A kind of preparation method of cyanomethylated imidazopyridine compound

A technology of cyanomethylated imidazole and methylated imidazole, which is applied in the field of medicinal chemistry, can solve the problems of low atom utilization rate, industrial production limitation, and long reaction steps, and achieve the effects of easy implementation, less pollution, and low production cost

Active Publication Date: 2019-02-22
NANJING NORMAL UNIVERSITY
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Problems solved by technology

Therefore, the current synthesis process generally has long reaction steps, cumbersome operation, various raw materials, and low atom utilization rate, which runs counter to the concept of green development and is greatly restricted in industrial production.

Method used

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  • A kind of preparation method of cyanomethylated imidazopyridine compound
  • A kind of preparation method of cyanomethylated imidazopyridine compound

Examples

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Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of 3-cyanomethyl-2-phenylimidazo[1,2-a]pyridine

[0026] Step 1. Under nitrogen protection, add 2-phenylimidazo[1,2-a]pyridine (0.97g, 5mmol) into a 100mL reaction flask, add fac-Ir(ppy) 3 (65.5mg, 2mol%), sodium bicarbonate (0.84g, 10mmol), bromoacetonitrile 1.39mL (2.40g, 20mmol), 30mL dimethyl sulfoxide as a solvent, react at room temperature, under the irradiation of a 5W blue LED lamp, Stir for 12 hours, add water to quench the reaction, extract with dichloromethane (60mL×3), wash with 50mL saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum, purify and isolate white solid 3-cyanoform Base-2-phenylimidazo[1,2-a]pyridine 1.01g, the yield is 87%, the structural detection data of this compound are as follows:

[0027] m.p.100-101°C (reported m.p.111°C); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.05 (d, J = 8.8Hz, 1H), 7.72–7.67 (m, 3H), 7.53–7.48 (m, 2H), 7.45–7.40 (m, 1H) ,7.34–7.30(m,1H),7.00(td,J=6.8,1.2Hz,1H),4.15(s,2H).13...

Embodiment 2

[0028] Example 2 Preparation of 3-cyanomethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine

[0029]As in Example 1, under nitrogen protection conditions, 2-(4-methylphenyl)-imidazo[1,2-a]pyridine (1.04g, 5mmol) was added to a 100mL reaction flask, and fac-Ir( ppy) 3 (65.5mg, 2mol%), sodium bicarbonate (0.84g, 10mmol), bromoacetonitrile 1.39mL (2.40g, 20mmol), 30mL dimethyl sulfoxide as a solvent, react at room temperature, under the irradiation of a 5W blue LED lamp, Stir for 12 hours, add water to quench the reaction, extract with dichloromethane (60mL×3), wash with 50mL saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum, purify and isolate white solid 3-cyanoform Base-2-(4-methylphenyl)-imidazo[1,2-a]pyridine 1.19g, the yield is 96%, the structural detection data of this compound are as follows:

[0030] m.p.123-124°C; 1 H NMR (400MHz, CDCl3): δ (ppm) 8.08 (d, J = 6.8Hz, 1H), 7.75 (d, J = 9.0Hz, 1H), 7.61 (d, J = 8.0Hz, 2H), 7.37– 7.33(m,3H),7.02(t...

Embodiment 3

[0031] Example 3 Preparation of 3-cyanomethyl-2-(4-methoxyphenyl)-imidazo[1,2-a]pyridine

[0032] As in Example 1, under nitrogen protection conditions, 2-(4-methoxyphenyl)-imidazo[1,2-a]pyridine (1.12g, 5mmol) was added to a 100mL reaction flask, and fac-Ir (ppy) 3 (65.5mg, 2mol%), sodium bicarbonate (0.84g, 10mmol), bromoacetonitrile 1.39mL (2.40g, 20mmol), 30mL dimethyl sulfoxide as a solvent, react at room temperature, under the irradiation of a 5W blue LED lamp, Stir for 12 hours, add water to quench the reaction, extract with dichloromethane (60mL×3), wash with 50mL saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum, purify and isolate white solid 3-cyanoform Base-2-(4-methoxyphenyl)-imidazo[1,2-a]pyridine 1.25g, the yield is 95%, the structural detection data of this compound are as follows:

[0033] mp 120–121°C; 1 H NMR (400MHz, CDCl 3 ): δ(ppm)8.06(d,J=6.8Hz,1H),7.73(d,J=9.1Hz,1H),7.65(d,J=8.6Hz,2H),7.37–7.32(m,1H) ,7.07–6.99(m,3H),4.16...

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Abstract

The invention discloses a preparation method for a cyanomethylation imidazopyridine compound. The preparation method comprises the steps of using an imidazo[1,2-a]pyridine compound as a raw material, and enabling the imidazo[1,2-a]pyridine compound to react with bromoacetonitrile or iodoacetonitrile under photocatalysis to obtain the cyanomethylation imidazopyridine compound. Compared with the prior art, the method disclosed by the invention avoids using highly toxic products such as potassium cyanide, sodium cyanide or methyl iodide; and in the process of preparing a cyanomethylation product of the imidazo[1,2-a]pyridine compound, the original three steps are cut down to one step in chemical conversion. According to the preparation method disclosed by the invention, the preparation route is short; the preparation method is simple; the production cost is low; the yield of products is high; the use of a solvent and pollution caused to the environment during pollution discharge are reduced; the implementation is easy; and the industrialization is convenient to realize.

Description

technical field [0001] The invention discloses a preparation method of cyanomethylated imidazopyridine compounds, belonging to the technical field of medicinal chemistry. Background technique [0002] Imidazo[1,2-a]pyridine is considered as a "predominant structure" because it can be structurally modified or functionalized at multiple sites, and compounds based on such heterocycles exhibit a variety of pharmacological activities . At present, many compounds containing imidazo[1,2-a]pyridine heterocycle have entered the drug market, such as Zolpidem, Alpidem, Minodronic Acid and Olprinone et al. [0003] Zolpidem is a non-benzodiazepine short-acting sedative-hypnotics developed by the French company Sanofi. It was launched in France in 1988 and officially imported into my country in 1995. At present, the trade names of zolpidem tartrate commonly used in the drug market in my country include Sinuosi, Letan, and Nuobin. Zolpidem, as an imidazopyridine hypnotic, can activate...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D513/04
CPCC07D471/04C07D513/04
Inventor 孙培培刘平昌青刘正易
Owner NANJING NORMAL UNIVERSITY
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