Hydrochloric Acid → n-(2,6-Difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}-7-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide

HRID 419624Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 419624
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=2)[C:23]([NH:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[O:24])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)[C:44]([CH3:59])=[CH:43][C:41]=1[NH2:42])[CH3:38].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:44]([CH3:59])[C:45]([N:47]4[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:35][CH3:36]

Komponenten

10

Edukt 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 594527752-(Ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}anilineHCID 594529085-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide

Produkt 1

HCID 59452806n-(2,6-Difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}-7-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamideAusbeute 73 %

Reagenzien, Katalysatoren, Lösungsmittel 4

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

Reaktionsbedingungen

Temperatur
170 °C

Versuchsvorschrift

To 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)-2-(methyloxy)benzamide (Example 197, step A) (132 mg, 0.26 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (Example 215, step C) (80 mg, 0.24 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (120 μL, 0.47 mmol). The mixture was stirred and heated on a microwave at 170° C. for 45 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 (139 mg, 0.17 mmol, 73%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 ppm 9.79 (s, 1H), 9.39-9.48 (m, 1H), 8.41 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.5, 1.7 Hz, 1H), 7.61 (dd, J=9.6, 2.5 Hz, 1H), 7.53 (s, 1H), 7.35-7.44 (m, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.17-7.23 (m, 2H), 6.99-7.04 (m, 1H), 6.76 (s, 1H), 6.59 (d, J=5.1 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.00 (s, 3H), 3.14-3.22 (m, 2H), 3.03-3.10 (m, 2H), 2.98 (s, 3H), 2.61 (t, J=10.9 Hz, 2H), 2.15 (s, 3H), 1.77-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.45-1.54 (m, 1H), 1.30-1.41 (m, 2H), 1.23-1.28 (m, 3H). MS (ESI): 813 [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-110b840b7c644c2ba169906144170ebb
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08093239B2

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