A method for resolving the racemate of oxiracetam and product thereof

Abstract

The present invention relates to the field of drug synthesis, and particularly to a method for resolving the racemate of oxiracetam and a product thereof. The resolution method includes: resolving the racemic oxiracetam precursor with quinine as a resolving agent to obtain the L-oxiracetam precursor, and obtaining L-oxiracetam after removing the protecting group from the L-oxiracetam precursor, wherein the protecting group is connected to the hydroxyl group on the molecular structural formula of oxiracetam through an ester group and contains at least one acidic group. The method for resolving the racemate of oxiracetam adopted in the present invention has the technical advantages of high optical purity, high resolution yield and easy purification.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly relates to a method for resolving the racemate of oxiracetam and a product thereof. Background Art

[0002] Oxiracetam is a nootropic drug first synthesized by the Italian company Schering-Plough in 1974, which can promote learning, enhance memory, and protect the central nervous system of damaged nerve cells. Oxiracetam is a racemate composed of two isomers, (S)-oxiracetam and (R)-oxiracetam. Research has shown that levo-oxiracetam is the main active ingredient of oxiracetam, and compared with racemic oxiracetam, levo-oxiracetam has higher absorption and slower elimination in vivo, making levo-oxiracetam have better clinical efficacy. For example, the patent document with the application number AU19920026456 discloses that levo-oxiracetam is particularly effective as a nootropic drug. The literature "Effect of levo-oxiracetam on learning and memory impairment in mice" (Fan Wenxiang et al., Journal of China Pharmaceutical University 2021, 52(1): 77-83) discloses that levo-oxiracetam can improve the learning and memory ability of animals in a memory impairment model, and its mechanism may be related to increasing the content of ACh in the brain and decreasing the activity of AChE in the brain, and improving the central cholinergic nervous system. The literature "Pharmacodynamic study of oxiracetam and its isomers on neuroprotection and anti-dementia" (Wang Ling et al., Acta Pharmaceutica Sinica 2022, 57(9): 2738-2742) discloses that oxiracetam has a certain therapeutic effect on primary neuron damage and animal dementia models, and levo-oxiracetam has the most obvious effect.

[0003] At present, methods for preparing optical isomers can adopt chiral source synthesis, asymmetric synthesis or racemate resolution. Due to the limited types of natural chiral substances, chiral source synthesis is greatly restricted by raw materials, and the synthetic route has many steps and high costs. At present, the reactions for synthesizing high optical yields by asymmetric synthesis are still limited, the optical rotation degree of the products is not high, and there are also defects such as slow reaction and difficult product separation. The racemate resolution method has low costs and is widely used. Currently, about two-thirds of non-natural chiral drugs are obtained by resolution. The racemate resolution method includes physical, chemical or biological methods. Among them, the chemical resolution method is the most important and commonly used resolution method. The chemical resolution method uses a chiral reagent to convert a pair of enantiomers into diastereomers through a chemical reaction, and then resolves the two according to the differences in physical properties between a pair of diastereomers. After separation, the introduced chiral factor is removed to obtain pure levorotatory or dextrorotatory forms. The key to successful resolution is to select a suitable resolving agent. However, the limitations of this method are: the selection of the resolving agent and solvent is relatively blind, the resolution yield and optical purity are not high, and the types of compounds suitable for chiral resolution are not many, etc.

[0004] And because levo-oxiracetam has stronger biological activity, it is of great significance to continue to resolve the oxiracetam racemate to obtain levo-oxiracetam with higher biological activity and greater clinical application potential. At present, there is no resolution method for oxiracetam racemate that can meet practical applications.

[0005] In view of this, the present invention is specifically proposed. Summary of the Invention

[0006] To solve the above technical problems, the present invention provides a method and product for resolving oxiracetam racemate.

[0007] The present invention proposes a method for resolving oxiracetam racemate, which resolves the racemic oxiracetam precursor with quinine as the resolving agent to obtain the levo-oxiracetam precursor, and the levo-oxiracetam precursor is obtained by removing the protecting group to obtain levo-oxiracetam; the protecting group is connected to the hydroxyl group on the molecular structure formula of oxiracetam through an ester group and contains at least one acidic group.

[0008] Optionally, the racemic oxiracetam precursor and quinine react in organic solvent I, and the organic solvent is selected from one or a mixed solvent of several of tetrahydrofuran, dioxane, methyl tert-butyl ether, diethyl ether, diisopropyl ether, ethyl acetate, acetone and 2-butanone, preferably tetrahydrofuran or dioxane.

[0009] Optionally, the resolution method of the present invention at least includes the following steps:

[0010] S1. Mix the racemic oxiracetam precursor and quinine in organic solvent I and heat. After separation, washing, and drying, obtain the quinine salt of the L-oxiracetam precursor.

[0011] S2. Dissolve the quinine salt of the L-oxiracetam precursor in an alkaline aqueous solution and extract to remove quinine.

[0012] S3. Adjust the pH of the reaction system to acidic. After extraction and washing, obtain the L-oxiracetam precursor.

[0013] S4. Remove the protecting group from the L-oxiracetam precursor through a transesterification reaction or an ester hydrolysis reaction to obtain L-oxiracetam.

[0014] The present invention also provides an L-oxiracetam product prepared by the above-mentioned resolution method.

[0015] The technical solution provided by the embodiment of the present invention has the following advantages compared with the prior art:

[0016] The resolution method of the oxiracetam racemate adopted by the present invention has the technical advantages of high optical purity, high resolution yield, and easy purification. Description of the Drawings

[0017] Figure 1 1H-NMR spectrum of the racemic oxiracetam hydrogen phthalate; 1 1H-NMR spectrum;

[0018] Figure 2 13C-NMR spectrum of the racemic oxiracetam hydrogen phthalate; 13 13C-NMR spectrum;

[0019] Figure 3 1H-NMR spectrum of the (S)-oxiracetam hydrogen phthalate; 1 1H-NMR spectrum;

[0020] Figure 4 13C-NMR spectrum of the (S)-oxiracetam hydrogen phthalate; 13 13C-NMR spectrum;

[0021] Figure 5 Mass spectrum of the (S)-oxiracetam hydrogen phthalate;

[0022] Figure 6 1H-NMR spectrum of the (S)-oxiracetam; 1 1H-NMR spectrum;

[0023] Figure 7 13C-NMR spectrum of the (S)-oxiracetam; 13 13C-NMR spectrum;

[0024] Figure 8 Mass spectrum of the (S)-oxiracetam. Detailed implementation mode

[0025] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, without conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other. Many specific details are set forth in the following description in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described herein; obviously, the embodiments in the specification are only part of the embodiments of the present invention, rather than all of the embodiments.

[0026] The list of abbreviations used in this application is as follows:

[0027] EA: Ethyl acetate;

[0028] DMF: N,N-Dimethylformamide;

[0029] THF: Tetrahydrofuran;

[0030] DMSO: Dimethyl sulfoxide;

[0031] DCM: Dichloromethane;

[0032] DMAP: 4-Dimethylaminopyridine;

[0033] EDC: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide;

[0034] TLC: Thin layer chromatography;

[0035] HPLC: High performance liquid chromatography;

[0036] HRMS: High resolution mass spectrometry;

[0037] 1 H-NMR: Proton nuclear magnetic resonance;

[0038] 13 C-NMR: Carbon-13 nuclear magnetic resonance.

[0039] According to the records in the background art, since there are defects in the chemical resolution method such as the relatively blind selection of the resolving agent and the solvent, and the low optical purity and resolution yield. In view of the problems and defects existing in the prior art, the embodiments of the present invention propose a method for resolving the racemate of oxiracetam.

