HCID 23582736, compound → HCID 23582737, compound

HRID 238760Notes

Reaction equation

HRID 238760 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([C@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[O:32])([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:8]([F:10])[CH:9]=1)(=[O:3])[CH3:2].[CH3:39][Li]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[O:32])([C:6]2[CH:5]=[C:4]([C:1]([OH:3])([CH3:39])[CH3:2])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]

Participants

4

Reactant 2

HCID 23582736HCID 23582736, compoundHCID 178418348HCID 178418348, compound

Product 1

HCID 23582737HCID 23582737, compoundYield 39%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 257, mg, 0.037 mmol) in THF (1 mL) at 0° C. under argon was added dropwise CH3Li (1.4 M in Et2O, 0.04 mL, 0.056 mmoL). The reaction mixture was stirred at room temperature for 2 h, then quenched with sat. NH4Cl and 0.5 N HCl and the aqueous layer was extracted with EtOAc. The combined organic portions were washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 258, 8 mg, yield 39%). LCMS: RT=3.89 min [M+H] 559.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4Cl; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 7.51-7.45 (m, 2H), 7.21-6.96 (m, 6H), 6.68 (d, J=6.8 Hz, 2H), 6.61 (d, J=9.9 Hz, 1H), 5.43 (s, br, 1H), 5.17 (m, 1H), 4.01 (d, J=13.2 Hz, 1H), 3.85-3.62 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H).

Workup

  1. customquenched with sat. NH4Cl and 0.5 N HCl
  2. extractionthe aqueous layer was extracted with EtOAc
  3. washThe combined organic portions were washed with H2O, sat. NaCl
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by flash chromatography (silica gel, hexanes/EtOAc)

Sources & evidence

ORD record
ord-0b8453c742a7411f9ca04e1684a9c269
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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