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【结 构 式】 
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【分子编号】50589 【品名】(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane-7-carbaldehyde 【CA登记号】 |
【 分 子 式 】C18H25NO3 【 分 子 量 】303.40144 【元素组成】C 71.26% H 8.31% N 4.62% O 15.82% |
合成路线1
该中间体在本合成路线中的序号：(XLVII)The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloromethane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV).
| 【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
| 【2】 Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fassler, A.; A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41, 51, 10091. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 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 |
| (XXXII) | 50576 | (3S,5S)-5-[(1R,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H40O6 | 详情 | 详情 | |
| (XXXIV) | 50578 | (3S,5S)-5-[(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39N3O5 | 详情 | 详情 | |
| (XLIII) | 50585 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N,3-dimethylbutanamide | C15H23NO2 | 详情 | 详情 | |
| (XLIV) | 50586 | (2S)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-isopropyl-N-methyl-4-pentenamide | C18H27NO2 | 详情 | 详情 | |
| (XLV) | 50587 | (2S,3S,5R,7S,9S)-7-(bromomethyl)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane | C18H26BrNO2 | 详情 | 详情 | |
| (XLVI) | 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 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XLVII)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3
该中间体在本合成路线中的序号：(II)
| 【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 |
合成路线4
该中间体在本合成路线中的序号：(X)
| 【1】 Sandham DA, Taylor RJ, Carey JS, et al. 2000. A convergent synthesis of the renin inhibitory CGP60536B. Tetrahedron Lett, 41(51): 10091～10094 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 50585 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N,3-dimethylbutanamide | C15H23NO2 | 详情 | 详情 | |
| (I) | 50580 | (E)-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-2-propenoic acid | C14H18O5 | 详情 | 详情 | |
| (II) | 50583 | N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-N-methylpropanamide | C24H33NO5 | 详情 | 详情 | |
| (III) | 50584 | (2R)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-N,3-dimethylbutanamide | C27H39NO5 | 详情 | 详情 | |
| (IV) | 50573 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methyl-1-butanol | C17H28O4 | 详情 | 详情 | |
| (V) | 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 |
| (VII) | 50586 | (2S)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-isopropyl-N-methyl-4-pentenamide | C18H27NO2 | 详情 | 详情 | |
| (VIII) | 50587 | (2S,3S,5R,7S,9S)-7-(bromomethyl)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane | C18H26BrNO2 | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 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 | |
| (XI) | 50576 | (3S,5S)-5-[(1R,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H40O6 | 详情 | 详情 | |
| (XII) | 50578 | (3S,5S)-5-[(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone | C25H39N3O5 | 详情 | 详情 | |
| (XIII) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
| (XIV) | 61613 | (2S,4S,5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide | C30H51N5O6 | 详情 | 详情 |