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Preparation method of zolpidem

A technology for zolpidem and a compound is applied in the field of preparation of zolpidem, which can solve the problems of unsuitable industrial production, poor atom economy, large amount of process waste water and the like, and achieves the effects of short preparation period, short operation period and short technological process.

Active Publication Date: 2019-09-24
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] However, the hydroxylation reagent HTIB or hypoiodinated benzene-p-toluenesulfonic acid used in the above synthetic route 5 has a high price, a large amount of process wastewater, low yield, poor atom economy, and is not suitable for industrial production.

Method used

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  • Preparation method of zolpidem

Examples

Experimental program
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Effect test

Embodiment 1

[0056] Example 1: Preparation of 2-methyl-4,4-dicyano-n-butyraldehyde (II)

[0057] To a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 100 g of tetrahydrofuran, 33.0 g (0.5 mole) of malononitrile, 35.0 g (0.5 mole) of 2-methacrolein, and 0.8 g of DBU, The reaction was stirred at 50 to 55°C for 4 hours. The solvent was recovered by distillation, and then distilled under reduced pressure (90-110° C. / 3-5 mmHg) to obtain 66.4 g of 2-methyl-4,4-dicyano-n-butyraldehyde, with a yield of 97.6% and a gas phase purity of 99.8%.

Embodiment 2

[0058] Example 2: Preparation of 2-methyl-4,4-dicyano-n-butyraldehyde (II)

[0059] In a 500 ml four-necked flask connected with stirring, a thermometer, and a reflux condenser, add 100 g of acetonitrile, 33.0 g (0.5 mole) of malononitrile, 38.5 g (0.55 mole) of 2-methacrolein, and 0.8 g of DBN, The reaction was stirred at 55 to 60°C for 4 hours. The solvent was recovered by distillation, and then distilled under reduced pressure (90-110° C. / 3-5 mmHg) to obtain 66.2 g of 2-methyl-4,4-dicyano-n-butyraldehyde, with a yield of 97.4% and a gas phase purity of 99.6%.

Embodiment 3

[0060] Example 3: Preparation of 2-methyl-4,4-dicyano-n-butyraldehyde (II)

[0061] Into a 250 ml four-necked flask connected with a stirring, thermometer, and reflux condenser, 33.0 g (0.5 mole) of malononitrile, 35.0 g (0.5 mole) of 2-methacrolein, and 0.8 g of DBU were stirred at 50 to 55 ° C. React for 5 hours. Then vacuum distillation (90-110° C. / 3-5 mmHg) yielded 66.0 g of 2-methyl-4,4-dicyano-n-butyraldehyde with a yield of 97.1% and a gas phase purity of 99.8%.

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Abstract

The invention provides a preparation method of zolpidem. The method comprises the following steps: malononitrile and 2-methacrolein which are used as raw materials undergo a 1,4-addition reaction to prepare 2-methyl-4,4-dicyano-n-butyraldehyde, the 2-methyl-4,4-dicyano-n-butyraldehyde and N,N-dimethyl-4-p-methylphenyl-4-oxo-3-amino-n-butyramide undergo a two-stage dehydration condensation reaction, and the obtained reaction product and an acid binding agent undergo an elimination agent to prepare the zolpidem. The method of the invention has the advantages of cheap and easily available raw materials, short process flow, mild reaction conditions, simplicity in operation, low cost, low amount of three wastes, greenness, environmental protection, good selectivity, high yield and high purity of the product, and facilitation of industrial production of the zolpidem.

Description

technical field [0001] The invention relates to a preparation method of zolpidem, which belongs to the technical field of medicinal chemistry. Background technique [0002] Zolpidem (Ⅰ), the English name is Zolpidem, the chemical name is N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[l,2-a]pyridine-3-ethane Amide is a non-benzodiazepine imidazopyridine short-acting sedative-hypnotic drug developed by Sanofi, France. It was first launched in 1988 for the treatment of insomnia and brain diseases. Clinical studies have shown that Zolpidem, as a new generation of hypnotics, has high selectivity, a stronger affinity for the benzodiazepine receptor BZR1 than BZR2, a short half-life, and the duration of action is only 1.6 hours. There is no rebound after drug withdrawal, and the side effects are small And it has no inhibitory effect on breathing, and is currently one of the most popular sedative-hypnotics. [0003] [0004] At present, the preparation of Zolpidem mainly contains t...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 戚聿新鞠立柱张明峰周立山
Owner XINFA PHARMA
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