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 1025581ノート

反応式

HRID 1025581 の反応式
[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]

参加物

10

反応物 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

生成物 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 amide収率 15.8%

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒2 回HCID 962Water溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
125 °C

実験手順

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)

後処理

  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)

出典と根拠

ORDレコード
ord-f3f9c571fd8942869c33df3b04f69d01
出典データセット
uspto-grants-2014_05
特許番号
US08729078B2

反応ノート

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