Cesium carbonate → 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile

HRID 1420566Notes

Reaction equation

HRID 1420566 reaction equation
[CH3:1][N:2]([C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13](F)[C:12]=1[F:20])[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:5])[CH3:4].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[OH:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[O:37][C:13]1[C:12]([F:20])=[C:11]([N:2]([CH3:1])[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:4])[CH3:5])[C:16]([F:17])=[C:15]([F:18])[N:14]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 14797Potassium HydroxideHCID 154534514-(Benzyloxy)-3-hydroxybenzonitrileHCID 211982104-[N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino]-2,3,5,6-tetrafluoropyridine

Product 1

HCID 211983374-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrileYield 72.8%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-[N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino]-2,3,5,6-tetrafluoropyridine (2.2 g, 6.6 mmol) in acetonitrile (60 mL) was added 2-benzyloxy-5-cyanophenol (1.5 g, 6.6 mmol) and cesium carbonate (2.8 g, 8.6 mmol). The resultant mixture was stirred at 40° C. for 2 days. The mixture was then cooled to ambient temperature and poured into 200 mL of 0.5 M aqueous KOH solution and 200 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (200 mL) then brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil which solidified upon standing. Recrystallization from 30% ethyl acetate/hexanes afforded 2.4 g (68% yield) of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile as a white, crystalline solid: NMR (CDCl3) 7.6-7.1 (m, 8), 5.2 (s, 2), 4.2 (q, 2), 3.1 (s, 3), 1.6 (s, 6), 1.3 (t, 3) ppm.

Workup

  1. customThe aqueous layer was separated
  2. extractionextracted with another 100 mL of ethyl acetate
  3. washThe combined organic extracts were washed with 0.5 M aqueous KOH solution (200 mL)
  4. dry with materialbrine (200 mL), dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto afford a yellow oil which
  8. customRecrystallization from 30% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-d2242b108f2d45efafa479976f65485d
Source dataset
uspto-grants-2000_06
Patent number
US06071912

Reaction notes

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