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

HRID 602418

Reaction equation

HRID 602418 reaction equation
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

Participants

9

Reactant 3

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

Product 1

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

Reagents, catalysts & solvents 5

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
110 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-e721ce2c65674960b49f339a50155b36
Source dataset
uspto-grants-2011_03
Patent number
US07906533B2

Linked notes

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