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

HRID 419650Notes

Reaction equation

HRID 419650 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: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:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].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]=[C:37]([CH3:36])[C:38]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:53][CH2:54][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:56][CH2:57]5)[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[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 594526035-Methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline

Product 1

HCID 59452946N-(2,6-difluorophenyl)-5-(3-{2-[(5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamideYield 30.2%

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) (0.075 g, 0.15 mmol), 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.058 g, 0.15 mmol) and para-toluenesulfonic acid (0.070 g, 0.37 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-[(5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.038 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 9.33-9.43 (m, 1H), 8.47 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.08-8.14 (m, 1H), 7.76-7.84 (m, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.34-7.55 (m, 3H), 7.30 (d, J=8.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.97 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.57 (d, J=5.1 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.06-3.19 (m, 6H), 2.88 (s, 3H), 2.59-2.72 (m, 6H), 2.38-2.44 (m, 1H), 2.16 (s, 3H), 1.80-1.91 (m, 2H), 1.50-1.71 (m, 2H). MS (M+2H, ES+) 839.

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-26cdd507349c48519b29120ab5bde3b1
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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