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

HRID 1664898Notes

Reaction equation

HRID 1664898 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])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]2[C:52](=[O:57])[NH:53][N:54]=[CH:55][CH:56]=2)[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[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])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:45]2[CH2:46][CH2:47][CH:48]([C:51]3[C:52](=[O:57])[NH:53][N:54]=[CH:55][CH:56]=3)[CH2:49][CH2:50]2)=[O:34])[CH2:18][CH2:17]1

Participants

8

Reactant 5

HCID 8471Triethylamine2×HCID 10340Sodium CarbonateHCID 821294-Nitrophenyl chloroformateHCID 57562526HCID 57562526, compoundHCID 67438873(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine

Product 1

HCID 11671198N-[(6S,9R)-6-(2,3-Difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-4-(3-oxo-2,3-dihydropyridazin-4-yl)piperidine-1-carboxamideYield 55.5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Triethylamine (37 μL, 0.50 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (70 mg, 0.167 mmol) and 4-nitrophenyl chloroformate (34 mg, 0.167 mmol) in tetrahydrofuran (1 mL) at 0° C. After 15 min, a solution of 4-piperidin-4-ylpyridazin-3(2H)-one (30 mg, 0.167 mmol) in dichloromethane (1 mL) and triethylamine (49 μL, 0.67 mmol) were added and the mixture allowed to warm to ambient temperature. After 4 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (51 mg). MS 551.2152 (M+1).

Workup

  1. waitAfter 4 h
  2. extractionthe mixture was extracted with ethyl acetate (3×)
  3. washThe organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol)

Sources & evidence

ORD record
ord-90a1c4ae43a74704b81a05aef60cc438
Source dataset
uspto-grants-2011_10
Patent number
US08039460B2

Reaction notes

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