Isobutyl nitrite → (R)-6-Benzyloxy-1-(2-hydroxypropyl)indazole

HRID 1715729Notes

Reaction equation

HRID 1715729 reaction equation
[PH2](O)=O.[CH2:4]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](N)=[N:17][N:18]2[CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N(OCC(C)C)=O>CO.O>[CH2:4]([O:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH2:21][C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1

Participants

6

Reactant 3

HCID 10958Isobutyl nitriteHCID 4124402Phosphinic AcidHCID 11635595(R)-6-Benzyloxy-1-(2-hydroxypropyl)-3-aminoindazole

Product 1

HCID 11587260(R)-6-Benzyloxy-1-(2-hydroxypropyl)indazole

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

Hypophosphorous acid (3.45 L of a 50% (w/w) aqueous solution) was added to a stirred solution of 2 (1975 g, 6.65 mol) in 23.7 L of methanol under a nitrogen atmosphere. Isobutyl nitrite (1576 mL, 13.3 mol) was added in two portions, keeping the reaction temperature below 53° C. After 3 hours, a solution of Na2HPO4 (8.5 kg) in 70 L of water was added, and the mixture was extracted with ethyl acetate (30 L then 15 L). The combined organic extracts were washed with brine, dried (Na2SO4), treated with decolorizing charcoal, filtered and concentrated in vacuo. The product was purified by trituration with ethyl acetate-hexane followed by elution through silica using an acetone-hexane gradient, to give after concentration in vacuo, 1260 g (67%) of 3.

Workup

  1. customthe reaction temperature below 53° C
  2. extractionthe mixture was extracted with ethyl acetate (30 L
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried (Na2SO4)
  5. additiontreated with decolorizing charcoal
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe product was purified by trituration with ethyl acetate-hexane
  9. washfollowed by elution through silica using an acetone-hexane gradient
  10. customto give
  11. concentrationafter concentration in vacuo, 1260 g (67%) of 3

Sources & evidence

ORD record
ord-859eade6e647493b9b7663af95578ffc
Source dataset
uspto-grants-2010_09
Patent number
US07799930B2

Reaction notes

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