Citric Acid → HCID 57504329, compound

HRID 1097993Notes

Reaction equation

HRID 1097993 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=3)[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=3)[N:28]=[CH:29][C:22]=12)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydride2×HCID 57504486HCID 57504486, compound2×HCID 57504487HCID 57504487, compound

Product 1

HCID 57504329HCID 57504329, compoundYield 47.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (22.06 mg, 0.55 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate C8) (110 mg, 0.46 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate I4) (125 mg, 0.51 mmol) in THF (2 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Further sodium hydride (22.06 mg, 0.55 mmol) was added and the reaction stirred for another hour at room temperature. The reaction mixture was neutralised with 1M citric acid, and then diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford (2S)-3-isopropoxy-N-(5-methylpyrazin-2-yl)-2-(1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (98 mg, 47.4%).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. stirringthe reaction stirred for another hour at room temperature
  4. customThe organic layer was separated
  5. extractionthe aqueous layer re-extracted with EtOAc (2×50 mL)
  6. washThe combined organics were washed with saturated brine (75 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. customevaporated
  10. customThe residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-35af6bb0095c4e5db7be90cf5fa2ffb8
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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