Water → 4-[(S)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester

HRID 589630

반응식

HRID 589630 반응식
FC(F)(F)C1C=C(NC2C(=O)C(=O)C=2N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@H]2CC3CCN2CC3C=C)C=C(C(F)(F)F)C=1.[C:46]([O:50][C:51](=[O:75])[C:52]1[CH:57]=[CH:56][C:55]([C:58](=[O:73])/[CH:59]=[C:60](\[C:65]2[CH:70]=[C:69]([Cl:71])[CH:68]=[C:67]([Cl:72])[CH:66]=2)/[C:61]([F:64])([F:63])[F:62])=[CH:54][C:53]=1[CH3:74])([CH3:49])([CH3:48])[CH3:47].[N+:76]([CH3:79])([O-:78])=[O:77].O>ClCCCl>[C:46]([O:50][C:51](=[O:75])[C:52]1[CH:57]=[CH:56][C:55]([C:58](=[O:73])[CH2:59][C@:60]([C:65]2[CH:70]=[C:69]([Cl:71])[CH:68]=[C:67]([Cl:72])[CH:66]=2)([CH2:79][N+:76]([O-:78])=[O:77])[C:61]([F:62])([F:64])[F:63])=[CH:54][C:53]=1[CH3:74])([CH3:49])([CH3:48])[CH3:47]

참가 물질

6

반응물 4

HCID 962WaterHCID 6375Nitromethane2회HCID 866959924-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl esterHCID 866959943-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione3회

생성물 1

HCID 547617394-[(S)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester

시약·촉매·용매 1

HCID 111,2-Dichloroethane용매

실험 절차

To a solution of 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (20 mg, prepared according to the literature: Org. Lett., 2010, 12 (23), 5450-5453) in 1,2-dichloroethane (1.5 mL) under argon, was added 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (300 mg) and nitromethane (0.35 ml). The solution was refluxed for 24 hours then more 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (20 mg) was added. The solution was refluxed for 48 hours then more nitromethane (0.35 mL) and 3-(3,5-Bis-trifluoromethyl-phenylamino)-4-{[(S)-(6-methoxy-quinolin-4-yl)-((R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-amino}-cyclobut-3-ene-1,2-dione (25 mg) were added. The solution was refluxed for another 16 hours and then the heating was stopped. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(S)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (127 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 7.52 minutes (major enantiomer), 6.30 minutes (minor enantiomer) indicated that the reaction proceeded with 93% enantioselectivity in favor of the S enantiomer.

후처리

  1. temperatureThe solution was refluxed for 24 hours
  2. temperatureThe solution was refluxed for 48 hours
  3. temperatureThe solution was refluxed for another 16 hours
  4. extractionThe resulting mixture was extracted with dichloromethane
  5. dry with materialthe combined organic fractions were dried over sodium sulfate
  6. customThe crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane)

출처 및 근거

ORD 기록
ord-ecd44248225742b5bc27c2eca8199ba6
출처 데이터셋
uspto-grants-2016_01
특허 번호
US09233920B2

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