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]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

HRID 1664892Notes

Reaction equation

HRID 1664892 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[C:49]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[C:48](=[O:55])[NH:47][C:46]1=[O:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CN(C)C=O>[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:52]2[CH2:53][CH2:54][C:49]3([NH:45][C:46](=[O:56])[NH:47][C:48]3=[O:55])[CH2:50][CH2:51]2)=[O:34])[CH2:18][CH2:17]1

Participants

8

Reactant 5

HCID 8471Triethylamine2×HCID 10340Sodium CarbonateHCID 821294-Nitrophenyl chloroformateHCID 1209891,3,8-Triazaspiro[4.5]decane-2,4-dioneHCID 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 11599128N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamideYield 25.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

Triethylamine (12 μL, 0.087 mmol) was added to a solution 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 (30 mg, 0.087 mmol) and 4-nitrophenyl chloroformate (18 mg, 0.091 mmol) in tetrahydrofuran (1 mL) at 0° C. After 1 h, 1,3,8-triazaspiro[4.5]decane-2,4-dione (15 mg, 0.091 mmol), triethylamine (48 μL, 0.348 mmol) and N,N-dimethylformamide (1 mL) were added and the mixture heated to 40° C. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→88% dichloromethane/methanol] gave the title compound (12 mg). MS 541.1955 (M+1).

Workup

  1. waitAfter 18 h
  2. extractionthe mixture was extracted with dichloromethane
  3. washThe organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by silica gel chromatography [100% dichloromethane→88% dichloromethane/methanol]

Sources & evidence

ORD record
ord-59fab068e94244db87388622c7180524
Source dataset
uspto-grants-2011_10
Patent number
US08039460B2

Reaction notes

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