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

HRID 419510Notes

Reaction equation

HRID 419510 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][N:50]([CH2:53][CH2:54][CH3:55])[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.C[O-].[Na+]>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][N:50]([CH2:53][CH2:54][CH3:55])[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

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 10942334Sodium MethoxideHCID 594526092-(Ethyloxy)-4-(4-propyl-1-piperazinyl)anilineHCID 594529415-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide

Product 1

HCID 59452743N-(2,6-difluorophenyl)-2-(ethyloxy)-5-[3-(2-{[2-(ethyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideYield 52%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
130 °C

Procedure

5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (Example 151, step B) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.48 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.091 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.33 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.04 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.34-7.45 (m, 3H), 7.24 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.59 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.53 (d, J=5.13 Hz, 1H), 6.45 (dd, J=8.70, 2.47 Hz, 1H), 4.24 (q, J=6.78 Hz, 2H), 4.04 (q, J=6.96 Hz, 2H), 3.06-3.16 (m, 4H), 2.43-2.52 (m, 4H), 2.25 (t, J=6.96 Hz, 2H), 1.39-1.48 (m, 5H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 733 [M+H]+.

Workup

  1. additionwas added
  2. customthe pre-adsorbed solids were purified by flash chromatography

Sources & evidence

ORD record
ord-1b7c01e294c54c9881f9c00f45d6e1f5
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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