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

HRID 419634Notes

Reaction equation

HRID 419634 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][CH2:35][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.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].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:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][CH:50]([N:53]5[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]5)[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 594529415-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamideHCID 594529942-(Ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline

Product 1

HCID 59452663N-(2,6-difluorophenyl)-2-(ethyloxy)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamideYield 43%

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-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.20 mmol), 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.076 g, 0.20 mmol) and para-toluenesulfonic acid (0.090 g, 0.47 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)-2-(ethyloxy)-5-(3-{2-[(2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide (0.072 g, 43%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.35 (br. s., 1H), 8.36 (s, 1H), 8.24 (d, J=5.2 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.66-7.81 (m, 2H), 7.35-7.48 (m, 3H), 7.15-7.32 (m, 3H), 6.89-7.01 (m, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.54-6.60 (m, 1H), 6.44-6.53 (m, 1H), 4.23-4.33 (m, 2H), 4.07 (q, J=6.9 Hz, 2H), 3.66-3.80 (m, 2H), 3.05-3.13 (m, 4H), 2.87 (s, 3H), 2.56-2.73 (m, 5H), 2.36-2.46 (m, 2H), 1.78-1.89 (m, 2H), 1.49-1.61 (m, 2H), 1.44 (t, J=6.9 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H). MS (M−H, ES−) 850.

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-a6ba8ae1ce5d4f3d814f3c411321f6d0
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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