Sodium hydride → HCID 89466173, compound

HRID 1184599Notes

Reaction equation

HRID 1184599 reaction equation
[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[CH2:20][N:14]4[CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][CH2:16][N:17]([CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=5)[C:18](=[O:19])[C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1230611-(Bromomethyl)-3-(trifluoromethyl)benzeneHCID 86680516HCID 86680516, compound

Product 1

HCID 89466173HCID 89466173, compoundYield 26.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (50 mg, 0.182 mmol) from Step 3 [3:1 (7R,8aS: 7R,8aR) diastereomer ratio] in N,N-dimethylformamide (0.7 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil; 8.75 mg, 0.219 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.033 mL, 0.219 mmol) with stirring continued for 4 hours at room temperature. The reaction mixture was partitioned between water (3 mL) and ethyl acetate (3×2 mL), and the organic phase was dried over sodium sulfate. The solvent was concentrated under a stream of nitrogen, and the crude material was purified by flash chromatography on a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give the crude product as an oil. The crude oil (40 mg) was loaded onto a 2×0.25 mm silica gel prep plate and eluted with ethyl acetate to give the title compound (21 mg, 0.049 mmol, 26.6% yield) as the first of 2 diastereomers to elute as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=1.0 Hz, 1H), 7.94 (d, J=1.1 Hz, 1H), 7.55 (dd, J=4.4, 3.4 Hz, 1H), 7.48 (t, J=9.0 Hz, 3H), 5.44 (dd, J=6.9, 5.7 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (dt, J=12.2, 7.1 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 3.9 Hz, 1H), 3.02 (dd, J=6.7, 3.8 Hz, 2H), 2.88 (dd, J=10.8, 2.9 Hz, 1H), 2.53 (dt, J=15.2, 7.6 Hz, 1H), 2.44 (dd, J=14.5, 7.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 433 (M+H)+.

Workup

  1. stirringwith stirring
  2. waitcontinued for 4 hours at room temperature
  3. customThe reaction mixture was partitioned between water (3 mL) and ethyl acetate (3×2 mL)
  4. dry with materialthe organic phase was dried over sodium sulfate
  5. concentrationThe solvent was concentrated under a stream of nitrogen
  6. customthe crude material was purified by flash chromatography on a 12 g silica gel cartridge
  7. washeluted with a gradient 0-5% methanol/dichloromethane over 17 minutes
  8. customto give the crude product as an oil
  9. washeluted with ethyl acetate

Sources & evidence

ORD record
ord-cb08736943fd49b7a4e1b70b3e089f6a
Source dataset
uspto-grants-2014_03
Patent number
US08669255B2

Reaction notes

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