Hydrochloric Acid → n-(2,6-Difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide

HRID 419597Notes

Reaction equation

HRID 419597 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]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][CH:52]([N:55]3[CH2:60][CH2:59][N:58]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:57][CH2:56]3)[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl>C(O)C(F)(F)F>[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:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:50][CH2:51][CH:52]([N:55]5[CH2:56][CH2:57][N:58]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:59][CH2:60]5)[CH2:53][CH2:54]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 594526865-Ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-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 59452902n-(2,6-Difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamideYield 64.3%

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
170 °C

Procedure

A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.198 mmol), 5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 204, Step E) (0.081 g, 0.198 mmol) and HCl (4N,1,4-Dioxane, 0.099 mL, 0.395 mmol) in Trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. The reaction was quenched with 7N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide (0.112 g, 61%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.26-9.40 (m, 1H), 8.40 (s, 1H), 8.27 (d, J=5.22 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.77 (dd, J=8.57, 2.25 Hz, 1H), 7.71 (d, J=8.98 Hz, 1H), 7.59 (s, 1H), 7.33-7.51 (m, 2H), 7.27 (d, J=8.61 Hz, 1H), 7.15-7.24 (m, 2H), 6.88-6.98 (m, 1H), 6.81 (s, 1H), 6.60 (d, J=5.22 Hz, 1H), 4.21-4.34 (m, 2H), 4.07 (q, J=6.93 Hz, 2H), 3.07-3.17 (m, 4H), 2.97-3.06 (m, 2H), 2.87 (s, 3H), 2.59-2.77 (m, 6H), 2.55 (q, J=7.45 Hz, 2H), 2.37-2.46 (m, 1H), 1.79-1.90 (m, 2H), 1.53-1.68 (m, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.26 (t, J=6.97 Hz, 3H), 1.10 (t, J=7.51 Hz, 3H). MS (M-2H, ES−) 878.

Workup

  1. customThe reaction was quenched with 7N NH3 in MeOH
  2. concentrationconcentrated to dryness
  3. dissolutionThe residue was then dissolved in DCM
  4. concentrationconcentrated onto silica gel
  5. customPurification by flash column chromatography
  6. customfollowed by recrystallization from DCM and EtOH

Sources & evidence

ORD record
ord-98d67868545d4b04a761e35c47ff9dd8
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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