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

HRID 419400Notes

Reaction equation

HRID 419400 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.[CH2:34]([O:36][C:37]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][F:57])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:38]=1[NH2:58])[CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[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:58][C:38]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH:49]5[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][F:57])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1

Participants

9

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10942334Sodium MethoxideHCID 59452599(2-(Ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amineHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide

Product 1

HCID 59452746N-(2,6-difluorophenyl)-3-(3-{2-[(2-(ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamideYield 55%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 64092,2,2-TrifluoroethanolSolventHCID 8058HexaneSolvent

Conditions

Temperature
150 °C

Procedure

To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol) and (2-(ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amine (68 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (140 mg, 0.74 mmol). The mixture was stirred and heated on a Biotage microwave at 150° C. for 45 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (90 mg, 0.11 mmol, 54%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (s, 1H), 8.36 (m, 2H), 8.22 (d, 1H, J=5.13 Hz), 8.05 (d, 1H, J=7.88 Hz), 7.81 (d, 1H, J=7.88 Hz), 7.73 (d, 1H, J=8.98 Hz), 7.61 (t, 1H, J=7.70 Hz), 7.35-7.50 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.97 (t, 1H, J=8.96 Hz), 6.65 (d, 1H, J=2.38 Hz), 6.44-6.50 (m, 2H), 4.56 (t, 1H, J=4.95 Hz), 4.44 (t, 1H, J=4.95 Hz), 4.06 (q, 2H, J=6.96 Hz), 3.11 (m, 4H), 2.92 (m, 2H), 2.60-2.64 (m, 4H), 2.49 (m, 1H), 2.18 (m, 1H), 1.94-2.03 (m, 2H), 1.72-1.79 (m, 2H), 1.37-1.48 (m, 2H), 1.24 (t, 3H, J=6.87 Hz), 0.82-0.87 (m, 1H). MS (ESI): 776 [M+H]+.

Workup

  1. temperaturecooled to rt
  2. concentrationThe mixture was concentrated under vacuum
  3. customthe residue purified by silica gel chromatography
  4. customto give a yellow solid
  5. customwas formed
  6. temperatureThe slurry was cooled at −10° C. for 30 min
  7. filtrationfilter
  8. washwashing the solids with cold hexanes
  9. customThe solids were dried under vacuum

Sources & evidence

ORD record
ord-909692990af54129a3e0948688966422
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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