Ammonia → 3-[3-(2-{[5-chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyl-oxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

HRID 419432Notes

Reaction equation

HRID 419432 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.[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][F:58])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][F:58])[CH2:54][CH2:55]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([NH:40][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=3)[C:20]([NH:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:41]=1

Participants

7

Reactant 4

HCID 222AmmoniaHCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)HCID 594529605-Chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)anilineHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide

Product 1

HCID 594525633-[3-(2-{[5-chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyl-oxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamideYield 12%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

In a 10 mL vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 5-chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (0.192 g, 0.520 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.203 g, 1.04 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.040 g, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.44 (br. s., 1H), 8.58 (s, 1H), 8.33 (s, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.78-7.95 (m, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.45-7.55 (m, 1H), 7.33-7.45 (m, 1H), 7.11-7.28 (m, 2H), 7.03 (t, J=7.0 Hz, 1H), 6.83 (s, 1H), 6.55 (d, J=5.3 Hz, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.84 (s, 3H), 3.08-3.51 (m, 2H), 2.09-2.92 (m, 13H), 1.72-2.00 (m, 2H), 1.41-1.72 (m, 2H). MS (M+H, ES+) 796.

Workup

  1. customIn a 10 mL vial with septum cap
  2. customThe vial was sealed
  3. customWhen reaction
  4. temperaturewas cooled rt
  5. customchromatographed
  6. additionFractions containing the desired product
  7. concentrationwere concentrated
  8. customthe resulting solid was triturated with diethyl ether
  9. filtrationfiltered
  10. customair dried

Sources & evidence

ORD record
ord-3148a12780654fe2b396fc1e7e72fbbd
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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