Sodium hydride → (2S)-3-isopropoxy-2-(1-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide

HRID 1098058Notes

Reaction equation

HRID 1098058 reaction equation
[H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34](OC3C=CC=CC=3)=[C:29]2[CH:28]=[N:27]1>C1COCC1>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[N:27]=[CH:28][C:29]=12)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 57504492HCID 57504492, compound2×HCID 575045581-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine

Product 1

HCID 57504439(2S)-3-isopropoxy-2-(1-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% in oil) (28.8 mg, 0.72 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (143 mg, 0.60 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 1-(1-methyl-1H-imidazol-2-yl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AV1) (193 mg, 0.66 mmol) in THF (1 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with 1M citric (2 mL), extracted with EtOAc, the organic layer was washed with water ×2 and brine, dried (MgSO4), filtered and evaporated to afford orange oil. The crude product 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 1% NH3) and MeCN as eluents to afford the product (90 mg, 34.4%, 100% ee). 1H NMR (400 MHz, CDCl3) δ 1.18 (6H, t), 2.29 (3H, s), 3.65 (3H, s), 3.67-3.76 (1H, m), 4.08 (2H, d), 6.01 (1H, t), 7.01 (1H, d), 7.17 (1H, d), 7.49-7.55 (1H, m), 8.06-8.14 (2H, m), 8.42 (1H, s), 8.65 (1H, s), 8.68 (1H, s); m/z (ES+) (M+H)+=437.51; HPLC tR=1.89 min.

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 2 hours
  3. customThe reaction mixture was quenched with 1M citric (2 mL)
  4. extractionextracted with EtOAc
  5. washthe organic layer was washed with water ×2 and brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customto afford orange oil
  10. customThe crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)
  11. customto afford the product (90 mg, 34.4%, 100% ee)

Sources & evidence

ORD record
ord-37af8147c5b641b795519aeca19fc4fc
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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