CN103664953A - Preparation method of eszopiclone - Google Patents
Preparation method of eszopiclone Download PDFInfo
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- CN103664953A CN103664953A CN201210335446.0A CN201210335446A CN103664953A CN 103664953 A CN103664953 A CN 103664953A CN 201210335446 A CN201210335446 A CN 201210335446A CN 103664953 A CN103664953 A CN 103664953A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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
The present invention relates to organic chemistry and pharmaceutical field, particularly, the present invention relates to a kind of preparation method of Eszopiclone.
Background technology
Zopiclone (zopiclone, ZOP), it is ZOP, chemistry 6-(5-chloro-2-pyridyl)-7-[(4-methylpiperazine-1-yl by name) carboxyl oxygen]-5,6-pyrrolin is [3,4-b] pyrazine-5-ketone also, belongs to pyrrole ring ketone compounds, as a kind of, for clinical novel Non-benzodiazepine sedative hypnotic, can be effectively used to the short of insomnia.
ZOP from the mid-80 by French rhone-poulenc. Lean (Rhone-Poulenc Rorer) company is more than 80 country's listings such as in Europe with trade(brand)name IMOVANE and AMOBAN, are used for the treatment of sleep disordered.Within 1999, recall dream and return the sales volume of (IMOVANE) and be approximately 100,000,000 6 thousand ten thousand dollars, for the sleep disordered lead drug of the outer treatment of American market, to FDA, do not send in one's application.
Sepracor company thinks that therefore racemic fugitive syngignoscism may develop Lunesta due to due to its S-isomer since 1998, has been successfully completed so far III clinical trial phase, in December, 2004 U.S. FDA approved Gai Yao U.S. listing.
At present, the preparation method about Eszopiclone is summarized as follows:
1992, European patent [EP495717] was reported, the method racemic R/S-Zopiclone being split by dibenzoyl tartaric acid.But it is not high that this method has the purity of the S-ZPC that this method for splitting of two problems (1) obtains, and need carry out repeatedly recrystallization and just can obtain the S-ZPC that purity is higher; (2) yield of this method for splitting is not high, only has 23% left and right; (3) this resolution process is used methylene dichloride, is not advocate to adopt in pharmaceutical technology design.
Gottfried Blaschke in 1993 etc. report [Preparative and Analytical Separation of the Zopiclone Enantiomers and Determination of their Affinity to the Benzodiazepine Receptor Binding Site.Blaschke G, Hempel G, Muller WE.Chirallty.1993, 5, 419-421] another disconnecting route, this disconnecting route is to react with optically pure D-(+)-oxysuccinic acid with ZOP, obtain the salt of S-ZPC and D-(+)-oxysuccinic acid, this salt further strong change obtains S-ZPC, as wish to get R-ZPC, to select L-(-)-oxysuccinic acid to react with ZOP.But this method has two problems (1) this method and splits for the first time that to obtain the optical purity of S-ZPC not high, needs recrystallization several times to obtain more than 98% S-ZPC of optical purity, will make the high cost of large-scale production; (2) this method is used methylene dichloride, because its injury to human body is larger, is not advocate to adopt in pharmaceutical technology design.
1997, [Enzymatic resolution of (±)-6-(the 5-chloropyridin-2-yl)-7-vinyloxy-carbonyloxy-6 such as Vicente Gotor, 7-dihydro[5H] pyrrolo[3,4-b] pyrazin-5-one.Synthesis of (+)-zopiclone.Tetrahedron:Asymmetry.1997 (8), 7,995-997] reported, with enzyme process, carry out the synthetic of S-ZPC, but this method has many shortcomings: (1) this method is used enzyme and reacted in dioxane, this will make high cost, severe reaction conditions; (2) yield of this method is not high, and the highest only have 50% left and right; (3) reaction time long, about about 6 days; (4) this method is used semi-preparative HPLC method to carry out separation, high cost, and unsuitable large-scale production is not advocate to adopt in pharmaceutical technology design.
The day by day increase of Eszopiclone market demand thereupon, therefore find a kind of more economically, effectively, the preparation method that is suitable for the optical purity Eszopiclone of suitability for industrialized production becomes the focus that the present invention pays close attention to.
