p-Toluenesulfonic acid monohydrate → 3-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

HRID 419574Notes

Reaction equation

HRID 419574 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:53]=[CH:52][C:50]([NH2:51])=[C:49]([O:54][CH3:55])[CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:53]=[CH:52][C:50]([NH:51][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]6=[N:10][C:9]=5[C:18]5[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=5)[C:21]([NH:23][C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])=[O:22])[CH:5]=[CH:4][N:3]=4)=[C:49]([O:54][CH3:55])[CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1

Participants

9

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10942334Sodium MethoxideHCID 594528703-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamideHCID 597120872-Methoxy-4-[4-(1-piperidyl)-1-piperidyl]aniline

Product 1

HCID 594527673-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamideYield 66%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
145 °C

Procedure

To 3-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 188, step A) (100 mg, 0.21 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (54 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol). The mixture was stirred and heated on a microwave at 145° C. for 30 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, 0.12 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.20 (br s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (d, 1H, J=5.13 Hz), 8.07 (d, 1H, J=7.88 Hz), 7.83 (d, 1H, J=7.70 Hz), 7.62 (t, 1H, J=7.79 Hz), 7.34-7.45 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.93-6.99 (m, 1H), 6.66 (d, 1H, J=2.20 Hz), 6.45-6.50 (m, 2H), 3.79 (s, 3H), 3.70-3.77 (m, 2H), 2.59-2.68 (m, 2H), 2.42-2.48 (m, 4H), 2.28-2.37 (m, 1H), 1.76-1.83 (m, 2H), 1.35-1.60 (m, 8H). MS (ESI): 733 [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-41828abd178f459cb17a0ed3ee812f2d
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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