A highly selective deuteration method for 2-methyl nitrogen heterocyclic compounds

A technology of compounds and heterocycles, applied in the field of synthesis of organic compounds, can solve problems such as limited application and general chemical selectivity

Active Publication Date: 2021-07-27
ZHEJIANG UNIV OF TECH
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Problems solved by technology

In 2017, Yin's group reported the deuteration method of 2-methyl nitrogen-containing heterocyclic rings under relatively mild conditions (80-120°C). However, this method not only requires an acid as a catalyst, but also has a general chemoselectivity (For example, there is no selectivity between the methyl group at position 2 of quinoline and the methyl group at position 4, see Org. Biomol. Chem., 2017, 15, 2507.)
To further reduce the reaction temperature of the deuteration reaction of 2-methyl nitrogen-containing heterocyclic ring, it is necessary to add a metal catalyst or use DMSO-d6 as a deuteration reagent, but the use of expensive metal catalysts and deuteration reagents will limit its Application in drug development (see Angew.Chem.Int.Ed.2017,56,1634. and J.Org.Chem.2017,82,4289.)

Method used

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  • A highly selective deuteration method for 2-methyl nitrogen heterocyclic compounds
  • A highly selective deuteration method for 2-methyl nitrogen heterocyclic compounds
  • A highly selective deuteration method for 2-methyl nitrogen heterocyclic compounds

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Experimental program
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Effect test

Embodiment 1

[0036]

[0037] 6-Methylphenanthridine (0.3 mmol, 58 mg), iodobenzene diacetate (0.45 mmol, 144.9 mg), and azobisisobutyronitrile (0.15 mmol, 24.6 mg) were added to a dry Schlenk reaction tube, which was replaced by vacuum. Under nitrogen protection three times, deuterium water (300 μL) and N,N-dimethylformamide (3 mL) were added to the above reaction tube, and the reaction tube was stirred at 100° C. for 12 hours. After the reaction, 10 mL of water was added to the obtained reaction solution, extracted with diethyl ether, the organic layer was collected, dried with anhydrous sodium sulfate, filtered, the filtrate was taken, and the solvent was evaporated to obtain 6-(methyl-d3)phenanthridine, which produced The rate of deuterium is 65%, and the rate of deuterium is 79%.

[0038] Characterization data: 1 H NMR (500MHz, CDCl 3 )δ8.54-8.51(m,1H),8.47-8.44(m,1H), 8.14-8.10(m,1H),8.09(dd,J1=8.1Hz,J2=1.0Hz,3H),7.75(m ,3H),7.70-7.66(m,1H),7.63-7.60(m,1H),7.59-7.55(m,1H),2.97(m...

Embodiment 2

[0040]

[0041] 8-Fluoro-6-methylphenanthridine (0.3 mmol, 63.3 mg), potassium persulfate (0.45 mmol, 121.6 mg), azobisisobutyronitrile (0.15 mmol, 24.6 mg) were added to a dry Schlenk reaction tube , evacuated and changed nitrogen three times. Under nitrogen protection, deuterium water (300 μL) and N,N-dimethylformamide (3 mL) were added to the above reaction tube, and the reaction tube was stirred and reacted at 100° C. for 12 hours. After the reaction, 10 mL of water was added to the obtained reaction solution, extracted with ether, the organic layer was collected, dried with anhydrous sodium sulfate, filtered, the filtrate was collected, and the solvent was evaporated to obtain 8-fluoro-6-(methyl-d3) Phenanthridine, 75% yield, 34% deuterated yield.

[0042] Characterization data: 1 H NMR (500MHz, CDCl 3 )δ8.57(dd,J 1 =9.1Hz,J 2 =5.3Hz,1H), 8.44(d,J=8.2Hz,1H), 8.09(dd,J 1 =8.2Hz,J 2 =1.1Hz,1H),7.78(dd,J 1 = 9.6 Hz, J 2 = 2.5Hz, 1H), 7.72-7.66(m, 1H), 7.64-7.58(m,...

Embodiment 3

[0044]

[0045] 9-tert-Butyl-6-methylphenanthridine (0.3 mmol, 74.8 mg), ceric ammonium nitrate (0.45 mmol, 246.7 mg), azobisisobutyronitrile (0.15 mmol, 24.6 mg) were added to the dry Schlenk reaction The tube was evacuated and replaced with nitrogen three times. Under nitrogen protection, deuterium water (300 μL) and N,N-dimethylformamide (3 mL) were added to the above reaction tube, and the reaction tube was stirred at 100 ° C for 12 Hour. After the reaction, 10 mL of water was added to the obtained reaction solution, extracted with ether, the organic layer was collected, dried with anhydrous sodium sulfate, filtered, the filtrate was collected, and the solvent was evaporated to obtain 9-tert-butyl-6-(methyl- d3) Phenanthridine, yield 69%, deuteration rate 84%. Characterization data: 1 H NMR (500MHz, CDCl 3 )δ8.57-8.50(m,2H),8.18(d,J=1.9Hz,1H),8.13(dd,J 1 =8.2Hz,J 2 =1.0Hz,1H),7.93(dd,J 1 =8.7Hz,J 2 = 2.0Hz, 1H), 7.72-7.69(m, 1H), 7.65-7.58(m, 1H), 3.09-3.06(m, 0....

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Abstract

The invention discloses a highly selective deuteration method for 2-methyl nitrogen heterocyclic compounds. The method is carried out as follows: the 2-methyl nitrogen-containing compound shown in formula I, formula II or formula III Heterocyclic compounds, oxidants, and additives are added to a dry Schlenk reaction tube. Under protective gas conditions, deuterium water and organic solvents are added to the above reaction tube, and the reaction is stirred at 50-100°C for 2-12 hours to obtain the reaction The solution is post-treated to obtain deuterated nitrogen-containing heterocyclic rings shown in formula IV, formula V or formula VI respectively. The method of the present invention is based on a free radical process, is efficient, and can synthesize methyl-d3 substituted nitrogen-containing heterocyclic compounds that are difficult to prepare by existing methods, and the deuteration rate of the reaction is high; it is carried out under neutral conditions, and requires equipment. low; using a catalytic amount of oxidant, the additives are cheap and easy to obtain; the reaction conditions are relatively mild, energy consumption is saved; the yield is high, the substrate universality is strong, and the operation is simple and so on.

Description

[0001] (1) Technical field [0002] The invention relates to a method for synthesizing organic compounds, in particular to a method for highly selective deuteration of 2-methyl nitrogen heterocyclic compounds. [0003] (2) Background technology [0004] Deuterated compounds are an important class of high value-added chemicals. It can be widely used as a solvent in the field of nuclear magnetic resonance spectroscopy, and can also be used to reveal the mechanism of organic reactions. More importantly, in the field of medicinal chemistry, replacing hydrogen atoms with deuterium atoms has become an ideal method for drug modification. On the one hand, the introduction of deuterium into the non-metabolized and non-acting sites of drug molecules can track the dynamics of drug molecules in the body, and study the absorption, distribution, metabolism and excretion of drug molecules without affecting drug action. . On the other hand, since the carbon-deuterium bond is about 6-9 times...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/12C07D215/18C07D215/26C07D241/42C07B59/00
CPCC07B59/002C07B2200/05C07D215/18C07D215/26C07D221/12C07D241/42
Inventor 刘运奎鲍汉扬郑立孟
Owner ZHEJIANG UNIV OF TECH
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