Potassium Carbonate → 4-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3-formylpyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxamide

HRID 1025598Notes

Reaction equation

HRID 1025598 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[C:3]1[C:16]([NH2:18])=[O:17].[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[N:42]=[CH:41][CH:40]=[C:39](I)[C:36]=1[CH:37]=[O:38])[N:27]=[CH:26]2)([CH3:22])([CH3:21])[CH3:20].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.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:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:36]([CH:37]=[O:38])=[C:39]([C:5]3[CH:4]=[C:3]([C:16]([NH2:18])=[O:17])[N:2]([CH3:1])[CH:6]=3)[CH:40]=[CH:41][N:42]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:20])[CH3:21]

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 710080811-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamideHCID 866737152-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-iodonicotinaldehyde

Product 1

HCID 866737144-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3-formylpyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxamideYield 28.2%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 100 mL round-bottomed flask, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide (61.0 mg, 244 μmol, Eq: 1.10), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-iodonicotinaldehyde (100 mg, 222 μmol, Eq: 1.00) and [1,1′-bis(Diphenylphosphino)ferrocene]dichloro palladium (II) (16.2 mg, 22.2 μmol, Eq: 0.1) were combined with dioxane (667 μl) to give a red solution. Potassium carbonate (61.3 mg, 443 μmol, Eq: 2) in water (66.7 μl) was added and the resultant suspension was heated to 70° C. and stirred for 32 h. The reaction was diluted with ethyl acetate (10 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 15% EtOAc in hexanes to give 4-[2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-formyl-pyridin-4-yl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (28 mgs, 28.2%) as an off white solid. 1H NMR (DMSO-d6) δ: 10.06 (s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 7.91 (d, J=1.8 Hz, 1H), 7.79 (dd, J=13.3, 1.8 Hz, 1H), 7.73 (d, J=5.3 Hz, 1H), 7.69-7.76 (m, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.12 (br. s., 1H), 3.93 (s, 3H), 1.39 (s, 9H); MS m/e 448.5 (M+H+).

Workup

  1. customto give a red solution
  2. washwashed with brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customThe crude material was purified by flash chromatography (silica gel, 12 g, 10% to 15% EtOAc in hexanes

Sources & evidence

ORD record
ord-f30bf4c31e8849a095f18ca807e65bf4
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

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