醋酸 → 2-((2-Chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

HRID 921663笔记

反应方程式

HRID 921663 反应方程式
[C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:19]([C:28]#[N:29])=[CH:18][C:17]=1[NH:30][C:31]1[N:36]=[C:35]([N:37]([CH:47]2[CH2:49][CH2:48]2)CC2C=CC(OC)=CC=2)[C:34]2=[N:50][CH:51]=[C:52]([C:53]#[N:54])[N:33]2[N:32]=1.C=O.O.CC(O)=O.C([O-])(O)=O.[Na+].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:15][C:16]1[C:21]([CH:22]2[CH2:23][CH2:24][N:25]([CH3:1])[CH2:26][CH2:27]2)=[CH:20][C:19]([C:28]#[N:29])=[CH:18][C:17]=1[NH:30][C:31]1[N:36]=[C:35]([NH:37][CH:47]2[CH2:49][CH2:48]2)[C:34]2=[N:50][CH:51]=[C:52]([C:53]#[N:54])[N:33]2[N:32]=1

参与物

10

反应物 8

HCID 176醋酸HCID 712多聚甲醛HCID 962聚[6-[4-(4-氰基苯基)苯氧基]己基甲基丙烯酸酯]HCID 6422三氟乙酸HCID 7519苯甲醚HCID 516892碳酸氢钠HCID 5049666三乙酰氧基硼氢化钠HCID 867085292-((2-Chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

产物 1

HCID 867085282-((2-Chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile收率 87.5%

试剂、催化剂与溶剂 1

HCID 111,2-二氯乙烷溶剂

反应条件

温度
50 °C

实验过程

Sodium triacetoxyborohydride (24.10 mg, 0.114 mmol) was added to a stirred suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (30.0 mg, 0.038 mmol), formaldehyde 37% in water (8.47 μL, 0.114 mmol) and HOAc (16.27 μL, 0.190 mmol) in DCE (379 μL) at room temperature for 30 min. Sat. aq. NaHCO3 solution was slowly added (gas evolution) and the reaction was left stirring for 10 min. It was extracted with DCM. The organic phase was dried with sodium sulfate and the solvents were removed. The crude intermediate was dissolved in DCE (1 mL) and anisole (20.70 μL, 0.190 mmol), and TFA (0.5 mL) were added. The resulting mixture was heated at 50° C. for 3 h. Removal of the solvents was followed by preparative HPLC (Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100%. B; Flow: 20 mL/min.). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 14.9 mg of 2-((2-chloro-5-cyano-3-(1-methylpiperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.

后处理

  1. waitthe reaction was left
  2. extractionIt was extracted with DCM
  3. dry with materialThe organic phase was dried with sodium sulfate
  4. customthe solvents were removed
  5. dissolutionThe crude intermediate was dissolved in DCE (1 mL)
  6. customRemoval of the solvents
  7. waitGradient: 40-80% B over 20 minutes
  8. customa 5-minute hold
  9. additionFractions containing the desired product
  10. customdried via centrifugal evaporation

来源与证据

ORD记录
ord-e8c99da390ba4adab0c4f0a87b3f38de
来源数据集
uspto-grants-2016_03
专利号
US09273057B2

反应笔记

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