Acetic Acid → N-[(1R)-1-(4-{[(2S)-2-(4-Fluorophenyl)morpholin-4-yl]methyl}phenyl)ethyl]methanesulfonamide

HRID 880242Notes

Reaction equation

HRID 880242 reaction equation
Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([C@H:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:31])=[CH:26][CH:25]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:22][C:24]3[CH:25]=[CH:26][C:27]([C@H:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:31])=[CH:28][CH:29]=3)[CH2:10]2)=[CH:7][CH:8]=1

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 57364135HCID 57364135, compoundHCID 86691231(R)-N-(1-(4-formylphenyl)ethyl)methanesulfonamide

Product 1

HCID 71660507N-[(1R)-1-(4-{[(2S)-2-(4-Fluorophenyl)morpholin-4-yl]methyl}phenyl)ethyl]methanesulfonamideYield 81.13%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Under a nitrogen atmosphere, suspend (2S)-2-(4-fluorophenyl)morpholine hydrochloride (29.5 g, 128.8 mmol) in DCM (17 L) at 22° C. and add triethylamine (35.89 mL, 257.5 mmol). Add N-[(1R)-1-(4-formylphenyl)ethyl]methanesulfonamide (29.26 g, 128.8 mmol) and stir the resulting solution for 30 min. Add acetic acid (8.85 mL, 154.5 mmol), then sodium triacetoxyborohydride (86.17 g, 386.3 mmol) portion-wise in 3 batches. Stir for 3 h; monitor the reaction via LCMS until completion. Quench the reaction via the slow addition of a saturated aqueous solution of sodium bicarbonate (259.31 mL) to give a solution with a pH of 8. Separate the layers, and extract the aqueous layer with 200 mL DCM. Combine the organic layers, wash with saturated sodium bicarbonate, water, brine, and then dry over MgSO4. Filter; collect the filtrate; and concentrate to give a residue. Purify the residue via silica gel flash column chromatography, using a gradient of 100% DCM to DCM:MeOH (95:5). Combine the product fractions, and concentrate to provide the title product as a yellow thick oil (41 g, 81.13%). MS (m/z): 393 (M+1)

Workup

  1. customat 22° C.
  2. customthe reaction via LCMS until completion
  3. customQuench
  4. customthe reaction
  5. customto give a solution with a pH of 8
  6. customSeparate the layers
  7. extractionextract the aqueous layer with 200 mL DCM
  8. washwash with saturated sodium bicarbonate, water, brine
  9. dry with materialdry over MgSO4
  10. filtrationFilter
  11. customcollect the filtrate
  12. concentrationand concentrate
  13. customto give a residue
  14. customPurify the residue via silica gel flash column chromatography
  15. concentrationCombine the product fractions, and concentrate

Sources & evidence

ORD record
ord-952ec87df99b446193851af0d77b484a
Source dataset
uspto-grants-2015_03
Patent number
US08993568B2

Reaction notes

Loading…