Dimethylformamide → thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide

HRID 2100423Notes

Reaction equation

HRID 2100423 reaction equation
Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH: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.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[N:40]1([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1>O1CCOCC1.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[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:48][C:46]([N:40]4[CH2:45][CH2:44][S:43][CH2:42][CH2:41]4)=[O:47])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 12517904Thiomorpholine-4-carboxamideHCID 231189722-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

Product 1

HCID 57798922thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amideYield 65%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (500 mg, 1.15 mmol) was suspended in dioxane (14 mL) and treated consecutively with DMF (5 mL), Pd2dba3 (23 mg, 0.023 mmol), Xantphos (42 mg, 0.07 mmol), cesium carbonate (454 mg, 1.38 mmol) and thiomorpholine-4-carboxylic acid amide (511 mg, 3.5 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 4 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (375 mg, 65%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.20 (1H, s), 8.25 (1H, s), 8.15 (1H, d), 8.11 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.33 (2H, m), 6.95 (1H, d), 6.67 (1H, t), 6.54 (1H, d), 4.44 (2H, d), 4.13 (3H, s), 3.70-3.73 (4H, m), 2.55-2.58 (4H, m); m/z (ES+) 502 [M+H]+.

Workup

  1. temperatureOn cooling the reaction
  2. customwas partitioned between EtOAc and water
  3. washThe organic phase was washed with brine
  4. customdried
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1)

Sources & evidence

ORD record
ord-08f3eea8fbb1455b86093887b3d896c6
Source dataset
uspto-grants-2009_08
Patent number
US07572794B2

Reaction notes

Loading…