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【结 构 式】 
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【分子编号】50597 【品名】benzyl[(E)-[(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]methylidene]ammoniumolate 【CA登记号】 |
【 分 子 式 】C25H32N2O3 【 分 子 量 】408.54076 【元素组成】C 73.5% H 7.89% N 6.86% O 11.75% |
合成路线1
该中间体在本合成路线中的序号：(LII)Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated.
| 【1】 De Lathauwer, G.; Perrone, D.; Dondoni, A.; A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42, 29, 4819. |
| 【2】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
| (XXX) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
| (XLVII) | 50589 | (2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane-7-carbaldehyde | C18H25NO3 | 详情 | 详情 | |
| (LII) | 50597 | benzyl[(E)-[(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]methylidene]ammoniumolate | C25H32N2O3 | 详情 | 详情 | |
| (LIII) | 50594 | N-benzyl-N-[(3S)-1-[(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]hydroxylamine; (2S,3S,5R,7S,9S)-7-[(3S)-1-[benzyl(hydroxy)amino]-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane | C42H60N2O6 | 详情 | 详情 | |
| (LIV) | 50595 | (3S,5S)-5-[(3S)-1-(benzylamino)-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C32H47NO5 | 详情 | 详情 | |
| (LV) | 50596 | (2S,4S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-(benzylamino)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide | C37H59N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)
| 【1】 Dondoni A, De Lathauwer G. 2001. A convergent synthesisi of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett. 42(29): 4819～4823 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R-5) | 50594 | N-benzyl-N-[(3S)-1-[(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]hydroxylamine; (2S,3S,5R,7S,9S)-7-[(3S)-1-[benzyl(hydroxy)amino]-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane | C42H60N2O6 | 详情 | 详情 | |
| (I) | 50588 | [(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]methanol | C18H27NO3 | 详情 | 详情 | |
| (II) | 50589 | (2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane-7-carbaldehyde | C18H25NO3 | 详情 | 详情 | |
| (III) | 50597 | benzyl[(E)-[(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]methylidene]ammoniumolate | C25H32N2O3 | 详情 | 详情 | |
| (IV) | 50574 | 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 324763-39-5 | C17H27ClO3 | 详情 | 详情 |
| (VI) | 67006 | 5-(1-(benzyl(hydroxy)amino)-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-4-methylpentyl)-3-isopropyldihydrofuran-2(3H)-one | C32H47NO6 | 详情 | 详情 | |
| (VII) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
| (VIII) | 67007 | N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-(benzylamino)-4-hydroxy-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-8-methylnonanamide | C37H59N3O6 | 详情 | 详情 |