[0040] First, the inventors studied the route of directly resolving racemic oxiracetam by reacting the hydroxyl group on racemic oxiracetam with a chiral acidic resolving agent, and conducted extensive research and screening on the acidic resolving agent. However, after a large number of experiments, it was found that although diastereoisomers could be obtained after binding with the acidic resolving agent, the resolution was not achieved. Analyzing the reasons, it might be due to the weak difference in the physical properties of the diastereoisomers or the failure to screen suitable solvent conditions.

[0041] To achieve the resolution, the inventors then studied the basic resolving agent. To enable the reaction between the basic resolving agent and racemic oxiracetam, the structure of racemic oxiracetam was first modified by connecting an acidic group to the molecular structural formula of racemic oxiracetam to obtain a racemic oxiracetam precursor for binding with the basic resolving agent. Preferably, a protecting group that is connected to the hydroxyl group on the molecular structural formula of oxiracetam through an ester group and contains at least one acidic group was used. The protecting group was obtained by reacting a protecting reagent with racemic oxiracetam. The acidic group can be selected from carboxyl group, sulfonic acid group, etc.

[0042] The inventors also conducted extensive research and screening on the basic resolving agent in the hope of obtaining diastereoisomers with extremely different solubilities to improve the optical purity and yield of the resolved product. After screening among L-phenylalanine methyl ester, quinine, quinidine, D-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol, 2-(dimethylamino)-1-(4-nitrophenyl)-1,3-propanediol, dehydroabietylamine, glucosamine, brucine, (S)-(+)-2-amino-1-butanol, it was finally found that when quinine was used as the resolving agent, it had the advantages of high yield, large difference in product solubility, and easy recovery. That is, the racemic oxiracetam precursor was resolved with quinine as the resolving agent to obtain the L-oxiracetam precursor, and then the L-oxiracetam was obtained after removing the protecting group from the L-oxiracetam precursor, thus realizing the resolution of the optical isomers of racemic oxiracetam. The overall reaction process is as follows:

[0043]

[0044] Among them, Pr- represents the protecting group.

[0045] In the embodiments of the present invention, the organic solvent I used for splitting was also studied. Since the solubility of oxiracetam in most organic solvents is poor, the solubility of the prepared oxiracetam precursor in the organic solvent has not been greatly improved. In order to improve the liposolubility of the oxiracetam precursor, the inventors conducted in-depth research. The inventors tried to design the racemic oxiracetam precursor to contain two ester groups to improve its liposolubility. It was found that although the liposolubility of the diester compound was greatly enhanced and it could be extracted from the reaction system using an organic solvent, the diester was oily, difficult to crystallize and purify, inconvenient to operate, and adding an additional reaction would reduce the yield and generate waste solvent, thus reducing efficiency. Therefore, this route was abandoned, and organic solvents with good solubility for the racemic oxiracetam precursor were further screened. Through in-depth research on the organic solvent I in the embodiments of the present invention, it was found that the organic solvent I can be selected from one or a mixture of several of tetrahydrofuran, dioxane, methyl tert-butyl ether, diethyl ether, diisopropyl ether, ethyl acetate, acetone, 2-butanone, and preferably tetrahydrofuran or dioxane.

[0046] Through the research on the above splitting route, resolving agent, and organic solvent, a method for splitting the racemate of oxiracetam with excellent optical purity and splitting yield was obtained. This method has simplified steps and is convenient to operate. In order to further purify the L-oxiracetam precursor, the inventors screened and studied the solvents used. Finally, it was found that a method of combining a mixed solvent of ethyl acetate and tetrahydrofuran with a saturated aqueous sodium chloride phase was used to crystallize the L-oxiracetam precursor, while ensuring the purity and yield of the optical isomers. Then, through steps such as washing, further treatment was carried out to remove the organic impurities in the L-oxiracetam precursor, thereby obtaining a product with further improved purity.

[0047] As an improvement of the embodiments of the present invention, in the reaction system where the racemic oxiracetam precursor reacts with quinine, adding 10 - 40 mL of the organic solvent I per gram of the racemic oxiracetam precursor can ensure both the splitting effect and the splitting yield. If too much solvent is used, the yield will decrease; if too little solvent is used, sufficient stirring cannot be achieved, so the splitting effect will decrease.

[0048] As a specific implementation manner of the embodiments of the present invention, the method for splitting the racemate precursor of oxiracetam at least includes the following steps:

[0049] S1. Mix the racemic oxiracetam precursor and quinine in the organic solvent I and heat, and obtain the L-oxiracetam precursor quinine salt through separation, washing, and drying;

[0050] S2. Dissolve the L-oxiracetam precursor quinine salt in an alkaline aqueous solution and extract to remove quinine;

[0051] S3. Adjust the pH of the reaction system to be acidic, and obtain the precursor of (S)-oxiracetam through extraction and washing.

[0052] S4. Remove the protecting group from the precursor of (S)-oxiracetam through transesterification or ester hydrolysis reaction to obtain (S)-oxiracetam.

[0053] The optical purity of the (S)-oxiracetam obtained by the embodiments of the present invention can reach 96.0% - 99.99%, and the resolution yield is more than 85%.

[0054] As an improvement of the embodiments of the present invention, in S1, mix the racemic oxiracetam precursor and organic solvent I and heat to the reflux temperature. According to the different boiling points of organic solvent I, the heating temperature can adopt the temperature condition that is 5°C - 10°C higher than the boiling point of the selected solvent.

[0055] As an improvement of the embodiments of the present invention, in S1, first dissolve the racemic oxiracetam precursor in organic solvent I, dissolve quinine in organic solvent I and then add it to the reaction system to ensure that quinine is fully dissolved. The reaction time after adding quinine can be 1 - 5 hours, such as 1 - 3 hours. The molar ratio of the racemic oxiracetam precursor to quinine is 1:1 - 1.1, such as 1:1, 1:1.05.

[0056] As an improvement of the embodiments of the present invention, in S1, the separation can adopt the separation methods commonly used in chemical synthesis, such as suction filtration. The washing is also carried out with organic solvent I, and it can be washed 1 - 3 times to further remove impurities. The drying can adopt vacuum drying, and preferably dry in a vacuum drying oven at 40°C - 50°C for 12 - 20 hours.

[0057] As an improvement of the embodiment of the present invention, in S1, after separation, a further purification step is included to improve the purity and yield of the quinine salt of the levocetirizine precursor. Specifically, it can be dissolved by heating with organic solvent II and then crystallized by cooling. Organic solvent II can be selected from one or a mixture of several of ester organic solvents, ketone organic solvents, ether organic solvents or aromatic compound solvents. Preferably, it is a mixture solvent of one or several of tetrahydrofuran, dioxane, methyl tert-butyl ether, diethyl ether, diisopropyl ether, ethyl acetate, acetone, 2-butanone, and more preferably dioxane. For example: Take the quinine salt of the levocetirizine precursor, add organic solvent II and heat for 1 to 4 hours, cool and crystallize, filter by suction, then wash with organic solvent II, and dry to obtain the purified quinine salt of the levocetirizine precursor. Among them, the heating temperature can be the reflux temperature of organic solvent II, and the time can be 1 to 3 hours. The conditions for cooling crystallization are to cool from the reflux temperature to 0 to 25 °C, and stir while cooling to accelerate crystallization. The added volume of organic solvent II is 10 to 20 mL per gram of the quinine salt of the levocetirizine precursor. This step can significantly improve the optical purity of the quinine salt of the levocetirizine precursor.

[0058] As an improvement of the embodiment of the present invention, in S2, the quinine salt of the levocetirizine precursor is dissolved in an alkaline aqueous solution. At this time, the carboxyl group on the levocetirizine precursor displaces the salt formed with quinine, and quinine becomes a free base state. The pH value of the alkaline aqueous solution is 8 to 11.6, and the alkaline aqueous solution is selected from aqueous solutions of inorganic bases such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, etc., and preferably an aqueous solution of sodium carbonate. The concentration of the aqueous solution of sodium carbonate can be 0.04 mol / L to 1.89 mol / L.

