Sodium Bicarbonate → HCID 86673709, compound

HRID 1025592Notes

Reaction equation

HRID 1025592 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[C:19]([CH:35]=[O:36])=[C:20]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]#[N:34])=[CH:25]2)[CH:21]=[CH:22][CH:23]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O.ClCCl.[Cu](I)I>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:18]1[C:19]([CH:35]=[O:36])=[C:20]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([C:33]#[N:34])=[CH:25]3)[CH:21]=[CH:22][CH:23]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 3

HCID 516892Sodium BicarbonateHCID 594737656-(tert-Butyl)-8-fluorophthalazin-1(2H)-oneHCID 86673710HCID 86673710, compound2×

Product 1

HCID 86673709HCID 86673709, compoundYield 77%

Reagents, catalysts & solvents 4

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 6-tert-butyl-8-fluorophthlazine-1(2H)-one (prepared according to US2010/0222325) 36 mg, 0.16 mmol) and 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (59 mg, 0.18 mmol) in dry dimethylsulfoxide (1.8 mL) was added sodium bicarbonate (31 mg, 0.36 mmol) under an argon atmosphere. Next copper iodide (35 mg, 0.18 mmol) was added and the mixture was heated to 110° C. for 2 hours. The reaction was cooled to ambient and taken up in water (40 ml) and dichloromethane (40 ml). The material was filtered through a plug of celite, rinsing well with dichloromethane. The filtrate was transferred to a reparatory funnel and the dichloromethane phase was collected. This was washed with a 50% solution of diluted brine (40 ml). The organic phase was collected and the aqueous phases back extracted with dichloromethane (2×35 ml). The dichloromethane phases were combined, dried (MgSO4), filtered and stripped. Then the identical reaction was repeated on a larger scale using 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (290 mg, 0.89 mmol) and similar scaled amounts of the reagents described above and under identical procedure and work up. The crude from the two reactions was combined and purified by HPLC (silica gel, eluting with 100% CH2Cl2 to 1% MeOH/CH2Cl2) to provide a semi-pure product. The material was further purified by preparative thin layer chromatography (3 plates, eluting with 0.5% MeOH/CH2Cl2 and then re-eluting with 0.75% and then 1% MeOH/CH2Cl2). The product band was collected to provide 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3 carbonitrile as a yellow foamy solid. (384 mg, 77% yield). LC/MS calcd for C28H21FN4O2 (m/e) 464.49, obsd 465.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9H) 7.24-7.32 (m, 1H) 7.34-7.41 (m, 2H) 7.46-7.60 (m, 3H) 7.75 (d, J=7.55 Hz, 1H) 7.81 (s, 1H) 7.83-7.87 (m, 1H) 7.90 (t, J=7.96 Hz, 1H) 8.25 (d, J=2.64 Hz, 1H) 9.56 (s, 1H).

Workup

  1. temperatureThe reaction was cooled to ambient and
  2. filtrationThe material was filtered through a plug of celite
  3. washrinsing well with dichloromethane
  4. customThe filtrate was transferred to a reparatory funnel
  5. customthe dichloromethane phase was collected
  6. washThis was washed with a 50% solution of diluted brine (40 ml)
  7. customThe organic phase was collected
  8. extractionthe aqueous phases back extracted with dichloromethane (2×35 ml)
  9. dry with materialdried (MgSO4)
  10. filtrationfiltered
  11. customThen the identical reaction
  12. custompurified by HPLC (silica gel, eluting with 100% CH2Cl2 to 1% MeOH/CH2Cl2)
  13. customto provide a semi-pure product
  14. customThe material was further purified by preparative thin layer chromatography (3 plates
  15. washeluting with 0.5% MeOH/CH2Cl2
  16. washre-eluting with 0.75%
  17. customThe product band was collected

Sources & evidence

ORD record
ord-b5dbf76874644f63ac158bd9ea8d633d
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

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