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【结 构 式】 
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【药物名称】 【化学名称】6-Carbamoyl-4(S)-[5(S)-(cyclopentylsulfanylcarboxamido)-2(R)-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]-2(E)-hexenoic acid ethyl ester 【CA登记号】 【 分 子 式 】C30H42FN3O6S 【 分 子 量 】591.74814 |
【开发单位】Agouron (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs |
合成路线1
Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-flourobenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.
| 【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. |
| 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) | 24605 | 4-methyl-1-penten-3-ol | C6H12O | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 24607 | diethyl 2-[(E)-4-methyl-2-pentenyl]malonate | C13H22O4 | 详情 | 详情 | |
| (VI) | 24608 | (E)-6-methyl-4-heptenoic acid | C8H14O2 | 详情 | 详情 | |
| (VII) | 24609 | (1R,2R)-2-(methylamino)-1-phenyl-1-propanol | C10H15NO | 详情 | 详情 | |
| (VIII) | 24610 | (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide | C18H27NO2 | 详情 | 详情 | |
| (IX) | 24611 | 1-(bromomethyl)-4-fluorobenzene | 459-46-1 | C7H6BrF | 详情 | 详情 |
| (X) | 24612 | (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide | C25H32FNO2 | 详情 | 详情 | |
| (XI) | 24613 | (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18BrFO2 | 详情 | 详情 | |
| (XII) | 24614 | (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone | C15H18FN3O2 | 详情 | 详情 | |
| (XIII) | 24615 | tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate | C20H28FNO4 | 详情 | 详情 | |
| (XIV) | 24616 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-4-hydroxy-6-methylheptanoic acid | C20H30FNO5 | 详情 | 详情 | |
| (XV) | 24617 | (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid | C20H28FNO5 | 详情 | 详情 |
合成路线2
Acid (XV) was coupled with protected amino acid (XVI) to give amide (XVII), and the Boc protecting group of (XVII) was then removed under acidic conditions. The resulting amine (XVIII) was condensed with cyclopentyl chlorothioformate (XIX) to provide thiocarbamate (XX). Finally, the title compound was obtained by trifluoroacetic acid-promoted cleavage of the trityl protecting group.
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 24617 | (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid | C20H28FNO5 | 详情 | 详情 | |
| (XVI) | 24618 | ethyl (E,4S)-4-amino-7-oxo-7-(tritylamino)-2-heptenoate | C28H30N2O3 | 详情 | 详情 | |
| (XVII) | 24619 | ethyl (E,4S)-4-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate | C48H56FN3O7 | 详情 | 详情 | |
| (XVIII) | 24620 | ethyl (E,4S)-4-[[(2R,5S)-5-amino-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate | C43H48FN3O5 | 详情 | 详情 | |
| (XIX) | 24621 | 1-[(chlorocarbonyl)sulfanyl]cyclopentane | C6H9ClOS | 详情 | 详情 | |
| (XX) | 24622 | ethyl (E,4S)-4-[[(2R,5S)-5-[[(cyclopentylsulfanyl)carbonyl]amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate | C49H56FN3O6S | 详情 | 详情 |