873140, GW-873140, ONO-4128, AK-602
4-[4-[[(3R)-1-丁基-3-[(R)-环己基羟基甲基]-2,5-二氧代-1,4,9-三氮杂螺[5.5]十一烷-9-基]甲基]苯氧基]苯甲酸 Chemical Name: 4-[4-[1-Butyl-3(R)-[1(R)-cyclohexyl-1-hydroxymethyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-ylmethyl]phenoxy]benzoic acid hydrochloride
CAS No. 461023-63-2, 461443-59-4 (free base)
项目整合开发状态: Phase II
项目研究机构: Ono (Originator), GlaxoSmithKline (Licensee)
合成路线:The cyclization of (3R)-N-Boc-3-cyclohexyl-D-serine (I) with 1-benzylpiperidin-4-one (II),benzyl isonitrile (III) and butylamine (IV) in refluxing methanol gives the piperidine derivative (V),whose Boc group is removed by treatment with TFA in dichloromethane,yielding compound (VI).The cyclization of (VI) by means of AcOH in hot toluene affords the spiro[piperazine-2,4'-piperidine] derivative (VII),which is hydrogenated in methanol over palladium hydroxide on carbon to cleave the benzyl protecting group and provide the unprotected spiro derivative (VIII).Finally,this compound is reductocondensed with 4-(4-formylphenoxy)benzoic acid (IX) by means of sodium triacetoxyborohydride in DMF/AcOH to give the target spiro[piperazine-2,4'-piperidine] derivative.
📌 参考资料/链接：
参考文献标题:Triazaspiro[5.5]undecane derivs.and drugs containing the same as the active ingredient
文献作者:Shibayama,S.; Hamano,S.; Takaoka,Y.; Habashita,H.(Ono Pharmaceutical Co.,Ltd.)
参考来源:EP 1378510; WO 0274770
📄 详细内容
合成路线:The cyclization of (3R)-N-Boc-3-cyclohexyl-D-serine (I) with 1-benzylpiperidin-4-one (II),benzyl isonitrile (III) and butylamine (IV) in refluxing methanol gives the piperidine derivative (V),whose Boc group is removed by treatment with TFA in dichloromethane,yielding compound (VI).The cyclization of (VI) by means of AcOH in hot toluene affords the spiro[piperazine-2,4'-piperidine] derivative (VII),which is hydrogenated in methanol over palladium hydroxide on carbon to cleave the benzyl protecting group and provide the unprotected spiro derivative (VIII).Finally,this compound is reductocondensed with 4-(4-formylphenoxy)benzoic acid (IX) by means of sodium triacetoxyborohydride in DMF/AcOH to give the target spiro[piperazine-2,4'-piperidine] derivative.
参考文献标题:GW-873140
文献作者:McIntyre,J.A.; Castar,J.
参考来源:Drugs Fut 2004,29(7),677
产品链接: CAS No. 461023-63-2›› 产品链接: CAS No.461443-59-4››