Tetrahydrofuran → HCID 118274924, compound

HRID 1777841Notes

Reaction equation

HRID 1777841 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[NH:9][C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C1C[O:29]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)[C:8]([OH:29])([CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 693291-(Bromomethyl)-4-chlorobenzeneHCID 118274944HCID 118274944, compound

Product 2

HCID 118274924HCID 118274924, compoundYield 29%HCID 118274959HCID 118274959, compoundYield 29%

Procedure

To a degassed solution of (S)-3-chloro-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (42.2 mg, 200 μmol) in THF (2 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 9.6 mg, 240 μmol). The mixture was stirred at 0° C. for 30 min, at which point 4-chlorobenzyl bromide (49.3 mg, 240 μmol) was added. The mixture was allowed to warm to rt and was stirred for 15 h. The mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes, gradient to 50%) to afford (S)-3-chloro-6-(4-chlorobenzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (19.6 mg, 29%) and 3-chloro-6-(4-chlorobenzyl)-7-hydroxy-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (20.1 mg, 29%). LCMS: tR=1.09 min in in 1 min chromatography, MS (ESI) m/z 335.3 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.74 (d, J=2.0 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.37-7.32 (m, 4H), 5.16 (d, J=15.6 Hz, 1H), 4.47 (d, J=15.2 Hz, 1H), 4.40 (d, J=3.2 Hz, 1H), 2.56-2.48 (m, 1H), 1.27 (d, J=7.2 Hz, 3H), 0.48 (d, J=7.2 Hz, 3H).

Workup

  1. additionwas added
  2. customThe mixture was quenched with saturated aqueous ammonium chloride (10 mL)
  3. extractionextracted with EtOAc (10 mL)
  4. washThe organic phase was washed with brine (10 mL)
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes, gradient to 50%)

Sources & evidence

ORD record
ord-6e8256b542d14964ae188f087eaa0656
Source dataset
uspto-grants-2016_02
Patent number
US09266886B2

Reaction notes

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