Summary of the invention:
The preparation method who the object of the present invention is to provide a kind of new Eszopiclone, specifically comprises the steps:
A. salify and fractionation: ZOP, D-(+)-oxysuccinic acid, methyl alcohol and acetone are mixed, be heated to reflux, react and solid was all dissolved in 20-40 minute; This solution is cooled, and crystallization, filters, and with washing with acetone, filters, and is dried to obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained mixes with water, ethyl acetate, adds KHCO
3or K
2cO
3in right amount, adjust pH is 7-10, is preferably 7-8, stirs 20-40 minute, standing separatory, and organic phase is dry, removes part ethyl acetate under reduced pressure, and residual volume is the 10-60% before distilling; Cooling, crystallization, filter, and ethyl acetate washing, filters, and is dried to obtain Eszopiclone;
Described KHCO
3and K
2cO
3can be solid or aqueous solution form.
Wherein,
The weight ratio of ZOP described in step a, D-(+)-oxysuccinic acid, methyl alcohol, acetone and washing use acetone preferably 1: 0.345: 6-8.5: 10-15: 0.4-1.5;
The weight ratio of D-described in step b (+)-oxysuccinic acid S-ZPC, water and ethyl acetate preferably 1: 4-40: 14-40.
Optimal technical scheme of the present invention is,
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 6-6.5: 10-10.5, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, dry, obtains D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in the water of 4-6 times of weight and the ethyl acetate of 14-16 times of weight, adds 0.26-0.3 anhydrous K doubly
2cO
3, back flow reaction 30 minutes, water transfer layer pH is greater than 7, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 2-3 times of ethyl acetate washing container wall, and organic phase is merged, and removes part ethyl acetate under reduced pressure, and residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
Or,
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 8-8.5: 14-15, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By this solution slow cooling, to 0-5 ℃, insulated and stirred 2 hours, filters, crystallization, and with 0.4-1.5 times of washing with acetone, filter, be dried to obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 35-40 times of weight water, stir, after to be dissolved, add again 35-40 times of weight ethyl acetate, 9% solution of potassium carbonate that slowly adds 5.8-6.2 times of weight under room temperature, add and survey pH value 7-8, continue to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
Further, in technical solution of the present invention,
In step a, also comprise refining process, be specially: D-(+)-oxysuccinic acid S-ZPC preparing is added to the acetone of 2-6.5 times of weight and the methyl alcohol of 1-4.5 times of weight, reflux, then cooling, crystallization, filters, with 0.4-1.5 times of washing with acetone, filter, be dried to obtain sample.
And/or,
In step b, also comprise refining process, be specially: the Eszopiclone preparing is added to the ethyl acetate of 25-35 times of weight, be heated to 70-75 ℃, insulated and stirred 10-60 minute, slow cooling, crystallization, filters, ethyl acetate washing, filters, and is dried to obtain sample.
The preferred technical scheme of the present invention is,
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 6-6.5: 10-10.5, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 6-6.5 times of acetone and 4-4.5 times of methyl alcohol, reflux, stops heating after dissolving, be down to room temperature, standing 8-24 hour, crystallization, filters, with 0.4-1.5 times of washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in the water of 4-6 times of weight and the ethyl acetate of 14-16 times of weight, adds 0.26-0.3 anhydrous K doubly
2cO
3, back flow reaction 30 minutes, water transfer layer pH is greater than 7, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds appropriate ethyl acetate washing container wall, and organic phase is merged, and removes part ethyl acetate under reduced pressure, and residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
Or,
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 8-8.5: 14-15, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By this solution slow cooling to 0-5 ℃, insulated and stirred 2 hours, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, dry D-(+)-oxysuccinic acid S-ZPC that to obtain;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 35-40 times of weight water, stir, after to be dissolved, add again 35-40 times of weight ethyl acetate, 9% solution of potassium carbonate that slowly adds 5.8-6.2 times of weight under room temperature, add and survey pH value 7-8, continue to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone crude product; The ethyl acetate that this crude product is added to 30-35 times of weight, is heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, then be cooled to 0 ℃, be incubated 2 hours, filter, ethyl acetate washing, filters, 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
The most preferred technical scheme of the present invention is,
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 6-6.5: 10-10.5, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 6-6.5 times of acetone and 4-4.5 times of methyl alcohol, reflux, stops heating after dissolving, be down to room temperature, standing 8-24 hour, crystallization, filters, with 0.4-1.5 times of washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in the water of 4-6 times of weight and the ethyl acetate of 14-16 times of weight, adds 0.26-0.3 anhydrous K doubly
2cO
3, back flow reaction 30 minutes, water transfer layer pH is greater than 7, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 2-3 times of ethyl acetate washing container wall, and organic phase is merged, and removes part ethyl acetate under reduced pressure, and residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone crude product, the ethyl acetate that this crude product is added to 30-35 times of weight, is heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, then be cooled to 0 ℃, be incubated 2 hours, filter, ethyl acetate washing, filter, 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
Or,
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 8-8.5: 14-15, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By this solution slow cooling to 0-5 ℃, insulated and stirred 2 hours, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 2-2.5 times of acetone and 1-1.5 times of methyl alcohol, reflux 30 minutes, then slow cooling is to 0-5 ℃, and insulated and stirred 2 hours, filters, with 0.4-1.5 times of washing with acetone, filter, obtain D-(+)-oxysuccinic acid S-ZPC.
