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【结 构 式】 
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【药物名称】GW-873140, ONO-4128, AK-602 【化学名称】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 【CA登记号】461023-63-2, 461443-59-4 (free base) 【 分 子 式 】C33H44ClN3O6 【 分 子 量 】614.18813 |
【开发单位】Ono (Originator), GlaxoSmithKline (Licensee) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Chemokine CCR5 Antagonists |
合成路线1
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.
| 【1】 Shibayama, S.; Hamano, S.; Takaoka, Y.; Habashita, H. (Ono Pharmaceutical Co., Ltd.); Triazaspiro[5.5]undecane derivs. and drugs containing the same as the active ingredient. EP 1378510; WO 0274770 . |
| 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) | 64663 | (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexyl-3-hydroxypropanoic acid | C14H25NO5 | 详情 | 详情 | |
| (II) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (III) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (IV) | 39041 | butylamine; 1-butanamine | 109-73-9 | C4H11N | 详情 | 详情 |
| (V) | 64664 | tert-butyl (1R)-2-[{1-benzyl-4-[(benzylamino)carbonyl]-4-piperidinyl}(butyl)amino]-1-[(R)-cyclohexyl(hydroxy)methyl]-2-oxoethylcarbamate | C38H56N4O5 | 详情 | 详情 | |
| (VI) | 64665 | 4-[[(2R,3R)-2-amino-3-cyclohexyl-3-hydroxypropanoyl](butyl)amino]-N,1-dibenzyl-4-piperidinecarboxamide | C33H48N4O3 | 详情 | 详情 | |
| (VII) | 64666 | (3R)-9-benzyl-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione | C26H39N3O3 | 详情 | 详情 | |
| (VIII) | 64667 | (3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione | C19H33N3O3 | 详情 | 详情 | |
| (IX) | 64668 | 4-(4-formylphenoxy)benzoic acid | C14H10O4 | 详情 | 详情 |