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

HRID 419553Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 419553
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][CH2:35][CH3:36])=[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.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:40]=1[NH2:54].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:54][C:40]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:46]4)=[CH:44][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]

Komponenten

10

Edukt 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 594529415-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamideHCID 598602822-(Methyloxy)-4-(4-propyl-1-piperazinyl)aniline

Produkt 1

HCID 59452957N-(2,6-difluorophenyl)-2-(ethyloxy)-5-[3-(2-{[2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideAusbeute 85 %

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-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.20 mmol) and [2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amine (Example 173, step B) (49 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (99 μL, 0.40 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 minutes, 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 minutes, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (120 mg, 0.16 mmol, 85%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.36 (br s, 1H), 8.45 (s, 1H), 8.20 (d, 1H, J=5.31 Hz), 8.05 (m, 1H), 7.74 (m, 1H), 7.69 (d, 1H, J=8.97 Hz), 7.34-7.46 (m, 3H), 7.27 (d, 1H, J=8.61 Hz), 7.19 (t, 2H, J=8.06 Hz), 6.95 (t, 1H, J=6.68 Hz), 6.68 (d, 1H, J=2.01 Hz), 6.53 (d, 1H, J=5.13 Hz), 6.48 (dd, 1H, J=2.20 and 8.61 Hz), 6.24-6.30 (m, 2H), 3.80 (s, 3H), 3.11-3.16 (m, 4H), 2.45-2.54 (m, 4H), 2.28 (t, 2H, J=7.42 Hz), 1.41-1.50 (m, 4H), 0.87 (t, 3H, J=7.42 Hz). MS (ESI): 719 [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 minutes
  7. filtrationfilter
  8. washwashing the solids with cold hexanes
  9. customThe solids were dried under vacuum

Quellen und Nachweise

ORD-Eintrag
ord-7e8c74ba252f4664bcf58709fe4436f7
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08093239B2

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