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 35-40 times of weight water, stir, after to be dissolved, add again 35-40 times of weight ethyl acetate, 9% solution of potassium carbonate that slowly adds 5.8-6.2 times of weight under room temperature, add and survey pH value 7-8, continue to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone crude product; The ethyl acetate that this crude product is added to 30-35 times of weight, is heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, then be cooled to 0 ℃, be incubated 2 hours, filter, ethyl acetate washing, filters, 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
Aforesaid method obtains through screening, is below screening process.
1. step b takes off in oxysuccinic acid process, the selection of pH
| PH value | 6.0 | 7.05 | 8.04 | 9.02 | 10.0 |
| Yield (%) | 64.4 | 88.3 | 90.2 | 90.5 | 90.4 |
In the de-oxysuccinic acid process of technical solution of the present invention step b, investigated while adding the different salt of wormwood of measuring or saleratus, each pH value impact on yield, sees the above table in detail.Visible, when pH < 7, yield is lower, and analysis is because alkali number is not enough, due to oxysuccinic acid removes not exclusively; When pH > 7, all can slough the oxysuccinic acid Eszopiclone that must dissociate, yield is basically identical, and pH is 8 when above, along with increasing yield, pH do not increase significantly, illustrate that now to increase the amount of alkali less on the impact of yield, so pH value is preferably 7-8 in step b of the present invention, optimum is 8.
2. in step a salify and split process, the selection of purification step and the consumption of solvent
Technical solution of the present invention can obtain through a step salify and fractionation D-(+)-oxysuccinic acid S-ZPC (> 98%) that optical purity is higher, in actual production process, D-(+)-oxysuccinic acid S-ZPC optical purity preparing is lower than 98% time, can increase the step of primary purification, can make like this D-(+)-oxysuccinic acid S-ZPC optical purity reach more than 98%.And contriver finds through craft screening, selects the mixed solvent of 2-6.5 times of weight acetone and 1-4.5 times of weight methyl alcohol to process in purification step, can improve the optical purity of product, guarantees again product yield.
3. step b takes off in oxysuccinic acid process, the selection of purification step and the consumption of solvent
Technical solution of the present invention is after adding the de-oxysuccinic acid of alkali, steam part ethyl acetate solvent, make to be suitable for volume for the 10-60% before distilling, crystallization can obtain the S-ZPC that chemical purity is higher (> 98.5%), but in order to adapt to the demand of preparing highly purified Eszopiclone in pharmaceutical production, in actual production process, can be at the S-ZPC chemical purity preparing lower than 99.5% time, increase the step of primary purification, can prepare like this chemical purity higher than 99.5% S-ZPC product, optical purity is brought up to more than 99.9% simultaneously.And contriver finds through technical study, in purification step, the selection of the kind of solvent and consumption, solvent temperature and soaking time is very large for purity and the yield impact of the finished product, finally determined following process for refining, the ethyl acetate that adds 25-35 times of weight, be heated to 70-75 ℃, insulated and stirred 10-60 minute, then slow cooling, crystallization.So, can improve the chemical purity of product, guarantee again product yield, simultaneously low, easy to operate, the ethyl acetate of energy consumption also can recycling, reduces production costs, and is suitable for suitability for industrialized production.
