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Preparation method of zopiclone

A technology of zopiclone and compounds, applied in the field of preparation of zopiclone, can solve the problems of less than 80% total yield, skin burns, unsafety, etc., achieve production conditions and environmental friendliness, reduce the discharge of three wastes, The effect of simplifying operations

Active Publication Date: 2014-03-26
迪嘉药业集团股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The second step of cyclization reaction needs to be carried out under the action of reagents such as acetic anhydride, thionyl chloride, and ethyl chloroformate, and the total yield of the two-step crude product cannot reach 80%.
[0008] Thionyl chloride is a strong irritating chemical reagent that can burn the skin, and protective equipment must be worn when it is used in large quantities; the residual liquid of acetic anhydride reaction is strongly acidic, and the waste liquid must be treated before it can be discharged. The whole reaction process is neither safe nor harmful. Environmental friendly

Method used

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  • Preparation method of zopiclone
  • Preparation method of zopiclone
  • Preparation method of zopiclone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of compound 3

[0026] Add 15g of 2,3-pyrazine dicarboxylic anhydride, 13g of 2-amino-5-chloropyridine, 0.12g of 4-dimethylaminopyridine, and 120mL of xylene to a 250mL three-neck flask equipped with mechanical stirring and a spherical reflux tube. , 20.2g triethylamine was added at 30°C. Raise the temperature to 80°C and react for 8h; continue to raise the temperature to reflux and react for 1h. Stop heating, naturally cool down to room temperature under mechanical stirring, and continue stirring for 2 hours; use an ice bath to cool down, control the internal temperature at 0-5°C, and stir for 2 hours. After suction filtration, the filter cake was washed once with 50 mL of 1N dilute hydrochloric acid, washed again with 50 mL of water, and dried in a 60°C oven for 8 hours to obtain 22.1 g of an off-white solid with a yield of 85%, a purity of 98%, and a melting point of 232-235°C.

Embodiment 2

[0027] Embodiment 2: the preparation of compound 4

[0028] Add 50 g of compound 3 and 300 mL of dioxane into a 1000 mL three-necked flask equipped with a mechanical stirrer and a thermometer, and stir to dissolve the solid. Cool down in an ice-water bath, control the internal temperature at 10-15°C, add 3.7g of potassium borohydride in batches, after the addition is complete, continue the reaction for 0.5h, add 50mL of tap water and continue stirring for about 6h. The reaction solution was poured into 500 g of ice water, stirred for 2 h, and then suction-filtered to obtain 44 g of a light yellow solid with a yield of 87.4% and a purity of 98% by HPLC.

Embodiment 3

[0029] Embodiment 3: the preparation of zopiclone

[0030] In a 500mL three-neck flask equipped with mechanical stirring and a spherical reflux condenser, add 20g of compound 4, 18.6g of compound 5, 300mL of dichloromethane, 35mL of anhydrous triethylamine, 2.0g of 4-dimethylaminopyridine, and stir at room temperature for 2h Afterwards, the reaction was carried out under reflux for 1 h, and TLC showed that the reaction of the substrate was completed. Naturally cooled to room temperature, a solid precipitated, suction filtered, the filtrate was washed with 1N hydrochloric acid (50mL x 2), and the solvent was evaporated to dryness under reduced pressure to obtain an off-white solid, which weighed 26.7g after drying. The solid was dissolved in 250 mL of ethyl acetate under reflux, decolorized with 2 g of activated carbon at the same time, filtered while hot after 1 h, the filtrate was cooled and crystallized for 4 h, and filtered with suction to obtain 23.6 g of white solid with ...

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Abstract

The invention relates to a preparation method of zopiclone for improving sleeping, belonging to the field of medicines. In the preparation process of 6-(5-chlro-2-pyridyl)-5, 7-dioxo-5, 6-dihydropyrrolo[3, 4-b] pyrazine, namely a compound 3, by taking DMAP (dimethylaminopyridine) as a catalyst, in the presence of triethylamine, cyclization is directly carried out to synthesize an intermediate 3. The crude product yield is 85%, the yield is improved, the operation is simplified, and irritant reagents such as acetic anhydride, thionyl chloride, ethyl chloroformate and the like are not used, thereby facilitating production, facilitating recovery of xylene as a solvent and reducing emission of three wastes. Zopiclone is further synthesized by the compound 3. The method is concise in whole line, simple and convenient to operate and more suitable for industrialized production.

Description

Technical field: [0001] The invention relates to a preparation method of Zopiclone for improving sleep, and belongs to the field of medicine. Background technique: [0002] Zopiclone is the third-generation sedative-hypnotics, which was launched by the French company Rhone-Poulenc Rorer in the mid-1980s under the trade names IMOVANE and AMOBAN in more than 80 countries including Europe, for the treatment of sleep. disorder. Zopiclone has the following chemical structural formula: [0003] [0004] In the traditional synthetic route of zopiclone, for example, the preparation disclosed in US Patent US3862149, Journal of Zhengzhou University (Natural Science Edition), 1993, 25, 4, 73-76 and Huanghuai Journal, 1996, 12, 4, 58-60 method, all need two-step reaction to synthesize intermediate 3: [0005] [0006] The first step reacts to synthesize intermediate 7, which can be used in the next step after being refined; [0007] The second-step cyclization reaction needs t...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 李光跃丁艳
Owner 迪嘉药业集团股份有限公司
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