Potassium Phosphate, Tribasic → 4-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-2-hydroxylmethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide

HRID 1025577ノート

反応式

HRID 1025577 の反応式
[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].Cl[C:20]1[C:21]([CH2:41][OH:42])=[C:22]([N:26]2[CH:35]=[CH:34][C:33]3[C:28](=[C:29]([F:39])[CH:30]=[C:31]([CH:36]4[CH2:38][CH2:37]4)[CH:32]=3)[C:27]2=[O:40])[CH:23]=[CH:24][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([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>[CH:36]1([C:31]2[CH:32]=[C:33]3[C:28](=[C:29]([F:39])[CH:30]=2)[C:27](=[O:40])[N:26]([C:22]2[C:21]([CH2:41][OH:42])=[C:20]([C:5]4[CH:4]=[C:3]([C:16]([NH2:18])=[O:17])[N:2]([CH3:1])[CH:6]=4)[CH:25]=[CH:24][CH:23]=2)[CH:35]=[CH:34]3)[CH2:38][CH2:37]1

参加物

8

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 594737982-(3-chloro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-oneHCID 710080811-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide

生成物 1

HCID 710079834-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-2-hydroxylmethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide収率 15%

試薬・触媒・溶媒 3

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

反応条件

温度
125 °C

実験手順

To a 10 mL microwave vial, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide (100 mg, 400 μmol, Eq: 1.00), 2-(3-chloro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one (137 mg, 400 μmol, Eq: 1.00), X-phos (19.1 mg, 40.0 μmol, Eq: 0.1), Pd2(dba)3 (18.3 mg, 20.0 μmol, Eq: 0.05), and potassium phosphate tribasic (212 mg, 1.00 mmol, Eq: 2.50) were added, followed by 1,4-dioxane (5 ml) and water (0.5 ml) to give a dark brown suspension. The reaction mixture was stirred while purging with argon for 10 min. The solution was heated at 125° C. in a microwave for 30 min. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 50 mL of dichloromethane and extracted with water. The aqueous was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 25%-50% [60:10:1 dichloromethane:methanol:aqueous ammonium hydroxide]/dichloromethane gradient) to give 4-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-2-hydroxylmethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (25.9 mg, 15%) as a white solid: LC/MS-ESI observed [M+H]+ 432.

後処理

  1. customto give a dark brown suspension
  2. customwhile purging with argon for 10 min
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additionThe reaction mixture was diluted with 50 mL of dichloromethane
  5. extractionextracted with water
  6. concentrationThe aqueous was concentrated in vacuo
  7. customThe crude material was purified by flash chromatography (silica gel, 25%-50% [60:10:1 dichloromethane:methanol:aqueous ammonium hydroxide]/dichloromethane gradient)

出典と根拠

ORDレコード
ord-46a2bd7884bd4ce19b23af3197fb5079
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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