Cesium carbonate → HCID 86652375, compound

HRID 2063710Notes

Reaction equation

HRID 2063710 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][C@H:9]2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([F:16])([F:14])[F:15])[CH2:10][C@H:9]2[CH2:17][C:18]#[N:19])=[CH:6][CH:7]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 157153Benzene, 2-chloro-1-fluoro-4-(trifluoromethyl)-HCID 67085721HCID 67085721, compound

Product 1

HCID 86652375HCID 86652375, compoundYield 87.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

2-((2S,4S)-1-(4-hydroxyphenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile (49A, 0.020 g, 0.074 mmol) and 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.029 g, 0.15 mmol) were dissolved in DMF (0.8 mL) and cesium carbonate (0.060 g, 0.19 mmol) was added. The mixture was heated to 110° C. for 2 h. The reaction was cooled to rt and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography to provide (S)-2-(1-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile (0.029 g, 0.065 mmol, 87% yield) as an inseparable mixture of diastereomers which was taken on to the next step. Example 59 (off white solid, 0.002 g, 5 μmol, 15% yield) was prepared from (S)-2-(1-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile following the procedure of 36C. LC-MS Anal. Calc'd for C20H16ClF6NO3 467.79. found [M+H] 468.0. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 7.78-7.86 (1 H, m), 7.51 (1 H, d, J=8.59 Hz), 7.01 (2 H, d, J=8.84 Hz), 6.89 (1 H, d, J=8.59 Hz), 6.75 (2 H, d, J=9.09 Hz), 4.21-4.33 (1 H, m), 3.62 (1 H, t, J=9.35 Hz), 3.48-3.56 (1 H, m), 3.12-3.28 (1 H, m), 2.85 (1 H, dd, J=15.92, 2.78 Hz), 2.65 (1 H, dt, J=13.64, 8.59 Hz), 2.28 (1 H, dd, J=15.92, 9.85 Hz), 2.02 (1 H, ddd, J=13.58, 7.89, 5.81 Hz). Analytical HPLC: RT=11.2 min, HI: 99.0%.

Workup

  1. temperatureThe reaction was cooled to rt
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×)
  4. washThe combined organic layers were washed with water (2×), brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customThe crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-0fbcb948cfcf4d9a88c460ce14ee3324
Source dataset
uspto-grants-2012_10
Patent number
US08288404B2

Reaction notes

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