Dichloromethane → 3-CinnolinecarboxaMide, 4-aMino-8-(2-fluoro-6-Methoxyphenyl)-N-propyl-

HRID 2375651Notes

Reaction equation

HRID 2375651 reaction equation
[NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)(C)C.O1CCCC1>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]

Participants

9

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 3294524(2-Fluoro-6-methoxyphenyl)boronic acidHCID 140123264-Amino-8-bromo-N-propylcinnoline-3-carboxamide

Product 1

HCID 235818693-CinnolinecarboxaMide, 4-aMino-8-(2-fluoro-6-Methoxyphenyl)-N-propyl-Yield 78%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 3776IsopropanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A 2 L, 3-necked flask equipped with a reflux condenser, mechanical stirrer, and 250 mL addition funnel was charged with 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (36.80 g, 119.09 mmol), 2-fluoro-6-methoxy-phenylboronic acid (60.70 g, 357.06 mmol), and Pd(dppf)Cl2.CH2Cl2 (7.40 g, 9.06 mmol) under Argon at ambient temperature. A gentle vacuum was applied and the apparatus was back-filled with Argon two times. Tetrahydrofuran (515 mL, anhydrous) and isopropanol (147 mL, anhydrous) were added and the resulting red suspension was stirred at room temperature for 15 minutes. A solution of sodium carbonate (57.0 g, 537.7 mmol) in water (220 mL) was added rapidly through the addition funnel and the resulting mixture immediately placed into a pre-heated 80° C. oil bath. After 90 minutes at reflux (observed internal temperature 65° C.), the reaction mixture was cooled to room temperature and filtered though a bed of Celite supported on a sintered glass funnel topped with Norite decolorizing carbon (30 g). The residual salts and filter-cake were washed with 4:1 (v/v) THF:isopropanol until no additional material could be detected in the eluent by TLC (silica gel, 1:1 (v/v) hexanes:ethyl acetate, UV detection, Rf=0.25). The dark red solution was concentrated to a small volume under reduced pressure and then diluted with ethyl acetate (250 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residues were passed through a small pad of silica gel on a sintered glass funnel washing with ethyl acetate until no more material was detected in the eluent. The solution was evaporated to afford the crude product as a foamy red-brown solid. This material was purified by flash chromatography on silica gel using a gradient of 40 to 50% ethyl acetate in hexanes. Product containing fractions were combined and evaporated. The residue was precipitated from dichloromethane by addition of hexanes at room temperature. Recrystallization of this material from hot 1:1 (v/v) ethanol:water afforded the title compound as off-white white crystals (32.78 g, 78% yield). Additional title compound (4.30 g, 10% yield) was isolated by processing the residues form the crystallization liquors through an acid-base extractive workup.

Workup

  1. customA 2 L, 3-necked flask equipped with a reflux condenser, mechanical stirrer, and 250 mL addition funnel
  2. customat ambient temperature
  3. additionthe apparatus was back-filled with Argon two times
  4. customimmediately placed into a pre-heated 80° C.
  5. temperatureAfter 90 minutes at reflux (observed internal temperature 65° C.)
  6. temperaturethe reaction mixture was cooled to room temperature
  7. filtrationfiltered though a bed of Celite
  8. customsupported on a sintered glass funnel
  9. filtrationThe residual salts and filter-cake
  10. washwere washed with 4:1 (v/v) THF
  11. concentrationThe dark red solution was concentrated to a small volume under reduced pressure
  12. additiondiluted with ethyl acetate (250 mL)
  13. customThe organic phase was separated
  14. extractionthe aqueous phase extracted with ethyl acetate (2×250 mL)
  15. washThe combined organic layers were washed with brine
  16. dry with materialdried over sodium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated under reduced pressure
  19. customThe residues were passed through a small pad of silica gel on a sintered glass funnel
  20. washwashing with ethyl acetate until no more material
  21. customThe solution was evaporated
  22. customto afford the crude product as a foamy red-brown solid
  23. customThis material was purified by flash chromatography on silica gel using a gradient of 40 to 50% ethyl acetate in hexanes
  24. additionProduct containing fractions
  25. customevaporated
  26. customThe residue was precipitated from dichloromethane by addition of hexanes at room temperature
  27. customRecrystallization of this material from hot 1:1 (v/v) ethanol

Sources & evidence

ORD record
ord-8d716b78957c4f51af130d5803a93d60
Source dataset
uspto-grants-2008_12
Patent number
US07465795B2

Reaction notes

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