Cesium carbonate → morpholine-4-carboxylic acid (4-{[3-(2-methyl-2H-indazol-6-ylcarbamoyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amide

HRID 602418

反応式

HRID 602418 の反応式
Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[N:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1.CN(C=O)C.C(=O)([O-])O.[Na+].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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[C:10]([NH:9][CH2:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:41]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:42])[CH:7]=4)=[N:28][CH:27]=[CH:26][CH:25]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1

参加物

9

反応物 3

HCID 10796Cesium carbonateHCID 75088Morpholine-4-carboxamideHCID 586749502-[(2-chloro-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide

生成物 1

HCID 58674948morpholine-4-carboxylic acid (4-{[3-(2-methyl-2H-indazol-6-ylcarbamoyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amide収率 48%

試薬・触媒・溶媒 5

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)触媒HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 6228Dimethylformamide溶媒HCID 312751,4-Dioxane溶媒HCID 516892Sodium Bicarbonate溶媒

反応条件

温度
110 °C

実験手順

A mixture of 2-[(2-chloro-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide (200 mg, 0.51 mmol), Pd2 dba3 (5.2 mg, 0.0051 mmol), xantphos (9.1 mg, 0.0153 mmol), cesium carbonate (169 mg, 0.54 mmol) and morpholine-4-carboxylic acid amide (332 mg, 2.55 mmol) in dioxane (12.1 mL) and DMF (4.1 mL) under nitrogen, was stirred at 110° C. for 11 hours. A second reaction was performed in duplicate. The two reactions were combined, diluted with dilute aqueous sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on Isolute® flash silica gel (Separtis) to give morpholine-4-carboxylic acid (4-{[3-(2-methyl-2H-indazol-6-ylcarbamoyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amide (119 mg) which was further purified by recrystallisation from EtOAc; 1H-NMR (300 MHz, d6-DMSO) 10.2 (1H, s), 9.06 (1H, s), 8.45 (1H, t), 8.22 (1H, s), 8.03-8.13 (4H, m), 7.73 (1H, s), 7.62 (1H, d), 7.27 (1H, unresolved dd), 6.89 (1H, unresolved dd), 6.67 (1H, dd), 4.62 (2H, d), 4.10 (3H, s), 3.52 (4H, t), 3.39 (4H, t).

後処理

  1. customA second reaction
  2. extractionextracted with EtOAc
  3. washThe combined organic layers were washed with brine
  4. customdried
  5. concentrationconcentrated in vacuo
  6. customPurification

出典と根拠

ORDレコード
ord-e721ce2c65674960b49f339a50155b36
出典データセット
uspto-grants-2011_03
特許番号
US07906533B2

関連ノート

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