p-Toluenesulfonic acid → N-(2,6-difluorophenyl)-3-(3-{2-[(2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide

HRID 419664Notes

Reaction equation

HRID 419664 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][C:35]1[C:36]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)=[CH:37][C:38]([O:42][CH2:43][CH3:44])=[C:39]([NH2:41])[CH:40]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[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:41][C:39]3[CH:40]=[C:35]([CH3:34])[C:36]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:37][C:38]=3[O:42][CH2:43][CH3:44])[N:7]=2)[CH:18]=1

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 594527225-Methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}anilineHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide

Product 1

HCID 59452863N-(2,6-difluorophenyl)-3-(3-{2-[(2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamideYield 15%

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
80 °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, 0.217 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (Example 248, Step B) (100 mg, 0.293 mmol) in trifluoroethanol (5 mL) was added p-toluene sulfonic acid (100 mg, 0.526 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (25 mg, 0.032 mmol, 15%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 9.36 (d, J=7.5 Hz, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.23 (d, J=5.1 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.48-7.32 (m, 2H), 7.17 (t, J=8.1 Hz, 2H), 6.95 (t, J=6.3 Hz, 1H), 6.71 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.36-3.24 (m, 2H), 3.03 (s, 3H), 2.86-2.79 (m, 4H), 2.74 (t, J=7.0 Hz, 2H), 2.64-2.50 (m, 4H), 2.10 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI) m/z=384 [M+2H]+2.

Workup

  1. customthe vial was sealed
  2. temperatureThe reaction was then cooled to rt
  3. additionsilica was added
  4. customThe solvent was removed on a rotovap
  5. customthe product purified on a 12 g ISCO column
  6. dissolutionThe resulting foam was dissolved in DCM
  7. additionether was added

Sources & evidence

ORD record
ord-8fe59e3de5c54e3a8c7102657e4718d6
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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