Citric Acid → (2S)-3-ethoxy-N-(5-methylpyrazin-2-yl)-2-[1-[2-(trifluoromethyl)phenyl]pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamide

HRID 1098002Notes

Reaction equation

HRID 1098002 reaction equation
[H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:18])[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:4].Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[N:27]=[CH:28][C:21]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:3]([O:5][CH2:6][C@H:7]([O:18][C:20]1[C:21]2[CH:28]=[N:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:37])([F:38])[F:36])[C:22]=2[N:23]=[CH:24][N:25]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:4]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 114834004-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 57504485(S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide

Product 1

HCID 57504369(2S)-3-ethoxy-N-(5-methylpyrazin-2-yl)-2-[1-[2-(trifluoromethyl)phenyl]pyrazolo[4,5-e]pyrimidin-4-yl]oxypropanamideYield 90.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (225 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm to ambient temperature and stirred for 2 hours. 1M Citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 60 to 100% ethyl acetate in isohexane to give the product (440 mg, 88%).

Workup

  1. stirringThe mixture was stirred at 0° C. for 15 mins
  2. temperatureto warm to ambient temperature
  3. stirringstirred for 2 hours
  4. extractionthe mixture extracted with ethyl acetate (2×20 mL)
  5. washThe organic extracts were washed with water (15 mL) and brine (15 mL)
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe residue was purified by flash silica chromatography
  9. washeluting with 60 to 100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-5db3c765b73d45baa96b3e90da90d9f8
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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