Triethylamine → N-[(6S,9R)-6-(2,3-Difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide

HRID 1664937Notes

Reaction equation

HRID 1664937 reaction equation
C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.[C:32]([N:39]1[CH:43]=[CH:42]N=[CH:40]1)(N1C=CN=C1)=[O:33].N1CC[CH:47]([C:50]2[C:51](=[O:60])[NH:52][C:53]3[C:58]([CH:59]=2)=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:46]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:32]([N:39]2[CH2:40][CH2:46][CH:47]([C:50]3[C:51](=[O:60])[NH:52][C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:42][CH2:43]2)=[O:33])[CH2:18][CH2:17]1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 516892Sodium BicarbonateHCID 183210463-(Piperidin-4-yl)quinolin-2(1H)-oneHCID 67439949(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine

Product 1

HCID 59722588N-[(6S,9R)-6-(2,3-Difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamideYield 67%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Triethylamine (50 μL, 0.358 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (60 mg, 0.143 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.25 mmol) in tetrahydrofuran (3 mL) at 0° C. After 25 min, 3-piperidin-4-ylquinolin-2(1H)-one (33 mg, 0.143 mmol) and dichloromethane (3 mL) were added and the mixture heated to 60° C. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)]. Repurification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (57.5 mg). MS 601.2312 (M+1).

Workup

  1. waitAfter 16 h
  2. extractionthe mixture was extracted with dichloromethane (3×)
  3. washThe organic layer was washed with saturated brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)]
  8. customRepurification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-6c0d020f9e094581b4bcff4ea93c1a2c
Source dataset
uspto-grants-2011_10
Patent number
US08039460B2

Reaction notes

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