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【结 构 式】 
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【药物名称】Delucemine hydrochloride, NPS-1506 【化学名称】N-[3,3-Bis(3-fluorophenyl)propyl]-N-methylamine hydrochloride 【CA登记号】186495-99-8, 186495-49-8 (free base) 【 分 子 式 】C16H18ClF2N 【 分 子 量 】297.77836 |
【开发单位】NPS Pharmaceuticals (Originator) 【药理作用】Antidepressants, Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Stroke, Treatment of, 5-HT Reuptake Inhibitors, NMDA Antagonists |
合成路线1
Treatment of ethyl acrylate (I) with N-benzylmethylamine (II) affords aminopropionate derivative (III), which is then subjected to Grignard reaction with 3-bromoflurobenzene (IV) by means of Mg and catalytic iodine in refluxing THF and crystallized as a hydrochloride salt by treatment with HCl to provide propylamino derivative (V). Alcohol (V) is converted into allylamine (VI) by elimination induced by heating with HCl/HOAc, and finally the target product is obtained by hydrogenation of (VI) catalyzed by Pd(OH)2/C in EtOH.
| 【1】 Moe, S.; Mueller, A.; Balandrin, M. (NPS Pharmaceuticals, Inc.); Methods and cpds. for treating depression and other disorders. EP 1096926; WO 0002551 . |
| 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) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 48848 | ethyl 3-[benzyl(methyl)amino]propanoate | C13H19NO2 | 详情 | 详情 | |
| (IV) | 28002 | 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene | 1073-06-9 | C6H4BrF | 详情 | 详情 |
| (V) | 48849 | 3-[benzyl(methyl)amino]-1,1-bis(3-fluorophenyl)-1-propanol | C23H23F2NO | 详情 | 详情 | |
| (VI) | 48850 | N-benzyl-N-[3,3-bis(3-fluorophenyl)-2-propenyl]-N-methylamine; N-benzyl-3,3-bis(3-fluorophenyl)-N-methyl-2-propen-1-amine | C23H21F2N | 详情 | 详情 |
合成路线2
Alternatively, the desired compound can be obtained as follows: Treatment of diethyl cyanomethyl phosphonate (VII) with NaH in dimethoxyethane (DME) followed by reaction with 3,3'-difluorobenzophenone (VIII) gives alkene derivative (IX), which is then hydrogenated over Pd(OH)2 to provide compound (X). Reduction of the cyano moiety of (X) by means of B2H6-THF followed by treatment with refluxing HCl yields substituted propylamine (XI), which is then converted into formamide (XIII) by treatment with refluxing ethyl formate (XII). Compound (XIII) is then reduced by means of borane-methyl sulfide in refluxing THF and finally treated with HCl. Propylamine (XI) can also be obtained following these steps: Treatment of benzophenone derivative (VIII) with n-BuLi and acetonitrile in THF affords cyano derivative (XIV), which is then hydrogenated over Ni/Al and NaOH in EtOH to furnish amine (XV). Elimination of the tertiary alcohol (XV) by refluxing with HCl in EtOH gives substituted diphenylpropenamine hydrochloride (XVI), which is hydrogenated over Pd/C in EtOH and finally subjected to hydrochloride salt neutralization.
| 【1】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 . |
| 【2】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (VIII) | 35077 | bis(3-fluorophenyl)methanone | 345-70-0 | C13H8F2O | 详情 | 详情 |
| (IX) | 35078 | 3,3-bis(3-fluorophenyl)acrylonitrile | C15H9F2N | 详情 | 详情 | |
| (X) | 35079 | 3,3-bis(3-fluorophenyl)propanenitrile | C15H11F2N | 详情 | 详情 | |
| (XI) | 48851 | 3,3-bis(3-fluorophenyl)-1-propanamine; 3,3-bis(3-fluorophenyl)propylamine | C15H15F2N | 详情 | 详情 | |
| (XII) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (XIII) | 48852 | 3,3-bis(3-fluorophenyl)propylformamide | C16H15F2NO | 详情 | 详情 | |
| (XIV) | 37211 | 3,3-bis(3-fluorophenyl)-3-hydroxypropanenitrile | C15H11F2NO | 详情 | 详情 | |
| (XV) | 37212 | 3-amino-1,1-bis(3-fluorophenyl)-1-propanol | C15H15F2NO | 详情 | 详情 | |
| (XVI) | 37213 | 3,3-bis(3-fluorophenyl)-2-propen-1-amine; 3,3-bis(3-fluorophenyl)-2-propenylamine | C15H13F2N | 详情 | 详情 |