[0059] As an improvement of the embodiment of the present invention, in S2, quinine in the reaction system is extracted with an organic solvent. The organic solvent is selected from non-polar organic solvents, such as dichloromethane.

[0060] As an improvement of the embodiment of the present invention, in S3, an acidic solvent is used to adjust the pH of the reaction system to be acidic to harvest the L-oxiracetam precursor. Specifically, the pH of the aqueous phase is adjusted to 1-2, and the acidic solution can be an inorganic acid such as sulfuric acid, phosphoric acid, hydrochloric acid, or nitric acid, and concentrated hydrochloric acid is preferably used. Then, an organic solvent is added to extract the L-oxiracetam precursor. Preferably, a mixed solvent with a volume ratio of ethyl acetate to tetrahydrofuran of 10:1-4 is used to extract the aqueous phase multiple times to improve the yield, specifically 2-7 times, preferably 3-6 times; the organic phases are combined. After extraction, purification is carried out by recrystallization. The specific steps of recrystallization include: drying the organic phase, removing part of the solvent, heating to reflux for 0.5-1 hour, and then cooling to 0-25°C to crystallize the L-oxiracetam precursor. The obtained crystals are washed to further remove organic impurities in the L-oxiracetam precursor, and the organic solvent for washing can be selected from one or more of ester solvents and alcohol solvents for washing in sequence. For example, ethyl acetate can be used.

[0061] As an improvement of the embodiment of the present invention, in S4, the protecting group of the L-oxiracetam precursor can be removed by hydrolysis reaction or transesterification reaction to obtain L-oxiracetam. If the hydrolysis method is used, inorganic salts will inevitably be produced. Since oxiracetam has very good water solubility, it is difficult to separate the inorganic salts generated during the preparation process by recrystallization. Although some technical routes use column chromatography to remove the generated inorganic salts, the column chromatography separation method not only has a high cost but also is difficult to produce on a large scale. Therefore, the embodiment of the present invention preferably uses transesterification to remove the protecting group of the L-oxiracetam precursor, solving the technical problem of generating inorganic salt substances during the hydrolysis of L-oxiracetam. Specifically, the above-mentioned L-oxiracetam precursor and an anhydrous alcohol compound can be used as raw materials to carry out transesterification under anhydrous conditions to obtain L-oxiracetam. Specifically, 0.5-5 mL of n-butanol is added per g of the L-oxiracetam precursor, and preferably 1-3 mL of n-butanol is added per g of the L-oxiracetam precursor. Heat under reflux and stir for 1-3 hours, and then dry to obtain the L-oxiracetam precursor. Organic impurities in the reaction system can be further removed to improve the purity of the reaction product.

[0062] The embodiment of the present invention uses transesterification to convert the ester group into a hydroxyl group, and sodium ions, chloride ions, etc. are not introduced during the reaction raw materials and the reaction process. The obtained L-oxiracetam product has the technical advantages of high purity and no inorganic salts.

[0063] To further promote the reaction in the forward direction, the raw material used in the embodiments of the present invention - the alcohol compound can simultaneously serve as a reactant and a solvent, and can be added in excess in the reaction system to promote the reaction in the forward direction. Further preferably, as the reaction solvent, the alcohol organic solvent preferably has good solubility with the levocetirizine precursor and has a relatively low solubility in levocetirizine. The reaction equation is as follows:

[0064]

[0065] Among them, R2-OH represents an alcohol compound.

[0066] When the protecting reagent is a compound with an anhydride group, the reaction equation is as follows:

[0067]

[0068] As an improvement in the embodiments of the present invention, the alcohol compound can be selected from C3-C8 straight-chain or branched-chain alkanes having at least one hydroxyl group. For example, it can be selected from propylene glycol having 2 hydroxyl groups, or glycerol having 3 hydroxyl groups, etc. Considering better solubility and fluidity, C3-C8 straight-chain or branched-chain alkanes having one hydroxyl group are used. For example, n-propanol, isopropanol, n-butanol, isobutanol, pentanol or its isomers, hexanol or its isomers can be selected. Specifically, pentanol or its isomers are selected from: CH2(OH)CH2CH2CH2CH3, CH(CH3)(OH)CH2CH2CH3, CH2(OH)CH(CH3)CH2CH3, CH2(OH)CH2CH(CH3)2, CH(OH)(C2H5)CH2CH3, C(OH)(CH3)2CH2CH3, CH(OH)(CH3)CH(CH3)2, CH2(OH)C(CH3)3; hexanol or its isomers can be selected from: CH2(OH)CH2CH2CH2CH2CH3, CH(OH)(CH3)CH2CH2CH2CH3, CH2(OH)CH(CH3)CH2CH2CH3, CH2(OH)CH2CH(CH3)CH2CH3, CH2(OH)CH2CH2CH(CH3)2, CH2(OH)CH(C2H5)C2H5, CH(OH)(C2H5)CH2CH2CH3, CH2(OH)CH2C(CH3)3, C(OH)(CH3)2CH2CH2CH3, CH2(OH)C(CH3)2C2H5, C2H5CH(OH)CH(CH3)2, CH(OH)(CH3)C(CH3)3, C2H5C(OH)(CH3)C2H5.

[0069] As an improvement of the embodiment of the present invention, the alcohol compound can be selected from C3-C6 straight-chain or branched-chain alkanes with one hydroxyl group, such as n-propanol, isopropanol, n-butanol, isobutanol. Considering the reaction rate and the convenience of extraction comprehensively, n-butanol is preferred.

[0070] In order to further accelerate the reaction rate, the transesterification reaction can be carried out under the catalysis of a catalyst. Specifically, the catalyst is selected from titanate catalysts or organotin catalysts; the titanate catalysts are selected from alkyl titanates; the alkyl titanates can be selected from tetra-n-butyl titanate and tetra-isopropyl titanate. As an improvement of the embodiment of the present invention, the molar ratio of the catalyst to the levocetirizine precursor is 0.05-0.3:1, preferably 0.1-0.2:1, and specifically can be selected from 0.1:1, 0.15:1, 0.2:1.

[0071] As an improvement of the embodiment of the present invention, the molar ratio of the levocetirizine precursor to the alcohol compound can be 1:1-200, preferably 1:1-100.

[0072] As an improvement of the embodiment of the present invention, the heating temperature of the transesterification reaction is the reflux temperature, which is 90°C-150°C. According to the different boiling points of the alcohol compounds used, the heating temperature can be: 90°C-100°C, 105°C-115°C, 117°C-130°C, 130°C-140°C, 150°C-160°C. For example, it can specifically be 118°C, 120°C, 125°C, 130°C. The time of the transesterification reaction can be 1-5 hours, such as 1-3 hours.

[0073] As an improvement of the embodiment of the present invention, after the transesterification reaction is completed, the reaction product is subjected to the first purification of levocetirizine. Specifically, the first purification can adopt the steps of distillation, washing and recrystallization.

[0074] As a specific implementation manner of the embodiment of the present invention, the first purification can adopt the following steps:

[0075] (1) Distill the reaction product to remove the unreacted alcohol compound; the distillation adopts vacuum distillation, and the temperature is preferably not more than 90°C, preferably not more than 80°C, for example, the condition of 70°C-75°C can be adopted; the distillation time is until the alcohol compound cannot be distilled out; preferably, the distillation is carried out under reduced pressure.

