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Preparation method of eszopiclone

A technology of eszopiclone and zopiclone, applied in the direction of organic chemistry, etc., can solve the problems of long reaction period, harsh reaction conditions, unsuitable for large-scale production and the like

Inactive Publication Date: 2014-03-26
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this method has two problems (1) the optical purity of S-zopiclone that this method splits for the first time is not high, needs several times of recrystallization to obtain the S-zopiclone of optical purity more than 98%, will make scale The cost of chemical production is too high; (2) This method uses dichloromethane, because it is relatively harmful to the human body, it is not advocated in the design of pharmaceutical processes
[0008] In 1997, Vicente Gotor et al[Enzymatic resolution of(±)-6-(5-chloropyridin-2-yl)-7-vinyloxy-carbonyloxy-6,7-dihydro[5H]pyrrolo[3,4-b]pyrazin- 5-one.Synthesis of (+)-zopiclone.Tetrahedron: Asymmetry.1997 (8), 7,995-997] reported that the synthesis of S-zopiclone was carried out by enzymatic methods, but this method has many disadvantages: ( 1) this method uses enzyme to react in dioxane, which will make the cost too high and the reaction conditions harsh; (2) the yield of this method is not high, only about 50% at the highest; (3) reaction cycle It is relatively long, about 6 days; (4) This method uses semi-preparative HPLC method for separation, the cost is too high, it is not suitable for large-scale production, and it is not advocated in the design of pharmaceutical processes

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] a. Salt formation and resolution: Mix 2.33kg racemic zopiclone, 0.81kg D-(+)-malic acid, 13.98kg methanol and 23.3kg acetone, heat to reflux, and react for 30 minutes to dissolve all the solids; The solution was cooled down to room temperature, allowed to stand for 8-24 hours, crystallized, filtered, washed with 0.93-3.5kg acetone, filtered, and dried to obtain 1.42kg crude product of D-(+)-malic acid S-zopiclone; The yield is 45.3%, and the optical purity is 96.6%.

[0051] b. Demalate: Add the D-(+)-malic acid S-zopiclone obtained in the previous step to 5.68kg water and 19.88kg ethyl acetate, add 0.43kg anhydrous K 2 CO 3 , reflux reaction for 30 minutes, use test paper to measure the pH of the water layer > 7, let stand to separate the liquid, wash the organic phase with saturated aqueous sodium chloride solution, then add 3.55kg ethyl acetate to wash the container wall, combine the organic phases, and evaporate under reduced pressure Part of ethyl acetate, the re...

Embodiment 2

[0053] a. Salt formation and resolution: Mix 2.33kg racemic zopiclone, 0.81kg D-(+)-malic acid, 15kg methanol and 24.5kg acetone, heat to reflux, and react for 30 minutes to dissolve all the solids; Cool the solution down to room temperature, let stand for 8-24 hours, crystallize, filter, and wash with 1-3.5kg acetone, filter to obtain the crude product of D-(+)-malic acid S-zopiclone; by weight of zopiclone , add 14kg of acetone and 9.4kg of methanol to this crude product, heat to reflux, stop heating after dissolving, drop to room temperature, let stand for 8-24 hours, crystallize, filter, wash with 1-3.5kg of acetone, filter, and dry to obtain D -(+)-malic acid S-zopiclone 1.27kg; molar yield 40.5%, optical purity 98.5%.

[0054] b. Demalate: add the D-(+)-malic acid S-zopiclone obtained in the previous step to 5.8kg water and 20kg ethyl acetate, add 0.38kg anhydrous K 2 CO 3 , reflux reaction for 30 minutes, use test paper to measure the pH of the water layer > 7, let st...

Embodiment 3

[0056] a. Salt formation and resolution: Mix 2.33kg racemic zopiclone, 0.81kg D-(+)-malic acid, 14.4kg methanol and 24.5kg acetone, heat to reflux, and react for 30 minutes to dissolve all the solids; The solution was cooled down to room temperature, left standing for 8-24 hours, crystallized, filtered, washed with 1-3.5kg acetone, filtered to obtain the crude product of D-(+)-malic acid S-zopiclone; Add 14.6kg of acetone and 10kg of methanol to this crude product, heat to reflux, stop heating after dissolving, drop to room temperature, let it stand for 8-24 hours, crystallize, filter, wash with 1-3.5kg of acetone, filter, and dry to obtain D-(+)-malic acid S-zopiclone 1.25kg; molar yield 39.9%, optical purity 98.8%.

[0057] b. Demalate: Add the D-(+)-malic acid S-zopiclone obtained in the previous step to 5.25kg of water and 18kg of ethyl acetate, and add 0.375kg of anhydrous K 2 CO 3 , reflux for 30 minutes, use test paper to measure the pH of the water layer > 7, let stand...

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Abstract

The invention provides a preparation method of eszopiclone. The method particularly comprises the following steps: reacting racemic eszopiclone with optical voidness D-(+)- malic acid, so as to obtain S-eszopiclone and a salt of D-(+)- malic acid; further alkalifying and deacidifying the acid to obtain S-eszopiclone. The eszopiclone prepared by the preparation method is high in yield, high in optical purity and high in chemical purity, and the method is simple to operate, and is more applicable to industrial production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and pharmacy, in particular to a preparation method of eszopiclone. Background technique [0002] Zopiclone (zopiclone, ZOP), racemic zopiclone, chemical name 6-(5-chloro-2-pyridyl)-7-[(4-methylpiperazin-1-yl) carboxyloxy] -5,6-dihydropyrrolo[3,4-b]pyrazin-5-one, which belongs to pyrrole cyclones, is a new type of non-benzodiazepine sedative-hypnotics that has been used clinically. Effective for short-term treatment of insomnia. [0003] Racemic zopiclone has been marketed by the French company Rhone-Poulenc Rorer under the trade names IMOVANE and AMOBAN in more than 80 countries including Europe since the mid-1980s for the treatment of sleep disorders. In 1999, the sales volume of IMOVANE was about 160 million US dollars. It was the leading drug for the treatment of sleep disorders outside the US market, and no application was submitted to the FDA. [0004] Sepracor believes that the short-ac...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王国成徐学宇孟巍郁达熹郑永锋秦丽范立君
Owner JIANGSU TASLY DIYI PHARMA CO LTD