Citric Acid → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide

HRID 1098243Notes

Reaction equation

HRID 1098243 reaction equation
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[C:48]([CH3:55])=[C:49]([CH:52]=[CH:53][CH:54]=3)[C:50]#[N:51])[N:45]=[CH:46][C:39]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[N:43]=[CH:42][N:41]=[C:40]2[N:44]([C:47]3[CH:54]=[CH:53][CH:52]=[C:49]([C:50]#[N:51])[C:48]=3[CH3:55])[N:45]=[CH:46][C:39]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57504665(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamideHCID 575046943-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile

Product 1

HCID 57504556(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamideYield 42.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% in oil) (92 mg, 2.30 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (500 mg, 1.04 mmol) in anhydrous THF (25 ml) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylbenzonitrile (Intermediate AT2) (282 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was neutralised with 1M citric acid and diluted with water and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with saturated brine, dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane. No separation was achieved. The column was repeated with a 0-10% MeOH/DCM gradient. Still no separation! Mixed fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (313 mg, 42.1%). m/z (ES+) (M+H)+=712.63; HPLC tR=3.85 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 4 hours
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with EtOAc
  5. washThe combined organics were washed with saturated brine
  6. dry with materialdried (MgSO4)
  7. customevaporated
  8. customThe crude product was purified by flash silica chromatography
  9. washeluting with 0 to 50% EtOAc in isohexane
  10. customNo separation
  11. customStill no separation
  12. customMixed fractions were evaporated to dryness

Sources & evidence

ORD record
ord-9254d9bec9994735a3b777d4607b1080
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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