Cesium carbonate → N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

HRID 529822Notes

Reaction equation

HRID 529822 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:36][C@@H:37]([N:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH3:40])[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:38][C@@H:37]([N:39]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[CH3:40])[CH3:36])[N:9]=2)[CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[N:9]([CH2:38][C@@H:37]([N:39]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[CH3:40])[CH3:36])[N:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 118522426[(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamineHCID 178522413HCID 178522413, compound

Product 2

HCID 118522420N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamideHCID 118522735N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 20-mL microwave vial was charged with N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide (400 mg, 0.99 mmol), Cs2CO3 (652 mg, 2.00 mmol), DMF (10 mL) and [(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamine (454 mg, 1.99 mmol). The vessel was evacuated and refilled with nitrogen 3 times. The final reaction mixture was irradiated with microwave radiation for 30 min at 120° C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with dichloromethane (×2) and the organic layers combined and the organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (1:1). This resulted in 420 m of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide mixture. LCMS (Method 25) [M+H]+=596.0, RT=0.81 min.

Workup

  1. customThe vessel was evacuated
  2. additionrefilled with nitrogen 3 times
  3. customThe final reaction mixture
  4. customwas irradiated with microwave radiation for 30 min at 120° C
  5. customThe reaction was then quenched by the addition of 50 mL of water
  6. extractionThe resulting solution was extracted with dichloromethane (×2)
  7. washthe organic layers were washed with brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. concentrationconcentrated under vacuum
  10. customThe residue was purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (1:1)

Sources & evidence

ORD record
ord-6191616be21548df85a26007121a3cb5
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

Loading…