Hydrochloric Acid → n-(2,6-Difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}-7-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide

HRID 419624노트

반응식

HRID 419624 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]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=2)[C:23]([NH:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[O:24])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)[C:44]([CH3:59])=[CH:43][C:41]=1[NH2:42])[CH3:38].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:44]([CH3:59])[C:45]([N:47]4[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:35][CH3:36]

참가 물질

10

반응물 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 594527752-(Ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}anilineHCID 594529085-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide

생성물 1

HCID 59452806n-(2,6-Difluorophenyl)-5-(3-{2-[(2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}-7-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide수율 73%

시약·촉매·용매 4

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

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온도
170 °C

실험 절차

To 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)-2-(methyloxy)benzamide (Example 197, step A) (132 mg, 0.26 mmol) and 2-(ethyloxy)-5-methyl-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (Example 215, step C) (80 mg, 0.24 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (120 μL, 0.47 mmol). The mixture was stirred and heated on a microwave at 170° 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 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 (139 mg, 0.17 mmol, 73%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 ppm 9.79 (s, 1H), 9.39-9.48 (m, 1H), 8.41 (s, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.5, 1.7 Hz, 1H), 7.61 (dd, J=9.6, 2.5 Hz, 1H), 7.53 (s, 1H), 7.35-7.44 (m, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.17-7.23 (m, 2H), 6.99-7.04 (m, 1H), 6.76 (s, 1H), 6.59 (d, J=5.1 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.00 (s, 3H), 3.14-3.22 (m, 2H), 3.03-3.10 (m, 2H), 2.98 (s, 3H), 2.61 (t, J=10.9 Hz, 2H), 2.15 (s, 3H), 1.77-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.45-1.54 (m, 1H), 1.30-1.41 (m, 2H), 1.23-1.28 (m, 3H). MS (ESI): 813 [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-110b840b7c644c2ba169906144170ebb
출처 데이터셋
uspto-grants-2012_01
특허 번호
US08093239B2

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