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

HRID 419506Notes

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]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[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]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[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

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) (115 mg, 0.227 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (Example 148, step D) (67 mg, 0.204 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 10 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 2 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 (82 mg, 0.103 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.36 (s, 1H), 8.46 (s, 1H), 8.22 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.73 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.49 (s, 1H), 7.40-7.45 (m, 1H), 7.32-7.39 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.15 Hz, 2H), 6.94 (t, J=6.87 Hz, 1H), 6.75 (s, 1H), 6.54 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.78 Hz, 2H), 3.79 (s, 3H), 3.31-3.34 (m, 2H), 3.05 (s, 3H), 2.82-2.89 (m, 4H), 2.76 (t, J=6.68 Hz, 2H), 2.52-2.63 (m, 4H), 2.13 (s, 3H), 1.41 (t, J=6.87 Hz, 3H). MS (ESI): 797 [M+H]+.

Workup

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

Sources & evidence

ORD record: ord-9f61dc9a30b445ba9fcc7ed3c209c7eb
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08093239B2

Reaction notes

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