Reaction #73405

Reaction equation

ethanolamine

Methanesulfonyl chloride

4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Et3N

→

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

Solvents

MeOH

CH2Cl2

Conditions

Workup

1. 1
   Temperaturethe resulting mixture is warmed to and
2. 2
   workup.STIRRINGthe reaction is stirred for another 15 h
3. 3
   OtherThe reaction mixture is partitioned between EtOAc (40 mL) and water (40 mL)
4. 4
   ExtractionThe aqueous layer is extracted with EtOAc (2×40 mL)
5. 5
   WashThe combined organic layers are washed with brine (30 mL)
6. 6
   Dryingdried (Na2SO4)
7. 7
   Concentrationconcentrated
8. 8
   OtherThe residue is purified by silica gel chromatography (0-10 MeOH/CH2Cl2)

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).

Source