Citric Acid → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(pyridin-2-yl)-2-(1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide

HRID 1098228Notes

Reaction equation

HRID 1098228 reaction equation
[H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:35])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[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:37]1[N:42]=[CH:41][N:40]=[C:39]2[N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:54])[F:53])[N:44]=[CH:45][C:38]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:35][C:37]1[N:42]=[CH:41][N:40]=[C:39]2[N:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:54])[F:53])[N:44]=[CH:45][C:38]=12)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[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

Participants

6

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 114834004-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine2×HCID 57504689(S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(pyridin-2-yl)propanamide

Product 1

HCID 57504546(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(pyridin-2-yl)-2-(1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamideYield 95.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (117 mg, 2.93 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(pyridin-2-yl)propanamide (618 mg, 1.33 mmol) (Intermediate AQ2) in anhydrous THF (20 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (514 mg, 1.46 mmol) (Intermediate B4) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 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 (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% EtOAc in isohexane to afford the product (919 mg, 95%). 1H NMR: (400 MHz, CDCl3) δ 0.99 (9H, t), 3.70-3.72 (2H, m), 3.82 (2H, t), 4.16-4.25 (2H, m), 6.05-6.07 (1H, m), 7.04-7.07 (1H, m), 7.31-7.75 (14H, m), 7.89-7.92 (1H, m), 8.24-8.28 (2H, m), 8.36 (1H, s), 8.55 (1H, s), 8.73 (1H, s); m/z (ES+) (M+H)+=279.1; HPLC Rt=3.71 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe reaction mixture was diluted with water (20 mL) and EtOAc (50 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with EtOAc (2×100 mL)
  7. washThe combined organics were washed with saturated brine (75 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography
  11. washeluting with 50 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-09667f239ee44bc6824314e4c65bec1c
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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