Sodium hydride → (S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate

HRID 1476872Notes

Reaction equation

HRID 1476872 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]=[CH:24][C:25]=2[F:27])[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[C:28]([C:19]1[N:18]=[C:17]([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)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][C:25]=2[F:27])#[N:29]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 854055tert-Butyl (3S)-3-hydroxypyrrolidine-1-carboxylateHCID 903868251-Chloro-8-fluoroisoquinoline-3-carbonitrile

Product 1

HCID 90387435(S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylateYield 60%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.18 g, 12 mmol) in THF (50 mL) was added NaH (0.464 g, 12 mmol) at 0° C. The mixture was stirred at RT for 30 minutes. Next, 1-chloro-8-fluoroisoquinoline-3-carbonitrile (1.6 g, 8 mmol) was added and the reaction mixture was warmed to RT and stirred for 4 hours. The reaction was subsequently quenched with H2O (20 mL) and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (1 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm 7.72 (s, 2H), 7.61-7.59 (d, J=8 Hz, 1H), 7.38-7.32 (t, J=12 Hz, 1H), 5.8 (s, 1H), 3.75-3.59 (m, 4H), 2.29-2.28 (d, J=4 Hz, 2H).

Workup

  1. temperaturethe reaction mixture was warmed to RT
  2. stirringstirred for 4 hours
  3. customThe reaction was subsequently quenched with H2O (20 mL)
  4. extractionthe mixture was extracted with EtOAc (3×50 mL)
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record
ord-1980baf9bd7a4f6eb4632b314ce3cbcf
Source dataset
uspto-grants-2016_08
Patent number
US09402841B2

Reaction notes

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