[0076] (2) After the distillation is completed, an organic solvent is further added to the reaction product to fully dissolve the organic impurities in the reaction product and precipitate the product. Preferably, after adding the organic solvent, heating is carried out under the condition of greater than 50 °C and less than 100 °C to promote the dissolution of the organic impurities and increase the yield; the heating time can be 0.5 to 2 hours; the volume ratio of the added organic solvent to the volume mass of the levocetirizine precursor is: the volume of the organic solvent added per gram of the levocetirizine precursor is 1 to 10 mL, preferably 2 to 5 mL of the organic solvent is added per gram of the levocetirizine precursor;

[0077] (3) Cool down for crystallization, filter the crystals, then add an organic solvent for washing, and dry to obtain levocetirizine. The temperature can be cooled down to 0 to 15 °C. To accelerate crystallization, it is preferably cooled down to 0 to 5 °C, and stirring is carried out after cooling. Washing can be carried out 1 to 3 times to further improve the purity. Drying is preferably carried out by low-temperature drying.

[0078] Specifically, in the first refining process, the organic solvent used can be selected from one or a mixture of ester organic solvents, ketone organic solvents, ether organic solvents or aromatic compound solvents, and a mixed solvent of one or several of tetrahydrofuran, dioxane, methyl tert-butyl ether, ether, diisopropyl ether, ethyl acetate, acetone or 2-butanone can be used. And tetrahydrofuran is preferred.

[0079] As an improvement of the embodiment of the present invention, after obtaining the first refined product of levocetirizine, it further includes the step of performing a second refinement by recrystallization. The recrystallization solvent can be anhydrous ethanol. Specifically, anhydrous ethanol is added to the obtained crude levocetirizine, heated to dissolve, activated carbon is added for adsorption and then filtered, and washed with anhydrous ethanol. After partially evaporating the anhydrous ethanol from the filtrate by rotary evaporation, the remaining filtrate is cooled and stirred for crystallization, washed with anhydrous ethanol, and dried to obtain the refined product of levocetirizine. During the refining process, organic impurities in the crude product can be further removed.

[0080] As a specific implementation manner of the embodiment of the present invention, the second refinement can adopt the following steps:

[0081] (1) Mix the obtained first refined product of levocetirizine and anhydrous ethanol, heat to reflux, after dissolving clearly, add activated carbon for adsorption, filter, and wash with anhydrous ethanol to obtain the total filtrate; preferably, the mass ratio of the first refined product of levocetirizine to anhydrous ethanol is 1:5 to 10; preferably, adsorption is carried out under heating conditions after adding activated carbon, and the heating temperature can be the reflux temperature.

[0082] (2) After partially evaporating anhydrous ethanol from the total filtrate by rotary evaporation, the remaining filtrate is cooled for crystallization, washed with anhydrous ethanol, and dried to obtain the second refined product of levocetirizine, namely the levocetirizine product. Preferably, the volume of the partially evaporated anhydrous ethanol accounts for 30% - 70% of the total volume to accelerate the crystallization process.

[0083] In the embodiments of the present invention, the racemic cetirizine precursor can be prepared by reacting racemic cetirizine with a protecting reagent. The inventors have conducted extensive research on the protecting reagent and finally adopted the route of converting the hydroxyl group in the racemic cetirizine structural formula into an ester group. The reaction process is as follows:

[0084]

[0085] Among them, Pr- represents a protecting group, and Pr-COOH represents a protecting reagent.

[0086] Through various comparisons and screenings, the embodiments of the present invention finally choose to react a protecting reagent with a carboxyl group or an acid anhydride group with racemic cetirizine. The structural formula of the protecting reagent is selected from one of the following structural formulas:

[0087] R 11 -(COOH) n Or

[0088] Among them, 2 ≤ n ≤ 4; R 11 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted C4 - C18 alkyl; R 12 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted C3 - C8 cycloalkyl, and the acid anhydride group is substituted on different carbon atoms of the R 12 group; the substituents of the substitution are selected from C1 - C6 alkyl. Among them, the alkyl can be a straight-chain alkyl or a branched-chain alkyl.

[0089] Specifically, the protecting reagent can be malonic acid, succinic acid, glutaric acid, adipic acid, phthalic acid, 1,2-cyclohexanedicarboxylic acid, 1,2-cyclopentanedicarboxylic acid, terephthalic acid, isophthalic acid, 1,4-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, 1,2-cyclobutanedicarboxylic acid, phthalic anhydride, 1,2-cyclohexanedicarboxylic anhydride, 1,2-cyclopentanedicarboxylic anhydride, etc.

[0090] Further preferably, the protecting reagent can be a compound with an acid anhydride group. The product formed by the reaction of the acid anhydride group contains a carboxyl group and an ester group, having the advantage of a unique reaction product structure. The reaction equation is as follows:

[0091]

[0092] As an improvement of the embodiment of the present invention, the preparation method of the racemic oxiracetam precursor can be as follows: a protecting reagent and racemic oxiracetam are subjected to a condensation reaction in an organic solvent III. After the reaction is completed, an organic solvent IV is added for crystallization to obtain the racemic oxiracetam precursor. Specifically, the temperature of the condensation reaction can be 80°C to 120°C, and preferably 92°C to 98°C. The time of the condensation reaction is 1 to 5 hours, preferably 2 to 4 hours. The molar ratio of racemic oxiracetam to the protecting reagent is 1:1 to 1.3, preferably 1:1.05 to 1.2. The condensation reaction is carried out under the catalysis of pyridine. The molar ratio of racemic oxiracetam to pyridine is 1:0.1 to 1.2, preferably 1:0.1 to 0.2.

[0093] During the research process, the inventors found that in the condensation reaction process of racemic oxiracetam and the protecting reagent, the presence of the solvent system has a relatively important influence on the control of the reaction rate and process. Since oxiracetam has good water solubility and poor solubility in organic solvents, the solubility of the racemic oxiracetam precursor after being connected with the protecting reagent still cannot be improved in organic solvents. Therefore, in the embodiment of the present invention, a polar organic solvent III is selected as the reaction solvent for racemic oxiracetam and the protecting reagent, such as DMF or DMSO.

[0094] Further research found that the mass-volume ratio of racemic oxiracetam to organic solvent III is 5:2 to 10, preferably 5:2 to 5. The unit of the mass of racemic oxiracetam is g, and the unit of the volume of organic solvent III is mL. The mass-volume ratio of the racemic oxiracetam raw material and organic solvent III has an impact on the reaction yield. If the addition amount of organic solvent III is too large, the product concentration will be too low, resulting in difficult crystallization. If the addition amount of organic solvent III is too small, the reaction will be difficult to proceed forward.

[0095] Specifically, the organic solvent IV can be selected from one or a mixture of ester organic solvents, ketone organic solvents, ether organic solvents or aromatic compound solvents, preferably one or a mixture of ethyl acetate, tetrahydrofuran, dioxane, acetone. In the research of the embodiment of the present invention, it was found that the reaction product of racemic oxiracetam and the protecting reagent has poor solubility in many solvents. Therefore, the above organic solvent IV is selected to promote the precipitation of solids. The added volume of the organic solvent IV is 5 to 20 times that of the organic solvent III.

[0096] The embodiment of the present invention also relates to the prepared (S)-oxiracetam by the above method. The purity of the compound in this product is 99.5%, the salt content is less than 0.01%, and the optical content (mass percentage) of (S)-oxiracetam can reach 99.99%.

[0097] Example 1

[0098] (1) Preparation of Racemic Oxiracetam Precursor

[0099]

[0100] 50.00 g of (±)-oxiracetam (1 eq, 0.316 mol), 56.2 g of phthalic anhydride (hereinafter referred to as phthalic anhydride) (1.2 eq, 0.379 mol), 2.5 g of pyridine (0.1 eq, 0.032 mol) and 30 mL of DMF were successively added to a three-necked flask, stirred magnetically, heated to 93 °C and reacted for 2 h. 400 mL of EA was added dropwise to the reaction solution, and suction filtration was carried out. The filter cake was washed twice with 50 mL of EA and then dried in vacuo to obtain racemic oxiracetam hydrogen phthalate (hereinafter referred to as racemic hydrogen phthalate), which was a white powdery solid, 88.01 g, with a yield of 90.9%, m.p.: 144 - 147 °C. The 1 1H-NMR spectrum is as Figure 1 shown, 13 and the 13C-NMR spectrum is as Figure 2 shown.

