Sodium hydride → (2S)-2-(1-(2-Chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)propanamide

HRID 1098017Notes

Reaction equation

HRID 1098017 reaction equation
[H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:29]=[CH:30][C:23]=12>C1COCC1.C(OCC)(=O)C>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:28]1[C:24]2=[N:25][CH:26]=[N:27][C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]3[CH2:6][CH2:5][CH2:4]3)[C:10]([NH:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)=[O:11])=[C:23]2[CH:30]=[N:29]1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 112655704-Chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-D]pyrimidine2×HCID 57504623HCID 57504623, compound

Product 1

HCID 59279550(2S)-2-(1-(2-Chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)propanamideYield 73.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (44.4 mg, 1.11 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (186 mg, 0.74 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (255 mg, 0.96 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (262 mg, 73.8%). 1H NMR (400 MHz, DMSO) δ 1.39-1.52 (m, 1H), 1.56-1.67 (m, 1H), 1.77-1.91 (m, 2H), 2.13-2.24 (m, 2H), 2.44 (s, 3H), 3.88-4.02 (m, 2H), 4.06-4.15 (m, 1H), 5.89-5.94 (m, 1H), 7.56-7.70 (m, 3H), 7.73-7.78 (m, 1H), 8.31-8.33 (m, 1H), 8.54 (s, 1H), 8.63 (s, 1H), 9.10 (s, 1H), 11.17 (s, 1H). m/z (ESI+) (M+H)+=480.33; HPLC tR=2.45 min.

Workup

  1. temperatureto warm up to room temperature
  2. stirringstirred for 30 minutes
  3. washwashed sequentially with water (10 mL) and saturated brine (5 mL)
  4. dry with materialThe organic layer was dried (MgSO4)
  5. customevaporated
  6. customThe crude product was purified by flash silica chromatography
  7. washeluting with 0-100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-5efe645ad8bc41878e99021ad7f4f0bf
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

Loading…