Acetic Acid → N-[(1S)-1-[4-[[4-(1,1-Dimethylethyl)-1-piperidinyl]methyl]phenyl]-2,2,2-trifluoroethyl]methanesulfonamide

HRID 1518981Notes

Reaction equation

HRID 1518981 reaction equation
Cl.[C:2]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]([F:36])([F:35])[C@@H:21]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:2]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C@H:21]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([F:35])([F:36])[F:19])=[CH:27][CH:26]=2)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 27946764-tert-butylpiperidine HydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 86691246HCID 86691246, compound

Product 1

HCID 71655815N-[(1S)-1-[4-[[4-(1,1-Dimethylethyl)-1-piperidinyl]methyl]phenyl]-2,2,2-trifluoroethyl]methanesulfonamideYield 62%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Charge a five liter round-bottom flask with DCM (1.5 L) and 4-tert-butylpiperidine hydrochloride (89 g, 0.5 mol). Add triethylamine (101.4 g, 1.0 mol) to the mixture at 21° C. followed by N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)ethyl]methanesulfonamide (155 g, 0.55 mol), and acetic acid (36 g, 0.6 mol). Add sodium triacetoxyborohydride (318.6 g, 1.5 mol) portion-wise and stir the suspension at 22° C. for 15 hours. Add saturated aqueous solution of sodium bicarbonate (1800 mL) slowly with stirring until pH of the mixture is 8. Separate the organic layer and extract the aqueous layer with DCM (3×2000 mL). Dry the combined organic layers over MgSO4; filter; collect the filtrate; and concentrate the filtrate under vacuum. Purify the residue on silica gel column chromatography eluting with DCM:MeOH (100 to 95%) to provide the title compound as an off-white solid (126 g, 61.9%). MS (m/z): 407 (M+1).

Workup

  1. customat 21° C.
  2. customSeparate the organic layer
  3. extractionextract the aqueous layer with DCM (3×2000 mL)
  4. dry with materialDry the combined organic layers over MgSO4
  5. filtrationfilter
  6. customcollect the filtrate
  7. concentrationand concentrate the filtrate under vacuum
  8. customPurify the residue on silica gel column chromatography
  9. washeluting with DCM

Sources & evidence

ORD record
ord-ff13d3e852b04bca8c465dee29d58174
Source dataset
uspto-grants-2015_07
Patent number
US09073856B2

Reaction notes

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