Methanol → 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester

HRID 268634Notes

Reaction equation

HRID 268634 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13](O)=[O:14])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].B.C1COCC1.CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([CH2:13][OH:14])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4]

Participants

5

Reactant 3

HCID 887MethanolHCID 2723981Borane;tetrahydrofuranHCID 247549721-(4-fluoro-phenyl)-4-isopropyl-1 H-pyrazole-3,5-dicarboxylic acid 3-methyl ester

Product 1

HCID 247546741-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl esterYield 90%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
25 °C

Procedure

(Reference: J. Med. Chem. 1996, 549-555) To a solution of 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester (15.9 g, 51.8 mmol) in THF (300 mL) at 0° C. was slowly added BH3.THF (1.0 M solution in THF, 104 mL, 104 mmol; commercially available from Sigma Aldrich). The reaction was allowed to warm to 25° C. for 30 min and then heated to 65° C. for 3 hr. After cooling to 25° C., MeOH (50 mL) was slowly added. Subsequently, the solvent was removed under reduced pressure and a second portion of MeOH (100 mL) was slowly added and the solution was stirred at 25° C. for an additional 20 min. The MeOH was then evaporated and EtOAc was added and the organic layer was washed with 1N NaOH and brine prior to drying over Na2SO4. The organic layer was concentrated and purified by silica gel chromatography (15-35% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (13.6 g, 90%): H-NMR (CDCl3) δ 7.59-7.56 (m, 2 H), 7.15-7.11 (m, 2 H), 4.57 (s, 2 H), 3.89 (s, 3 H), 3.66-3.62 (m, 1 H), 1.36 (d, 6 H).

Workup

  1. customat 0° C.
  2. temperatureheated to 65° C. for 3 hr
  3. temperatureAfter cooling to 25° C.
  4. customSubsequently, the solvent was removed under reduced pressure
  5. additiona second portion of MeOH (100 mL) was slowly added
  6. customThe MeOH was then evaporated
  7. additionEtOAc was added
  8. washthe organic layer was washed with 1N NaOH and brine
  9. dry with materialto drying over Na2SO4
  10. concentrationThe organic layer was concentrated
  11. custompurified by silica gel chromatography (15-35% EtOAc/Hex)

Sources & evidence

ORD record
ord-a6942598239645e99e42b4b6d1c24e73
Source dataset
uspto-grants-2008_11
Patent number
US07446121B2

Reaction notes

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