[0101] Racemic oxiracetam hydrogen phthalate, molecular formula: C 14 H 14 N2O6, molecular weight: 306.27.

[0102] 1 1H NMR (600 MHz, DMSO-d6) δ13.28 (s, 1H), 7.83–7.75 (m, 1H), 7.70–7.61 (m, 3H), 7.43 (s, 1H), 7.13 (s, 1H), 5.48 (m, 1H), 3.96 (d, J = 16.7 Hz, 1H), 3.90 (dd, J = 11.3, 6.0 Hz, 1H), 3.69 (d, J = 16.7 Hz, 1H), 3.51 (dd, J = 11.2, 1.8 Hz, 1H), 2.86 (dd, J = 17.7, 7.2 Hz, 1H), 2.44 (dd, J = 17.7, 2.0 Hz, 1H). 13 13C NMR (126 MHz, DMSO-d6) δ171.69, 169.52, 167.81, 167.46, 132.50, 131.61, 131.54, 131.15, 129.07, 128.30, 68.53, 53.19, 44.53, 36.61. HRMS [M+H] + calcd. for C 14 H 15N2O6, m / z: 307.0925, found: 307.0926.

[0103] (2) Resolution of racemic oxiracetam precursor

[0104]

[0105] S1. Add 50.00 g of racemic oxiracetam hydrogen phthalate (1.00 eq, 0.163 mol) and 500 mL of THF into a three-necked flask. After heating to reflux, add dropwise a solution formed by dissolving 53.00 g of quinine (1.00 eq, 0.16 mol) in 450 mL of THF. A white solid precipitates. After the addition is complete, continue heating under reflux and stirring for 1 h. Then cool to room temperature and stir for another 1 h. Filter by suction and wash the filter cake twice with 50 mL of THF. Dry the filter cake in a vacuum drying oven at 45 °C to obtain 51.2 g of quinine salt of (S)-oxiracetam hydrogen phthalate (abbreviated as (S)-hydrogen phthalate quinine salt), which is a white powdery solid with a yield of 99.5% (calculated based on the levorotatory raw material), m.p.: 130 - 133 °C. As determined by HPLC analysis, the content of the (R)-isomer is 5.48%, and the content of quinine salt of (S)-oxiracetam hydrogen phthalate is 89.52%. Specific rotation: -92.957 m 2 ·kg -1 (Concentration: 10.0 mg / mL, sample temperature 21.3 °C, methanol as the solvent).

[0106] S2. Add 89.0 g of quinine salt of (S)-oxiracetam hydrogen phthalate (1.0 eq, 141.10 mmol) into a conical flask, and add a solution formed by dissolving 8.9 g of sodium carbonate (0.6 eq, 17.55 mmol) in 450 mL of water. After adding, stir for 5 minutes, then add 360 mL of DCM and continue stirring for 5 minutes. After liquid separation in a separatory funnel, wash the aqueous phase 3 times with 450 mL of DCM.

[0107] S3. Adjust the aqueous phase to pH = 2 with concentrated hydrochloric acid. Add solid sodium chloride to the aqueous phase until it is dissolved to saturation, then extract the aqueous phase 4 times with 450 mL of a mixed solvent of EA:THF (v:v = 10:1). Combine the organic phases, dry over anhydrous sodium sulfate, concentrate the volume of the organic phase under reduced pressure to 200 mL, heat under reflux with magnetic stirring for 1 h, cool to 0 °C and keep for 0.5 h to precipitate crystals, filter by suction, wash with 30 mL of EA twice, add n-butanol to the filter cake, heat under reflux and stir for 1 h for pulping treatment, filter and concentrate to dryness under reduced pressure to obtain 38.5 g of (S)-oxiracetam hydrogen phthalate (abbreviated as (S)-hydrogen ester), which is a white powdery solid with a yield of 89.1%. m.p.: 114 - 117 °C. As determined by HPLC analysis, the content of the (R)-isomer is 3.35%, and the content of phthalic acid-(S)-oxiracetam hydrogen ester is 91.65%. Specific rotation: -20.818 m 2 ·kg -1 (Concentration: 10.0 mg / mL, sample temperature 21.6 °C, using methanol as the solvent).

[0108] (S)-Oxiracetam hydrogen phthalate, molecular formula: C 14 H 14 N2O6, molecular weight: 306.27. The 1 1H-NMR spectrum of (S)-oxiracetam hydrogen phthalate is as Figure 3 shown, 13 the 13C-NMR spectrum is as Figure 4 shown, and the mass spectrum is as shown in Figure 5.

[0109] 1 1H NMR (600 MHz, DMSO-d6) δ 13.40 (s, 1H), 7.77 - 7.79 (m, 1H), 7.74–7.55 (m, 3H), 7.45 (s, 1H), 7.13 (s, 1H), 5.47 (m, 1H), 3.96 (d, J = 16.7 Hz, 1H), 3.89 (dd, J = 11.3, 6.0 Hz, 1H), 3.69 (d, J = 16.7 Hz, 1H), 3.51 (dd, J = 11.2, 1.7 Hz, 1H), 2.86 (dd, J = 17.7, 7.2 Hz, 1H), 2.43 (dd, J = 17.7, 1.9 Hz, 1H). 13 13C NMR (126 MHz, DMSO-d6) δ 171.66, 169.50, 167.77, 167.45, 132.49, 131.57 (2C), 131.12, 129.04, 128.27, 68.51, 53.16, 44.52, 36.60. HRMS.

[0110] (3) Obtaining (S)-oxiracetam through transesterification reaction:

[0111]

[0112] In a three-necked flask, add 92 mL of n-butanol (13.3 eq, 1000 mmol), 23.0 g of the raw material (S)-oxiracetam hydrogen phthalate (1 eq, 75.10 mmol), heat to reflux at 130 °C, and add 2.55 g of tetrabutyl titanate (0.100 eq, 75.00 mmol). Carry out the reflux reaction for 1.5 h.

[0113] First purification:

[0114] (1) Rotavaporize the low-boiling substances from the reaction solution under reduced pressure to obtain a red oily substance;

[0115] (2) Add 60 mL of tetrahydrofuran with stirring. After solids are produced, reflux for another hour;

[0116] (3) Gradually cool down to 0 °C, stir for 1 h, carry out suction filtration, and wash the filter cake twice with 10 mL of tetrahydrofuran. Dry to obtain 7.72 g of the first purified product of (S)-oxiracetam, with a yield of 65.0%, m.p.: 131 - 133 °C. Specific rotation: -23.220 m 2 ·kg -1 (Concentration: 10.0 mg / mL, sample temperature 23.3 °C, using methanol as the solvent). Determined by HPLC analysis, the content of the (R)-isomer is 2.25%, that is, the purity of the main component (S)-oxiracetam is 95.70%.

[0117] Second purification:

[0118] (1) In a three-necked flask, add 6.45 g of the first purified product of (S)-oxiracetam (1 eq, 740.78 mmol) and 58 mL of absolute ethanol, heat to reflux. After it becomes clear, add 0.13 g of activated carbon, reflux for 0.5 h, filter while hot, and wash with 8 mL of absolute ethanol.