Beneficial effect of the present invention is: adopt technical scheme of the present invention, the Eszopiclone yield preparing is higher, and optical purity is high, reaches more than 99.9%; Chemical purity is high, also can reach more than 99.5%.In addition, in the method for the invention, while preparing D-(+)-oxysuccinic acid S-ZPC with D-(+)-oxysuccinic acid fractionation ZOP, without gradient cooling, avoided complicated operation, be more suitable for suitability for industrialized production, and in this technique also without adding crystal seed, can realize smooth crystallization, reduce like this production cost, simplify technique.
Embodiment:
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 13.98kg methyl alcohol and 23.3kg acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and uses 0.93-3.5kg washing with acetone, filters, dry, obtains D-(+)-oxysuccinic acid S-ZPC crude product 1.42kg; Molar yield 45.3%, optical purity 96.6%.
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in 5.68kg water and 19.88kg ethyl acetate, adds 0.43kg anhydrous K
2cO
3, back flow reaction 30 minutes, surveys water layer pH > 7 with test paper, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 3.55kg ethyl acetate washing container wall, organic phase is merged, remove part ethyl acetate under reduced pressure, residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone 0.86kg, molar yield 81.5%, optical purity 98.1%, chemical purity 98.6%.
Embodiment 2
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 15kg methyl alcohol and 24.5kg acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and uses 1-3.5kg washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 14kg acetone and 9.4kg methyl alcohol, reflux, stops heating after dissolving, be down to room temperature, standing 8-24 hour, crystallization, filters, use 1-3.5kg washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC 1.27kg; Molar yield 40.5%, optical purity 98.5%.
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in 5.8kg water and 20kg ethyl acetate, adds 0.38kg anhydrous K
2cO
3, back flow reaction 30 minutes, surveys water layer pH > 7 with test paper, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 2.9kg ethyl acetate washing container wall, organic phase is merged, remove part ethyl acetate under reduced pressure, residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone 0.76kg, molar yield 80.5%, optical purity 99.2%, chemical purity 98.8%.
Embodiment 3
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 14.4kg methyl alcohol and 24.5kg acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and uses 1-3.5kg washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 14.6kg acetone and 10kg methyl alcohol, reflux, stops heating after dissolving, be down to room temperature, standing 8-24 hour, crystallization, filters, use 1-3.5kg washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC 1.25kg; Molar yield 39.9%, optical purity 98.8%.
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in 5.25kg water and 18kg ethyl acetate, adds 0.375kg anhydrous K
2cO
3, back flow reaction 30 minutes, surveys water layer pH > 7 with test paper, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 3.1kg ethyl acetate washing container wall, organic phase is merged, remove part ethyl acetate under reduced pressure, residual volume is the 50-60% before distilling, be cooled to room temperature, standing 8-24 hour, crystallization, filter, ethyl acetate washing, filter, 40-65 ℃ of vacuum-drying, obtain Eszopiclone crude product 0.74kg, molar yield 79.6%, this crude product is added to 24.4kg ethyl acetate, be heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, be cooled to again 0 ℃, be incubated 2 hours, filter, ethyl acetate is washed, filter, 40-65 ℃ of vacuum-drying, obtain Eszopiclone 0.68kg, molar yield 73.2%, optical purity 99.9%, chemical purity 99.6%.
Embodiment 4
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 19.8 methyl alcohol and 32.6 acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By this solution slow cooling, to 0-5 ℃, insulated and stirred 2 hours, filters, and uses 1-3kg washing with acetone, is dried to obtain D-(+)-oxysuccinic acid S-ZPC 1.32kg, molar yield 42.1%, optical purity 98.3%;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 46.2kg water, stir, after to be dissolved, add again 50kg ethyl acetate, under room temperature, slowly add 9% solution of potassium carbonate 7.84kg, adding and surveying pH value is 8, continues to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, insulated and stirred 2 hours, filter, filter cake washs by ethyl acetate, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone 0.82kg, molar yield 83.5%, optical purity 99.1%, chemical purity 99.0%.
