N-methyl-2-pyrrolidone → HCID 131736612, compound

HRID 1480793Notes

Reaction equation

HRID 1480793 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.[H-].[Na+].Cl[C:21]1[C:26]2[N:27]=[C:28](S(C)(=O)=O)[N:29]=[CH:30][C:25]=2[C:24]([CH3:35])=[CH:23][N:22]=1.[OH-].[Na+].[CH3:38][C:39](C)([CH3:42])[CH2:40]N.C[N:45]1CCCC1=O>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]1[N:27]=[C:26]2[C:21]([NH2:45])=[N:22][CH:23]=[C:24]([CH3:35])[C:25]2=[CH:30][N:29]1[CH2:28][C:39]([CH3:42])([CH3:40])[CH3:38]

Participants

9

Reactant 6

HCID 13387N-methyl-2-pyrrolidoneHCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 79882Neopentylamine2×HCID 89996087HCID 89996087, compoundHCID 89996185HCID 89996185, compound

Product 1

HCID 131736612HCID 131736612, compoundYield 50%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 35 mg, 0.151 mmol) in THF (1 mL) was treated with sodium hydride (60% w/w, 8 mg, 0.200 mmol) at 0° C. After stirring for 20 minutes at room temperature the mixture was cooled to 0° C. and 8-chloro-5-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 184, 42 mg, 0.163 mmol) in THF (2 mL) was added. The reaction was allowed to reach room temperature and stirred for 18 hours. A solution of aqueous 2M NaOH (1 mL) and MeOH (1 mL) were added and the resulting mixture stirred at room temperature for 1 hour before concentrating in vacuo. The residue was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0 to 75% EtOAc in cyclohexanes to afford the intermediate that was combined with 2,2-dimethylpropan-1-amine (110 μl, 0.934 mmol) in N-methyl-2-pyrrolidinone (0.7 mL) and stirred at 130° C. for 13 hours. An additional batch of 2,2-dimethylpropan-1-amine (55 μl, 0.47 mmol) was added and the mixture heated to 130° C. for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (40% to 100% MeOH in H2O (0.1% formic acid)) to give the title compound (20 mg, 50%).

Workup

  1. temperaturewas cooled to 0° C.
  2. customto reach room temperature
  3. stirringstirred for 18 hours
  4. stirringthe resulting mixture stirred at room temperature for 1 hour
  5. concentrationbefore concentrating in vacuo
  6. customThe residue was partitioned between DCM and water
  7. extractionThe aqueous layer was extracted with DCM
  8. customthe combined organic layers were dried
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel column chromatography
  11. washeluting with 0 to 75% EtOAc in cyclohexanes
  12. customto afford the intermediate
  13. stirringstirred at 130° C. for 13 hours
  14. temperaturethe mixture heated to 130° C. for 18 hours
  15. customThe reaction was quenched with saturated aqueous NaHCO3
  16. extractionextracted with EtOAc
  17. washThe combined organic layers were washed with water and brine
  18. customdried
  19. concentrationconcentrated in vacuo
  20. customThe residue was purified by preparative HPLC (40% to 100% MeOH in H2O (0.1% formic acid))

Sources & evidence

ORD record
ord-a2ee75a2673c4bc598a63978068c05b2
Source dataset
uspto-grants-2016_08
Patent number
US09409907B2

Reaction notes

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