Sodium hydride → (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate

HRID 1476881Notes

Reaction equation

HRID 1476881 reaction equation
[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[Cl:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[C:19]([C:28]#[N:29])[N:18]=[C:17]2[O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:22][CH:23]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 854055tert-Butyl (3S)-3-hydroxypyrrolidine-1-carboxylateHCID 846880831,7-Dichloroisoquinoline-3-carbonitrile

Product 1

HCID 90387178(S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylateYield 59.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (201 mg, 1.076 mmol) in THF (5 mL) at 0° C. was added NaH (81 mg, 1.35 mmol). The reaction mixture was stirred at RT for 30 minutes. Next, 1,7-dichloroisoquinoline-3-carbonitrile (200 mg, 0.897 mmol) was added and the reaction mixture was warmed to RT over a 1 hour period. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and the resulting mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative TLC eluting with petroleum ether and ethyl acetate (PE/EtOAc=3:1) to give the title compound (200 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1H), 7.65-7.71 (m, 3H), 5.74 (br, 1H), 3.46-3.69 (m, 4H), 2.23 (s, 1H), 1.49 (s, 9H).

Workup

  1. temperaturethe reaction mixture was warmed to RT over a 1 hour period
  2. customThe reaction was quenched with saturated aqueous NH4Cl (10 mL)
  3. extractionthe resulting mixture was extracted with EtOAc (3×50 mL)
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude product was purified by preparative TLC
  8. washeluting with petroleum ether and ethyl acetate (PE/EtOAc=3:1)

Sources & evidence

ORD record
ord-f1c9e3d82fda4fada26f4608dd700843
Source dataset
uspto-grants-2016_08
Patent number
US09402841B2

Reaction notes

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