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【结 构 式】 
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【分子编号】18806 【品名】1,1,1-trifluoro-2-iodoethane 【CA登记号】353-83-3 |
【 分 子 式 】C2H2F3I 【 分 子 量 】209.9375596 【元素组成】C 11.44% H 0.96% F 27.15% I 60.45% |
合成路线1
该中间体在本合成路线中的序号：1) The alkylation of 2-amino-5-chlorobenzophenone (I) with 2,2,2-trifluoroethyl trichloromethansulfonate (II) in refluxing xylene gives the N-trifluoroethyl derivative (III), which is then cyclized with glycine ethyl ester (A) in refluxing pyridine. 2) Compound (III) can also be bromoacetylated with bromoacetyl bromide (B) in refluxing benzene yielding the N-bromoacetyl compound (IV), which is then cyclized with ammonia in CHCl3. 3) By alkylation of 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IX) with NaOMe and 2,2,2-trifluoroethyl iodide in MeOH.
| 【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 . |
| 【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 . |
| 【3】 Topliss, J.G.; Verfahren zur Herstellung von neuen 1,4-benzodiazepinen bzw. ihren 4-Oxyden. CH 505842; DE 1793682; FR 1518382; GB 1179125 . |
| 【4】 Castaner, J.; Thorpe, P.; Halazepam. Drugs Fut 1978, 3, 2, 109. |
| 【5】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18806 | 1,1,1-trifluoro-2-iodoethane | 353-83-3 | C2H2F3I | 详情 | 详情 | |
| (A) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (B) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (I) | 10279 | (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone | 719-59-5 | C13H10ClNO | 详情 | 详情 |
| (II) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |
| (III) | 33848 | [5-chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](phenyl)methanone | C15H11ClF3NO | 详情 | 详情 | |
| (IV) | 33849 | N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide | C17H12BrClF3NO2 | 详情 | 详情 | |
| (IX) | 10281 | 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro | 1088-11-5 | C15H11ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).
| 【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; KMD-3213. Drugs Fut 2001, 26, 6, 553. |
| 【2】 Kitazawa, M.; Ban, M.; Okazaki, K.; Ozawa, M.; Yazaki, T.; Yamagishi, R. (Kissei Pharmaceutical Co., Ltd.); Indoline cpds. for the treatment of dysuria. EP 0600675; JP 1994220015; US 5387603 . |
| 【3】 Kitazawa, M.; Ozawa, M.; Okazaki, K.; Yamagishi, R.; Yazaki, T.; Saka, M. (Kissei Pharmaceutical Co., Ltd.); Indole derivs.. JP 1995330726 . |
| 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) | 47548 | 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-1-propanone | C13H15NO2 | 详情 | 详情 | |
| (II) | 47549 | 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromo-1-propanone | C13H14BrNO2 | 详情 | 详情 | |
| (III) | 47550 | 1-[5-(2-bromopropyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C13H16BrNO | 详情 | 详情 | |
| (IV) | 47551 | 1-[5-(2-bromopropyl)-7-nitro-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C13H15BrN2O3 | 详情 | 详情 | |
| (V) | 47552 | 1-[7-amino-5-(2-bromopropyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C13H17BrN2O | 详情 | 详情 | |
| (VI) | 47553 | 1-acetyl-5-(2-bromopropyl)-7-indolinecarbonitrile | C14H15BrN2O | 详情 | 详情 | |
| (VII) | 47554 | 1-acetyl-5-(2-azidopropyl)-7-indolinecarbonitrile | C14H15N5O | 详情 | 详情 | |
| (VIII) | 47555 | 1-acetyl-5-(2-aminopropyl)-7-indolinecarbonitrile | C14H17N3O | 详情 | 详情 | |
| (IX) | 47556 | 1-(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene; 2-(2-bromoethoxy)phenyl 2,2,2-trifluoroethyl ether | C10H10BrF3O2 | 详情 | 详情 | |
| (X) | 47557 | 1-acetyl-5-[2-([2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-7-indolinecarbonitrile | C24H26F3N3O3 | 详情 | 详情 | |
| (XVIII) | 13182 | Guaiacol; 2-Methoxyphenol | 90-05-1 | C7H8O2 | 详情 | 详情 |
| (XIX) | 18806 | 1,1,1-trifluoro-2-iodoethane | 353-83-3 | C2H2F3I | 详情 | 详情 |
| (XX) | 47558 | 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene; 2-methoxyphenyl 2,2,2-trifluoroethyl ether | C9H9F3O2 | 详情 | 详情 | |
| (XXI) | 47559 | 2-(2,2,2-trifluoroethoxy)phenol | C8H7F3O2 | 详情 | 详情 | |
| (XXII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Alkylation of 2-(S)-tert-butyl-5-(S)-methyl-1,3-dioxolan-4-one (I) with 1,1,1-trifluoro-2-iodoethane (II) in the presence of LDA in THF at -72 C provided trifluoroethyl compound (III). Condensation of (III) with 4-(methylthio)phenyllithium (IV), prepared from 4-bromothioanisole and BuLi, gave (V), which was hydrolyzed with p-toluenesulfonic acid in boiling water to afford ketone (VI). Subsequent oxidation of sulfide group with KHSO5 (Oxone(R)) in the presence of Oct3NMeCl (Aliquat 336(R)) produced sulfone (VII). Esterification of (VII) with chloroacetic acid using 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC) as the condensing agent provided chloroacetate (VIII). Finally, condensation with 3,4-difluorophenol (IX) in the presence of DBU in acetonitrile gave the intermediate ether (X), which cyclized to produce the target furanone.
| 【1】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 . |
| 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) | 18805 | (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolan-4-one | C8H14O3 | 详情 | 详情 | |
| (II) | 18806 | 1,1,1-trifluoro-2-iodoethane | 353-83-3 | C2H2F3I | 详情 | 详情 |
| (III) | 18807 | (2S,5R)-2-(tert-butyl)-5-methyl-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-one | C10H15F3O3 | 详情 | 详情 | |
| (IV) | 18808 | [4-(methylsulfanyl)phenyl]lithium | C7H7LiS | 详情 | 详情 | |
| (V) | 18809 | (2S,5R)-2-(tert-butyl)-5-methyl-4-[4-(methylsulfanyl)phenyl]-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-ol | C17H23F3O3S | 详情 | 详情 | |
| (VI) | 18810 | (2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-butanone | C12H13F3O2S | 详情 | 详情 | |
| (VII) | 18811 | (2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone | C12H13F3O4S | 详情 | 详情 | |
| (VIII) | 18812 | (1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-chloroacetate | C14H14ClF3O5S | 详情 | 详情 | |
| (IX) | 16739 | 3,4-difluorophenol | 2713-33-9 | C6H4F2O | 详情 | 详情 |
| (X) | 18814 | (1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-(3,4-difluorophenoxy)acetate | C20H17F5O6S | 详情 | 详情 |