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【结 构 式】 
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【分子编号】16515 【品名】methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate 【CA登记号】 |
【 分 子 式 】C21H25NO5 【 分 子 量 】371.43324 【元素组成】C 67.91% H 6.78% N 3.77% O 21.54% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxocyclohexanecarboxylic acid methyl ester (I) with trifluoromethanesulfonic anhydride gives the enol triflate (II), which is desulfonated with triphenylphosphine, palladium acetate and formic acid yielding 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-1-clohexene-1-carboxylic acid methyl ester (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in methanol affords the cis carboxylic ester (IV), which is hydrolyzed with KOH in in methanol to provide the free carboxylic acid (V). The reaction of (V) with isobutyl chloroformate and then with NH4OH gives the corresponding amide (VI), which is finally cyclized with N,N-dimethylacetamide dimethylacetal (VII) by heating at 110 C to obtain target compound as a racemate.
| 【1】 Board, M.; Newsholme, E.A. (Isis Pharmaceuticals, Inc.); Use of glucokinase inhibitors for the manufacture of a medicament for treating tumours. WO 9503809 . |
| 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) | 16515 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate | C21H25NO5 | 详情 | 详情 | |
| (II) | 26690 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate | C22H24F3NO7S | 详情 | 详情 | |
| (III) | 26691 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-cyclohexene-1-carboxylate | C21H25NO4 | 详情 | 详情 | |
| (IV) | 26692 | methyl (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate | C21H27NO4 | 详情 | 详情 | |
| (V) | 26693 | (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid | C20H25NO4 | 详情 | 详情 | |
| (VI) | 26694 | (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxamide | C20H26N2O3 | 详情 | 详情 | |
| (VII) | 22915 | 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine | 18871-66-4 | C6H15NO2 | 详情 | 详情 |