Cesium carbonate → benzyl 2-oxo-5-phenyl-1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate

HRID 593478Notes

Reaction equation

HRID 593478 reaction equation
[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.CCOC(C)=O.P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+]>[O:1]=[C:2]1[N:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 438061,2-Diaminocyclohexane, trans-HCID 2211262-IodopyridineHCID 2756242Benzyl (2-oxo-5-phenyl-2,3-dihydro-1h-benzo[e][1,4]diazepin-3-yl)carbamate

Product 1

HCID 90082795benzyl 2-oxo-5-phenyl-1-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamateYield 61.2%

Reagents, catalysts & solvents 4

HCID 1061PhosphateSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred mixture of benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (1.20 g, 3.11 mmol, prepared according to J. Med. Chem., 49:2311-2319 (2006), compound #4a), 2-iodopyridine (1.00 g, 4.88 mmol), cuprous iodide (0.15 g, 0.788 mmol) and Cs2CO3 (3.05 g, 9.36 mmol) in dioxane (25 mL) was added (+/−)-trans-1,2-diaminocyclohexane (0.19 mL, 1.58 mmol) under nitrogen. The reaction mixture was then heated to 120° C. and gently refluxed for 10 min. It was then cooled to room temperature under nitrogen. This mixture was diluted with 100 mL of EtOAc, 40 mL of pH 4 phosphate buffer and 40 mL of saturated NaHCO3 solution. The insoluble material was removed by filtration through a 2 inch pad of CELITE®, and rinsed with EtOAc (2×30 mL). The aqueous phase was separated and extracted with 160 mL of EtOAc. The combined EtOAc extracts were washed with saturated NaHCO3 solution (1×30 mL) and brine (1×20 mL), then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to afford Intermediate 1A (0.88 g, 61%): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (1 H, d, J=8.14 Hz), 8.47 (1 H, dd, J=4.73, 1.21 Hz), 7.94-8.03 (1 H, m), 7.64 (2 H, d, J=7.92 Hz), 7.47-7.60 (4 H, m), 7.27-7.44 (9 H, m), 6.97 (1 H, d, J=8.14 Hz), 5.39 (1 H, d, J=8.36 Hz), 5.10 (2 H, s); HPLC: RT=2.930 min (CHROMOLITH® ODS 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS(ES): m/z=463.3 [M+H]+.

Workup

  1. temperaturegently refluxed for 10 min
  2. temperatureIt was then cooled to room temperature under nitrogen
  3. customThe insoluble material was removed by filtration through a 2 inch pad of CELITE®
  4. washrinsed with EtOAc (2×30 mL)
  5. customThe aqueous phase was separated
  6. extractionextracted with 160 mL of EtOAc
  7. washThe combined EtOAc extracts were washed with saturated NaHCO3 solution (1×30 mL) and brine (1×20 mL)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by silica gel chromatography (hexane/EtOAc)

Sources & evidence

ORD record
ord-4d1deb89bdc347d39193113205adc58a
Source dataset
uspto-grants-2016_01
Patent number
US09242940B2

Reaction notes

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