【结 构 式】 |
【分子编号】60551 【品名】3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate 【CA登记号】 |
【 分 子 式 】C20H21F3O5S 【 分 子 量 】430.4449496 【元素组成】C 55.81% H 4.92% F 13.24% O 18.58% S 7.45% |
合成路线1
该中间体在本合成路线中的序号:(VIII)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 |
合成路线2
该中间体在本合成路线中的序号:(XI)The condensation of 2,3-dimethylphenol (I) with 3-bromoanisole (II) by means of K2CO3 and CuO in pyridine gives the diaryl ether (III), which is demethylated by means of HBr in refluxing acetic acid to yield the phenol (IV). The condensation of (IV) with 4,4,4-trifluorobutylsulfonyl chloride (V) by means of t-BuOK in THF affords the sulfonate (VI), which is brominated by means of NBS in refluxing CCl4 to provide the bis(bromomethyl)compound (VII). The cyclization of (VII) with dimethyl malonate (VIII) by means of K2CO3 in refluxing butanone furnishes the indane-dicarboxylate (IX), which is hydrolyzed and monodecarboxylated by means of HBr in refluxing acetic acid/water to give the indane-carboxylic acid (X). The reduction of the CO2H group of (X) by means of BH3/Me2S in THF yields the racemic hydroxymethyl derivative (XI), which is finally submitted to optical resolution by means of chiral preparative HPLC over Chiracel OD to provide the target (R)-enantiomer.
【1】 Dressel, J.; Matzke, M.; Mittendorf, J.; De Vry, J.-M.V.; Mauler, F.; Friedl, A.; Horvath, E.; Keldenich, J.; Franz, J.; Spreyer, P.; Vöhringer, V.; Rock, M.-H.; Schumacher, J. (Bayer AG); Novel aryl sulphonamide amino acid esters and analogues. CA 2341028; DE 19837627; EP 1105371; US 6545050; WO 0010968 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(B) | 60555 | 4,4,4-trifluorobutyl methanesulfonate | C5H9F3O3S | 详情 | 详情 | |
(A) | 60556 | 4,4,4-trifluoro-1-butanol | C4H7F3O | 详情 | 详情 | |
(I) | 40074 | 2,3-dimethylphenol | 526-75-0 | C8H10O | 详情 | 详情 |
(II) | 35983 | m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether | 2398-37-0 | C7H7BrO | 详情 | 详情 |
(III) | 60552 | 3-(2,3-dimethylphenoxy)phenyl methyl ether; 1-(3-methoxyphenoxy)-2,3-dimethylbenzene | C15H16O2 | 详情 | 详情 | |
(IV) | 60553 | 3-(2,3-dimethylphenoxy)phenol | C14H14O2 | 详情 | 详情 | |
(V) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
(VI) | 60557 | 3-(2,3-dimethylphenoxy)phenyl 4,4,4-trifluoro-1-butanesulfonate | C18H19F3O4S | 详情 | 详情 | |
(VII) | 60558 | 3-[2,3-bis(bromomethyl)phenoxy]phenyl 4,4,4-trifluoro-1-butanesulfonate | C18H17Br2F3O4S | 详情 | 详情 | |
(VIII) | 19373 | dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
(IX) | 60559 | dimethyl 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-1,3-dihydro-2H-indene-2,2-dicarboxylate | C23H23F3O8S | 详情 | 详情 | |
(X) | 60560 | 4-(3-{[(4,4,4-trifluorobutyl)sulfonyl]oxy}phenoxy)-2-indanecarboxylic acid | C20H19F3O6S | 详情 | 详情 | |
(XI) | 60551 | 3-{[2-(hydroxymethyl)-2,3-dihydro-1H-inden-4-yl]oxy}phenyl 4,4,4-trifluoro-1-butanesulfonate | C20H21F3O5S | 详情 | 详情 | |
(C) | 60554 | 4,4,4-trifluoro-1-butanesulfenyl cyanide | C5H6F3NS | 详情 | 详情 |