Hydrochloric Acid → N-(2,6-difluorophenyl)-2-(methyloxy)-5-[3-(2-{[2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide

HRID 419548Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 419548
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:39]=1[NH2:53].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:53][C:39]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]4)=[CH:43][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]

Komponenten

10

Edukt 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 594525905-(3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridin-2-yl)-N-(2,6-difluorophenyl)-2-methoxybenzamideHCID 598602822-(Methyloxy)-4-(4-propyl-1-piperazinyl)aniline

Produkt 1

HCID 59452586N-(2,6-difluorophenyl)-2-(methyloxy)-5-[3-(2-{[2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideAusbeute 70 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 64092,2,2-TrifluoroethanolLösungsmittelHCID 8058HexaneLösungsmittel

Reaktionsbedingungen

Temperatur
175 °C

Versuchsvorschrift

To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.20 mmol) and [2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amine (Example 173, step B) (51 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (102 μL, 0.41 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (100 mg, 0.14 mmol, 70%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 9.35 (br s, 1H), 8.43 (s, 1H), 8.19 (d, 1H, J=5.13 Hz), 8.09 (m, 1H), 7.76 (m, 1H), 7.68 (d, 1H, J=8.97 Hz), 7.33-7.44 (m, 3H), 7.27 (d, 1H, J=8.61 Hz), 7.17 (t, 2H, J=8.06 Hz), 6.93 (t, 1H, J=6.87 Hz), 6.66 (d, 1H, J=2.20 Hz), 6.44-6.53 (m, 2H), 3.97 (s, 3H), 3.78 (s, 3H), 3.10-3.15 (m, 4H), 2.44-2.54 (m, 4H), 2.27 (t, 2H, J=7.42 Hz), 1.45 (q, 2H, J=7.45 Hz), 0.86 (t, 3H, J=7.32 Hz). MS (ESI): 705 [M+H]+.

Aufarbeitung

  1. temperaturecooled to rt
  2. concentrationThe mixture was concentrated under vacuum
  3. customthe residue purified by silica gel chromatography
  4. customto give a yellow oil
  5. customwas formed
  6. temperatureThe slurry was cooled at −10° C. for 30 min
  7. filtrationfilter
  8. washwashing the solids with cold hexanes
  9. customThe solids were dried under vacuum

Quellen und Nachweise

ORD-Eintrag
ord-b88ceba0aae54feca0e658b6bece0e55
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08093239B2

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