Methanol → 5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrile

HRID 220219Notes

Reaction equation

HRID 220219 reaction equation
[C:1]([C:3]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16](OC)=[O:17])[N:10]=[CH:9]2)#[N:2].CO.[BH4-].[Na+]>C(Cl)Cl>[F:24][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[C:3]([CH:23]=1)[C:1]#[N:2]

Participants

5

Reactant 3

HCID 887MethanolHCID 4311764Sodium borohydrideHCID 57552286methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate

Product 1

HCID 445421215-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrileYield 92.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A flask was charged with methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate (100.0 g, 307.4 mmol) and MeOH (620 mL, 0.5M) and purged with nitrogen, Sodium borohydride (40.00 g, 1057 mmol) was added portionwise to the reaction mixture over 2.5 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. To the residue were added 1000 mL of saturated aqueous NH4Cl solution and 1000 mL of EtOAc. The mixture was stirred for 1 hour at ambient temperature. The layers were separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with saturated NH4Cl and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to provide 91.1 g of the crude product. The crude solid was dissolved in CH2Cl2 (1500 mL). Hexanes (2500 mL) were added to the solution with stirring. The light brown solid which crashed out of solution was filtered, washed with 1:2 CH2Cl2:hexanes and dried under high vacuum to provide 84.8 g (92.8%) of the title product. 1H NMR (400 MHz, CdCl3) δ 7.98 (s, 1H), 7.50 (d, J=8.98 Hz, 1H), 7.39-7.35 (m, 2H), 7.21-7.15 (m, 2H), 6.80 (dd, J=4.29 Hz. 9.37 Hz, 1H), 4.49 (t, J=5.00 Hz, 2H), 4.19-4.10 (m, 2H), 2.90 (br s, 1H).

Workup

  1. additionwas added portionwise to the reaction mixture over 2.5 hours
  2. concentrationconcentrated under reduced pressure
  3. additionTo the residue were added 1000 mL of saturated aqueous NH4Cl solution and 1000 mL of EtOAc
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc
  6. washThe combined extracts were washed with saturated NH4Cl and brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered through a Celite pad
  9. concentrationconcentrated under reduced pressure
  10. customto provide 91.1 g of the crude product
  11. stirringwith stirring
  12. filtrationwas filtered
  13. washwashed with 1:2 CH2Cl2
  14. dry with materialhexanes and dried under high vacuum

Sources & evidence

ORD record
ord-6d24f8633f054cb5bb8732b0dd525c17
Source dataset
uspto-grants-2012_06
Patent number
US08202899B2

Reaction notes

Loading…