Diisopropylethylamine → N-(3-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

HRID 527437노트

반응식

HRID 527437 반응식
[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:17][C:18]1[C:27]2[CH:26]=[N:25][C:24](S(C)=O)=[N:23][C:22]=2[N:21]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=2)[C:20](=[O:42])[CH:19]=1.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O.CC#N>C(O)(C)(C)C.C(O)(C(F)(F)F)=O.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:24]1[N:25]=[CH:26][C:27]2[C:18]([CH3:17])=[CH:19][C:20](=[O:42])[N:21]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[C:22]=2[N:23]=1

참가 물질

7

반응물 4

HCID 81531DiisopropylethylamineHCID 21924481TFA acetonitrileHCID 574160862-Methoxy-4-(1-methylpiperidin-4-yl)anilineHCID 86732024HCID 86732024, 화합물

생성물 1

HCID 78319001N-(3-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide수율 5.2%

시약·촉매·용매 2

HCID 6386tert-Butanol용매HCID 22392675Trifluoroacetic acid water용매

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온도
100 °C

실험 절차

To a suspension of 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (19b, 363 mg, 1.65 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b, 300 mg, 0.81 mmol) in tert-butanol (15 mL) at RT was added diisopropylethylamine (0.43 mL, 2.443 mmol). The mixture was heated at 100° C. for 48 h. The reaction mixture was concentrated on the rotovap and the crude residue was suspended in Et2O and filtered. The resulting light yellow amorphous solid was washed with Et2O (3×50 mL) and chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 0-15% MeOH in DCM) affording enriched product. It was repurifed on a Gilson (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated in the genevac overnight and then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 20% MeOH/DCM to remove any residual salt then dried under vacuum affording N-(3-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (22 mg) as a light yellow solid. m/z (ESI, +ve ion) 525.0 (M+H)+. 1H NMR (400 MHz, DMSO6) δ ppm 10.34 (1H, s), 8.85 (1H, s), 8.16 (1H, s), 7.85 (1H, d, J=9.2 Hz), 7.63 (1H, s), 7.48-7.56 (1H, m), 7.36 (1H, d, J=8.4 Hz), 7.00 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=1.4 Hz), 6.38-6.47 (1H, In), 6.30-6.38 (2H, m), 6.19-6.29 (1H, m), 5.70-5.78 (1H, m), 3.80 (3H, s), 2.84 (2H, d, J=11.2 Hz), 2.47 (3H, s), 2.25-2.36 (1H, m), 2.19 (3H, s), 1.92 (2H, td, J=11.1, 3.7 Hz), 1.52-1.69 (4H, m).

후처리

  1. concentrationThe reaction mixture was concentrated on the rotovap
  2. filtrationfiltered
  3. washThe resulting light yellow amorphous solid was washed with Et2O (3×50 mL)
  4. customchromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column
  5. customaffording
  6. concentrationconcentrated in the genevac overnight
  7. customto remove any residual salt
  8. customthen dried under vacuum

출처 및 근거

ORD 기록
ord-b2e0b752afe84c99a722078c3794826d
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09346801B2

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