Hydrochloric Acid → N-(2,6-difluorophenyl)-3-[8-fluoro-3-(2-{[2-(methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide

HRID 419577Notes

Reaction equation

HRID 419577 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[CH3:35][O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.ClCCl.CCCCCC>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:32]=[CH:33][CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:45][CH2:46][CH:47]([N:50]5[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:55]5)[CH2:48][CH2:49]4)=[CH:43][C:37]=3[O:36][CH3:35])[N:7]=2)[CH:19]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 594528703-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamideHCID 598602832-(Methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)aniline

Product 1

HCID 59860284N-(2,6-difluorophenyl)-3-[8-fluoro-3-(2-{[2-(methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideYield 71%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 64092,2,2-TrifluoroethanolSolventHCID 8058HexaneSolvent

Conditions

Temperature
175 °C

Procedure

To 3-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 188, step A) (90 mg, 0.19 mmol) and 2-(methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)aniline (Example 60, step B) (74 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (0.90 mL) was added 4 M hydrochloric acid in dioxane (94 μL, 0.38 mmol). The mixture was stirred and heated on a microwave at 175° C. for 40 minutes, then cooled to room temperature. The mixture was neutralized with 0.5M sodium methoxide in methanol. 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 dichloromethane, 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 (110 mg, 0.13 mmol, 71%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ10.27 (s, 1H), 9.20 (brs, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (d, 1H, J=5.13 Hz), 8.07 (d, 1H, J=7.70 Hz), 7.83 (d, 1H, J=7.88 Hz), 7.62 (t, 1H, J=7.70 Hz), 7.34-7.45 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.92-6.99 (m, 1H), 6.65-6.68 (m, 1H), 6.45-6.50 (m, 2H), 3.79 (s, 3H), 3.68-3.75 (m, 2H), 3.19-3.30 (m, 2H), 3.02 (s, 3H), 2.61-2.70 (m, 6H), 2.38-2.46 (m, 6H), 2.26-2.34 (m, 1H), 1.80-1.87 (m, 2H), 1.45-1.56 (m, 2H). MS (ESI): 840 [M+H]+.

Workup

  1. temperaturecooled to room temperature
  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

Sources & evidence

ORD record
ord-32b916480bf0495fb8cee24cc2c04cea
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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