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

HRID 419575노트

반응식

HRID 419575 반응식
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]3=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[C:24]([NH:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[O:25])[CH:5]=[CH:4][N:3]=1.[N:38]1([CH:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:56]=[CH:55][C:53]([NH2:54])=[C:52]([O:57][CH3:58])[CH:51]=3)[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]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:38]1([CH:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:56]=[CH:55][C:53]([NH:54][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:20])[F:18])=[CH:16][C:11]6=[N:10][C:9]=5[C:21]5[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=5)[C:24]([NH:26][C:27]5[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=5[F:33])=[O:25])[CH:5]=[CH:4][N:3]=4)=[C:52]([O:57][CH3:58])[CH:51]=3)[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1

참가 물질

9

반응물 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10942334Sodium MethoxideHCID 594528983-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamideHCID 597120872-Methoxy-4-[4-(1-piperidyl)-1-piperidyl]aniline

생성물 1

HCID 594529593-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide수율 65%

시약·촉매·용매 4

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

반응 조건

온도
145 °C

실험 절차

To 3-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Example 189, step A) (110 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 40 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 (95 mg, 0.12 mmol, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.46 (br s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.23-8.28 (m, 2H), 8.08 (d, 1H, J=7.88 Hz), 7.84 (d, 1H, J=7.70 Hz), 7.64 (t, 1H, J=7.70 Hz), 7.18-7.45 (m, 5H), 6.70 (d, 1H, J=2.20 Hz), 6.47-6.53 (m, 2H), 3.74-3.81 (m, 5H), 2.61-2.68 (m, 2H), 2.42-2.48 (m, 4H), 2.28-2.37 (m, 1H), 1.75-1.82 (m, 2H), 1.34-1.59 (m, 8H). MS (ESI): 782 [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 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

출처 및 근거

ORD 기록
ord-b7d710686e2548dfa421cfd468dd6105
출처 데이터셋
uspto-grants-2012_01
특허 번호
US08093239B2

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