Nitromethane → 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester

HRID 589627

Reaction equation

HRID 589627 reaction equation
FC(F)(F)C1C=C(NC(N[C@@H](C2C3C(=CC=C(OC)C=3)N=CC=2)[C@@H]2CC3CCN2CC3)=O)C=C(C(F)(F)F)C=1.C=CC.[N+:43]([CH3:46])([O-:45])=[O:44].[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])/[CH:60]=[C:61](\[C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)/[C:62]([F:65])([F:64])[F:63])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]>O>[C:47]([O:51][C:52](=[O:76])[C:53]1[CH:58]=[CH:57][C:56]([C:59](=[O:74])[CH2:60][C@@:61]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[C:68]([Cl:73])[CH:67]=2)([CH2:46][N+:43]([O-:45])=[O:44])[C:62]([F:64])([F:63])[F:65])=[CH:55][C:54]=1[CH3:75])([CH3:50])([CH3:49])[CH3:48]

Participants

6

Reactant 4

HCID 6375NitromethaneHCID 8252PropyleneHCID 866959924-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl esterHCID 866959931-[3,5-bis(trifluoromethyl)phenyl]-3-[(S)-(6-methoxy-4-quinolyl)-[(2S)-quinuclidin-2-yl]methyl]urea

Product 1

HCID 547615654-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

Alternatively, to a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-3-[(S)-(6-methoxy-4-quinolyl)-[(2S)-quinuclidin-2-yl]methyl]urea; prop-1-ene (09 mg, prepared according to the literature: Organic Letters 2007, 9, (14), 2621-2624) and nitromethane (0.6 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 (100 mg). The solution was heated for 3 days at 50° C. then allowed to stand at room temperature for 2 days. Water was then added and the resulting mixture was extracted with diethyl ether 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-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (100 mg). Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=90:10, 1 ml/min, retention time 6.43 minutes (major enantiomer), 7.78 minutes (minor enantiomer) indicated that the reaction proceeded with 95% enantioselectivity in favor of the R enantiomer.

Workup

  1. extractionthe resulting mixture was extracted with diethyl ether
  2. dry with materialthe combined organic fractions were dried over sodium sulfate
  3. customThe crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-3ce2f1484aa54c8eab46976c92283e4b
Source dataset
uspto-grants-2016_01
Patent number
US09233920B2

Linked notes

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