Sodium hydride → HCID 89466021, compound

HRID 1184600Notes

Reaction equation

HRID 1184600 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][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][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:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=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 1230621-(Bromomethyl)-4-(trifluoromethyl)benzeneHCID 86680516HCID 86680516, compound

Product 1

HCID 89466021HCID 89466021, compoundYield 18.69%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]-pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](112 mg, 0.408 mmol) from Example 163 Step 3 in N,N-dimethylformamide (1 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil) (19.60 mg, 0.490 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.076 mL, 0.490 mmol). The resulting solution was stirred at room temperature for 3 hours, and it was then partitioned between water and ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate and then filtered. The filtrate was concentrated under a stream of nitrogen, and the crude material was purified with a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give an oil. The oil (54 mg) was loaded onto 2×0.25 mm silica gel prep plates and eluted with 5% methanol/ethyl acetate to give the title compound (33 mg, 0.076 mmol, 18.69% yield) as the first eluting diastereomer as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (d, J=1.4 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 5.49-5.39 (m, 1H), 4.71 (d, J=14.9 Hz, 1H), 4.60 (d, J=14.9 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (ddd, J=12.1, 7.9, 6.6 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 4.0 Hz, 1H), 3.07-2.99 (m, 2H), 2.88 (dd, J=10.8, 3.0 Hz, 1H), 2.53 (ddd, J=15.1, 8.0, 7.3 Hz, 1H), 2.44 (ddd, J=14.6, 7.9, 1.7 Hz, 1H), 1.99 (tt, J=7.8, 5.3 Hz, 1H), 1.01-0.90 (m, 4H); MS (ESI+) m/z 433 (M+H)+.

Workup

  1. stirringThe resulting solution was stirred at room temperature for 3 hours
  2. customit was then partitioned between water and ethyl acetate (3×)
  3. dry with materialThe combined organic extracts were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under a stream of nitrogen
  6. customthe crude material was purified with a 12 g silica gel cartridge
  7. washeluted with a gradient 0-5% methanol/dichloromethane over 17 minutes
  8. customto give an oil
  9. washeluted with 5% methanol/ethyl acetate

Sources & evidence

ORD record
ord-3e2e575d837b40b0b42b198ad28d16ea
Source dataset
uspto-grants-2014_03
Patent number
US08669255B2

Reaction notes

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