Sodium hydride → 3-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile Trifluoroacetate

HRID 1271231Notes

Reaction equation

HRID 1271231 reaction equation
[H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[NH:5]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.[F:34][C:35]([F:40])([F:39])[C:36]([O-:38])=[O:37]>O1CCCC1.O1CCCC1.CN1CCCC1=O>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[C:16]([CH:12]1[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=3)[NH:5][C:4]1=[O:3])=[N:17][CH:18]=[CH:19]2

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 84468TrifluoroacetateHCID 27733462-Oxo-2,3-dihydro-1H-indole-5-carbonitrileHCID 18452920Chloro-6-[2-(2-methoxyethoxy)ethoxy]isoquinoline

Product 1

HCID 98494573-{6-[2-(2-Methoxyethoxy)ethoxy]isoquinolin-1-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile TrifluoroacetateYield 27%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22156051tetrahydrofuran N-methylpyrrolidinoneSolvent

Procedure

A suspension of sodium hydride (92 mg, 3.55 mmol, 95% powder) in tetrahydrofuran (10 mL) was slowly added via a cannula to a solution of 2-oxo-5-indolinecarbonitrile (292 mg, 1.85 mmol) in tetrahydrofuran/N-methylpyrrolidinone (15 mL, 2:1) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 25 min. A solution of chloro-6-[2-(2-methoxyethoxy)ethoxy]isoquinoline (400 mg, 1.42 mmol) in tetrahydrofuran (10 mL) was added and the reaction solution was stirred at room temperature over night. The reaction was quenched by slow addition of hydrochloric acid (1 M) and concentrated in vacuo to a slurry. The slurry was diluted with acetonitrile (5 mL) and purified by prep RP-HPLC (C18 2″ column, gradient:acetonitril/water, 20:80→0:100+0.1% TFA). The appropriate fractions were pooled and lyophilized giving 193 mg (27% yield) of the title compound as an orange trifluoroacetate salt. MS (AP+) m/z 404 (M+1).

Workup

  1. stirringthe reaction solution was stirred at room temperature over night
  2. customThe reaction was quenched by slow addition of hydrochloric acid (1 M)
  3. concentrationconcentrated in vacuo to a slurry
  4. additionThe slurry was diluted with acetonitrile (5 mL)
  5. custompurified by prep RP-HPLC (C18 2″ column

Sources & evidence

ORD record
ord-6ff0d6fcb50f406c8800b8630bed7c77
Source dataset
uspto-grants-2007_04
Patent number
US07205314B2

Reaction notes

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