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Method for preparing zolpidem

A technology for zolpidem and pyridine, which is applied in the field of preparation of zolpidem, can solve the problems of industrial production limitation, low atom utilization rate, long reaction steps, etc., and achieves the effects of reducing pollution, being easy to implement, and having low production cost.

Active Publication Date: 2017-07-14
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

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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  • Method for preparing zolpidem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Under nitrogen protection conditions, add 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine (1.11g, 5mmol) into a 100mL reaction flask, add Ir(ppy) 2 (dtbbpy)PF 6 (65.5mg, 2mol%), 2-bromo-N,N-dimethylacetamide (1.66g, 10mmol), N,N-dicyclohexylmethylamine 2.14mL (1.95g, 10mmol), 30mL acetonitrile as solvent , under the irradiation of a 5W blue LED lamp, stirred at 40°C for 18h, quenched the reaction with water, extracted with dichloromethane (60mL×3), washed with 50mL saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. Purified and separated by column chromatography to obtain white solid N,N,6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide (zolpidem) 0.97 g, the yield is 63%, and the structure detection data of the prepared Zolpidem are as follows:

[0021] m.p.193-195°C (reported m.p.194-196°C); 1 H NMR (400MHz, CDCl 3 ):δ(ppm)7.93(s,1H),7.52–7.49(m,3H),7.22(d,J=7.6Hz,2H),7.03(d,J=8.8Hz,1H),4.03(s, 2H), 2.92(s,3H), 2....

Embodiment 2

[0023] Same as Example 1, the difference is:

[0024] The molar ratio of 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine to 2-bromo-N,N-dimethylacetamide is 1:2, and the reaction The temperature was 20°C and the reaction time was 18 hours.

[0025] The photocatalyst is fac-Ir(ppy) 3 , its dosage is 0.5% (molar ratio) of 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine; the base is sodium bicarbonate, the base and 6-methyl The molar ratio of -2-(4-methylphenyl)-imidazo[1,2-a]pyridine is 2:1; the organic solvent used for extraction is ethyl acetate.

[0026] N,N,6-Methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide (zolpidem) was isolated as a white solid in 65% yield .

[0027] The structure detection data of the prepared Zolpidem are basically the same as in Example 1.

Embodiment 3

[0029] Same as Example 1, the difference is:

[0030] The molar ratio of 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine to 2-bromo-N,N-dimethylacetamide is 1:4, and the reaction The temperature was 60°C and the reaction time was 12 hours.

[0031] The photocatalyst is Ir(ppy) 2 (dtbbpy)PF 6 , its dosage is 2.8% (molar ratio) of 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine; the base is sodium acetate, the base and 6-methyl- The molar ratio of 2-(4-methylphenyl)-imidazo[1,2-a]pyridine is 2:1.

[0032] N,N,6-Methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide (zolpidem) was isolated as a white solid in a yield of 66% .

[0033] The structure detection data of the prepared Zolpidem are basically the same as in Example 1.

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Abstract

The invention discloses a method for preparing zolpidem. The method comprises the step of subjecting 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine, which serves as a raw material, to a reaction with 2-bromo-N,N-dimethylacetamide under the action of photocatalysis, thereby obtaining the zolpidem. Compared with the prior art, the method has the advantages that environment-friendly and pollution-free LED light serves as an energy source, so that an environment-friendly sustainable development idea is embodied; and during the preparation of the zolpidem, five steps in the prior art are shortened to one step. According to the method, the preparation route is short, the preparation method is simple, the production cost is low, the product yield is high, the consumption of a solvent and the pollution to environments during blowdown are reduced, the implementation is easy, and thus, the industrialization is facilitated.

Description

technical field [0001] The invention discloses a preparation method of zolpidem, which belongs 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 γ-aminobutyric acid type A r...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 孙培培刘平昌青刘正易
Owner NANJING NORMAL UNIVERSITY
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