Cesium carbonate → HCID 66883198, compound

HRID 915375Notes

Reaction equation

HRID 915375 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:8]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:36]1[N:43]=[CH:42][CH:41]=[CH:40][C:37]=1[C:38]#[N:39]>CN(C)C=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:8]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:36]3[N:43]=[CH:42][CH:41]=[CH:40][C:37]=3[C:38]#[N:39])=[CH:26][CH:27]=1)=[CH:7]2

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 810792-Chloronicotinonitrile2×HCID 10475949HCID 10475949, compound2×

Product 1

HCID 66883198HCID 66883198, compoundYield 57%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
105 °C

Procedure

To a solution of 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (54 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL), was added powdered Cs2CO3 (89 mg, 0.27 mmol), followed by 2-chloronicotinonitrile (33 mg, 0.23 mmol). The resulting suspension was stirred and heated in a 105° C. oil bath. After stirring for 64 h at 105° C., HPLC analysis of the reaction mixture showed no 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, nor 2-chloronicotinonitrile remaining. The reaction was allowed to cool to ambient temperature and was diluted with H2O (15 mL), and Et2O (50 mL). The layers were separated, the organic layer was washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a yellow liquid. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 10% to 40% EtOAc/hexane. The product peak was collected to afford 2-{4-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenoxy}nicotinonitrile, a compound of formula (Id), (36 mg, 57% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.35 (1H, dd, J=5.0, 2.0 Hz), 8.05 (1H, dd, J=7.6, 1.8 Hz), 7.54-7.51 (2H, m), 7.42-7.38 (1 H, m), 7.27-7.24 (2H, m), 7.22-7.18 (2H, m), 7.15 (1H, dd, J=7.6, 5.0 Hz), 7.08-7.00 (1H, m), 6.80-6.74 (1H, m), 6.71-6.65 (1H, m), 6.46 (1H, s), 5.22 (2H, s).

Workup

  1. stirringAfter stirring for 64 h at 105° C.
  2. temperatureto cool to ambient temperature
  3. customThe layers were separated
  4. washthe organic layer was washed with H2O (10 mL), brine (10 mL)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customto afford a yellow liquid
  9. customThe crude product was purified by silica gel column chromatography
  10. washeluting with a gradient from 10% to 40% EtOAc/hexane
  11. customThe product peak was collected

Sources & evidence

ORD record
ord-80bc9b5b08cd4a8fa23f085105921ebc
Source dataset
uspto-grants-2007_09
Patent number
US07265131B2

Reaction notes

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