【结 构 式】 |
【分子编号】31863 【品名】(E)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-3-buten-1-one 【CA登记号】 |
【 分 子 式 】C28H36N2O2 【 分 子 量 】432.60612 【元素组成】C 77.74% H 8.39% N 6.48% O 7.4% |
合成路线1
该中间体在本合成路线中的序号:(IX)This compound has been obtained by three related ways: 1.- The Grignard condensation of ethyl cyclohexanecarboxylate (I) with benzylmagnesium bromide (II) in THF gives 1-cyclohexyl-2-phenylethanone (III), which is condensed with bromoacetaldehyde diethyl acetal (IV) by means of potassium tert-butoxide in DMSO to yield 4-cyclohexyl-4-oxo-3-phenylbutyraldehyde diethylacetal (V). The methylation of (V) by means of methyl iodide and potassium tert-butoxide in the same solvent affords 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde diethylacetal (VI), which is treated with HCl in acetone to give the corresponding aldehyde (VII). The reductocondensation of (VII) with 1-(2-methoxyphenyl)piperazine (VIII) by means of sodium triacetoxyborohydride in dichloromethane/acetic acid yields 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-1-butanone (X) as a racemic mixture, which is resolved by chiral chromatography over a Chiralpak AD column. 2.- The Grignard condensation of 2-phenylpropionaldehyde (XI) with cyclohexylmagnesium chloride (XII) in ethyl ether/THF gives 1-cyclohexyl-2-phenyl-1-propanol (XIII), which is oxidized with DMSO and P2O5 in dichloromethane yielding the corresponding ketone (XIV). The condensation of (XIV) with allyl bromide by means of potassium tert-butoxide in THF affords 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one (XV), which is ozonolyzed with O3 in methanol catalyzed by a small amount of Sudan III affording the previously reported aldehyde (VII). 3.- The condensation of aldehyde (VII) with 1-(2-methoxyphenyl)piperazine (VIII) can also be performed in isopropyl acetate giving 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-3-buten-1-one (IX), which is hydrogenated with H2 over Pd/C in isopropanol to afford the previously reported racemic mixture (X).
【1】 Xu, Y.C.; et al.; Synthesis and pharmacology of LY426965: A potent, selective orally active, and long-lasting 5-HT1A receptor antagonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 107. |
【2】 Kohlman, D.T.; O'Toole, J.C.; Godfrey, A.G.; Xu, Y.-C.; Zhang, T.Y. (Eli Lilly and Company); Arylpiperazines having activity at the serotonin 1A receptor. EP 0924205; WO 9931077 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
11463 | 3-Bromo-1-propene; 3-Bromopropene;allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
(I) | 31858 | ethyl cyclohexanecarboxylate | 3289-28-9 | C9H16O2 | 详情 | 详情 |
(II) | 28308 | benzyl(bromo)magnesium; benzylmagnesium bromide | 1589-82-8 | C7H7BrMg | 详情 | 详情 |
(III) | 31859 | 1-cyclohexyl-2-phenyl-1-ethanone | C14H18O | 详情 | 详情 | |
(IV) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
(V) | 31860 | 1-cyclohexyl-4,4-diethoxy-2-phenyl-1-butanone | C20H30O3 | 详情 | 详情 | |
(VI) | 31861 | 1-cyclohexyl-4,4-diethoxy-2-methyl-2-phenyl-1-butanone | C21H32O3 | 详情 | 详情 | |
(VII) | 31862 | 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal | C17H22O2 | 详情 | 详情 | |
(VIII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
(IX) | 31863 | (E)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-3-buten-1-one | C28H36N2O2 | 详情 | 详情 | |
(X) | 31864 | 1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-1-butanone | C28H38N2O2 | 详情 | 详情 | |
(XI) | 31865 | hydratropaldehyde | 93-53-8 | C9H10O | 详情 | 详情 |
(XII) | 31866 | chloro(cyclohexyl)magnesium | C6H11ClMg | 详情 | 详情 | |
(XIII) | 31867 | 1-cyclohexyl-2-phenyl-1-propanol | C15H22O | 详情 | 详情 | |
(XIV) | 31868 | 1-cyclohexyl-2-phenyl-1-propanone | C15H20O | 详情 | 详情 | |
(XV) | 31869 | 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one | C18H24O | 详情 | 详情 |