Toluene → 2-Fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile

HRID 2367508Notes

Reaction equation

HRID 2367508 reaction equation
F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([F:27])[C:3]=1[C:4]#[N:5].C1(C)C=CC=CC=1.[H-].[Na+].CN([CH:40]=[O:41])C>CO>[F:27][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:9]=[C:2]([O:41][CH3:40])[C:3]=1[C:4]#[N:5]

Participants

6

Reactant 4

HCID 1140TolueneHCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 585046702,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile

Product 1

HCID 585047242-Fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (360 mg, 0.96 mmol) was azeotroped with toluene (2×12 mL). The resulting residue was taken up in 7.5 mL of CH3OH as a suspension. NaH (260 mg, 60% wt in mineral oil, 6.5 mmol) was added to a chilled (ice bath) solution of CH3OH (12.5 mL) under nitrogen portion-wise. After completion of addition, the ice bath was removed. The resulting mixture was stirred at ambient temperature for 10 minutes (concentration of CH3ONa was assumed to be 0.52 mmol/mL). A 2.25 mL portion (1.17 mmol, 1.2 equiv) of this mixture was added to the above suspension at room temperature in one portion. The resulting suspension was stirred at room temperature for 2 hours. LCMS showed no conversion. After another 1 h, 5 mL of DMF was added to the mixture, which became milky. The mixture was stirred at room temperature for another 16 hours, upon which time, it became a clear solution. LCMS showed conversion complete. The mixture was concentrated in vacuo. The residue was taken up in water (20 mL) as a suspension, which was sonicated briefly, and then filtered. The solids collected were dried under house vacuum at room temperature for 1 hour. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (350 mg) as a foam. LC-MS (ES) m/z=386 [M+H]+.

Workup

  1. additionAfter completion of addition
  2. customthe ice bath was removed
  3. stirringThe resulting suspension was stirred at room temperature for 2 hours
  4. waitAfter another 1 h
  5. stirringThe mixture was stirred at room temperature for another 16 hours, upon which time, it
  6. concentrationThe mixture was concentrated in vacuo
  7. customwhich was sonicated briefly
  8. filtrationfiltered
  9. customThe solids collected
  10. customwere dried under house vacuum at room temperature for 1 hour
  11. customPurification by silica gel column chromatography
  12. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

Sources & evidence

ORD record
ord-e5b0ce4e0deb43c4b915ed4559b768b7
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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