Sodium hydride → tert-butyl (S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

HRID 1777810Notes

Reaction equation

HRID 1777810 reaction equation
CS(O[CH2:6][C:7]1[C:8]([C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.ClC1C=C(CCl)C([C@@H](NC(=O)OC(C)(C)C)C(C)C)=NC=1.[H-].[Na+]>C1COCC1>[Cl:13][C:11]1[CH:12]=[C:7]2[CH2:6][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH:15]([CH3:17])[CH3:16])[C:8]2=[N:9][CH:10]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 118274937(S)-(2-(1-((tert-Butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methyl methanesulfonateHCID 118282495tert-butyl (S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate

Product 1

HCID 118274870tert-butyl (S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateYield 85%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methyl methanesulfonate and tert-butyl(S)-(1-(5-chloro-3-(chloromethyl)pyridin-2-yl)-2-methylpropyl)carbamate (3:1 mixture, 6.39 g, 16.9 mmol) in THF (75 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 811 mg, 20.3 mmol). The mixture was warmed to rt and stirred for 15 h, at which point it was quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (50 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 10%) to give tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (4.31 g, 85% yield over 3 steps) as a yellow oil. LC-MS tR=1.12 min in 1 min chromatography, MS (ESI) m/z 297.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, mixture of rotamers): δ 8.43 (s, 1H), 7.56 (s, 0.6H), 7.50 (s, 0.4H), 4.96 (s, 0.4H), 4.87 (s, 0.6H), 4.86 (d, J=16.0 Hz, 0.6H), 4.74 (d, J=15.6 Hz, 0.4H), 4.52 (d, J=12.0 Hz, 0.4H), 4.49 (d, J=15.2 Hz, 0.6H), 2.60-2.51 (m, 0.4H), 2.40-2.36 (m, 0.6H), 1.49 (s, 9H), 1.08 (d, J=7.2 Hz, 1.2H), 0.99 (d, J=7.2 Hz, 1.8H), 0.78 (d, J=6.8 Hz, 1.8H), 0.72 (d, J=6.8 Hz, 1.2H).

Workup

  1. customwas quenched with saturated aqueous ammonium chloride solution (100 mL)
  2. extractionThe aqueous phase was extracted with ethyl acetate (3×100 mL)
  3. washThe combined organic layer was washed with brine (50 mL)
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes, gradient to 10%)

Sources & evidence

ORD record
ord-757fd8a0115e48a9846ad729147e07e6
Source dataset
uspto-grants-2016_02
Patent number
US09266886B2

Reaction notes

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