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【结 构 式】 
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【分子编号】16519 【品名】methyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate 【CA登记号】 |
【 分 子 式 】C21H27NO4 【 分 子 量 】357.44972 【元素组成】C 70.56% H 7.61% N 3.92% O 17.9% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr, trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II), which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III). The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V), which is cyclized by means of NaH in refluxing DME, giving the 2-oxocyclohexanecarboxylic ester (VI). The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII), which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF, affording the cyclohexylidene-dithiane (IX). The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII). Finally, this compound is hydrolyzed with KOH in methanol/THF/water.
| 【1】 Graul, A.; Castañer, J.; Silvestre, J.S.; SB-207499. Drugs Fut 1998, 23, 6, 607. |
| 【2】 Christensen, S.B.; Forster, C.J.; Guider, A.; et al.; 1,4-Cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma. J Med Chem 1998, 41, 6, 821-35. |
| 【3】 Bordas-Nagy, J.; Gorycki, P.; Webb, K.S. (SmithKline Beecham plc); Cyano cpds. and preparation thereof. JP 1997510213; WO 9524381 . |
| 【4】 Christensen, S.B. IV (SmithKline Beecham plc); Cpds. useful for treating allergic and inflammatory diseases. EP 0633776; EP 0919544; JP 1995508508; US 5552438; US 5602157; WO 9319749 . |
| 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) | 16510 | 3-(cyclopentyloxy)-4-methoxybenzaldehyde | C13H16O3 | 详情 | 详情 | |
| (II) | 16511 | 4-(bromomethyl)-2-(cyclopentyloxy)phenyl methyl ether; 4-(bromomethyl)-2-(cyclopentyloxy)-1-methoxybenzene | C13H17BrO2 | 详情 | 详情 | |
| (III) | 16512 | 2-[3-(cyclopentyloxy)-4-methoxyphenyl]acetonitrile | C14H17NO2 | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 16514 | dimethyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]heptanedioate | C22H29NO6 | 详情 | 详情 | |
| (VI) | 16515 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate | C21H25NO5 | 详情 | 详情 | |
| (VII) | 16516 | 1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-oxocyclohexanecarbonitrile | C19H23NO3 | 详情 | 详情 | |
| (VIII) | 16517 | 1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane | 13411-42-2 | C7H16S2Si | 详情 | 详情 |
| (IX) | 16518 | 1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-(1,3-dithian-2-ylidene)cyclohexanecarbonitrile | C23H29NO2S2 | 详情 | 详情 | |
| (XII) | 16519 | methyl 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate | C21H27NO4 | 详情 | 详情 |