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

HRID 419525Notes

Reaction equation

HRID 419525 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.[CH3:37][C:38]1[C:39]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.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:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([CH:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 10942334Sodium MethoxideHCID 594528145-Methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)anilineHCID 594529415-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide

Product 1

HCID 59452887N-(2,6-difluorophenyl)-2-(ethyloxy)-5-[3-(2-{[5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideYield 50%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °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), 5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 157, step D) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 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 (65 mg, 0.089 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.38 (d, J=6.41 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.66-7.76 (m, 2H), 7.53 (s, 1H), 7.41-7.46 (m, 1H), 7.32-7.41 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.95 (t, J=6.68 Hz, 1H), 6.89 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 4.25 (q, J=6.90 Hz, 2H), 3.80 (s, 3H), 2.90-3.02 (m, 2H), 2.57-2.68 (m, 1H), 2.21-2.32 (m, 2H), 2.17 (s, 3H), 1.91-2.02 (m, 2H), 1.62-1.74 (m, 4H), 1.38-1.49 (m, 5H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 732 [M+H]+.

Workup

  1. addition1 g of silica gel was added
  2. customthe pre-adsorbed solids were purified by flash chromatography

Sources & evidence

ORD record
ord-418e9faf4e274078ba6b849b9313d01e
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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