p-Toluenesulfonic acid monohydrate → N-(2,6-difluorophenyl)-5-[3-(2-{[4-[1-(2-fluoroethyl)-4-piperidinyl]-2-(methyloxy)-phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-2-(methyloxy)benzamide

HRID 419557ノート

反応式

HRID 419557 の反応式
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][CH3:35])=[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.[F:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)[CH2:41][CH2:40]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[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:49][C:48]3[CH:50]=[CH:51][C:45]([CH:42]4[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][F:36])[CH2:44][CH2:43]4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]

参加物

5

反応物 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 594525905-(3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridin-2-yl)-N-(2,6-difluorophenyl)-2-methoxybenzamideHCID 594527574-[1-(2-Fluoroethyl)-4-piperidinyl]-2-(methyloxy)aniline

生成物 1

HCID 59452850N-(2,6-difluorophenyl)-5-[3-(2-{[4-[1-(2-fluoroethyl)-4-piperidinyl]-2-(methyloxy)-phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-2-(methyloxy)benzamide

試薬・触媒・溶媒 1

HCID 3776Isopropanol溶媒

反応条件

温度
175 °C

実験手順

To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (238 mg, 0.50 mmol) and 4-[1-(2-fluoroethyl)-4-piperidinyl]-2-(methyloxy)aniline (140 mg, 0.50 mmol) in iPrOH (1 mL) in a microwave vial was added p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol). The reaction was heated in a microwave at 175° C. for 1000 seconds. After cooling to rt the material was transferred to another flask, rinsing with a solution of DCM/MeOH. Silica gel was added and the solvent removed on the rotovap. The preabsorbed solids were purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product contaminated with an impurity. The material was placed under vacuum for 3 days then triturated with diethyl ether. The desired product was obtained as a white solid (23 mg, 0.033 mmol, 6.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.35 (d, J=6.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.08, (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.60 (m, 2H), 7.42 (dd, J=8.4, 7.3 Hz, 1H), 7.35 (dd, J=7.1, 6.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.1, 7.9 Hz, 2H), 6.97-6.90 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.51 (dt, J=48.0, 4.8 Hz, 2H), 3.95, (s, 3H), 3.80 (s, 3H), 2.97 (d, J=11.0 Hz, 2H), 2.60 (dt, J=28.2, 4.8 Hz, 2H), 2.08 (dd, J=11.5, 8.8 Hz, 2H), 1.77-1.59 (m, 4H). MS (ESI) m/z=708 [M+1].

後処理

  1. temperatureAfter cooling to rt the material
  2. customwas transferred to another flask
  3. washrinsing with a solution of DCM/MeOH
  4. additionSilica gel was added
  5. customthe solvent removed on the rotovap
  6. customThe preabsorbed solids were purified by flash chromatography
  7. customthe solvent removed on the rotovap
  8. customto give product
  9. customthen triturated with diethyl ether

出典と根拠

ORDレコード
ord-3847c4819a7142a3b2b63125d78531e1
出典データセット
uspto-grants-2012_01
特許番号
US08093239B2

反応ノート

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