Acetone → HCID 58801813, compound

HRID 347896Notes

Reaction equation

HRID 347896 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([N+:18]([O-])=O)[CH:17]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:14])[CH3:13])[CH2:7]1.FC1C=C(C=C(F)C=1)O[C@@H]1CCCN(C(=O)C)C1.C([O-])=O.[NH4+].CC(C)=O>CO.O>[NH2:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([F:1])[CH:17]=1)[O:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:14])[CH3:13])[CH2:7]1

Participants

7

Reactant 4

HCID 180AcetoneHCID 2723923Ammonium formateHCID 588018141-[(3R)-3-(3-Fluoro-5-nitrophenoxy)piperidin-1-yl]ethan-1-oneHCID 588018151-[(3R)-3-(3,5-Difluorophenoxy)piperidin-1-yl]ethan-1-one

Product 1

HCID 58801813HCID 58801813, compoundYield 75%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 962WaterSolvent

Procedure

Three 22 L 3-neck RBFs equipped with heating mantles, mechanical stirrers, thermowells, condensers, and nitrogen bubblers were purged under nitrogen for at least ten minutes. The flasks were charged with 0.454 kg (10 wt %) Pd/C, and 13.62 L (3 vol) methanol. A solution of 4.54 kg (˜16.1 mol) of a mixture of 1-[(R)-3-(3-fluoro-5-nitro-phenoxy) -piperidin-1-yl]-ethanone and 1-[(R)-3-(3,5-difluoro-phenoxy)-piperidin-1-yl]-ethanone in 4.54 L (1 vol) methanol was then charged to the flasks, and an additional 4.54 L (1 vol) methanol was added to the flasks. The solutions were warmed to a gentle reflux, and a solution of 5.07 kg (80.4 mol) ammonium formate in 3.63 L water was then added drop-wise for 10 hours. The reactions were deemed complete by TLC (1:1 hexanes:acetone/PMA stain) and HPLC, and were filtered through celite and concentrated. The concentrate was transferred to two 50 L extractors, and was partitioned between 47.2 L MTBE and 17.7 L 3N HCl. The layers were separated, and the organics were extracted with 6 L (2×) 3N HCl. The aqueous layers were neutralized with 3.54 kg NaOH to pH ˜7, then 9.6 L saturated sodium bicarbonate was added. The aqueous layers were then extracted with 6 L (3×) DCM. The combined organics were washed with 18 L brine, dried over sodium sulfate, filtered and concentrated to yield 3.06 kg of 1-[(R)-3-(3-amino-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone in 75% yield as a thick brown oil (theoretical yield=4.06 kg, purity=90.7% and 95.4% ee).

Workup

  1. customwere purged under nitrogen for at least ten minutes
  2. additionThe flasks were charged with 0.454 kg (10 wt %) Pd/C, and 13.62 L (3 vol) methanol
  3. temperatureThe solutions were warmed to a gentle reflux
  4. filtrationwere filtered through celite and
  5. concentrationconcentrated
  6. customwas partitioned between 47.2 L MTBE and 17.7 L 3N HCl
  7. customThe layers were separated
  8. extractionthe organics were extracted with 6 L (2×) 3N HCl
  9. addition9.6 L saturated sodium bicarbonate was added
  10. extractionThe aqueous layers were then extracted with 6 L (3×) DCM
  11. washThe combined organics were washed with 18 L brine
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-a4e9d367eb144ec48d06ed3ff7c3c485
Source dataset
uspto-grants-2007_02
Patent number
US07176222B2

Reaction notes

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