Triethylamine → 4-Fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 45128Notes

Reaction equation

HRID 45128 reaction equation
[CH3:1][S:2](Cl)(=[O:4])=[O:3].[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.CS([O-])=O.[Na+]>C(Cl)Cl.CO>[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][S:2]([CH3:1])(=[O:4])=[O:3])[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 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 2733271Sodium methanesulfinateHCID 593945384-Fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide

Product 1

HCID 674316094-Fluoro-5-(2-methanesulfonylmethyl-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, methanol is added, followed by sodium methanesulfinate (798 mg, 7.82 mmol). The resulting mixture is warmed to and stirred at 23° C. for 14 h. The mixture is concentrated and the residue is taken up in DMF (5 mL). The resulting mixture is stirred at 23° C. for 24 h, then 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 (20 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give 4-fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 474.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1 H) 8.76 (d, J=5.81 Hz, 1 H)8.12 (s, 1 H)7.91 (d, J=8.34 Hz, 1 H)7.64-7.69 (m, 1 H)7.53 (d, J=8.84 Hz, 2 H)7.18-7.25 (m, 2 H)6.63 (s, 1 H)4.55 (s, 2 H)2.97 (s, 3 H)2.59 (s, 3 H)

Workup

  1. temperatureThe resulting mixture is warmed to and
  2. concentrationThe mixture is concentrated
  3. stirringThe resulting mixture is stirred at 23° C. for 24 h
  4. custompartitioned between EtOAc (40 mL) and water (40 mL)
  5. extractionThe aqueous layer is extracted with EtOAc (2×40 mL)
  6. washThe combined organic layers are washed with brine (20 mL)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customThe residue is purified by silica gel chromatography (0-100% EtOAc/heptane)

Sources & evidence

ORD record
ord-b3ba76ec2ccb4b539502a0e39aaca3cf
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

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