【结 构 式】 |
【分子编号】55147 【品名】di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate 【CA登记号】 |
【 分 子 式 】C30H56N2O6Si 【 分 子 量 】568.87002 【元素组成】C 63.34% H 9.92% N 4.92% O 16.87% Si 4.94% |
合成路线1
该中间体在本合成路线中的序号:(XV)The mixture of amines (XI) was converted to the respective acetamides, and the desired isomer (XII) was then isolated by column chromatography. Hydrolysis of the acetate ester function of (XII) provided alcohol (XIII), which was oxidized to aldehyde (XIV) under Swern conditions. Wittig reaction of aldehyde (XIV) with ethyl triphenylphosphonium bromide and potassium tert-butoxide led to the (Z)-olefin (XV). After removal of the O-silyl protecting group of (XV) by means of tetrabutylammonium fluoride, the resultant alcohol (XVI) was oxidized to aldehyde (XVII) employing the Dess-Martin periodinane reagent. Addition of propylmagnesium bromide to aldehyde (XVII) furnished the alcohol adduct (XVIII).
【1】 Inhibitors of neuraminidases. WO 0128996 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 55143 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 | |
(XII) | 55144 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(acetyloxy)methyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O8Si | 详情 | 详情 | |
(XIII) | 55145 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 | |
(XIV) | 55146 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-formyl-1,2-pyrrolidinedicarboxylate | C28H52N2O7Si | 详情 | 详情 | |
(XV) | 55147 | di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O6Si | 详情 | 详情 | |
(XVI) | 55148 | di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-hydroxyethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C21H36N2O6 | 详情 | 详情 | |
(XVII) | 55149 | di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxoethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C21H34N2O6 | 详情 | 详情 | |
(XVIII) | 55150 | di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C24H42N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XV)The mixture of amines (XI) was converted to the respective acetamides, and the desired isomer (XII) was then isolated by column chromatography. Hydrolysis of the acetate ester function of (XII) provided alcohol (XIII), which was oxidized to aldehyde (XIV) under Swern conditions. Wittig reaction of aldehyde (XIV) with ethyl triphenylphosphonium bromide and potassium tert-butoxide led to the (Z)-olefin (XV). After removal of the O-silyl protecting group of (XV) by means of tetrabutylammonium fluoride, the resultant alcohol (XVI) was oxidized to aldehyde (XVII) employing the Dess-Martin periodinane reagent. Addition of propylmagnesium bromide to aldehyde (XVII) furnished the alcohol adduct (XVIII).
【1】 Inhibitors of neuraminidases. WO 0128996 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 55143 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 | |
(XII) | 55144 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(acetyloxy)methyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O8Si | 详情 | 详情 | |
(XIII) | 55145 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 | |
(XIV) | 55146 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-formyl-1,2-pyrrolidinedicarboxylate | C28H52N2O7Si | 详情 | 详情 | |
(XV) | 55147 | di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O6Si | 详情 | 详情 | |
(XVI) | 55148 | di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-hydroxyethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C21H36N2O6 | 详情 | 详情 | |
(XVII) | 55149 | di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxoethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C21H34N2O6 | 详情 | 详情 | |
(XVIII) | 55150 | di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C24H42N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XV)The mixture of amines (XI) was converted to the respective acetamides and the desired isomer (XII) was then isolated by column chromatography. Hydrolysis of the acetate ester function of (XII) provided alcohol (XIII), which was oxidized to aldehyde (XIV) under Swern conditions. Wittig reaction of aldehyde (XIV) with ethyl triphenylphosphonium bromide and potassium tert-butoxide led to the (Z)-olefin (XV). After removal of the O-silyl protecting group of (XV) by means of tetrabutylammonium fluoride, the resultant alcohol (XVI) was oxidized to aldehyde (XVII) employing the Dess-Martin periodinane reagent. Addition of propylmagnesium bromide to aldehyde (XVII) furnished the alcohol adduct (XVIII).
【1】 Inhibitors of neuraminidases. WO 0128996 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 55143 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 | |
(XII) | 55144 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(acetyloxy)methyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O8Si | 详情 | 详情 | |
(XIII) | 55145 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 | |
(XIV) | 55146 | di(tert-butyl) (2R,4R,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-formyl-1,2-pyrrolidinedicarboxylate | C28H52N2O7Si | 详情 | 详情 | |
(XV) | 55147 | di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O6Si | 详情 | 详情 | |
(XVI) | 55148 | di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-hydroxyethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C21H36N2O6 | 详情 | 详情 | |
(XVII) | 55149 | di(tert-butyl) (2R,4S,5R)-5-[(1R)-1-(acetylamino)-2-oxoethyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C21H34N2O6 | 详情 | 详情 | |
(XVIII) | 55150 | di(tert-butyl) (2R,4S,5R)-5-[(1R,2R)-1-(acetylamino)-2-hydroxypentyl]-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C24H42N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(III)The reduction of 4-hydroxyindane-2-carboxylic acid ethyl ester (I) by means of LiAlH4 in THF gives the hydroxymethyl derivative (II), which is condensed with 3-fluoronitrobenzene (III) by means of K2CO3 in DMF to yield the diaryl ether (IV). The reduction of the nitro group of (IV) by means of H2 over Pd/C in THF/methanol affords the aniline derivative (V), which is treated with NaNO2 and H2SO4 and heated at 100 C to provide the phenol (VI). The condensation of (VI) with 4,4,4-trifluorobutylsulfonyl chloride (VII) by means of t-BuOK in THF leads to the racemic sulfonate (VIII), which is finally submitted to optical resolution by preparative chiral HPLC over Chiracel OD to furnish the target (R)-enantiomer.
【1】 Raddatz, S.; De Vry, J.-M.-V.; Mohrs, K.-H.; Dressel, J.; Matzke, M.; Mittendorf, J.; Mauler, F.; Schuhmacher, J.; Friedl, A.; Horvath, E.; Jork, R.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H. (Bayer AG); Aryl sulfonamides and analogues thereof and their use in the treatment of neurodegenerative diseases. DE 19740785; EP 0966436; JP 2001515470; US 2002072529; US 6262112; US 6573278; WO 9837061 . |
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) | 60546 | ethyl 4-hydroxy-2-indanecarboxylate | C12H14O3 | 详情 | 详情 | |
(II) | 60547 | 2-(hydroxymethyl)-4-indanol | C10H12O2 | 详情 | 详情 | |
(III) | 55147 | di(tert-butyl) (2R,4S,5R)-5-{(1R)-1-(acetylamino)-2-[(triisopropylsilyl)oxy]ethyl}-4-[(Z)-1-propenyl]-1,2-pyrrolidinedicarboxylate | C30H56N2O6Si | 详情 | 详情 | |
(IV) | 60548 | [4-(3-nitrophenoxy)-2,3-dihydro-1H-inden-2-yl]methanol | C16H15NO4 | 详情 | 详情 | |
(V) | 60549 | [4-(3-aminophenoxy)-2,3-dihydro-1H-inden-2-yl]methanol | C16H17NO2 | 详情 | 详情 | |
(VI) | 60550 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenol | C16H16O3 | 详情 | 详情 | |
(VII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
(VIII) | 60551 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate | C20H21F3O5S | 详情 | 详情 |