[0119] (2) Rotavaporize 16 mL of absolute ethanol from the filtrate. Cool the remaining filtrate to 0 °C, stir for 2 h, carry out suction filtration, and wash the filter cake twice with 2.4 mL of absolute ethanol. Dry the filter cake to obtain 5.45 g of a white powdery solid, with a yield of 84.5%. m.p.: 133 - 135 °C. Specific rotation: -27.356 m 2 ·kg -1 (Concentration: 10.0 mg / mL, sample temperature 23.6 °C, using methanol as the solvent). Determined by HPLC analysis, the content of the (R)-isomer is 1.35%, that is, the content of the main component (S)-oxiracetam is 97.65%. The 1H-NMR spectrum of (S)-oxiracetam is as follows 1 asFigure 6 As shown 13 the C-NMR spectrum is as Figure 7 shown, and the mass spectrum is as Figure 8 shown.

[0120] Example 2

[0121] Effect of reaction conditions on the results when the protecting reagent reacts with racemic oxiracetam:

[0122] Condition 1: Prepared according to the method of step (1) of Example 1, with the difference that 1.05 equivalents of phthalic anhydride and 0.1 equivalent of pyridine are used, reacted at 80 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield of racemic hydroester is 84.5%.

[0123] Condition 2: Prepared according to the method of step (1) of Example 1, with the difference that 1.05 equivalents of phthalic anhydride and 0.1 equivalent of pyridine are used, reacted at 92 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield of racemic hydroester is 82.6%.

[0124] Condition 3: Prepared according to the method of step (1) of Example 1, with the difference that 1.1 equivalents of phthalic anhydride and 0.1 equivalent of pyridine are used, reacted at 92 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield of racemic hydroester is 86.7%.

[0125] Condition 4: Prepared according to the method of step (1) of Example 1, with the difference that 1.2 equivalents of phthalic anhydride and 1.2 equivalents of pyridine are used, reacted at 92 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield is 87.1%.

[0126] Condition 5: Prepared according to the method of step (1) of Example 1, with the difference that 1.2 equivalents of phthalic anhydride and 0.1 equivalent of pyridine are used, reacted at 98 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield of racemic hydroester is 85.5%.

[0127] Condition 6: Prepared according to the method of step (1) of Example 1, with the difference that 20 mL of N,N-dimethylformamide is added, reacted at 92 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield of racemic hydroester is 80.2%.

[0128] Condition 7: Prepared according to the method of step (1) of Example 1, with the difference that 50 mL of N,N-dimethylformamide is added, reacted at 92 °C for 2 h, ethyl acetate is added during heating, and crystallization occurs at room temperature. The yield of racemic hydroester is 76.3%.

[0129] Example 3

[0130] Screening of conditions with quinine as the resolving agent:

[0131] Condition 1: In step (2) S1 of Example 1, dioxane was used instead of tetrahydrofuran as the solvent, and 53.00 g of quinine (1.00 eq, 0.16 mol) was dissolved in 750 mL of dioxane to form a solution. The yield of (S)-hydroxy ester quinine salt was 72.8% (calculated based on the levorotatory raw material), and the specific rotation was measured as: -113.62 m 2 ·kg -1 (concentration 0.5 g / 100 mL, sample temperature 23.6 °C, methanol as the solvent). The filtrate was concentrated to dryness to obtain 120 mg of the (R)-isomer, and the specific rotation was measured as: -30.482 m 2 ·kg -1 (concentration 0.5 g / 100 mL, sample temperature 23.6 °C, methanol as the solvent).

[0132] Condition 2: In step (2) S1 of Example 1, acetone was used instead of tetrahydrofuran as the solvent. The yield of (S)-hydroxy ester quinine salt was 75.7% (calculated based on the levorotatory raw material), and the specific rotation was measured as: -130.10 m 2 ·kg -1 (concentration 0.5 g / 100 mL, methanol as the solvent). The filtrate was concentrated to dryness to obtain 142 mg of the (R)-isomer, and the specific rotation was measured as: -11.940 m 2 ·kg -1 (concentration 0.5 g / 100 mL, sample temperature 23.6 °C, methanol as the solvent).

[0133] Condition 3: In step (2) S1 of Example 1, acetonitrile was used instead of tetrahydrofuran as the solvent. The yield of (S)-hydroxy ester quinine salt was 68.0% (calculated based on the levorotatory raw material), and the specific rotation was measured as: -110.82 m 2 ·kg -1 (concentration 0.5 g / 100 mL, sample temperature 23.6 °C, methanol as the solvent). The filtrate was concentrated to dryness to obtain 118 mg of the (R)-isomer, and the specific rotation was measured as: -79.943 m 2 ·kg -1 (concentration 0.5 g / 100 mL, sample temperature 23.6 °C, methanol as the solvent).

[0134] Example 4

[0135] Screening of extraction reagents for (S)-oxiracetam hydrogen phthalate:

[0136] Condition 1: In step (2) of Example 1, the aqueous phase was adjusted to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was dissolved to saturation, and then the aqueous phase was extracted 4 times with EA, 450 mL each time. The yield of (S)-hydroxy ester was 9.8%.

[0137] Condition 2: In step (2) of Example 1, the aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was saturated in dissolution, and then the aqueous phase was extracted with THF 4 times, 450 mL each time, and no product was obtained.

[0138] Condition 3: In step (2) of Example 1, the aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was saturated in dissolution, and then the aqueous phase was extracted with an EA:THF mixed solvent (v:v = 1:1) 4 times, 450 mL each time, and the yield of (S)-hydroxy ester was 30.7%.

[0139] Condition 4: In step (2) of Example 1, the aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was saturated in dissolution, and then the aqueous phase was extracted with an EA:THF mixed solvent (v:v = 2:1) 4 times, 450 mL each time, and the yield of (S)-hydroxy ester was 38.6%.

[0140] Condition 5: In step (2) of Example 1, the aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was saturated in dissolution, and then the aqueous phase was extracted with an EA:THF mixed solvent (v:v = 1:2) 4 times, 450 mL each time, and the yield of (S)-hydroxy ester was 42.3%.

[0141] Condition 6: In step (2) of Example 1, the aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was saturated in dissolution, and then the aqueous phase was extracted with an EA:methanol mixed solvent (v:v = 1:2) 4 times, 450 mL each time, and the yield of (S)-hydroxy ester was 30.7%. 1 1H-NMR showed that there was unreacted oxiracetam raw material in the organic phase.

[0142] Condition 7: In step (2) of Example 1, the aqueous phase was acidified to pH = 2 with concentrated hydrochloric acid. Analytical pure sodium chloride solid was added to the aqueous phase until it was saturated in dissolution, and then the aqueous phase was extracted with an EA:acetone mixed solvent (v:v = 1:2) 4 times, 450 mL each time, and the yield of (S)-hydroxy ester was 33.3%.

[0143] Example 5

[0144] The experimental results when different alcohols were selected in the transesterification reaction are as follows:

[0145] Condition 1: Prepared by the method of step (3) of Example 1, the difference is that n-butanol was replaced by ethanol, heated to the reflux temperature, and no reaction product was detected by TLC after the reaction was completed.

[0146] Condition 2: Prepared by the method of step (3) of Example 1, with the difference that: n-butanol is replaced by methanol, heated to the reflux temperature, and no reaction product can be detected by TLC after the reaction is completed.

[0147] Condition 3: Prepared by the method of step (3) of Example 1, with the difference that: n-butanol is replaced by n-propanol, the temperature is 100 °C, the reaction is carried out for 1.5 hours, the yield of the first refined product of (S)-oxiracetam is 45%, and the reaction time is increased to 3 h, the yield of the first refined product of (S)-oxiracetam is 55%.

[0148] Condition 4: Prepared by the method of step (3) of Example 1, with the difference that: n-butanol is replaced by n-pentanol, the temperature is 140 °C, n-pentanol cannot be distilled off under reduced pressure after the reaction is completed, and crystallization is carried out by cooling. After filtration, the yield of the first refined product of (S)-oxiracetam is 52%.

