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【结 构 式】 
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【分子编号】33607 【品名】4-(trifluoromethyl)phenol 【CA登记号】402-45-9 |
【 分 子 式 】C7H5F3O 【 分 子 量 】162.1113096 【元素组成】C 51.86% H 3.11% F 35.16% O 9.87% |
合成路线1
该中间体在本合成路线中的序号：(A)The reduction of beta-dimethylaminopropiophenone (I) with diborane in THF gives N,N-dimethyl-3-phenyl-3-hydroxypropylamine (II), which is converted into N,N-dimethyl-3-phenyl-3-chloropropylamine (III) wtih refluxing SOCl2. The condensation of 4-trifluoromethylphenol (A) with (III) by means of NaOH in refluxing methanol affords N,N-dimethyl-3-phenyl-3-(p-trifluoromethylphenoxy) propylamine (IV), which is treated with BrCN in benzene to yield N-methyl-N-cyano-3-phenyl-3-(p-trifluoromethylphenoxy)propylamine (V). Finally, (V) is hydrolyzed with KOH in ethylene glycol at 130 C.
| 【1】 Molloy, B.B.; Schmiegel, K.K. (Eli Lilly and Company); Arloxyphenylpropylamines. DE 2500110; ES 433720; FR 2257288; GB 1493961; JP 50101333; US 4314081 . |
| 【2】 Paton, D.M.; Castaner, J.; Fluoxetine. Drugs Fut 1977, 2, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 33607 | 4-(trifluoromethyl)phenol | 402-45-9 | C7H5F3O | 详情 | 详情 |
| (I) | 33602 | 3-(Dimethylamino)propiophenone; beta-Dimethylaminopropiophenone; 3-(dimethylamino)-1-phenyl-1-propanone | 879-72-1 | C11H15NO | 详情 | 详情 |
| (II) | 33603 | 3-(dimethylamino)-1-phenyl-1-propanol | C11H17NO | 详情 | 详情 | |
| (III) | 33604 | N-(3-chloro-3-phenylpropyl)-N,N-dimethylamine; 3-chloro-N,N-dimethyl-3-phenyl-1-propanamine | C11H16ClN | 详情 | 详情 | |
| (IV) | 33605 | N,N-dimethyl-N-[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]amine; N,N-dimethyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine | C18H20F3NO | 详情 | 详情 | |
| (V) | 33606 | methyl[3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]cyanamide | C18H17F3N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The enantioselective reduction of 2-benzoylacetonitrile (I) with BH3/Me2S complex catalyzed by the chiral catalyst (II) in THF gives 3(S)-hydroxy-3-phenylpropylamine (III), which is protected with tert-butyl dicarbonate and NaOH to yield the carbamate (IV). The condensation of (IV) with 4-(trifluoromethyl)phenol (V) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF affords N-[3(S)-phenyl-3-[4-(trifluoromethyl) phenoxy]propyl]carbamic acid tert-butyl ester (VI), which is finally reduced with LiAlH4 in refluxing THF to give the target (S)-Fluoxetine.
| 【1】 Jurgens, A.R.; Hilborn, J.W. (Sepracor Inc.); Fluoxetine process from benzoylacetonitrile. WO 0007976 . |
| 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) | 34897 | 3-oxo-3-phenylpropanenitrile | 614-16-4 | C9H7NO | 详情 | 详情 |
| (II) | 34898 | (3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C10H12BNO | 详情 | 详情 | |
| (III) | 34899 | (1S)-3-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (IV) | 34900 | tert-butyl (3S)-3-hydroxy-3-phenylpropylcarbamate | C14H21NO3 | 详情 | 详情 | |
| (V) | 33607 | 4-(trifluoromethyl)phenol | 402-45-9 | C7H5F3O | 详情 | 详情 |
| (VI) | 34901 | tert-butyl (3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate | C21H24F3NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The reduction of omega-chloropropiophenone (I) with NaBH4 in ethanol gives 3-chloro-1-phenyl-1-propanol (II), which is treated with butyric anhydride and pyridine in dichloromethane, yielding the corresponding racemic ester (III). The optical resolution of (III) with immobilized lipase B from Candida antarctica (CALB) affords a mixture of unreacted (S)-ester and (R)-alcohol (IV), which are separated by column chromatography. The condensation of alcohol (IV) with 4-(trifluoromethyl)phenol (V) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF gives the corresponding ether (VI), which is finally treated with methylamine in refluxing ethanol.
| 【1】 Anthonsen, T.; Ho, B.H.; Liu, H.L.; Chemoenzymatic synthesis of the non-tricyclic antidepressants fluoxetine, tomoxetine and nisoxetine. J Chem Soc - Perkins Trans I 2000, 11, 11, 1767. |
| 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) | 28073 | 3-chloro-1-phenyl-1-propanone | 936-59-4 | C9H9ClO | 详情 | 详情 |
| (II) | 28074 | 3-chloro-1-phenyl-1-propanol | C9H11ClO | 详情 | 详情 | |
| (III) | 37781 | 3-chloro-1-phenylpropyl butyrate | C13H17ClO2 | 详情 | 详情 | |
| (IV) | 37782 | (1R)-3-chloro-1-phenyl-1-propanol | C9H11ClO | 详情 | 详情 | |
| (V) | 33607 | 4-(trifluoromethyl)phenol | 402-45-9 | C7H5F3O | 详情 | 详情 |
| (VI) | 43106 | 1-[[(1R)-3-chloro-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzene; (1R)-3-chloro-1-phenylpropyl 4-(trifluoromethyl)phenyl ether | C16H14ClF3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Coupling of dihydroartemisinin (I) with p-trifluoromethylphenol (II) in the presence of trimethylsilyl triflate and silver perchlorate at -78 C produced the corresponding aryl ether as an epimeric mixture. The major 10-beta isomer was then isolated from the reaction mixture by column chromatography.
| 【1】 O'Neill, P.M.; et al.; Application of the TMSOTf-AgClO4 activator system to the synthesis of novel, potent, C-10 phenoxy derivatives of dihydroartemisinin. Tetrahedron Lett 1999, 40, 51, 9129. |
| 【2】 O'Neill, P.M.; Miller, A.; Bishop, L.P.D.; et al.; Synthesis, antimalarial activity, biomimetic iron(I) chemistry, and in vivo metabolism of novel, potent C-10-phenoxy derivatives of dihydroartemisinin. J Med Chem 2001, 44, 1, 58. |
| 【3】 Ward, S.A.; O'Neill, P.M. (Ultrafine Ltd.); Peroxide-based antimalarial cpds.. WO 0104123 . |