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

HRID 419665Notes

Reaction equation

HRID 419665 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]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:39][C:40]([O:44][CH2:45][CH3:46])=[C:41]([NH2:43])[CH:42]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[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:43][C:41]3[CH:42]=[C:37]([CH3:36])[C:38]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:39][C:40]=3[O:44][CH2:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 594525905-(3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridin-2-yl)-N-(2,6-difluorophenyl)-2-methoxybenzamideHCID 594527225-Methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline

Product 1

HCID 59452859N-(2,6-difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-5-methyl-4-[4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamideYield 31%

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
80 °C

Procedure

To 5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.407 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (200 mg, 0.586 mmol) (Example 248, Step B) in trifluoroethanol (10 mL) was added p-toluene sulfonic acid (200 mg, 1.05 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 (100 mg, 0.125 mmol, 31%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.33 (d, J=7.1 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.08 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.53 (s, 1H), 7.43-7.33 (m, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.0 Hz, 2H), 6.92 (t, J=6.9 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J=5.3 Hz, 1H), 4.03 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.36-3.25 (m, 2H), 3.03 (s, 3H), 2.86-2.78 (m, 4H), 2.74 (t, J=6.7 Hz, 2H), 2.63-2.50 (m, 4H), 2.11 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI) m/z=398 [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-1d1b96c1464a4e6787cfcb105c6203b7
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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