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Hydrochloric Acid → N-(2,6-difluorophenyl)-5-(7-fluoro-3-{2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide

HRID 419584
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HRID 419584 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.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].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:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([N:52]5[CH2:57][CH2:56][N:55]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:53]5)[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:35][CH3:36]
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참가 물질

10

반응물 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10942334Sodium MethoxideHCID 574161512-(Methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-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 25124476
N-(2,6-difluorophenyl)-5-(7-fluoro-3-{2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide
수율 61%

시약·촉매·용매 4

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

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온도
175 °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) (85 mg, 0.17 mmol) and 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, step B) (61 mg, 0.17 mmol) in 2,2,2-trifluoroethanol (0.80 mL) was added 4 M HCl in dioxane (83 μL, 0.33 mmol). The mixture was stirred and heated on a microwave at 175° C. for 35 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 (85 mg, 0.10 mmol, 61%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.78 (s, 1H), 9.44 (br s, 1H), 8.49 (s, 1H), 8.20 (d, 1H, J=5.31 Hz), 8.07-8.11 (m, 1H), 7.75-7.80 (m, 1H), 7.58 (dd, 1H, J=2.56, 9.52 Hz), 7.35-7.42 (m, 2H), 7.29 (d, 1H, J=8.61 Hz), 7.18 (t, 2H, J=7.97 Hz), 6.97-7.04 (m, 1H), 6.68-6.70 (m, 1H), 6.48-6.53 (m, 2H), 3.99 (s, 3H), 3.73-3.81 (m, 5H), 3.06-3.11 (m, 4H), 2.85 (s, 3H), 2.68 (t, 2H, J=11.54 Hz), 2.58-2.62 (m, 4H), 2.38-2.46 (m, 1H), 1.80-1.87 (m, 2H), 1.48-1.60 (m, 2H). MS (ESI): 842 [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-0e4bac5390d74d8898d87d94ec6f3d77
출처 데이터셋
uspto-grants-2012_01
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08093239B2

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