Ammonia → N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide

HRID 419606Notes

Reaction equation

HRID 419606 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]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[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.O1CCOCC1.N>CO>[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]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[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

7

Reactant 5

HCID 222AmmoniaHCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 594526665-Ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-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 59452613N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamideYield 58%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
180 °C

Procedure

In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.148 g, 0.293 mmol) and 5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.104 g, 0.293 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.147 mL, 0.587 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.14 g, 0.17 mmol, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 9.29 (d, J=6.8 Hz, 1H), 8.34 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 7.61-7.79 (m, 2H), 7.55 (s, 1H), 7.29-7.48 (m, 2H), 7.08-7.28 (m, 3H), 6.89 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 4.03 (q, J=6.9 Hz, 2H), 3.07-3.20 (m, 2H), 2.84-3.04 (m, 5H), 2.60 (t, J=10.9 Hz, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (d, J=11.2 Hz, 2H), 1.60-1.70 (m, 2H), 1.35-1.55 (m, 4H), 1.15-1.36 (m, 5H), 1.05 (td, J=7.2, 1.9 Hz, 3H). MS (M+H, ES+) 824.

Workup

  1. customIn a microwave vial with septum cap
  2. customThe vial was sealed
  3. customReaction
  4. temperaturewas cooled to rt
  5. concentrationconcentrated in vacuo onto silica gel and flash
  6. customchromatographed
  7. concentrationconcentrated
  8. customthe resulting solid was triturated with diethyl ether
  9. filtrationfiltered
  10. customair dried

Sources & evidence

ORD record
ord-9659ff71c22b4b69bf2f135710f5cec1
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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