Nitrogen → 2-((2-(2,4-Difluorophenyl)oxiran-2-yl)difluoromethyl)-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyridine

HRID 63256Notes

Reaction equation

HRID 63256 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[CH:14]=[CH:15][C:16]([O:19][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)=[CH:17][N:18]=2)[CH2:11][O:10]1

Participants

6

Reactant 4

HCID 947NitrogenHCID 10796Cesium carbonateHCID 923422-Chloro-5-(trifluoromethyl)pyridineHCID 866755046-((2-(2,4-Difluorophenyl)oxiran-2-yl) difluoromethyl)pyridin-3-ol

Product 1

HCID 1177203842-((2-(2,4-Difluorophenyl)oxiran-2-yl)difluoromethyl)-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyridineYield 78.1%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
60 °C

Procedure

To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (250 mg, 0.836 mmol) (prepared as in WO 2012/177635 A1) and 2-chloro-5-(trifluoromethyl)pyridine (910 mg, 5.01 mmol) in dry DMSO (10.4 mL) was added cesium carbonate (Cs2CO3) (544 mg, 1.671 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. for 2.5 h, then the reaction was stopped by allowing it to cool to rt. The reaction was quenched with H2O, then extracted Et2O (3×). The combined organic extracts were washed with H2O (2×) and brine, dried by passing through a phase separator and volatiles were removed under rotary evaporation. The resulting residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 10-30% EtOAc/Hexanes over 10 min) to yield the title compound as a colorless oil (290 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.5 Hz, 1H), 8.44-8.39 (m, 1H), 7.98 (dd, J=8.6, 2.4 Hz, 1H), 7.62 (dd, J=8.6, 2.5 Hz, 1H), 7.59-7.53 (m, 1H), 7.41 (dd, J=14.7, 8.2 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.89-6.82 (m, 1H), 6.77 (ddd, J=9.8, 9.0, 2.5 Hz, 1H), 3.47 (d, J=5.0 Hz, 1H), 3.03-2.97 (m, 1H). 19F NMR (376 MHz, CDCl3) δ −61.78 (s, 3F), −106.89 (dd, J=257.7, 8.4 Hz, 1F), −107.48-−108.26 (m, 2F), −109.29 (q, J=8.3 Hz, 1F); ESIMS m/z 446 ([M+H]+).

Workup

  1. temperatureto cool to rt
  2. customThe reaction was quenched with H2O
  3. washThe combined organic extracts were washed with H2O (2×) and brine
  4. customdried
  5. customwere removed under rotary evaporation
  6. custompurified by flash chromatography (SiO2, 10-30% EtOAc/Hexanes over 10 min)

Sources & evidence

ORD record
ord-7528956c890e480593c7e25aff1d2a26
Source dataset
uspto-grants-2016_09
Patent number
US09447073B2

Reaction notes

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