Diethyl Ether → HCID 67955066, compound

HRID 717879Notes

Reaction equation

HRID 717879 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C=[N+]=[N-])(C)C.CCOCC.[BH4-].[Na+]>CO.C(O)(=O)C>[OH:19][CH2:18][C:17]1[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:23]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:16]=1

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 167693TrimethylsilyldiazomethaneHCID 4311764Sodium borohydride2×HCID 86706859HCID 86706859, compound

Product 1

HCID 67955066HCID 67955066, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-6-(trifluoromethyl)isonicotinic acid (1.4 g, 3.6 mmol, prepared by the method of Step 2) in methanol (70. mL) at 0° C. was added 2.0 M trimethylsilyldiazomethane in ether (18 mL, 36 mmol) dropwise until TLC indicated complete reaction. Excess reagent was discharged by dropwise addition of acetic acid to the mixture cooled in an ice bath. Solvent was removed by rotary evaporation. The residue was dissolved in ethanol (28 mL), cooled to 0° C., and sodium tetrahydroborate (0.26 g, 7.0 mmol) was added. The cooling was discontinued and the reaction was allowed to stir at room temperature for 30 minutes. It was re-cooled in an ice bath and an additional portion of Sodium tetrahydroborate (0.27 g, 7.2 mmol) was added. The reaction mixture was allowed to reach room temperature and stir until the reaction was complete as determined by analytical LCMS and TLC. The reaction was quenched by the addition of saturated ammonium chloride, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, using a 120 g silica gel cartridge and eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a colorless oil (0.90 g, 67%). 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 6.90 (s, 1H), 5.27 (tt, J=7.7, 3.7 Hz, 1H), 4.74 (d, J=2.5 Hz, 2H), 3.81-3.63 (m, 2H), 3.31 (ddd, J=13.4, 8.4, 3.7 Hz, 2H), 1.98 (ddt, J=13.5, 7.0, 3.8 Hz, 2H), 1.72 (dtd, J=12.5, 8.2, 4.0 Hz, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −69.21 (s). LCMS (M-tBu+H)+: 321.1.

Workup

  1. customreaction
  2. temperaturecooled in an ice bath
  3. customSolvent was removed by rotary evaporation
  4. dissolutionThe residue was dissolved in ethanol (28 mL)
  5. temperatureIt was re-cooled in an ice bath
  6. customto reach room temperature
  7. stirringstir until the reaction
  8. customThe reaction was quenched by the addition of saturated ammonium chloride
  9. additiondiluted with water
  10. extractionextracted with EtOAc (2×)
  11. washThe combined organic extracts were washed with brine
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated
  15. washeluting with a gradient from 0-30% EtOAc in hexanes afforded product as a colorless oil (0.90 g, 67%)

Sources & evidence

ORD record
ord-09e2123e0ad94320ad631510222b3387
Source dataset
uspto-grants-2015_11
Patent number
US09193733B2

Reaction notes

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