Embodiment 5
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 18.6 methyl alcohol and 34.7 acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By this solution slow cooling, to 0-5 ℃, insulated and stirred 2 hours, filters, and uses 1-3kg washing with acetone, is dried to obtain D-(+)-oxysuccinic acid S-ZPC 1.33kg, molar yield 42.4%, optical purity 98.1%;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 46.5kg water, stir, after to be dissolved, add again 53.2kg ethyl acetate, under room temperature, slowly add 9% solution of potassium carbonate 7.9kg, adding and surveying pH value is 8, continues to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, and 40-65 ℃ of vacuum-drying obtains Eszopiclone crude product 0.82kg, molar yield 82.9%.This crude product is added to 26.2kg ethyl acetate, be heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, be cooled to again 0 ℃, be incubated 2 hours, filter, ethyl acetate is washed, and filters 40-65 ℃ of vacuum-drying, obtain Eszopiclone 0.73kg, molar yield 73.8%, optical purity 99.9%, chemical purity 99.8%.Embodiment 6
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 18.6 methyl alcohol and 34.7 acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By this solution slow cooling, to 0-5 ℃, insulated and stirred 2 hours, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 4.7kg acetone and 2.5kg methyl alcohol, reflux 30 minutes, then slow cooling is to 0-5 ℃, insulated and stirred 2 hours, filter, use 1-3kg washing with acetone, filter, obtain D-(+)-oxysuccinic acid S-ZPC 1.23kg, molar yield 39.3%, optical purity 99.2%;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 43kg water, stir, after to be dissolved, add again 49.2kg ethyl acetate, under room temperature, slowly add 9% solution of potassium carbonate 7.3kg, adding and surveying pH value is 8, continues to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, and 40-65 ℃ of vacuum-drying obtains Eszopiclone crude product 0.75kg, molar yield 82.0%.This crude product is added to 24kg ethyl acetate, be heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, be cooled to again 0 ℃, be incubated 2 hours, filter, ethyl acetate is washed, and filters 40-65 ℃ of vacuum-drying, obtain Eszopiclone 0.69kg, molar yield 75.4%, optical purity 100%, chemical purity 99.7%.
Embodiment 7
A. salify and fractionation: 2.33kg ZOP, 0.81kg D-(+)-oxysuccinic acid, 17.5 methyl alcohol and 29.1 acetone are mixed, be heated to reflux, react and solid was all dissolved in 30 minutes; By this solution slow cooling, to 0-5 ℃, insulated and stirred 2 hours, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 8.2kg acetone and 5.8kg methyl alcohol, reflux 30 minutes, then slow cooling is to 0-5 ℃, insulated and stirred 2 hours, filter, use 1-3kg washing with acetone, filter, obtain D-(+)-oxysuccinic acid S-ZPC 1.25kg, molar yield 39.9%, optical purity 99.1%;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 31.3kg water, stir, after to be dissolved, add again 31.3kg ethyl acetate, under room temperature, slowly add 9% solution of potassium carbonate 6.4kg, adding and surveying pH value is 8, continues to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, and 40-65 ℃ of vacuum-drying obtains Eszopiclone crude product 0.78kg, molar yield 82.9%.This crude product is added to 23kg ethyl acetate, be heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, be cooled to again 0 ℃, be incubated 2 hours, filter, ethyl acetate is washed, and filters 40-65 ℃ of vacuum-drying, obtain Eszopiclone 0.70kg, molar yield 75.3%, optical purity 100%, chemical purity 99.7%.
Claims (9)
1. a preparation method for Eszopiclone, is characterized in that comprising the steps:
A. salify and fractionation: ZOP, D-(+)-oxysuccinic acid, methyl alcohol and acetone are mixed, be heated to reflux, react and solid was all dissolved in 20-40 minute; This solution is cooled, and crystallization, filters, and with washing with acetone, filters, and is dried to obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained mixes with water, ethyl acetate, adds KHCO
3or K
2cO
3in right amount, adjust pH is 7-10, stirs 20-40 minute, standing separatory, and organic phase is dry, removes part ethyl acetate under reduced pressure, and residual volume is the 10-60% before distilling; Cooling, crystallization, filter, and ethyl acetate washing, filters, and is dried to obtain Eszopiclone;
Wherein, KHCO
3and K
2cO
3can be solid or aqueous solution form.
