Cesium carbonate → 2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde

HRID 2069856Notes

Reaction equation

HRID 2069856 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:57])[C:35]=1[CH:36]=[O:37].O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].ClCCl>[C:52]([C:47]1[CH:48]=[C:49]2[C:44](=[C:45]([F:56])[CH:46]=1)[C:43](=[O:57])[N:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH:36]=[O:37])[N:51]=[CH:50]2)([CH3:55])([CH3:53])[CH3:54]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 592164661-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-oneHCID 594737882-Bromo-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzaldehyde

Product 1

HCID 594738092-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehydeYield 60.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

88 mg (0.20 mmol) of 1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one and 81 mg (0.20 mmol) of 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzaldehyde were weighed into a 4 mL reaction vial fitted with a stir bar and septum cap. Added 2 mL of dioxane. Added 222 μL of an 0.88 mg/μL solution of cesium carbonate in water. Added 7.8 mg (0.0096 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane. The reaction was sparged with nitrogen for 5 min. Sealed the vial with a cap and stirred at 100° for 60 min. Poured the reaction mixture into 10 mL CH2Cl2 and 10 mL water. Separated phases and extracted the aqueous phase with 5 mL CH2Cl2. Combined the organic extracts, dried over Na2SO4 and removed the solvent on rotavap. Purified by silica gel flash chromatography using gradient elution with 100% hexane to 100% 5:6:1 hexane:CH2Cl2:2-PrOH. Recrystallized the product from 2-PrOH. Dried under high vacuum at 120° overnight to obtain 77 mg of the title compound as a pale yellow solid. MS (ESI) 637 (M+H)+.

Workup

  1. customvial fitted with a stir bar
  2. customseptum cap
  3. customThe reaction was sparged with nitrogen for 5 min
  4. customSealed the vial with
  5. customa cap
  6. additionPoured the reaction mixture into 10 mL CH2Cl2 and 10 mL water
  7. extractionSeparated phases and extracted the aqueous phase with 5 mL CH2Cl2
  8. dry with materialdried over Na2SO4
  9. customremoved the solvent on rotavap
  10. customPurified by silica gel flash chromatography
  11. washelution with 100% hexane to 100% 5:6:1 hexane
  12. customRecrystallized the product from 2-PrOH
  13. customDried under high vacuum at 120° overnight

Sources & evidence

ORD record
ord-e3389d277db5453abc35ae8a93aca5f2
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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