Sodium hydride → HCID 57504366, compound

HRID 1097999Notes

Reaction equation

HRID 1097999 reaction equation
P(Cl)(Cl)(Cl)=O.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([OH:25])=[C:19]2[CH:18]=[N:17]1)(=[O:9])=[O:8].[H-].[Na+].O[C@@H:29]([CH2:40][O:41][CH:42]([CH3:44])[CH3:43])[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31]>C1COCC1>[CH:42]([O:41][CH2:40][C@H:29]([O:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:7]([CH3:6])(=[O:9])=[O:8])[N:17]=[CH:18][C:19]=12)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1)=[O:31])([CH3:44])[CH3:43]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 24813Phosphorus oxychlorideHCID 57504492HCID 57504492, compound2×HCID 178504711HCID 178504711, compound

Product 1

HCID 57504366HCID 57504366, compoundYield 47.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
100 °C

Procedure

Phosphorus oxychloride (1.864 ml, 20.00 mmol) was added to 1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate N1) (0.290 g, 1 mmol), at ambient temperature. The resulting mixture was stirred at 100° C. for 4 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was evaporated. The residue was dissolved in DCM (30 mL). MP-Carbonate was added and the mixture stirred for 30 minutes then evaporated. The residue was dissolved in THF (5 mL). Sodium hydride (55.9 mg, 1.40 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (238 mg, 1.00 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes and then the THF solution prepared above was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was concentrated, diluted with water (10 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (25 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluent to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(2-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (242 mg, 47.5%, 81% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.12 (6H, dd), 2.24 (3H, s), 3.38 (3H, s), 3.72-3.80 (1H, m), 3.96-4.05 (2H, m), 5.87-5.91 (1H, m), 7.58 (1H, dd), 7.77 (1H, dd), 7.86-7.92 (2H, m), 7.94-7.99 (1H, m), 8.16-8.21 (2H, m), 8.53 (1H, s), 8.60 (1H, s), 10.82 (1H, s); m/z (ESI+) (M+H)+=511; HPLC tR=2.07 min.

Workup

  1. temperatureto cool to ambient temperature
  2. customThe reaction mixture was evaporated
  3. dissolutionThe residue was dissolved in DCM (30 mL)
  4. additionMP-Carbonate was added
  5. stirringthe mixture stirred for 30 minutes
  6. customthen evaporated
  7. dissolutionThe residue was dissolved in THF (5 mL)
  8. stirringThe resulting solution was stirred at 0° C. for 15 minutes
  9. additionabove was added
  10. temperatureto warm to ambient temperature
  11. stirringwas stirred for 16 hours
  12. concentrationThe reaction mixture was concentrated
  13. additiondiluted with water (10 mL) and EtOAc (50 mL)
  14. customThe organic layer was separated
  15. extractionthe aqueous layer re-extracted with EtOAc (25 mL)
  16. washThe combined organics were washed with saturated brine (25 mL)
  17. dry with materialdried (MgSO4)
  18. customevaporated
  19. customThe residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)

Sources & evidence

ORD record
ord-a55d23ab74ce4436bec32db0e2cbc3f0
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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