Hydrochloric Acid → (2S)-Methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate

HRID 1098130Notes

Reaction equation

HRID 1098130 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12.Cl>C1COCC1>[CH:11]([O:10][CH2:9][C@H:4]([O:3][C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12)[C:5]([O:7][CH3:8])=[O:6])([CH3:13])[CH3:12]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 575046114-Chloro-1-(3-methylpyridin-2-YL)-1H-pyrazolo[3,4-D]pyrimidineHCID 59279510(S)-methyl 2-hydroxy-3-isopropoxypropanoate

Product 1

HCID 59279495(2S)-Methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoateYield 79.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
5 °C

Procedure

60% Sodium hydride (0.720 g, 18.00 mmol) was added to a solution of (S)-methyl 2-hydroxy-3-isopropoxypropanoate (2.353 g, 12.00 mmol) in anhydrous THF (100 mL) at 5° C., under nitrogen. The resulting suspension was stirred at 5° C. for 10 minutes and then a solution of 4-chloro-1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate J4) (2.95 g, 12 mmol) in dry THF (50 mL) was added dropwise maintaining a temperature below 5° C. The reaction mixture was stirred at 5° C. for 10 mins and then allowed to warm to room temperature. The reaction was stirred at room temperature for 1 hour. The reaction mixture was neutralised with HCl (1M, aq). The majority of the THF was evaporated in vacuo and then EtOAc (75 mL) and water (50 mL) were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 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 (120 g), elution gradient 30 to 80% EtOAc in isohexane to afford (2S)-methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (3.53 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.11-1.14 (6H, m), 2.11 (3H, s), 3.68-3.74 (4H, m), 3.95-4.03 (2H, m), 5.79-5.81 (1H, m), 7.56-7.59 (1H, dd), 7.98-8.00 (1H, d), 8.49 (1H, m), 8.57 (2H, d). m/z (ESI+) (M+H)+=372; HPLC tR=1.99 min.

Workup

  1. temperaturemaintaining a temperature below 5° C
  2. stirringThe reaction mixture was stirred at 5° C. for 10 mins
  3. temperatureto warm to room temperature
  4. stirringThe reaction was stirred at room temperature for 1 hour
  5. customThe majority of the THF was evaporated in vacuo
  6. additionEtOAc (75 mL) and water (50 mL) were added
  7. customThe organic layer was separated
  8. extractionthe aqueous layer re-extracted with EtOAc (2×50 mL)
  9. washThe combined organics were washed with saturated brine (50 mL)
  10. dry with materialdried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe crude product was purified by flash silica chromatography (120 g), elution gradient 30 to 80% EtOAc in isohexane

Sources & evidence

ORD record
ord-730fd951d3844c5c88a49d5f1402e00d
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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