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

HRID 419573노트

반응식

HRID 419573 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.[F:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][N:50]([C:53]3[CH:59]=[CH:58][C:56]([NH2:57])=[C:55]([O:60][CH3:61])[CH:54]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[NH:26][C:24](=[O:25])[C:23]1[CH:35]=[CH:36][CH:37]=[C:21]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:57][C:56]3[CH:58]=[CH:59][C:53]([N:50]4[CH2:49][CH2:48][CH:47]([N:44]5[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][F:38])[CH2:46][CH2:45]5)[CH2:52][CH2:51]4)=[CH:54][C:55]=3[O:60][CH3:61])[N:7]=2)[CH:22]=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 598602604-[4-[4-(2-Fluoroethyl)-1-piperazinyl]-1-piperidinyl]-2-(methyloxy)aniline

생성물 1

HCID 59452611N-(2,6-difluorophenyl)-3-[3-(2-{[4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)phenyl]amino}-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]benzamide수율 38%

시약·촉매·용매 4

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

반응 조건

온도
150 °C

실험 절차

To 3-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (110 mg, 0.21 mmol) and 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (Example 57, step E) (63 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (134 mg, 0.71 mmol). The mixture was stirred and heated on a microwave at 150° C. for 45 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 (59 mg, 0.07 mmol, 38%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.47 (br s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.27 (d, 1H, J=5.32 Hz), 8.24 (s, 1H), 8.08 (d, 1H, J=7.88 Hz), 7.84 (d, 1H, J=7.70 Hz), 7.64 (t, 1H, J=7.79 Hz), 7.31-7.45 (m, 2H), 7.21 (t, 3H, J=8.06 Hz), 6.70-6.72 (m, 1H), 6.47-6.53 (m, 2H), 4.56 (t, 1H, J=4.86 Hz), 4.44 (t, 1H, J=4.86 Hz), 3.80 (s, 3H), 3.71-3.77 (m, 2H), 2.59-2.70 (m, 4H), 2.40-2.55 (m, 8H), 2.25-2.34 (m, 1H), 1.81-1.87 (m, 2H), 1.46-1.56 (m, 2H). MS (ESI): 830 [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-926e3d6beca74640ba7203235fbb43b6
출처 데이터셋
uspto-grants-2012_01
특허 번호
US08093239B2

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