1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-oxocyclohexanecarbonitrile -Drug Synthesis Database

【结构式】

【分子编号】16516

【品名】1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-oxocyclohexanecarbonitrile

【CA登记号】

【分子式】C₁₉H₂₃NO₃

【分子量】313.39656

【元素组成】C 72.82% H 7.4% N 4.47% O 15.32%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

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.

参考文献中间体

合成目标

【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 cyclohexanone (I) with chloroacetonitrile, KOH and benzyltriethylammonium chloride in THF gives the cyanoepoxide (II), which is treated with LiBr and LiOH in DMF/acetonitrile/water to yield the lithium salt (III) of the title product. Finally, this salt is treated with HCl in ethyl acetate to afford the target Cilomilast.

参考文献中间体

合成目标

【1】 Badham, N.F.; Chen, J.-H.; Cummings, P.G.; Dell'Orco, P.C.; Diederich, A.M.; Eldridge, A.M.; Mendelson, W.L.; Mills, R.J.; Novack, V.J.; Olsen, M.A.; Rustum, A.M.; Webb, K.S.; Yang, S.; A practical synthesis of the PDE4 inhibitor, SB-207499, from a cyclohexanone precursor. Org Process Res Dev 2003, 7, 1, 101.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	31937	Triethylbenzylammonium chloride; N-benzyl-N,N-diethyl-1-ethanaminium chloride; Benzyltriethylammonium chloride	56-37-1	C₁₃H₂₂ClN	详情	详情
(I)	16516	1-[3-(cyclopentyloxy)-4-methoxyphenyl]-4-oxocyclohexanecarbonitrile		C₁₉H₂₃NO₃	详情	详情
(II)	61562	(2R)-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-oxaspiro[2.5]octane-2,6-dicarbonitrile		C₂₁H₂₄N₂O₃	详情	详情
(III)	61563	lithium 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate		C₂₀H₂₄LiNO₄	详情	详情

Extended Information