[0149] The above experimental results show that: methanol and ethanol do not react, the yields of n-propanol and n-pentanol are relatively low, and n-butanol is the best.

[0150] Example 6

[0151] When the transesterification reaction is carried out with n-butanol, the effects of temperature and time on the results are as follows:

[0152] Condition 1: Prepared by the method of Example 1, with the difference that: heated under the condition of 130 °C for 1 h. After the reaction is completed, the yield of the first refined product is detected to be 63.9%. Detected by LC-MS, it shows that there is raw material remaining in the product.

[0153] Condition 2: Prepared by the method of Example 1, with the difference that: heated under the condition of 130 °C for 2 h. The yield of the first refined product is 62.7%.

[0154] Condition 3: Prepared by the method of Example 1, with the difference that: heated under the condition of 130 °C for 3 h. The yield of the first refined product is 61.5%.

[0155] Condition 4: Prepared by the method of Example 1, with the difference that: heated under the condition of 130 °C for 5 h. The yield of the first refined product is 60.3%.

[0156] Condition 5: Prepared by the method of Example 1, with the difference that: heated under the condition of 140 °C for 1 h. The yield of the first refined product is 64.5%.

[0157] Example 7

[0158] When the transesterification reaction is carried out with n-butanol, the effects of the molar ratio of phthalic acid-(S)-oxiracetam hydrogen ester to n-butanol on the results are as follows:

[0159] Condition 1: Prepared by the method of Example 1, with the difference that: 7 mL (1 eq) of n-butanol was used and it could not be dissolved clearly.

[0160] Condition 2: Prepared by the method of Example 1, with the difference that: 70 mL (10 eq) of n-butanol was used, and the yield of the first refined product of (S)-oxiracetam was 60.5%.

[0161] Condition 3: Prepared by the method of Example 1, with the difference that: 350 mL (50 eq) of n-butanol was used, and the yield of the first refined product of (S)-oxiracetam was 61.7%.

[0162] Condition 4: Prepared by the method of Example 1, with the difference that: 700 mL (100 eq) of n-butanol was used, and the yield of the first refined product of (S)-oxiracetam was 62.5%.

[0163] Example 8

[0164] The influence results of the conditions for the first refining in the transesterification reaction with n-butanol are as follows:

[0165] Condition 1: Prepared by the method of Example 1, with the difference that: in step (2) of the first refining, tetrahydrofuran was replaced by ethyl acetate, and the filter cake in step (2) was also washed with ethyl acetate, with a yield of 54.3%; the purity of (S)-oxiracetam was 81.78%.

[0166] Condition 2: Prepared by the method of Example 1, with the difference that: in step (2) of the first refining, tetrahydrofuran was replaced by dioxane, and no solid was produced.

[0167] Condition 3: Prepared by the method of Example 1, with the difference that: in step (2) of the first refining, tetrahydrofuran was replaced by acetone, and no solid was produced.

[0168] Condition 4: Prepared by the method of Example 1, with the difference that: in step (2) of the first refining, tetrahydrofuran was replaced by diethyl ether, and no solid was produced.

[0169] Condition 5: Prepared by the method of Example 1, with the difference that: in step (2) of the first refining, tetrahydrofuran was replaced by methyl ethyl ketone, a reaction occurred, the reaction solution turned black, and TLC detection showed the generation of impurities.

[0170] Condition 6: Prepared by the method of Example 1, with the difference that: in step (2) of the first refining, tetrahydrofuran was replaced by n-butyl ether, an oil-like substance precipitated, and TLC detection showed a lower purity.

[0171] Example 9

[0172] Prepared by the method of Example 1, except that after the end of S1 in (2) "resolution of racemic oxiracetam precursor", the following steps are added:

[0173] Take 10.0 g of phthalic acid-(S)-oxiracetam hydroquinine salt prepared, add 120 mL of dioxane, reflux for two hours, cool to room temperature and stir for 2 h, filter by suction, wash the filter cake with 10 mL of dioxane twice, and dry to obtain 8.9 g, with a yield of 89.0%.

[0174] Continue to prepare (S)-oxiracetam according to the method of Example 1. m.p.: 133 - 135 °C. Specific rotation: -28.476 m 2 ·kg -1 (Concentration: 10.0 mg / mL, sample temperature 23.6 °C, methanol as solvent). The content of the (R)-isomer is 0.01%, and the purity of (S)-oxiracetam is 99.50%.

[0175] Comparative Example 1

[0176] Reaction exploration of the esterification of oxiracetam with (1S)-(+)-camphor-10-sulfonyl chloride. The theoretical reaction equation is:

[0177]

[0178] In a 25 mL three-necked flask, add 63 mg of oxiracetam (1 eq, 0.40 mmol), 1 mL of DMF, heat to 80 °C until dissolved clearly, cool to room temperature, and successively add 120 mg of TEA (3 eq, 1.19 mmol), 100 mg of (1S)-(+)-camphor-10-sulfonyl chloride (1 eq, 0.40 mmol, dissolved in 0.5 mL of DMF), and stir at room temperature for 1 h. Filter by suction, concentrate the filtrate under reduced pressure to obtain 100 mg of a colorless oily substance. Column chromatography (mobile phase: DCM:MeOH = 10:1) gives 40 mg of the product. After 5 TLC plate separations, two very close spots can be separated, indicating that the chromatographic behavior of the diastereomeric sulfonates is very similar.

[0179] Comparative Example 2

[0180] Exploration of the conditions for adding phthalic anhydride:

[0181] Condition 1: Prepared according to step (1) of Example 1, except that phthalic anhydride is used in an amount of 1.05 equivalents, pyridine is used in an amount of 1.2 equivalents, no solvent is added, and the reaction is carried out at 90 °C for about 1 h. The reactants gradually become viscous and the reaction cannot proceed.

[0182] Condition 2: Prepared according to step (1) of Example 1, with the difference that: 1.1 equivalents of phthalic anhydride and 0.1 equivalent of pyridine were used, reacted overnight at 92 °C, ethyl acetate was added during heating, and crystallization occurred at room temperature. The yield was 53.5%. TLC detection showed impurity bands.

[0183] Condition 3: Prepared according to step (1) of Example 1, with the difference that: 1.1 equivalents of phthalic anhydride and 0.1 equivalent of pyridine were used, reacted for 2 hours at 122 °C, ethyl acetate was added during heating, and crystallization occurred at room temperature. The yield was 61.4%. TLC detection showed impurity bands.

[0184] Condition 4: Prepared according to step (1) of Example 1, with the difference that: 10 mL of N,N-dimethylformamide was added, reacted for 2 h at 92 °C, ethyl acetate was added during heating, and crystallization occurred at room temperature. The yield was 85.3%.

[0185] Condition 5: Prepared according to step (1) of Example 1, with the difference that: 100 mL of N,N-dimethylformamide was added, reacted for 2 h at 92 °C, ethyl acetate was added during heating, and crystallization occurred at room temperature. The yield was 70.2%.

[0186] Condition 6: Prepared according to step (1) of Example 1, with the difference that: after reacting for 2 h, while maintaining the heating state, 200 mL of acetone was added dropwise to the reaction solution, and no solid was precipitated.

[0187] Condition 7: Prepared according to step (1) of Example 1, with the difference that: after reacting for 2 h, while maintaining the heating state, 200 mL of ethanol was added dropwise to the reaction solution, and no solid was precipitated.

[0188] Comparative Example 3

[0189] Selection of the resolving agent:

[0190] 1. Using 2-aminoethanol as the resolving agent, condition exploration was carried out under different solvent conditions:

[0191] Condition 1: Using ethanol as the solvent, after dissolution, ethyl acetate was added dropwise, no crystals were precipitated, and there was no optical activity;

[0192] Condition 2: Using acetone as the solvent, no crystals were precipitated, and there was no optical activity;

[0193] Condition 3: Using ethyl acetate as the solvent, no crystals were precipitated, and there was no optical activity;

[0194] Condition 4: Using tetrahydrofuran as the solvent, no crystals were precipitated, and there was no optical activity.

