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【结 构 式】 
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【分子编号】50587 【品名】(2S,3S,5R,7S,9S)-7-(bromomethyl)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane 【CA登记号】 |
【 分 子 式 】C18H26BrNO2 【 分 子 量 】368.31398 【元素组成】C 58.7% H 7.12% Br 21.69% N 3.8% O 8.69% |
合成路线1
该中间体在本合成路线中的序号：(XLV)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：(VIII)
| 【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 |