Cesium carbonate → Methyl 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate

HRID 1643855Notes

Reaction equation

HRID 1643855 reaction equation
[F:1][C:2]1[C:3]([C:9]([N:11]2[CH2:14][CH:13]([F:15])[CH2:12]2)=[O:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[OH:16][C:17]1[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=2[CH:20]=[C:19]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28]([O:30][CH3:31])=[O:29])[CH:18]=2)[CH:5]=[N:4][C:3]=1[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 25067323Methyl 4-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-carboxylateHCID 59559983(3,5-Difluoropyridin-2-yl)(3-fluoroazetidin-1-yl)methanone

Product 1

HCID 59559847Methyl 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylateYield 72%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of (3,5-difluoropyridin-2-yl)(3-fluoroazetidin-1-yl)methanone (7.49 g, 34.60 mmol), methyl 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (7.69 g, 34.60 mmol) and Cs2CO3 (16.90 g, 52.0 mmol) in DMF was heated to 110° C. for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a white foam with ˜20% impurity (10.49 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.27 Hz, 1 H) 7.21-7.30 (m, 2 H) 6.98-7.06 (m, 1 H) 5.26-5.49 (m, 1 H) 4.64-4.77 (m, 1 H) 4.46-4.60 (m, 1 H) 4.28-4.42 (m, 1 H) 4.07-4.23 (m, 1 H) 3.88 (s, 3 H) 2.91 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H20F2N2O5 m/z 419.20 (M+H)+.

Workup

  1. temperaturecooled to room temperature
  2. customquenched with H2O
  3. extractionextracted with 3×EtOAc
  4. washThe combined organic layer was washed with 2×H2O
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue was purified by Biotage
  8. washeluting with 25-40% EtOAc in hexanes
  9. customto give a white foam with ˜20% impurity (10.49 g, 72% yield)

Sources & evidence

ORD record
ord-7e3e9ecbc2664c0eb7ad5be007085cd9
Source dataset
uspto-grants-2012_02
Patent number
US08119624B2

Reaction notes

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