide (XI),which is finally converted into the target compound by hydrolysis with HCl in acetone.
参考文献标题:Covalently induced activation of the delta opioid receptor by a fluorogenic affinity label,7'-(phthalaldehyde-carboxamido)naltrindole (PNTI)
文献作者:Le Bourdonnec,B.; El Kouhen,R.; Poda,G.; Law,P.Y.; Loh,H.H.; Ferguson,D.M.; Portoghese,P.S.
参考来源:J Med Chem 2001,44(7),1017
合成路线:Treatment of naltrexone hydrochloride (I) with 2-nitrophenylhydrazine (II) under Fischer conditions in HCl:HOAc provides nitroindole derivative (III),which is reduced by means of hydrazine and Ni Raney in EtOH to afford amine (IV).Separately,3,4-dimethylbenzoic acid (V) is brominated with NBS and benzoyl peroxide in refluxing CCl4 to furnish tetrabromo derivative (VI),which is then hydrolyzed with Na2CO3 in H2O to yield 3,4-diformylbenzoic acid (VII).Bis acetalization of (VII) with ethylene glycol (VIII) in benzene in the presence of p-TsOH affords carboxylic acid (IX),which is then coupled with intermediate (IV) by means of DCC and HOBt in DMF to give the corresponding amido ester derivative (X).Selective saponification of (X) with K2CO3 in MeOH affords amide (XI),which is finally converted into the target compound by hydrolysis with HCl in acetone.
参考文献标题:delta Opioid antagonist activity and binding studies of regioisomeric isothiocyanate derivatives of naltrindole: Evidence for delta receptor subtypes
文献作者:Portoghese,P.S.; Sultana,M.; Nelson,W.L.; Klein,P.; Takemori,A.E.
参考来源:J Med Chem 1992,35(22),4086