4-Amino-1-Boc-piperidine → tert-butyl 4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidine-1-carboxylate

HRID 705519Notes

Reaction equation

HRID 705519 reaction equation
[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:41])([F:40])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[C:35](=O)[CH2:34][CH2:33]4)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[F:41][C:16]([F:15])([F:40])[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][CH:26]([O:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[CH:35]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH2:34][CH2:33]4)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1

Participants

6

Reactant 3

HCID 12682914-Amino-1-Boc-piperidineHCID 4311764Sodium borohydrideHCID 667570455-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-one

Product 1

HCID 57765814tert-butyl 4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-ylamino)piperidine-1-carboxylateYield 65.2%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolvent

Procedure

Tert-butyl 4-aminopiperidine-1-carboxylate (0.48 g, 2.4 mmol) and 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-one (0.75 g, 2.0 mmol) were mixed in neat titanium(IV) isopropoxide (2.85 g, 10.0 mmol) and stirred at room temperature overnight. Methanol (10 mL) was added followed by addition of sodium borohydride (0.12 g, 3.2 mmol). The reaction was stirred at room temperature for 3 h and then quenched by adding 0.1N aqueous sodium hydroxide. The resulting mixture was filtered through celite, and the residue was washed with ethyl acetate (2×10 mL) and with dichloromethane (10 mL). The organic layer was separated and dried over sodium sulfate. The drying agent was filtered off, and the filtrate concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/4) to afford the title compound as a off-white solid (0.73 g, 65%). 1H NMR (CDCl3, 300 MHz) 7.64 (m, 1H), 7.48 (m, 2H), 6.95 (m, 2H), 6.76 (m, 2H), 4.68 (m, 1H), 4.44 (m, 1H), 3.53 (m, 2H), 3.18 (m, 2H), 2.85 (m, 4H), 2.47 (m, 2H), 2.24-1.79 (m, 12H), 1.46 (s, 9H) ppm; MS (ES) 560.6 (M+H).

Workup

  1. stirringThe reaction was stirred at room temperature for 3 h
  2. customquenched
  3. additionby adding 0.1N aqueous sodium hydroxide
  4. filtrationThe resulting mixture was filtered through celite
  5. washthe residue was washed with ethyl acetate (2×10 mL) and with dichloromethane (10 mL)
  6. customThe organic layer was separated
  7. dry with materialdried over sodium sulfate
  8. filtrationThe drying agent was filtered off
  9. concentrationthe filtrate concentrated under reduced pressure
  10. customThe residue obtained
  11. customwas purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/4)

Sources & evidence

ORD record
ord-aec286d9cc7c47d8b558895fc952d825
Source dataset
uspto-grants-2015_11
Patent number
US09174964B2

Reaction notes

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