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-[(1-methylethyl)oxy]benzamide

HRID 419669Notes

Reaction equation

HRID 419669 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][CH:35]([CH3:37])[CH3:36])=[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.[CH3:38][C:39]1[C:40]([N:49]2[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([NH2:45])[CH:44]=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:45][C:43]3[CH:44]=[C:39]([CH3:38])[C:40]([N:49]4[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 594527225-Methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}anilineHCID 59452852HCID 59452852, compound

Product 1

HCID 59452933N-(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-[(1-methylethyl)oxy]benzamideYield 35%

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-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (200 mg, 0.385 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (Example 248, Step B) (200 mg, 0.586 mmol) 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 (110 mg, 0.133 mmol, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.34 (d, J=7.0 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.75-7.73 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.46-7.34 (m, 2H), 7.29 (d, J=8.8 Hz, 1H), 7.19 (t, J=8.0 Hz, 2H), 6.95 (t, J=7.1 Hz, 1H), 6.74 (s, 1H), 6.61 (d, J=5.2 Hz, 1H), 4.91-4.81 (m, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.39-3.28 (m, 2H), 3.06 (s, 3H), 2.88-2.81 (m, 4H), 2.77 (t, J=6.8 Hz, 2H), 2.67-2.53 (m, 4H), 2.13 (s, 3H), 1.39 (d, J=5.8 Hz, 6H), 1.25 (t, J=7.0 Hz, 3H). MS (ESI) m/z=412 [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-52b26f175f0140c78a3617730c8e5541
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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