Nitroimidazole derivative for preparing hypoxic developer, preparation method and application thereof
A technology of nitroimidazoles and derivatives, which is applied in the fields of medical imaging materials and medicinal chemistry, can solve the problems of low brain intake, low hypoxia sensitivity, and low brain intake.
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example 1
[0035] Example 1 1-(4-(2-fluoroethyl)piperidin-1-yl)-2-(2-nitro-1H-imidazol-1-yl)ethan-1-one
[0036] The structural formula is as follows:
[0037]
[0038] The synthetic route is as follows:
[0039]
[0040] 1) 2-(2-nitro-1H-imidazol-1-yl)-1-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidine- 1-yl)ethane
[0041]Dissolve 2-(2-nitro-1H-imidazol-1-yl)acetic acid (120mg, 0.70mmol) in DMF, add 5mL triethylamine, stir at room temperature for 15min, then add 4-(2-((tetrahydro -2H-pyran-2-yl)oxy)ethyl)piperidine (150mg, 0.70mmol), 1-hydroxybenzotriazole (HOBT, 30mg, 0.19mmol), O-benzotriazole-tetra Methylurea hexafluorophosphate (HBTU, 800mg, 2.11mmol), react at room temperature for 1h, then extract with ethyl acetate, wash with saturated brine three times, collect the organic layer, and wash with Na 2 SO 4 dry. Purification by flash chromatography (ethyl acetate) afforded 2-(2-nitro-1H-imidazol-1-yl)-1-(4-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)piperidin-1-yl)eth...
Embodiment 2
[0048] Example 2 4-(2-fluoroethyl)-1-(2-(2-nitro-1H-imidazol-1-yl)ethyl)piperidine
[0049] The structural formula is as follows:
[0050]
[0051] The synthetic route is as follows:
[0052]
[0053] 1) 2-(1-(2-(2-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)ethan-1-ol
[0054] Dissolve 2-(2-nitro-1H-imidazol-1-yl)ethyl 4-methylbenzenesulfonate (353mg, 1.13mmol) and 4-piperidineethanol (220mg, 1.70mmol) in acetonitrile, add K 2 CO 3 2-(1-(2-( 2-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)ethan-1-ol (200 mg, 66.0%). 1 H NMR (300MHz, CDCl 3 )δ7.14(s,1H),7.00(s,1H),4.42(t,J=6.1Hz,2H),3.55(t,J=6.5Hz,2H),3.04(s,1H),2.68( d,J=11.2Hz,2H),2.58(t,J=6.1Hz,2H),2.01(s,2H),1.56(d,J=12.4Hz,2H),1.39(dd,J=12.7,6.3 Hz,3H),1.14–0.91(m,2H). 13 C NMR (75MHz, CDCl 3 )δ145.00,127.87,126.38,59.88,58.24,54.05,47.41,39.11,32.14,31.95.HRMS calcd for C12H20N4O3 268.1535;found,269.2187[M+H] + .
[0055] 2) 2-(1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethyl)piperidin-4-yl)ethyl 4-methylbenzenesul...
Embodiment 3
[0059] Example 3 1-(4-(2-fluoroethyl)piperidin-1-yl)-3-(2-nitro-1H-imidazol-1-yl)propanol
[0060] The structural formula is as follows:
[0061]
[0062] The synthetic route is as follows:
[0063]
[0064] 1) 2-(1-(3-(2-nitro-1H-imidazol-1-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperidine- 4-yl)ethanol
[0065] 3-(2-nitro-1H-imidazol-1-yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 4-toluenesulfonate (150mg, 0.35mmol ) and 4-piperidine ethanol (68mg, 0.52mmol) were dissolved in acetonitrile, added K 2 CO 3 (487mg, 3.52mmol), reflux at 90°C for 24h, then spin dry and mix the sample, and pass through flash purification chromatography (ethyl acetate) to obtain 2-(1-(3-(2-nitro-1H-imidazole-1- yl)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)piperidin-4-yl)ethanol (100 mg, 74.8%). 1 H NMR (300MHz, CDCl 3 )δ7.19(s,1H),7.09(s,1H),4.99(dd,J=14.0,2.9Hz,1H),4.36–4.28(m,2H),4.10(d,J=5.0Hz,1H ),3.82–3.65(m,1H),3.82–3.65(m,3H),3.42-3.39(m,1H),2.91(d,J=10.5Hz,1H),2.76(d,J=10.7...
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