SCH-400
Chemical Name: 4-[8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(S)-yl]-2(R)-[3(S)-(4-methyl-1H-imidazol-1-ylmethyl)piperidin-1-ylcarbonyl]piperazine-1-carboxylic acid cyclohexyl ester
CAS No. 278785-78-7, 278785-72-1 (diastereomer), 278785-73-2 (diastereomer), 278785-79-8 (diastereomer)
项目整合开发状态: Preclinical
项目研究机构: Schering-Plough (Originator)
合成路线:(R)-Piperazinecarboxylic acid (I) is sequentially protected with 2-(t-butoxycarbonyloxy)imino-2-phenylacetonitrile to produce the 4N-Boc-piperazine (II),and then with cyclohexyl chloroformate,yielding the 1N-cyclohexyl carbamate (III).Selective N-Boc group cleavage in (III) under acidic conditions provides piperazine (IV).This is condensed with the tricyclic chloride (V) to furnish,after chromatographic separation of the isomers,the required intermediate (VI).
合成路线:Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII),which is further protected as the N-Boc derivative (IX) by using Boc2O.Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X).Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles,which are chromatographically separated after derivatization with trityl chloride.The desired isomer (XII) is then deprotected under acidic conditions,giving piperidine (XIII).Finally,EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.
📌 参考资料/链接：
参考文献标题:Farnesyl protein transferase inhibitors
文献作者:Cooper,A.B.; Girijavallabhan,V.M.; Mallams,A.K.; Doll,R.J.; Kelly,J.M.; Rane,D.F.; Taveras,A.G.; Guzi,T.; Strickland,C.; Chao,J.(Schering Corp.)
参考来源:EP 1140904; JP 2002533335; WO 0037458
📄 详细内容
合成路线:(R)-Piperazinecarboxylic acid (I) is sequentially protected with 2-(t-butoxycarbonyloxy)imino-2-phenylacetonitrile to produce the 4N-Boc-piperazine (II),and then with cyclohexyl chloroformate,yielding the 1N-cyclohexyl carbamate (III).Selective N-Boc group cleavage in (III) under acidic conditions provides piperazine (IV).This is condensed with the tricyclic chloride (V) to furnish,after chromatographic separation of the isomers,the required intermediate (VI).
合成路线:Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII),which is further protected as the N-Boc derivative (IX) by using Boc2O.Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X).Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles,which are chromatographically separated after derivatization with trityl chloride.The desired isomer (XII) is then deprotected under acidic conditions,giving piperidine (XIII).Finally,EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.
参考文献标题:Farnesyl protein transferase inhibitors
文献作者:Cooper,A.B.; Girijavallabhan,V.M.; Mallams,A.K.; Doll,R.J.; Kelly,J.M.; Rane,D.F.; Taveras,A.G.; Guzi,T.; Strickland,C.; Chao,J.(Schering Corp.)
参考来源:US 6362188