[0195] 2. Using L-phenylalanine methyl ester as the resolving agent;

[0196] Condition 1: Using ethanol as the solvent, after dissolution, ethyl acetate was added dropwise, no crystals were precipitated, and there was no optical activity;

[0197] Condition 2: Using acetone as the solvent, no crystals precipitate, and there is no optical activity.

[0198] Condition 3: Using ethyl acetate as the solvent, no crystals precipitate, and there is no optical activity.

[0199] Condition 4: Using tetrahydrofuran as the solvent, no crystals precipitate, and there is no optical activity.

[0200] 3. Using D-threo-1-p-nitrophenyl-1,3-propanediol as the resolving agent;

[0201] Condition 1: Using ethanol as the solvent, after dissolution, ethyl acetate is added dropwise, no crystals precipitate, and there is no optical activity.

[0202] Condition 2: Using acetone as the solvent, no crystals precipitate, and there is no optical activity.

[0203] Condition 3: Using ethyl acetate as the solvent, no crystals precipitate, and there is no optical activity.

[0204] Condition 4: Using tetrahydrofuran as the solvent, no crystals precipitate, and there is no optical activity.

[0205] Comparative Example 4

[0206] 1. Preparation of ethyl phthalate-(S)-oxiracetam diester (abbreviation: (S)-diester)

[0207]

[0208] Add 770 mg of (S)-hydroester (prepared in Example 2) (1 eq, 2.51 mmol), 5 mL of ethanol, 307 mg of DMAP (1 eq, 2.51 mmol), and 962 mg of EDC hydrochloride (2 eq, 5.02 mmol) into a 100 mL single-necked flask. Stir at room temperature for 0.5 h, evaporate to dryness, add 20 mL of EA to dissolve, add 10 mL of 2N hydrochloric acid for extraction and separation. The aqueous phase is extracted three times with 20 mL of EA again. Combine the organic phases, dry over anhydrous Na2SO4 and then evaporate to dryness to obtain 680 mg of a colorless oily substance, and the crude product yield is 81.0%. Column chromatography (EA), evaporate to dryness to obtain 560 mg of a colorless oily substance, with a yield of 66.6%. After NMR identification, the chemical structure formula of the product is correct.

[0209] 2. Aminolysis of (S)-diester

[0210]

[0211] Condition 1: Aminolysis with 4eq potassium tert-butoxide: Add 100 mg of ethyl phthalate-(S)-oxiracetam diester (1eq, 0.30 mmol) and 5 mL of tetrahydrofuran into a single-necked flask. Dropwise add a solution of 134 mg of potassium tert-butoxide (4eq, 1.20 mmol) dissolved in 5 mL of tetrahydrofuran. A solid precipitates. Add 58 mg of ethylamine (70%, W / W in H2O) (3eq, 0.90 mmol). React at room temperature for 0.5 h. The reaction product is detected by LC-MS, showing no signal of oxiracetam.

[0212] Condition 2: Aminolysis with 0.1eq potassium tert-butoxide: Add 100 mg of ethyl phthalate-(S)-oxiracetam diester (1eq, 0.30 mmol) and 5 mL of tetrahydrofuran into a single-necked flask. Dropwise add a solution of 3.3 mg of potassium tert-butoxide (0.1eq, 0.03 mmol) dissolved in 1 mL of tetrahydrofuran. No solid precipitates. Add 58 mg of ethylamine (70%, W / W in H2O) (3eq, 0.90 mmol). React at room temperature for 0.5 h, then heat to reflux overnight. Detect by TLC, showing that there is remaining raw material. The reaction product is detected by LC-MS, showing no signal of oxiracetam.

[0213] Comparative Example 5

[0214] After the transesterification reaction using n-butanol, the influence results of the catalyst are as follows:

[0215] Experiment 1: Prepared by the method of Example 1, with the difference that in step (3), EtONa is used as the catalyst, the addition amount is 0.1eq, and the reaction is carried out overnight at the reflux temperature. Detect by TLC, and the reaction is not complete.

[0216] Experiment 2: Prepared by the method of Example 1, with the difference that in step (3), EtONa is used as the catalyst, the addition amount is 1eq, and the reaction is carried out for 4 hours at the reflux temperature. Detect by TLC, the reaction is complete, but the target product is not obtained.

[0217] The above experimental results show that: EtONa cannot catalyze the reaction as a catalyst.

[0218] The above are only specific embodiments of the present invention, enabling those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments described herein, but rather will conform to the broadest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for resolving the racemate of oxiracetam, characterized in that, The racemic oxiracetam precursor is resolved using quinine as a resolving agent to obtain the L-oxiracetam precursor. After removing the protecting group from the L-oxiracetam precursor, L-oxiracetam is obtained; the protecting group is connected to the hydroxyl group on the molecular structure of oxiracetam through an ester group and contains at least one acidic group; the racemic oxiracetam precursor is prepared by reacting racemic oxiracetam with the protecting reagent phthalic acid; the resolution method at least includes the following steps: S1. Mix the racemic oxiracetam precursor and quinine in organic solvent I and heat. After separation, washing, and drying, the L-oxiracetam precursor quinine salt is obtained; the organic solvent I is selected from tetrahydrofuran. In the reaction system, 10 - 40 mL of the organic solvent I is added per gram of the racemic oxiracetam precursor. S2. Dissolve the L-oxiracetam precursor quinine salt in an alkaline aqueous solution and extract to remove quinine. S3. Adjust the pH of the reaction system to 1 - 2. After extraction and washing, the L-oxiracetam precursor is obtained; the extraction is carried out 2 - 7 times using a mixed solvent of ethyl acetate and tetrahydrofuran, and the volume ratio of ethyl acetate to tetrahydrofuran is 10:1 - 4. When extracting, sodium chloride is added to saturation in the aqueous phase; after the extraction is completed, the organic phases are combined and the L-oxiracetam precursor solid is obtained by recrystallization; the organic solvent used for washing is selected from ethyl acetate. S4. The L-oxiracetam precursor is obtained by removing the protecting group through a transesterification reaction to obtain L-oxiracetam; n-butanol is added in a ratio of 0.5 - 5 mL / g, heated under reflux and stirred for 1 - 3 hours, and dried to obtain L-oxiracetam; the transesterification reaction is carried out under the catalysis of a titanate catalyst.

2. The splitting method according to claim 1, wherein In S1, the heating temperature is 65 - 80 °C and the heating time is 1 - 5 hours; and / or, The molar ratio of the racemic oxiracetam precursor to quinine is 1:1 - 1.1; and / or, First, dissolve the racemic oxiracetam precursor in the organic solvent I, and after dissolving quinine in the organic solvent I, add it to the reaction system.

3. The splitting method according to claim 1, wherein In S1, there is also a further purification step, including: taking the L-oxiracetam precursor quinine salt, adding organic solvent II and heating for 1 - 4 hours, cooling for crystallization, filtering by suction, washing with the organic solvent, and drying to obtain the purified L-oxiracetam precursor quinine salt; and / or, The organic solvent II is selected from one or a mixture of several of tetrahydrofuran, dioxane, methyl tert-butyl ether, ether, diisopropyl ether, ethyl acetate, acetone, 2-butanone.

4. The splitting method according to claim 3, characterized in that, The organic solvent II is dioxane.

5. The splitting method according to claim 1, characterized in that, In S2, the pH value of the alkaline aqueous solution is 8 - 11.6; and / or, The alkaline aqueous solution is selected from sodium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium hydroxide aqueous solution, potassium carbonate aqueous solution; and / or, The organic solvent used for extraction is selected from dichloromethane.

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