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

HRID 419635Notes

Reaction equation

HRID 419635 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.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[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:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]5)[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[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 594529942-(Ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline

Product 1

HCID 59452987N-(2,6-difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamideYield 53.7%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
175 °C

Procedure

A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.10 g, 0.20 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 222, Step D) (0.078 g, 0.20 mmol) and para-toluenesulfonic acid (0.093 g, 0.49 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.090 g, 53%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.35 (br. s., 1H), 8.36 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.75-7.83 (m, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.36-7.49 (m, 3H), 7.29 (d, J=8.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.88-7.01 (m, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 6.49 (dd, J=8.7, 2.4 Hz, 1H), 4.07 (q, J=6.9 Hz, 2H), 4.00 (s, 3H), 3.68-3.80 (m, 2H), 3.04-3.17 (m, 4H), 2.87 (s, 3H), 2.57-2.73 (m, 6H), 2.38-2.46 (m, 1H), 1.79-1.89 (m, 2H), 1.47-1.61 (m, 2H), 1.25 (t, J=6.9 Hz, 3H). MS (M−H, ES−) 836.

Workup

  1. concentrationThe reaction mixture was concentrated onto silica gel
  2. custompurified by flash chromatography
  3. customRecrystallization from DCM and diethyl ether

Sources & evidence

ORD record
ord-e34945a1b4a942a38d0f2853996a5aba
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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