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

HRID 419477Notes

Reaction equation

HRID 419477 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]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][CH3:51])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][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:38][C:37]3[CH:39]=[CH:40][C:41]([CH:43]4[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][CH3:51])[CH2:47][CH2:48]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 10942334Sodium MethoxideHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamideHCID 598602732-Methoxy-4-(1-propylpiperidin-4-yl)aniline

Product 1

HCID 59452875n-(2,6-Difluorophenyl)-3-[3-(2-{[2-(methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamideYield 81.1%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.2 mmol), a different batch of 2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 137, step D) (48 mg, 0.19 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 24 hours. 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 (104 mg, 0.154 mmol, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (d, J=6.59 Hz, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.60 (q, J=7.63 Hz, 2H), 7.44-7.49 (m, 1H), 7.35-7.42 (m, 1H), 7.19 (t, J=8.15 Hz, 2H), 6.99 (t, J=6.96 Hz, 1H), 6.96 (d, J=1.47 Hz, 1H), 6.78 (dd, J=8.24, 1.65 Hz, 1H), 6.52 (d, J=5.31 Hz, 1H), 3.81 (s, 3H), 2.89-2.99 (m, J=8.79 Hz, 2H), 2.39-2.46 (m, 1H), 2.18-2.28 (m, 2H), 1.87-1.98 (m, 2H), 1.64-1.76 (m, 4H), 1.39-1.48 (m, 2H), 0.84 (t, J=7.33 Hz, 3H). MS (ESI): 674 [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-d82a0de49c86437199d07bb53b0ed96b
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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