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Preparation method of zolpidem impurities

A zolpidem and impurity technology, which is applied in the field of preparation of zolpidem impurities, can solve the problems of low content, lack of reference substances, monitoring, etc., and achieve the effect of simple operation and high product yield

Pending Publication Date: 2020-04-03
ZHUZHOU QIANJIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] But impurity compound I content is very low in the synthetic process of zolpidem, is difficult to separate, and prior art still does not have the synthetic method for impurity compound I, is difficult to obtain a large amount of compound I, lacks corresponding reference substance, in zolpidem It is difficult to monitor the detection of this impurity during the synthesis process

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  • Preparation method of zolpidem impurities
  • Preparation method of zolpidem impurities
  • Preparation method of zolpidem impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 Preparation of a zolpidem impurity compound I

[0049]The Zolpidem impurity compound I was prepared and separated by the following method:

[0050] in N 2 Under protection, 970mg of compound II (1.0eq, 3mmol) was stirred and mixed with 5mL of polyphosphoric acid, and reacted at 100°C for 2h. After the reaction, 5mL of ice water was added and extracted twice with 10mL of ethyl acetate. Dry, concentrate under reduced pressure, mix the sample with silica gel, and perform column chromatography (developing solvent: ethyl acetate:petroleum ether=1:3) to obtain 742 mg off-white solid, ESI: m / z [M+H] + 306.10, 1 H NMR (CDCl 3 ):δ2.35(s,3H),2.56(s,3H),3.27(s,3H),3.47(s,3H),6.36(s,1H),6.86-6.91(m,2H),7.16- 7.19 (m, 1H), 7.44-7.49 (m, 2H), 8.06-80.8 (m, 1H), Zolpidem impurity compound I, the yield is 81%.

[0051] With reference to the above preparation method, the difference is that different additions of polyphosphoric acid or reaction temperature are used to prep...

Embodiment 2

[0055] Example 2 Preparation of a zolpidem impurity compound I

[0056] The Zolpidem impurity compound I was prepared and separated by the following method:

[0057] in N 2 Under protection, 970mg of compound II (1.0eq, 3mmol) was stirred and mixed with 5mL of dichloroethane, 815μL of 98% concentrated sulfuric acid (5.0eq, 15mmol) was added, and reacted at 80°C for 5h. After the reaction was completed, 5mL of ice water was added, Extract twice with 10 mL of dichloromethane, dry over anhydrous sodium sulfate, concentrate under reduced pressure, mix the sample with silica gel, and perform column chromatography (developing solvent: ethyl acetate:petroleum ether=1:3) to obtain 623 mg of off-white solid ,ESI:m / z[M+H] + 306.10, 1 H NMR (CDCl 3 ):δ2.35(s,3H),2.56(s,3H),3.27(s,3H),3.47(s,3H),6.36(s,1H),6.86-6.91(m,2H),7.16- 7.19 (m, 1H), 7.44-7.49 (m, 2H), 8.06-80.8 (m, 1H), Zolpidem impurity compound I, the yield is 68%.

[0058] Referring to the above preparation method, the d...

Embodiment 3

[0062] Example 3 Preparation of a zolpidem impurity compound I

[0063] The Zolpidem impurity compound I was prepared and separated by the following method:

[0064] in N 2 Under protection, stir and mix 970mg of compound II (1.0eq, 3mmol) with 5mL of dimethylformamide, add 2.0g of aluminum trichloride (5.0eq, 15mmol), and react at 100°C for 12h. After the reaction is completed, concentrate and add Ethyl acetate, repeated concentration 2 to 3 times, mixed the sample with silica gel, and carried out column chromatography (developing solvent is ethyl acetate:petroleum ether=1:3), to obtain 567mg off-white solid, ESI: m / z [M+ H] + 306.10, 1 H NMR (CDCl 3 ):δ2.35(s,3H),2.56(s,3H),3.27(s,3H),3.47(s,3H),6.36(s,1H),6.86-6.91(m,2H),7.16- 7.19 (m, 1H), 7.44-7.49 (m, 2H), 8.06-80.8 (m, 1H), Zolpidem impurity compound I, the yield is 62%.

[0065] Referring to the above preparation method, the difference is that different aprotic organic solvents or reaction temperatures are used t...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of zolpidem impurities. The method is a brand-new zolpidem impurity preparation method. According to the method, a compound II (N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo[1, 2-alpha]pyridin-3-alpha-hydroxyacetamide) is used as a raw material and is combined with a specific polyphosphoric acid, concentrated sulfuric acid and aluminum trichloride acid catalysis system, and the mixture undergoes a reaction at the temperature of 80-140 DEG C. The product yield is high, the operation is simple, the method is suitable for the large-scale industrial production of the zolpidem impurity compound I, and the impurity detection monitoring during the zolpidem synthesis process is easily achieved.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis. More specifically, it relates to a method for preparing zolpidem impurities. Background technique [0002] Zolpidem is a new generation of non-benzodiazepine short-acting imidazopyridine sedative-hypnotics. It is clinically administered orally in the form of zolpidem tartrate for the treatment of insomnia and brain diseases. The principle of action is that it can selectively bind to the ω1-receptor subtype of the central nervous system, open the chloride ion channel, allow chloride ions to flow into nerve cells, cause cell membrane hypertrophy, thereby inhibiting nerve cell source excitation, and benzodiazepine Compared with other drugs, it has higher selectivity. And long-term clinical trials have shown that zolpidem rarely produces tolerance and addiction in the normal treatment cycle, and rarely has adverse reactions such as memory impairment, depression syndrome, and mental disor...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 周泽银刘丽龙世玉刘秀朱维君李翼
Owner ZHUZHOU QIANJIN PHARMA