Ethanolamine → 4-Fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 45127Notes

Reaction equation

HRID 45127 reaction equation
CS(Cl)(=O)=O.[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33]O)[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1.CCN(CC)CC.[CH2:46]([CH2:48][NH2:49])[OH:47]>C(Cl)Cl.CO>[F:38][C:7]([F:6])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH:49][CH2:48][CH2:46][OH:47])[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1

Participants

7

Reactant 4

HCID 700EthanolamineHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 593945384-Fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Product 1

HCID 593944284-Fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
23 °C

Procedure

Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solution of 4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et3N (0.109 mL, 0.782 mmol) in CH2Cl2 (5 mL) at 0° C. After 10 min, ethanolamine (0.236 mL, 3.91 mmol) is added and the resulting mixture is warmed to and stirred at 23° C. for 4 h. MeOH (2 mL) is added and the reaction is stirred for another 15 h. The reaction mixture is partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer is extracted with EtOAc (2×40 mL). The combined organic layers are washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-10 MeOH/CH2Cl2) to give 4-fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 504.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.60 (d, J=5.81 Hz, 1 H)8.07 (s, 1 H)7.86 (s, 1 H)7.57-7.62 (m, 1 H)7.46-7.51 (m, 2 H)7.09 (dd, J=8.84, 7.33 Hz, 1 H)6.98 (d, J=5.81 Hz, 1 H)6.54 (s, 1 H) 3.82 (s, 2 H)3.55-3.58 (m, 2 H)2.65-2.71 (m, 2 H)2.62 (s, 3 H).

Workup

  1. temperaturethe resulting mixture is warmed to and
  2. stirringthe reaction is stirred for another 15 h
  3. customThe reaction mixture is partitioned between EtOAc (40 mL) and water (40 mL)
  4. extractionThe aqueous layer is extracted with EtOAc (2×40 mL)
  5. washThe combined organic layers are washed with brine (30 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe residue is purified by silica gel chromatography (0-10 MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-cce951371e24429ea54d4d0482ac34e9
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

Loading…