2. preparation method according to claim 1, is characterized in that:
ZOP described in step a, D-(+)-oxysuccinic acid, methyl alcohol, acetone and washing are 1: 0.345 by the weight ratio of acetone: 6-8.5: 10-15: 0.4-1.5;
The weight ratio of D-described in step b (+)-oxysuccinic acid S-ZPC, water and ethyl acetate is 1: 4-40: 14-40.
3. preparation method according to claim 2, is characterized in that comprising the steps:
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 6-6.5: 10-10.5, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, dry, obtains D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in the water of 4-6 times of weight and the ethyl acetate of 14-16 times of weight, adds 0.26-0.3 anhydrous K doubly
2cO
3, back flow reaction 30 minutes, water transfer layer pH is greater than 7, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 2-3 times of ethyl acetate washing container wall, and organic phase is merged, and removes part ethyl acetate under reduced pressure, and residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
4. preparation method according to claim 2, is characterized in that comprising the steps:
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 8-8.5: 14-15, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By this solution slow cooling to 0-5 ℃, insulated and stirred 2 hours, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, dry, obtains D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 35-40 times of weight water, stir, after to be dissolved, add again 35-40 times of weight ethyl acetate, 9% solution of potassium carbonate that slowly adds 5.8-6.2 times of weight under room temperature, add and survey pH value 7-8, continue to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, and 40-65 ℃ of vacuum-drying obtains Eszopiclone.
5. according to the arbitrary described preparation method of claim 1-4, it is characterized in that:
In step a, also comprise refining process, be specially: with ZOP weighing scale, D-(+)-oxysuccinic acid S-ZPC preparing is added to the acetone of 2-6.5 times of weight and the methyl alcohol of 1-4.5 times of weight, reflux, then cooling, crystallization, filter, with 0.4-1.5 times of washing with acetone, filter, be dried to obtain sample.
And/or,
In step b, also comprise refining process, be specially: the Eszopiclone preparing is added to the ethyl acetate of 25-35 times of weight, be heated to 70-75 ℃, insulated and stirred 10-60 minute, slow cooling, crystallization, filters, ethyl acetate washing, filters, and is dried to obtain sample.
6. preparation method according to claim 5, is characterized in that comprising the steps:
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 6-6.5: 10-10.5, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 6-6.5 times of acetone and 4-4.5 times of methyl alcohol, reflux, stops heating after dissolving, be down to room temperature, standing 8-24 hour, crystallization, filters, with 0.4-1.5 times of washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in the water of 4-6 times of weight and the ethyl acetate of 14-16 times of weight, adds 0.26-0.3 anhydrous K doubly
2cO
3, back flow reaction 30 minutes, water transfer layer pH is greater than 7, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 2-3 times of ethyl acetate washing container wall, and organic phase is merged, and removes part ethyl acetate under reduced pressure, and residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
7. preparation method according to claim 5, is characterized in that comprising the steps:
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 8-8.5: 14-15, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By this solution slow cooling to 0-5 ℃, insulated and stirred 2 hours, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, dry, obtains D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 35-40 times of weight water, stir, after to be dissolved, add again 35-40 times of weight ethyl acetate, 9% solution of potassium carbonate that slowly adds 5.8-6.2 times of weight under room temperature, add and survey pH value 7-8, continue to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, filters, and 45-65 ℃ of vacuum-drying, obtains Eszopiclone crude product; The ethyl acetate that this crude product is added to 30-35 times of weight, is heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, then be cooled to 0 ℃, be incubated 2 hours, filter, ethyl acetate washing, filters, 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
8. preparation method according to claim 5, is characterized in that comprising the steps:
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 6-6.5: 10-10.5, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By the cooling room temperature of being down to of this solution, standing 8-24 hour, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 6-6.5 times of acetone and 4-4.5 times of methyl alcohol, reflux, stops heating after dissolving, be down to room temperature, standing 8-24 hour, crystallization, filters, with 0.4-1.5 times of washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC;
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained adds in the water of 4-6 times of weight and the ethyl acetate of 14-16 times of weight, adds 0.26-0.3 anhydrous K doubly
2c0
3, back flow reaction 30 minutes, water transfer layer pH is greater than 7, standing separatory, organic phase is washed with saturated sodium-chloride water solution, then adds 2-3 times of ethyl acetate washing container wall, and organic phase is merged, and removes part ethyl acetate under reduced pressure, and residual volume is the 50-60% before distilling; Be cooled to room temperature, standing 8-24 hour, crystallization, filters, and ethyl acetate washing, filters, and 40-65 ℃ of vacuum-drying, obtains Eszopiclone crude product; The ethyl acetate that this crude product is added to 30-35 times of weight, is heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, then be cooled to 0 ℃, be incubated 2 hours, filter, ethyl acetate washing, filters, 45-60 ℃ of vacuum-drying, obtains Eszopiclone.
