Cesium carbonate → (5-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-indol-3-yl)-acetic acid

HRID 2110711Notes

Reaction equation

HRID 2110711 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[NH:30][CH:29]=1)([OH:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO.O>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[C:28]3[CH2:27][C:24]([OH:26])=[O:25])[CH:3]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 576360782-(5-borono-1H-indol-3-yl)acetic acidHCID 57636111(6-Chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine

Product 1

HCID 11627268(5-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-indol-3-yl)-acetic acidYield 17%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine (493 mg, 1.408 mmol) and 3-carboxymethyl-1H-indol-5-yl boronic acid (370 mg, 1.689 mmol) in toluene (9 mL), EtOH (4.5 mL) and water (1 mL) is added Cs2CO3 (1.146 g, 3.52 mmol) and degassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium (0) (81.3 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 15 minutes. To the reaction mixture is added 1N hydrochloric acid to adjust pH to about 2. This mixture is extracted three times with EtOAc (40 mL). The combined, extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to give (5-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-indol-3-yl)-acetic acid [116 mg, 17%, Example 52] as a solid. LC/MS: RT=2.57 minutes, MS: 489 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □12.18 (1H, s), 11.05 (1H, s), 8.18 (1H, s), 7.24-7.76 (7H, m), 6.6 (1H, s), 3.87 (3H, s), 3.7 (2H, s), 3.6 (2H, m), 3 (2H, m). IC50=0.4 nM

Workup

  1. customdegassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium (0) (81.3 mg, 5 mol %)
  2. customThe reaction vessel is sealed
  3. additionTo the reaction mixture is added 1N hydrochloric acid
  4. extractionThis mixture is extracted three times with EtOAc (40 mL)
  5. washextracts are washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-197e32403b8247b1b8cc320bfbcb1860
Source dataset
uspto-grants-2009_04
Patent number
US07517889B2

Reaction notes

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