Citric Acid → HCID 57504529, compound

HRID 1098195Notes

Reaction equation

HRID 1098195 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:43]2[CH:42]=[N:41]1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 575045663-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrileHCID 57504669HCID 57504669, compound

Product 1

HCID 57504529HCID 57504529, compoundYield 68.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (64.3 mg, 1.61 mmol) was added to (S)-2-hydroxy-N-(5-methylpyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AU4) (300 mg, 0.73 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (212 mg, 0.73 mmol) added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane to afford the product (334 mg, 68.8%). 1H NMR (400 MHz, DMSO) δ 0.98-0.86 (21H, m), 1.09 (3H, d), 2.24 (3H, s), 3.58-3.47 (1H, m), 3.64 (1H, m), 3.81-3.71 (1H, m), 4.10 (2H, m), 5.92 (1H, s), 7.58 (1H, d), 7.89 (2H, t), 8.18 (3H, m), 8.59 (1H, s), 8.72 (1H, s), 10.88 (1H, s). m/z (ES+) (M+H)+=664; HPLC tR=3.99 min.

Workup

  1. temperatureto warm to ambient temperature
  2. stirringstirred for 2 hours
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with EtOAc (2×100 mL)
  5. washThe combined organics were washed with saturated brine (50 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane

Sources & evidence

ORD record
ord-b90654da41094348a887c007cead28bc
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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