Tert-Butylamine → Ethyl 4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate

HRID 714547Notes

Reaction equation

HRID 714547 reaction equation
S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[CH2:22][CH2:21][C:20]([F:26])([C:23]([OH:25])=O)[CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:9])[CH3:6].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:20]1([C:23](=[O:25])[NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18][N:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])[CH2:11][CH2:12]2)[CH2:22][CH2:21]1

Participants

6

Reactant 4

HCID 6385Tert-ButylamineHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 895795461-[1-(Ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid

Product 1

HCID 71570878Ethyl 4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylateYield 46.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

Thionyl chloride (4 mL) was added to a solution of 1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid (1.24 g, assume 3.92 mmol) and the reaction was stirred at 90° C. for 3 h. The reaction mixture was cooled to rt and concentrated in vacuo. DCM (4 mL) was added to a portion of the residue (0.65 mmol) followed by tert-butylamine (0.14 mL, 1.31 mmol) and DIPEA (0.57 ml, 3.27 mmol), the reaction mixture was stirred at rt for 48 h. The solvents were removed in vacuo, and the residue was partitioned between DCM (50 mL) and sat. NaHCO3 sol. (25 mL), organic layer washed with sat. NaCl sol. (25 mL) and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 7% MeOH in DCM]) to give ethyl 4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (0.11 g, 46.8%) as a yellow oil.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. concentrationconcentrated in vacuo
  3. stirringthe reaction mixture was stirred at rt for 48 h
  4. customThe solvents were removed in vacuo
  5. customthe residue was partitioned between DCM (50 mL) and sat. NaHCO3 sol. (25 mL), organic layer
  6. washwashed with sat. NaCl sol. (25 mL)
  7. dry with materialdried over MgSO4
  8. customThe residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL per min, gradient 0% to 7% MeOH in DCM])

Sources & evidence

ORD record
ord-eb1d3c915f53441d9577f8d9fdc464b1
Source dataset
uspto-grants-2015_11
Patent number
US09187451B2

Reaction notes

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