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

HRID 216184

반응식

HRID 216184 반응식
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

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 3

HCID 702Ethanol용매HCID 962Water용매HCID 1140Toluene용매

반응 조건

온도
130 °C

실험 절차

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

후처리

  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

출처 및 근거

ORD 기록
ord-28351ea77db0409da911843b522bae4e
출처 데이터셋
uspto-grants-2012_06
특허 번호
US08193183B2

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