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【结 构 式】 
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【药物名称】LY-426965 【化学名称】(+)-1-Cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2(S)-methyl-2-phenylbutan-1-one monohydrochloride 【CA登记号】228418-79-9 (undefined isomer free base), 228418-81-3 (undefined isomer, diHCl salt), 228418-80-2 (undefined isomer, monomaleate 【 分 子 式 】C28H39ClN2O2 【 分 子 量 】471.08823 |
【开发单位】Lilly (Originator), Synaptic (Codevelopment) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Smoking Cessation, Aid to, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, 5-HT1A Antagonists |
合成路线1
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 |
合成路线2
The alkylation of phenylacetylene (I) with AlMe3 and ZnCl2CP2 gives the alpha-methylstyrene (II), which is treated with paraformaldehyde and BuLi to yield 3-phenyl-2-buten-1-ol (III). The reaction of (III) with NCS and DMS affords the butenyl chloride (IV), which is treated with trichlorosilane, TEA and CuCl to provide the allylic trichlorosilane (V). The condensation of (V) with benzaldehyde (VI) by means of the chiral catalyst (VII) and tetrabutylammonium iodide in dichloromethane gives the chiral diphenylcarbinol (VIII), which is submitted to hydroboration by means of 9-BBN and NaBO3 to yield the diol (IX). The selective, two step reduction of one phenyl group of (IX) with H2 over Rh/alumina and H2 over Pt/C affords the chiral cyclohexyl-butanediol derivative (X), which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to provide the keto-aldehyde (XI). Finally, this compound is reductocondensed with 1-(2-methoxyphenyl)piperazine (XII) by means of NaBH(OAc)3 in 1,2-dichloroethane to give the target disubstituted piperazine.
| 【1】 Denmark, S.E.; Fu, J.; Asymmetric construction of quaternary centers by enantioselective allylation: Application to the synthesis of the serotonin antagonist lY426965. Org Lett 2002, 4, 11, 1951. |
| 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) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
| (II) | 28450 | 1-isopropenylbenzene | 98-83-9 | C9H10 | 详情 | 详情 |
| (III) | 57208 | (E)-3-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (IV) | 57209 | 1-[(E)-3-chloro-1-methyl-1-propenyl]benzene | C10H11Cl | 详情 | 详情 | |
| (V) | 57210 | trichloro[(E)-3-phenyl-2-butenyl]silane | C10H11Cl3Si | 详情 | 详情 | |
| (VI) | 57211 | (9aS,9bS)-5-[{5-[[(9aS,9bS)-5-oxooctahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-yl](methyl)amino]pentyl}(methyl)amino]octahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-one | C23H44N6O2P2 | 详情 | 详情 | |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 57212 | (1S,2S)-2-methyl-1,2-diphenyl-3-buten-1-ol | C17H18O | 详情 | 详情 | |
| (IX) | 57213 | (1S,2S)-2-methyl-1,2-diphenyl-1,4-butanediol | C17H20O2 | 详情 | 详情 | |
| (X) | 57214 | (1S,2S)-1-cyclohexyl-2-methyl-2-phenyl-1,4-butanediol | C17H26O2 | 详情 | 详情 | |
| (XI) | 57215 | (3S)-4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal | C17H22O2 | 详情 | 详情 | |
| (XII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |