Sodium hydride → 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one

HRID 1676220Notes

Reaction equation

HRID 1676220 reaction equation
[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]([C:26]4[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=4[F:36])[C:18](=[O:22])[CH:17]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 27827431,2-Difluoro-4-(methylsulfonyl)benzeneHCID 673672944-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one

Product 1

HCID 574684534-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-oneYield 45.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A suspension of 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (127 mg, 0.424 mmol, prepared according to procedures described in Example 230 Step C substituting 2-chloro-5-ethylpyrimidine (Aldrich) for 2-chloro-5-cyclopropylpyrimidine), sodium hydride (60 wt % mineral oil, 21 mg, 0.51 mmol) and DMF (5 mL) was purged with Argon and then stirred at room temperature for 1 h. To the reaction was added 1,2-difluoro-4-(methylsulfonyl)benzene (90 mg, 0.47 mmol, Matrix Scientific) and then heated at 110° C. for 1 h. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a yellow solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 91 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 2H), 7.83-7.91 (m, 2H), 7.64 (dd, J=8.53, 6.78 Hz, 1H), 7.13 (dd, J=7.53, 1.00 Hz, 1H), 6.08 (dd, J=7.65, 2.64 Hz, 1 H), 6.03 (d, J=2.51 Hz, 1H), 4.54-4.63 (m, 1H), 4.16-4.27 (m, 2H), 3.60-3.70 (m, 2H), 3.12 (s, 3H), 2.49 (q, J=7.53 Hz, 2H),1.97-2.15 (m, 2H),1.78-1.97 (m, 2 H),1.21 (t, J=7.53 Hz, 3H). MS (ESI) 473 (M+H).

Workup

  1. customwas purged with Argon
  2. temperatureheated at 110° C. for 1 h
  3. customThe resulting mixture was quenched with H2O
  4. extractionextracted with EtOAc
  5. concentrationThe organic layer was concentrated in vacuo to a yellow solid
  6. customThe solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2)

Sources & evidence

ORD record
ord-81a0e2ceed314a90baeee50c5d92d9aa
Source dataset
uspto-grants-2011_08
Patent number
US08003796B2

Reaction notes

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