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

HRID 589630

Reaction equation

HRID 589630 reaction equation
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]

Participants

6

Reactant 4

HCID 962WaterHCID 6375Nitromethane2×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×

Product 1

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

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-ecd44248225742b5bc27c2eca8199ba6
Source dataset
uspto-grants-2016_01
Patent number
US09233920B2

Linked notes

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