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

HRID 419547Notes

Reaction equation

HRID 419547 reaction equation
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]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH3:50])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:51].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][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:51][C:37]3[CH:38]=[CH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH3:50])[CH2:44][CH2:43]4)=[CH:41][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamideHCID 598602822-(Methyloxy)-4-(4-propyl-1-piperazinyl)aniline

Product 1

HCID 59452681N-(2,6-difluorophenyl)-3-[3-(2-{[2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideYield 70%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
175 °C

Procedure

To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol) and [2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amine (54 mg, 0.22 mmol) in 2,2,2-trifluoroethanol (1.1 mL) was added 4 M HCl in dioxane (108 μL, 0.43 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 (103 mg, 0.15 mmol, 70%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ10.24 (s, 1H), 9.40 (brs, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.20 (d, 1H, J=5.13 Hz), 8.05 (d, 1H, J=7.69 Hz), 7.82 (d, 1H, J=7.69 Hz), 7.73 (d, 1H, J=8.97 Hz), 7.61 (t, 1H, J=7.78 Hz), 7.36-7.49 (m, 3H), 7.21 (t, 2H, J=8.15 Hz), 6.98 (t, 1H, J=6.87 Hz), 6.68 (d, 1H, J=2.20 Hz), 6.45-6.50 (m, 2H), 3.80 (s, 3H), 3.12-3.17 (m, 4H), 2.45-2.55 (m, 4H), 2.28 (t, 2H, J=7.42 Hz), 1.47 (q, 2H, J=7.39 Hz), 0.87 (T, 3H, J=7.32 Hz). MS (ESI): 675 [M+H]+.

Workup

  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

Sources & evidence

ORD record
ord-bbff3fcb0cba4b3d9d3b120b1f6227ec
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

Loading…