Sodium hydride → 1-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-pyridin-3-yl-propan-2-ol

HRID 1469547Notes

Reaction equation

HRID 1469547 reaction equation
[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][O:22]1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:20][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)([OH:22])[CH3:23])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 230811803-(2-Methyloxiran-2-yl)pyridineHCID 6703672110-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole

Product 1

HCID 682839051-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-pyridin-3-yl-propan-2-olYield 33.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (150 mg, 0.66 mmol) was dissolved in DMF (1 mL), sodium hydride (47 mg, 1.98 mmol) was added and the mixture was stirred at RT for 5 min. 3-(2-Methyl-oxiranyl)-pyridine (143 mg, 1.06 mmol) was added dropwise into the reaction mixture and stirred at RT for 2 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel 100-200 mesh, Eluent: −15% MeOH in DCM) to obtain 80 mg of 1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.66 (dd, 2H), 8.56 (s, 1H), 7.92 (t, 1H), 7.20 (s, 1H), 6.77 (t, 2H), 5.04 (t, 1H), 3.75 (dd, 2H), 3.72 (m, 2H), 3.6 (m, 1H), 3.44 (m, 2H), 3.22 (d, 1H), 2.75 (m, 1H), 2.73 (s, 3H), 2.16 (m, 3H), 1.8 (s, 3H). Separation by chiral HPLC provided enantiomers II-127a-b.

Workup

  1. stirringstirred at RT for 2 h
  2. customAfter consumption of starting material
  3. customthe reaction mixture was quenched with ice cold water (20 mL)
  4. extractionextracted with EtOAc (2×100 mL)
  5. washThe combined organic layer was washed with water (2×100 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated
  8. customto obtain the crude product, which
  9. customwas purified by column chromatography (silica gel 100-200 mesh, Eluent: −15% MeOH in DCM)

Sources & evidence

ORD record
ord-5fdc336b159f45f39d13c4bb358aec56
Source dataset
uspto-grants-2015_04
Patent number
US09006263B2

Reaction notes

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