Hydrochloric Acid → Tavaborole

HRID 424371Notes

Reaction equation

HRID 424371 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])CCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C.Cl>C1COCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:19]([OH:20])[O:10][CH2:9][C:3]=2[CH:4]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 21531Triisopropyl borateHCID 118455732-Bromo-5-fluoro-[1-(methoxymethoxy)methyl]benzeneHCID 178418339Butyllithium

Product 1

HCID 11499245TavaboroleYield 60.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.

Workup

  1. customAnion precipitated
  2. customthe solvent was removed under reduced pressure to about a half volume
  3. additionThe mixture was poured into ethyl acetate and water
  4. washThe organic layer was washed with brine
  5. dry with materialdried over anhydrous Na2SO4
  6. customThe solvent was removed under reduced pressure
  7. additionTo a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL)
  8. customThe solvent was removed under reduced pressure to about a half volume
  9. additionThe mixture was poured into ethyl acetate and water
  10. washThe organic layer was washed with brine
  11. dry with materialdried over anhydrous Na2SO4
  12. customThe solvent was removed under reduced pressure
  13. additionthe residue was treated with i-Pr2O/hexane

Sources & evidence

ORD record
ord-dd911e66d9bc4006b4bf089e17cb3007
Source dataset
uspto-grants-2012_01
Patent number
US08106031B2

Reaction notes

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