Tetrahydrofuran → (R)-4a-Ethoxymethyl-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]-sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalene

HRID 1907275Notes

Reaction equation

HRID 1907275 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]4[C@:21]([CH2:23][OH:24])([CH2:22][C:13]=3[CH:12]=[N:11]2)[CH2:20][N:19]([S:25]([C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:18][CH2:17]4)=[CH:6][CH:5]=1.O1CC[CH2:42][CH2:41]1>ICC>[CH2:41]([O:24][CH2:23][C@@:21]12[CH2:20][N:19]([S:25]([C:28]3[CH:29]=[N:30][C:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:32][CH:33]=3)(=[O:26])=[O:27])[CH2:18][CH2:17][C:16]1=[CH:15][C:14]1[N:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[N:11]=[CH:12][C:13]=1[CH2:22]2)[CH3:42]

Participants

5

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 24758Sodium hydrideHCID 66780233[(R)-1-(4-Fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol

Product 1

HCID 56848863(R)-4a-Ethoxymethyl-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]-sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalene

Reagents, catalysts & solvents 1

HCID 6340IodoethaneSolvent

Conditions

Temperature
50 °C

Procedure

A suspension of sodium hydride (1.5 g) in tetrahydrofuran (20 mL) at room temperature was treated sequentially with a solution of [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triaza-cyclopent-a[b]naphthalen-4a-yl]methanol (8.0 g) in tetrahydrofuran (60 mL) and iodoethane (3.7 mL), and the resulting mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature and partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with aqueous sodium thiosulfate solution, aqueous potassium carbonate solution, water and brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and diethyl ether (1:20 to 1:10 by volume), to afford a cream foam (7.5 g). The cream foam was crystallized from industrial methylated spirits to afford the title compound as a white solid (6.3 g). LCMS (Method A): 552 (M+H)+, Retention time 5.0 minutes. 1H NMR (CDCl3): δ 8.53-8.49 (d, 1H, J=2.4 Hz), 7.79-7.73 (dd, 1H, J=9.2, 2.5 Hz), 7.41-7.33 (m, 3H), 7.15-7.07 (t, 2H, J=8.0 Hz), 6.62-6.55 (d, 1H, J=9.0 Hz), 6.25-6.21 (d, 1H, J=2.3 Hz), 4.15-4.08 (dd, 1H, J=12, 2.3 Hz), 3.89-3.80 (m, 1H), 3.80-3.73 (m, 4H), 3.67-3.59 (m, 4H), 3.52-3.35 (m, 3H), 3.14-3.02 (m, 2H), 2.74-2.61 (m, 1H), 2.41-2.29 (m, 2H), 2.20-2.04 (dd, 2H, J=34, 16 Hz), 1.19-1.11 (t, 3H, J=7.0 Hz).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. custompartitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid solution
  3. extractionThe aqueous phase was extracted with ethyl acetate
  4. washthe combined organic phase was washed with aqueous sodium thiosulfate solution, aqueous potassium carbonate solution, water and brine
  5. dry with materialdried over sodium sulfate
  6. customThe solvent was removed under reduced pressure
  7. customthe residue was purified by column chromatography on silica gel
  8. washeluting with a mixture of dichloromethane and diethyl ether (1:20 to 1:10 by volume)

Sources & evidence

ORD record
ord-909be682aacc4de2a991b644a376cb15
Source dataset
uspto-grants-2013_12
Patent number
US08598154B2

Reaction notes

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