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【结 构 式】 
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【分子编号】32099 【品名】(E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide 【CA登记号】 |
【 分 子 式 】C17H25NO2 【 分 子 量 】275.39104 【元素组成】C 74.14% H 9.15% N 5.09% O 11.62% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Tetrahydrofuranone (XIII): The Grignard condensation of isobutyraldehyde (I) with vinylmagnesium bromide (II) in THF gives the magnesium alcoholate (III), which is condensed with ethyl malonyl chloride (IV) in the same solvent, yielding the mixed ester (V). Treatment of (V) with Ti(OEt)4 at 190 C affords 6-methyl-4(E)-heptenoic acid methyl ester (VI), which by reaction with (R,R)-(-)-pseudoephedrine (VII), oxalyl chloride and DMF in benzene gives the amide (VIII). The regiocontrolled addition of 4-fluorobenzyl chloride (IX) to the chiral amide (VIII) by means of BuLi and LiCl in THF yields the 2(S)-(4-fluorobenzyl)heptanamide (X), which by reaction with NBS in THF/water/acetic acid at 0 C, followed by reflux for 45 min, affords 5(S)-[1(R)-bromo-2-methylpropyl]-3(R)-(4-fluorobenzyl)tetrahydrofuran-2-one (XI). The reaction of (XI) with NaN3 in DMF gives the corresponding azide (XII), which is reduced with H2 over Pd/C, and the resulting amine is protected with tert-butoxycarbonyl anhydride to obtain the desired tetrahydrofuranone (XIII).
| 【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203. |
| 【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 . |
| 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) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 32096 | 4-Methyl-1-penten-3-ol bromomagnesium salt | C6H11BrMgO | 详情 | 详情 | |
| (IV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (V) | 32097 | 1-ethyl 3-(1-isopropyl-2-propenyl) malonate | C11H18O4 | 详情 | 详情 | |
| (VI) | 32098 | methyl (E)-6-methyl-4-heptenoate | C9H16O2 | 详情 | 详情 | |
| (VII) | 32104 | (1R,2R)-2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (VIII) | 32099 | (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide | C17H25NO2 | 详情 | 详情 | |
| (IX) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (X) | 32100 | (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide | C24H30FNO2 | 详情 | 详情 | |
| (XI) | 32101 | (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18BrFO2 | 详情 | 详情 | |
| (XII) | 32102 | (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18FN3O2 | 详情 | 详情 | |
| (XIII) | 32103 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 |