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【结 构 式】 
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【药物名称】Venlafaxine hydrochloride, Wy-45030, Effexor LP, Efexor XL, Efexor XR, Efectin, Trevilor, Vandral, Dobupal, Efexor, Effexor 【化学名称】(±)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride 【CA登记号】99300-78-4, 93413-78-6 (deleted CAS), 93413-69-5 (free base) 【 分 子 式 】C17H28ClNO2 【 分 子 量 】313.87121 |
【开发单位】Wyeth Pharmaceuticals (Originator), Solvay (Marketer), Almirall Prodesfarma (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antidepressants, Anxiolytics, Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Generalized Anxiety Disorder (GAD), Treatment of, Mood Disorders, Treatment of, Neuropathic Pain, Treatment of, Posttraumatic Stress Disorder (PTSD), Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Social Phobia, Treatment for, Treatment of Diabetic Complications, 5-HT Reuptake Inhibitors, Norepinephrine Reuptake Inhibitors |
合成路线1
The condensation of cyclohexanone (I) with 4 methoxyphenylacetonitrile (II) by means of n-butyllithium in THF gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl) acetonitrile (III), which is reduced with H2 over Rh/A12O3 in ethanol-ammonia yielding 1-[2-amino-1-(4 methoxyphenyl)ethyl]cyclohexanol (IV). Finally, this compound is methylated with formaldehyde and formic acid in refluxing water.
| 【1】 Husbands, G.E.; et al.; Novel phenethylamine antidepressants. 190th ACS Natl Meet (Chicago) 1985, 20, 29-30, Abst MEDI 80. |
| 【2】 Morris, G.E.; Muth, E.A.; Yardley, J.P. (American Home Products Corp.); Phenethylamine derivs.. EP 0112669; ES 8702336; GB 2133788; JP 1991135948; JP 1991178953; US 4535186 . |
| 【3】 Prous, J.; Castaner, J.; WY-45030. Drugs Fut 1988, 13, 9, 839. |
| 【4】 Yardley, J.P.; Husbands, G.E.M.; Stack, G.; et al.; 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: Synthesis and antidepressant activity. J Med Chem 1990, 33, 10, 2899-905. |
| 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) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (II) | 23242 | 2-(4-methoxyphenyl)acetonitrile; 4-methoxybenzeneacetonitrile | 104-47-2 | C9H9NO | 详情 | 详情 |
| (III) | 23243 | 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile | C15H19NO2 | 详情 | 详情 | |
| (IV) | 23244 | 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol | 93413-77-5 | C15H23NO2 | 详情 | 详情 |
合成路线2
The condensation of 2-(4-methoxyphenyl)-N,N-dimethylthioacetamide (I) with cyclohexanone (II) by means of isopropylmagnesium bromide in toluene/methyl tert-butyl ether gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylthioacetamide (III), which is finally desulfurized by means of Raney-nickel in dioxane/acetic acid.
| 【1】 Shepard, R.G. (John Wyeth & Brother Ltd.); Preparation of cyclohexanol derivs. and novel thioamide intermediates. US 5043466 . |
合成路线3
A new process for the production of venlafaxine has been reported: Esterification of 2-(4-methoxyphenyl)-acetic acid (I) with ethanol and sulfuric acid gives the corresponding ethyl ester (II), which is condensed with ethyl formate by means of NaH to yield 2-formyl-3-(4-methoxyphenyl)acetic acid ethyl ester (III). Reaction of (III) with dimethylamine and K2CO3 in EtOH affords 3-(dimethylamino)-2-(4-methoxyphenyl)acrylic acid ethyl ester (IV), which is reduced with either NaBH4, LiAlH4 or H2 over Pd/C or Pt/C in ethanol to provide the corresponding propionic ester (V). Finally, this compound is cyclized with the bismagnesiane (VI) in THF. Alternatively, acrylic ester (IV) can be obtained directly by condensation of acetate (II) with dimethylformamide diethylacetal (VII) at 135 C. Alternatively, propionic ester (V) can be obtained by condensation of acetate (II) with N,N-dimethylmethylene-iminium iodide (VIII) by means of LDA in THF/heptane/ ethylbenzene.
| 【1】 Camps Garcia, P.; Bosch i Llado, J.; Onrubia Miguel, M.C.; Arnalot i Aguilar, C.; Soldevila Madrid, N. (Medichem SA); Venlafaxine production process. WO 0107397 . |
| 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) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (II) | 48550 | 4-methoxyphenylacetic acid ethyl ester; Ethyl 4-methoxyphenylacetate; Homoanisic acid ethyl ester | 14062-18-1 | C11H14O3 | 详情 | 详情 |
| (III) | 48551 | ethyl 2-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (IV) | 48552 | ethyl (E)-3-(dimethylamino)-2-(4-methoxyphenyl)-2-propenoate | C14H19NO3 | 详情 | 详情 | |
| (V) | 48553 | ethyl 3-(dimethylamino)-2-(4-methoxyphenyl)propanoate | C14H21NO3 | 详情 | 详情 | |
| (VI) | 48554 | Pentamethylenebis(magnesium bromide); Pentane-1,5-di(magnesium bromide) | C5H10Br2Mg2 | 详情 | 详情 | |
| (VII) | 31457 | N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine | 1188-33-6 | C7H17NO2 | 详情 | 详情 |
| (VIII) | 48555 | Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide | C3H8IN | 详情 | 详情 |