p-Toluenesulfonic acid monohydrate → N-(2,6-difluorophenyl)-3-[7-fluoro-3-(2-{[4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide

HRID 419579Notes

Reaction equation

HRID 419579 reaction equation
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]=[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.[F:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:56]=[CH:55][C:53]([NH2:54])=[C:52]([O:57][CH3:58])[CH:51]=3)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.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[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:54][C:53]3[CH:55]=[CH:56][C:50]([N:47]4[CH2:46][CH2:45][CH:44]([N:41]5[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][F:35])[CH2:43][CH2:42]5)[CH2:49][CH2:48]4)=[CH:51][C:52]=3[O:57][CH3:58])[N:7]=2)[CH:19]=1

Participants

9

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10942334Sodium MethoxideHCID 594529173-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamideHCID 598602604-[4-[4-(2-Fluoroethyl)-1-piperazinyl]-1-piperidinyl]-2-(methyloxy)aniline

Product 1

HCID 59860249N-(2,6-difluorophenyl)-3-[7-fluoro-3-(2-{[4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideYield 55%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
150 °C

Procedure

To 3-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (100 mg, 0.21 mmol) and 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (Example 59, step E) (63 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (135 mg, 0.71 mmol). The mixture was stirred and heated on a microwave at 150° C. for 30 minutes, then cooled to room temperature. 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 (81 mg, 0.10 mmol, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ10.24 (s, 1H), 9.47 (brs, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 8.20 (d, 1H, J=5.32 Hz), 8.06 (d, 1H, J=7.70 Hz), 7.81 (d, 1H, J=7.70 Hz), 7.59-7.64 (m, 2H), 7.34-7.44 (m, 2H), 7.21 (t, 2H, J=8.06 Hz), 7.02-7.08 (m, 1H), 6.69 (d, 1H, J=2.20 Hz), 6.43-6.51 (m, 2H), 4.57 (t, 1H, J=4.95 Hz), 4.45 (t, 1H, J=4.86 Hz), 3.80 (s, 3H), 3.71-3.77 (m, 2H), 2.59-2.70 (m, 4H), 2.40-2.46 (m, 8H), 2.26-2.34 (m, 1H), 1.81-1.87 (m, 2H), 1.46-1.56 (m, 2H). MS (ESI): 780 [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 min
  7. filtrationfilter
  8. washwashing the solids with cold hexanes
  9. customThe solids were dried under vacuum

Sources & evidence

ORD record
ord-d31a3814cc0d482abfe7c7b5ea6d1bd5
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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