Citric Acid → (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoate

HRID 1098282Notes

Reaction equation

HRID 1098282 reaction equation
[H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[N:30]=[CH:31][C:24]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([O:21][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([C:32]4[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:39])[N:30]=[CH:31][C:24]=23)[C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 574386694-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidineHCID 57504648(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate

Product 1

HCID 66813287(S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)propanoateYield 30.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% dispersion in mineral oil) (127 mg, 3.17 mmol) was added to (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (765 mg, 2.64 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (871 mg, 2.91 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was neutralised with 1M citric acid and the reaction mixture 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 concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (445 mg, 30.5%).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred overnight
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with EtOAc (2×50 mL)
  5. washThe combined organics were washed with saturated brine (75 mL),dried (MgSO4),
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-68e200acf09b4836830ce2b3e0cebd5c
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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