Borate → 4-[3-(6-tert-butyl-8-hydroxymethyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide

HRID 1025581Notes

Reaction equation

HRID 1025581 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:11](=[O:17])[N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[C:19]=1[CH2:25][OH:26])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]1[C:42]([NH2:44])=[O:43].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.B([O-])([O-])[O-].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:11](=[O:17])[N:10]([C:18]1[C:19]([CH2:25][OH:26])=[C:20]([C:31]3[CH:30]=[C:29]([C:42]([NH2:44])=[O:43])[N:28]([CH3:27])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]

Participants

10

Reactant 6

HCID 26574BorateHCID 62657Potassium Phosphate, TribasicHCID 2733548Bis(pinacolato)diboraneHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 710080811-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamideHCID 710084996-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-(hydroxymethyl)phthalazin-1(2H)-one

Product 1

HCID 710084794-[3-(6-tert-butyl-8-hydroxymethyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amideYield 15.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

To a 15 mL tube were added 6-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-(hydroxymethyl)phthalazin-1(2H)-one (39 mg, 0.105 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide (26.2 mg, 0.105 mmol, prepared from Intermediate-3 and bis(pinacolato)diboron under the same condition of borate formation described in the preparation of Intermediate-4), X-Phos (4.99 mg, 0.0105 mmol) and tris-potassium phosphate (55.5 mg, 0.262 mmol). Dioxane (5 mL) and water (0.5 mL) were added followed by the addition of Pd2(dba)3 (4.79 mg, 0.00523 mmol). The mixture was purged with argon and then heated to 125° C. with stirring for 30 minutes. Additional Pd2(dba)3 (6.0 mg, 0.00655 mmol) was added and the mixture was further stirred at 125° C. for 30 minutes. The mixture was extracted with dichloromethane and water. The organic layer was washed with brine and dried over sodium sulfate. Solvents were evaporated and the residue was purified by flash column chromatography (12 g silica gel, 0% to 10% methanol in dichloromethane). The desired fraction was further purified by preparative TLC (silica gel, dichloromethane/methanol/ammonium hydroxide 90/10/1) to give 4-[3-(6-tert-butyl-8-hydroxymethyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide as a light yellow powder (7.6 mg, 15.8% yield). LC/MS clacd for C26H28N4O4 (m/e) 460.21, obsd 459.0 (M−H, ES−). 1H-NMR (300 MHz, CDCl3)

Workup

  1. customThe mixture was purged with argon
  2. stirringthe mixture was further stirred at 125° C. for 30 minutes
  3. extractionThe mixture was extracted with dichloromethane and water
  4. washThe organic layer was washed with brine
  5. dry with materialdried over sodium sulfate
  6. customSolvents were evaporated
  7. customthe residue was purified by flash column chromatography (12 g silica gel, 0% to 10% methanol in dichloromethane)
  8. customThe desired fraction was further purified by preparative TLC (silica gel, dichloromethane/methanol/ammonium hydroxide 90/10/1)

Sources & evidence

ORD record
ord-f3f9c571fd8942869c33df3b04f69d01
Source dataset
uspto-grants-2014_05
Patent number
US08729078B2

Reaction notes

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