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Method for resoluting zopiclone

A technology of zopiclone and eszopiclone, which is applied in the field of resolution of zopiclone, can solve the problems of low yield, harsh reaction conditions, and low optical purity of S-zopiclone

Inactive Publication Date: 2006-11-01
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, Viceme 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 method, and the enzymatic synthesis of zopiclone Route is as follows, but this method has many disadvantages (1) this method uses enzyme to carry out reaction in dioxane, and this method will make cost too high, harsh reaction condition; (2) the yield of this method is not high, at most Only have 50% yield; (3) reaction cycle is longer, about 6 days, is not advocated adopting on pharmaceutical process design; (4) this method uses the HPLC method separation of semi-preparation, and cost is too high, This method is not suitable for large-scale production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 1. Add 110 g of racemic zopiclone, 34 g of D-(+)-malic acid, 1100 ml of methanol, and 1600 ml of acetone into a 3 L reaction flask, stir and dissolve at room temperature (about 25°C) for 2.0 hours. The solution was cooled to 6°C, and stored at 6°C for about 24 hours, continued to stir for 1 hour, filtered, washed twice with 100ml of methanol, and dried to obtain 60g of D-(+)-malic acid S-zopiclone;

[0029] 2. Dissolve 50 g of D-(+)-malic acid S-zopiclone obtained in the previous step reaction in 1000 ml of water, and adjust the pH to 8 with 8% KHCO3, at this time crystals are precipitated, and the solid-liquid mixture is mixed with 1000 ml The ethyl acetate was extracted four times, the ethyl acetate layer was dried with anhydrous NaSO4 for 5 hours, the ethyl acetate was evaporated to obtain white crystals, washed with 100ml ethyl acetate for 3 times, filtered, and dried to obtain 35.0g eszopi clone.

Embodiment 2

[0031] 1. Add 100 g of racemic zopiclone, 34 g of D-(+)-malic acid, 1000 ml of methanol, and 1500 ml of acetone into a 3 L reaction flask, and stir to dissolve at room temperature (about 25 °C) for 2.0 hours. The solution was cooled to 6°C, and stored at 6°C for about 24 hours, continued to stir for 1 hour, filtered, washed twice with 100ml of methanol, and dried to obtain 57g of D-(+)-malic acid S-zopiclone;

[0032] 2. Dissolve 50 g of D-(+)-malic acid S-zopiclone obtained in the previous step reaction in 1000 ml of water, and adjust the pH to 8 with 8% KHCO3. At this time, crystals are precipitated, and the solid-liquid mixture is mixed with 1000 ml The ethyl acetate was extracted four times, the ethyl acetate layer was dried with anhydrous NaSO4 for 5 hours, the ethyl acetate was evaporated to obtain white crystals, washed with 100ml ethyl acetate for 3 times, filtered, and dried to obtain 35.0g eszopi clone;

[0033] 3. Take 20 g of crude eszopiclone, dissolve it in 200 ...

Embodiment 3

[0035]1. Add 100 g of racemic zopiclone, 34 g of L-(+)-malic acid, 1000 ml of methanol, and 1500 ml of acetone into a 3L reaction flask, and stir to dissolve at room temperature (about 25°C) for 2.0 hours. The solution was cooled to 6°C, and stored at 6°C for about 24 hours, continued to stir for 1 hour, filtered, washed twice with 100ml of methanol, and dried to obtain 57g of D-(+)-malic acid S-zopiclone;

[0036] 2. Dissolve 50 g of L-(+)-malic acid S-zopiclone obtained in the previous step reaction in 1000 ml of water, and adjust the pH to 8 with 8% KHCO3, at this time crystals are precipitated, and the solid-liquid mixture is mixed with 1000 ml The ethyl acetate was extracted four times, the ethyl acetate layer was dried with anhydrous NaSO4 for 5 hours, the ethyl acetate was evaporated to obtain white crystals, washed with 100ml ethyl acetate for 3 times, filtered, and dried to obtain 35.0g of levzopic clone;

[0037] 3. Take 20 g of the crude product of es-zopiclone, he...

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Abstract

Resolution of zopiclone is carried out by reacting zopiclone with D-(+)-malic acid to obtain D-(+)malic acid S-zopiclone, dissolving it into water, adjusting pH, precipitating out crystal, extracting by acetic ether, drying acetic ether layer, distilling to remove acetic ether and obtaining white crystal.

Description

technical field [0001] The invention relates to a synthesis method of a compound, in particular to a resolution method of zopiclone. Background technique [0002] Zopiclone (Zopiclone, ZOP), the chemical name is 6-(5-chloro-2-pyridinyl)-7-[(4-methylpiperazin-1-yl) carboxyloxy]-5,6-di Hydropyrrolo[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, and can be effectively used for insomnia short-term treatment. [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 beli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D209/00C07D241/00
Inventor 王国成宋炜张广明
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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