4-(Trifluoromethyl)phenyl isocyanate → (4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamide

HRID 750395Notes

Reaction equation

HRID 750395 reaction equation
Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@H:4]1[OH:8].C(N(CC)C(C)C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[C:20]=[O:21]>ClCCl.C(OCC)(=O)C>[OH:8][C@@H:4]1[CH2:5][N:6]([C:20]([NH:19][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:21])[CH2:7][C:3]1([CH3:9])[CH3:2]

Participants

6

Reactant 3

HCID 737684-(Trifluoromethyl)phenyl isocyanateHCID 81531DiisopropylethylamineHCID 66936381(S)-4,4-Dimethylpyrrolidin-3-OL hydrochloride

Product 1

HCID 59752173(4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamideYield 99.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To 200 mg (1.3 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 0.25 mL (1.3 mmol) of N,N-diisopropylethylamine in 4 mL of dichloromethane was added dropwise 0.19 mL (1.3 mmol) of 1-isocyanato-4-(trifluoromethyl)benzene. The reaction mixture was stirred at room temperature for 18 h. It was then diluted with ethyl acetate, and the resulting solution was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 390 mg (quantitative yield) of (4S)-4-hydroxy-3,3-dimethyl-N-[4-(trifluoromethyl)phenyl]-1-pyrrolidinecarboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.73 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 5.08 (s, 1H), 3.74-3.55 (m, 2H), 3.27-3.09 (m, 3H), 0.97 (s, 3H), 0.95 (s, 3H). Cl-LCMS m/z 303 (M+H).

Workup

  1. washthe resulting solution was washed with 1 N hydrochloric acid and brine
  2. dry with materialdried over magnesium sulfate
  3. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-e5fae84885fa470a8b6ec9bf50519b6e
Source dataset
uspto-grants-2008_07
Patent number
US07402606B2

Reaction notes

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