Phosphorus oxychloride → 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine

HRID 2241222Notes

Reaction equation

HRID 2241222 reaction equation
P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[C:17]3[N:18]=[CH:19][CH:20]=[C:21](O)[C:16]=3[C:15]([CH3:23])=[N:14]2)=[CH:10][CH:9]=1>ClC(Cl)C>[Cl:3][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH2:12][C:11]3[CH:24]=[CH:25][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)[N:14]=[C:15]([CH3:23])[C:16]=12

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 178490909HCID 178490909, compound

Product 1

HCID 685123991-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridineYield 95.2%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
115 °C

Procedure

To a 500 mL round bottom flask was added phosphorous oxychloride (6.63 mL, 72.4 mmol) followed by dichloroethane (120 mL). 1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (6.5 g, 24.1 mmol), prepared according to the procedure of Example 5, Step B, was added directly as a solid. The reaction mixture was stirred for 1 hour at refluxing temperature (115° C.) under N2. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduce pressure. Any remaining solvent was removed by toluene azeotrope (2×50 mL). The resulting crude material was dissolved in dichloromethane (50 mL), and saturated NaHCO3 was added slowly until vigorous bubbling ceased. The biphasic mixture was diluted with additional dichloromethane and aqueous sodium bicarbonate and the organic layer washed separated, washed with brine, dried over sodium sulfate and evaporated to afford 6.6 g of off-white solid. The crude was chromatographed on Silica (Biotage 40M) loading with dichloromethane and eluting with 80/20 hexanes/ethyl acetate to obtain the product (6.0 g, 87%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 5.46 (s, 2H), 3.64 (s, 3H), 2.57 (s, 3H).

Workup

  1. additionwas added directly as a solid
  2. temperatureThe reaction mixture was cooled to room temperature
  3. customthe solvent was evaporated
  4. customAny remaining solvent was removed by toluene
  5. dissolutionThe resulting crude material was dissolved in dichloromethane (50 mL)
  6. additionsaturated NaHCO3 was added slowly
  7. customuntil vigorous bubbling
  8. additionThe biphasic mixture was diluted with additional dichloromethane and aqueous sodium bicarbonate
  9. washthe organic layer washed
  10. customseparated
  11. washwashed with brine
  12. dry with materialdried over sodium sulfate
  13. customevaporated

Sources & evidence

ORD record
ord-a60eb92844704d12838c511060b3b395
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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