Sodium Bicarbonate → 2-[2-(3-Bromo-2-formyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile

HRID 1431070Notes

Reaction equation

HRID 1431070 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:20]=1[CH:21]=[O:22].C(=O)(O)[O-].[Na+]>CS(C)=O.[Cu](I)I>[Br:18][C:19]1[C:20]([CH:21]=[O:22])=[C:23]([N:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([F:1])[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=3)[C:10]2=[O:12])[CH:24]=[CH:25][CH:26]=1

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 126486412,6-DibromobenzaldehydeHCID 667426112-(8-Fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile

Product 1

HCID 866900472-[2-(3-Bromo-2-formyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrileYield 63.3%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
110 °C

Procedure

A solution of 2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile (250 mg, 1.09 mmol), 2,6-dibromobenzaldehyde (459 mg, 1.74 mmol) and sodium bicarbonate (182 mg, 2.17 mmol) in dry dimethylsulfoxide (8 ml) was placed under vacuum and back-filled with argon (repeat twice more). To this was added copper iodide (207 mg, 1.09 mmol) and the flask was evacuated and back-filled with argon (repeat twice more). The mixture was heated in an oil bath to 110° C. and stirred for 3.5 hours. The reaction mixture was cooled to ambient and taken up in ethyl acetate (40 ml) and water (40 ml). The biphasic material was filtered through a plug of celite, rinsing well with ethyl acetate. The filtrate and washes were transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the ethyl acetate phase collected. The aqueous phases were back extracted with ethyl acetate (2×30 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% methanol/dichloromethane to provide the desired product as a light yellow solid (285 mg). (M+H)+=413/415 m/e.

Workup

  1. additionback-filled with argon (repeat twice more)
  2. customthe flask was evacuated
  3. additionback-filled with argon (repeat twice more)
  4. temperatureThe reaction mixture was cooled to ambient and
  5. filtrationThe biphasic material was filtered through a plug of celite
  6. washrinsing well with ethyl acetate
  7. customThe filtrate and washes were transferred to a separatory funnel
  8. customthe organic phase was collected
  9. washThis was washed with an equal volume of 50% diluted brine solution
  10. customthe ethyl acetate phase collected
  11. extractionThe aqueous phases were back extracted with ethyl acetate (2×30 ml)
  12. dry with materialThe combined organic phase was dried with magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by HPLC on silica gel
  16. washeluting with 1% methanol/dichloromethane

Sources & evidence

ORD record
ord-273ae271b2c1401d9376226b17144367
Source dataset
uspto-grants-2015_01
Patent number
US08940741B2

Reaction notes

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