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【结 构 式】 
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【分子编号】35079 【品名】3,3-bis(3-fluorophenyl)propanenitrile 【CA登记号】 |
【 分 子 式 】C15H11F2N 【 分 子 量 】243.2558864 【元素组成】C 74.06% H 4.56% F 15.62% N 5.76% |
合成路线1
该中间体在本合成路线中的序号：(IV)This compound has been obtained by two related ways: 1) The condensation of 3,3'-difluorobenzophenone (I) with diethyl cyanomethylphosphonate (II) by means of NaH in dimethoxyethane gives 3,3-bis(3-fluorophenyl)-2-propenenitrile (III), which is reduced with H2 over Pd(OH)2 in ethanol yielding 3,3-bis(3-fluorophenyl)propionitrile (IV). Finally, this compound is reduced with B2H6 in THF. 2) The condensation of 3,3'-difluorobenzophenone (I) with acetonitrile (V) by means of BuLi in THF gives 3,3-bis(3-fluorophenyl)-3-hydroxypropionitrile (VI), which is reduced with H2 over Ni/Al in ethanol yielding 3,3-bis(3-fluorophenyl)-3-hydroxypropylamine (VII). The dehydration of (VII) by means of HCl in refluxing ethanol affords 3,3-bis(3-fluorophenyl)-2-propenamine (VIII), which is finally reduced with H2 over Pd/C in ethanol.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 35077 | bis(3-fluorophenyl)methanone | 345-70-0 | C13H8F2O | 详情 | 详情 |
| (II) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (III) | 35078 | 3,3-bis(3-fluorophenyl)acrylonitrile | C15H9F2N | 详情 | 详情 | |
| (IV) | 35079 | 3,3-bis(3-fluorophenyl)propanenitrile | C15H11F2N | 详情 | 详情 | |
| (V) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (VI) | 37211 | 3,3-bis(3-fluorophenyl)-3-hydroxypropanenitrile | C15H11F2NO | 详情 | 详情 | |
| (VII) | 37212 | 3-amino-1,1-bis(3-fluorophenyl)-1-propanol | C15H15F2NO | 详情 | 详情 | |
| (VIII) | 37213 | 3,3-bis(3-fluorophenyl)-2-propen-1-amine; 3,3-bis(3-fluorophenyl)-2-propenylamine | C15H13F2N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Horner-Emmons condensation of 3,3'-difluorobenzophenone (I) with diethyl (cyanomethyl)phosphonate provided 3,3-bis(3-fluorophenyl)acrylonitrile (II). The olefinic double bond of (II) was then reduced using catalytic hydrogenation to give (III). After deprotonation of (III) with either lithium diisopropylamide or lithium hexamethyldisilazide at -78 C, alkylation with iodomethane afforded the racemic alpha-methyl nitrile (IV). Isolation of the required (R)-enantiomer (V) was accomplished by means of chiral HPLC. Finally, reduction of the nitrile group of (V) with borane-dimethyl sulfide complex provided the title amine, which was isolated as the hydrochloride salt.
| 【1】 Moe, S.T.; Shimizu, S.M.; Smith, D.L.; et al.; Synthesis, biological activity, and absolute stereochemical assignment NPS 1392: A potent and stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 1999, 9, 14, 1915. |
| 【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 . |
| 【3】 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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 | |
| (I) | 35077 | bis(3-fluorophenyl)methanone | 345-70-0 | C13H8F2O | 详情 | 详情 |
| (II) | 35078 | 3,3-bis(3-fluorophenyl)acrylonitrile | C15H9F2N | 详情 | 详情 | |
| (III) | 35079 | 3,3-bis(3-fluorophenyl)propanenitrile | C15H11F2N | 详情 | 详情 | |
| (IV) | 35080 | 3,3-bis(3-fluorophenyl)-2-methylpropanenitrile | C16H13F2N | 详情 | 详情 | |
| (V) | 35081 | (2R)-3,3-bis(3-fluorophenyl)-2-methylpropanenitrile | C16H13F2N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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 |