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

HRID 216184

Reaktionsgleichung

Reaktionsgleichung von HRID 216184
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

Komponenten

7

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 702EthanolLösungsmittelHCID 962WaterLösungsmittelHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
130 °C

Versuchsvorschrift

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

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-28351ea77db0409da911843b522bae4e
Quelldatensatz
uspto-grants-2012_06
Patentnummer
US08193183B2

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