Sodium Carbonate → (8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one

HRID 1050313Notes

Reaction equation

HRID 1050313 reaction equation
Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 923422-Chloro-5-(trifluoromethyl)pyridineHCID 86723197(8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride

Product 1

HCID 76287561(8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-oneYield 47%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
115 °C

Procedure

(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride was dissolved in dimethyl sulfoxide (1.0 mL). 2-Chloro-5-(trifluoromethyl)pyridine (36.0 mg, 0.198 mmol, 1.9 equivalents) and sodium carbonate (82.0 mg, 0.774 mmol, 7.5 equivalents) were added, and the resulting suspension was heated to 115° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, and then dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified via silica chromatography on 2 sequentially linked 4 g silica cartridges, eluted with 25:75 to 0:100 heptanes:ethyl acetate to give the titled compound (26 mg, 0.055 mmol, 47% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.66 (dd, J=9.0, 2.2 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 5.56-5.20 (m, 1H), 4.63 (d, J=14.4 Hz, 1H), 4.34 (d, J=15.2 Hz, 1H), 4.03 (td, J=9.3, 3.7 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.83 (dd, J=16.0, 8.0 Hz, 1H), 3.56-3.41 (m, 1H), 3.36 (dd, J=14.4, 9.7 Hz, 1H), 2.72 (dd, J=12.1, 7.3 Hz, 2H), 2.66 (ddd, J=14.2, 9.1, 5.1 Hz, 1H), 2.15 (d, J=14.0 Hz, 1H), 2.06-1.91 (m, 1H), 1.04-0.88 (m, 4H); 1H NMR (400 MHz, pyridine-d5) δ ppm 8.64 (s, 1H), 8.25 (d, J=1.2 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.79 (dd, J=9.1, 2.4 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 5.53-5.38 (m, 1H), 4.67 (d, J=14.3 Hz, 1H), 4.46 (d, J=15.4 Hz, 1H), 4.14 (d, J=13.2 Hz, 1H), 4.04 (ddd, J=18.1, 11.2, 4.4 Hz, 2H), 3.57-3.40 (m, 2H), 2.96-2.80 (m, 2H), 2.62 (ddd, J=14.1, 9.0, 5.3 Hz, 1H), 2.16 (dd, J=14.0, 3.3 Hz, 1H), 2.04 (td, J=8.2, 4.1 Hz, 1H), 1.15-1.04 (m, 2H), 1.04-0.83 (m, 2H); MS (ESI+) m/z 434.1 (M+H)+; [α]D24.6=37.3 (c=0.85, CH3OH).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washwashed with water and brine
  3. dry with materialdried over sodium sulfate
  4. customThe solvent was removed in vacuo
  5. customthe residue was purified via silica chromatography on 2 sequentially linked 4 g silica cartridges
  6. washeluted with 25:75 to 0:100 heptanes

Sources & evidence

ORD record
ord-f3033aab8f3a40ff8ffa0655bc81e058
Source dataset
uspto-grants-2016_07
Patent number
US09382258B2

Reaction notes

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