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

HRID 419400ノート

反応式

HRID 419400 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]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][F:57])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:38]=1[NH2:58])[CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][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:58][C:38]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH:49]5[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][F:57])[CH2:51][CH2:50]5)[CH2:45][CH2:44]4)=[CH:42][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1

参加物

9

反応物 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 10942334Sodium MethoxideHCID 59452599(2-(Ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amineHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide

生成物 1

HCID 59452746N-(2,6-difluorophenyl)-3-(3-{2-[(2-(ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide収率 55%

試薬・触媒・溶媒 4

HCID 887Methanol溶媒HCID 6344Dichloromethane溶媒HCID 64092,2,2-Trifluoroethanol溶媒HCID 8058Hexane溶媒

反応条件

温度
150 °C

実験手順

To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol) and (2-(ethyloxy)-4-{4-[1-(2-fluoroethyl)-4-piperidinyl]-1-piperazinyl}phenyl)amine (68 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (140 mg, 0.74 mmol). The mixture was stirred and heated on a Biotage 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 (90 mg, 0.11 mmol, 54%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (s, 1H), 8.36 (m, 2H), 8.22 (d, 1H, J=5.13 Hz), 8.05 (d, 1H, J=7.88 Hz), 7.81 (d, 1H, J=7.88 Hz), 7.73 (d, 1H, J=8.98 Hz), 7.61 (t, 1H, J=7.70 Hz), 7.35-7.50 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.97 (t, 1H, J=8.96 Hz), 6.65 (d, 1H, J=2.38 Hz), 6.44-6.50 (m, 2H), 4.56 (t, 1H, J=4.95 Hz), 4.44 (t, 1H, J=4.95 Hz), 4.06 (q, 2H, J=6.96 Hz), 3.11 (m, 4H), 2.92 (m, 2H), 2.60-2.64 (m, 4H), 2.49 (m, 1H), 2.18 (m, 1H), 1.94-2.03 (m, 2H), 1.72-1.79 (m, 2H), 1.37-1.48 (m, 2H), 1.24 (t, 3H, J=6.87 Hz), 0.82-0.87 (m, 1H). MS (ESI): 776 [M+H]+.

後処理

  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

出典と根拠

ORDレコード
ord-909692990af54129a3e0948688966422
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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