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

HRID 589630

反応式

HRID 589630 の反応式
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]

参加物

6

反応物 4

HCID 962WaterHCID 6375Nitromethane2 回HCID 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-dione3 回

生成物 1

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

試薬・触媒・溶媒 1

HCID 111,2-Dichloroethane溶媒

実験手順

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.

後処理

  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)

出典と根拠

ORDレコード
ord-ecd44248225742b5bc27c2eca8199ba6
出典データセット
uspto-grants-2016_01
特許番号
US09233920B2

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