Citric Acid → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide

HRID 1098194Notes

Reaction equation

HRID 1098194 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]([Cl: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:37][C:38]1[C:39]([N:46]2[C:50]3=[N:51][CH:52]=[N:53][C:54](Cl)=[C:49]3[CH:48]=[N:47]2)=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]#[N:42].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:54]1[N:53]=[CH:52][N:51]=[C:50]2[N:46]([C:39]3[C:40]([C:41]#[N:42])=[CH:43][CH:44]=[CH:45][C:38]=3[Cl:37])[N:47]=[CH:48][C:49]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([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 575045663-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrileHCID 57504653(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide

Product 1

HCID 57504528(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamideYield 57.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

60% Sodium hydride (95 mg, 2.38 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (540 mg, 1.08 mmol) in anhydrous THF (15 mL), at 0° C., under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (314 mg, 1.08 mmol) was added. The reaction mixture was allowed to warm to room temperature and was then 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 30 to 50% EtOAc in isohexane. Fractions were evaporated to dryness to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)propanamide (466 mg, 57.2%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, d), 3.83-3.66 (4H, m), 4.11-4.04 (1H, m), 4.20-4.12 (1H, m), 6.00 (1H, s), 7.44-7.31 (6H, m), 7.60 (4H, m), 7.87 (2H, m), 8.03 (1H, t), 8.22-8.13 (2H, m), 8.39 (1H, d), 8.62 (1H, d), 8.68 (1H, d), 11.23 (1H, s). m/z (ES+) (M+H)+=752; HPLC tR=3.89 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringwas then stirred 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 30 to 50% EtOAc in isohexane
  10. customFractions were evaporated to dryness

Sources & evidence

ORD record
ord-e524c61883504ef8ab12c6fe26db00e5
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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