p-Toluenesulfonic acid monohydrate → 3-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

HRID 419580노트

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HRID 419580 반응식
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][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][C:15]([F:17])=[CH:16][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:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=5[F:30])=[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

참가 물질

9

반응물 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10942334Sodium MethoxideHCID 594529173-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamideHCID 597120872-Methoxy-4-[4-(1-piperidyl)-1-piperidyl]aniline

생성물 1

HCID 594527303-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide수율 62%

시약·촉매·용매 4

HCID 887Methanol용매HCID 6344Dichloromethane용매HCID 64092,2,2-Trifluoroethanol용매HCID 8058Hexane용매

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온도
150 °C

실험 절차

To 3-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 194, step B) (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 150° 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 oil. The oil 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 (84 mg, 0.11 mmol, 62%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.48 (br s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 8.20 (d, 1H, J=5.13 Hz), 8.06 (d, 1H, J=7.88 Hz), 7.82 (d, 1H, J=7.88 Hz), 7.59-7.64 (m, 2H), 7.35-7.45 (m, 2H), 7.21 (t, 2H, J=8.06 HZ), 7.01-7.09 (m, 1H), 6.67-6.69 (m, 1H), 6.43-6.51 (m, 2H), 3.70-3.81 (m, 5H), 2.65 (t, 2H, J=11.36 Hz), 2.42-2.48 (m, 4H), 2.29-2.37 (m, 1H), 1.75-1.83 (m, 2H), 1.44-1.59 (m, 6H), 1.34-1.41 (m, 2H). MS (ESI): 733 [M+H]+.

후처리

  1. temperaturecooled to rt
  2. concentrationThe mixture was concentrated under vacuum
  3. customthe residue purified by silica gel chromatography
  4. customto give a yellow oil
  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

출처 및 근거

ORD 기록
ord-87de0e1ea8564ee2a2936ca1d58b7cec
출처 데이터셋
uspto-grants-2012_01
특허 번호
US08093239B2

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