9. preparation method according to claim 5, is characterized in that comprising the steps:
A. salify and fractionation: be 1: 0.345 by weight ratio: the ZOP of 8-8.5: 14-15, D-(+)-oxysuccinic acid, methyl alcohol and acetone mix, is heated to reflux, and reacts and solid is all dissolved in 30 minutes; By this solution slow cooling to 0-5 ℃, insulated and stirred 2 hours, crystallization, filters, and with 0.4-1.5 times of washing with acetone, filters, and obtains D-(+)-oxysuccinic acid S-ZPC crude product; With Zopiclone weighing scale, this crude product is added to 2-2.5 times of acetone and 1-1.5 times of methyl alcohol, reflux 30 minutes, then slow cooling is to 0-5 ℃, insulated and stirred 2 hours, filters, with 0.4-1.5 times of washing with acetone, filter, dry, obtain D-(+)-oxysuccinic acid S-ZPC.
B. take off oxysuccinic acid: D-(+)-oxysuccinic acid S-ZPC that upper step reaction is obtained drops in 35-40 times of weight water, stir, after to be dissolved, add again 35-40 times of weight ethyl acetate, 9% solution of potassium carbonate that slowly adds 5.8-6.2 times of weight under room temperature, add and survey pH value 7-8, continue to stir 30 minutes standing separatory, water divides three extractions by ethyl acetate, merges organic phase anhydrous sodium sulfate drying; Steam except ethyl acetate, residual volume, for the 20-30% before distilling, is cooled to 0 ℃, and insulated and stirred 2 hours is filtered, and filter cake washs by ethyl acetate, filters, and 45-60 ℃ of vacuum-drying, obtains Eszopiclone crude product; The ethyl acetate that this crude product is added to 30-35 times of weight, is heated to 70-75 ℃, insulated and stirred 30 minutes, filtered while hot, slow cooling is to 30-35 ℃, insulated and stirred 1 hour, then be cooled to 0 ℃, be incubated 2 hours, filter, ethyl acetate washing, filters, 40-65 ℃ of vacuum-drying, obtains Eszopiclone.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447273A (en) * | 2014-10-27 | 2015-03-25 | 天津华津制药有限公司 | Recovery method of zopiclone resolving agent D-(+)-malic acid |
| CN107445961A (en) * | 2016-06-01 | 2017-12-08 | 中山大学 | A kind of method for synthesizing Eszopiclone |
| CN113214267A (en) * | 2021-05-08 | 2021-08-06 | 上海中西三维药业有限公司 | Refining method for preparing pure and optically enriched eszopiclone |
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| CN1854137A (en) * | 2005-04-27 | 2006-11-01 | 天津帝士力投资控股集团有限公司 | Method for resoluting zopiclone |
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| EP2345655A1 (en) * | 2010-01-05 | 2011-07-20 | LEK Pharmaceuticals d.d. | A process for racemisation of 6-(5-chloropyridin-2-yl)-7-(4-methyl-1-piperazinyl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine |
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| CN104447273A (en) * | 2014-10-27 | 2015-03-25 | 天津华津制药有限公司 | Recovery method of zopiclone resolving agent D-(+)-malic acid |
| CN107445961A (en) * | 2016-06-01 | 2017-12-08 | 中山大学 | A kind of method for synthesizing Eszopiclone |
| CN107445961B (en) * | 2016-06-01 | 2019-11-22 | 中山大学 | A method of synthesis Eszopiclone |
| CN113214267A (en) * | 2021-05-08 | 2021-08-06 | 上海中西三维药业有限公司 | Refining method for preparing pure and optically enriched eszopiclone |
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