CN113582903B - Method for synthesizing medicine for treating epilepsy by using L-2-aminobutanamide hydrochloride - Google Patents
Method for synthesizing medicine for treating epilepsy by using L-2-aminobutanamide hydrochloride Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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Abstract
The invention discloses a method for synthesizing a medicament for treating epilepsy by using L-2-aminobutanamide hydrochloride, and relates to the technical field of medicament synthesis. The invention adopts a milder alkaline substance and synthesizes levetiracetam by a one-pot method, the operation is simple, the levetiracetam can be prepared without post-treatment in the middle, the levetiracetam obtained by the invention has low impurity content, high chemical purity, the yield can reach more than 83.43 percent, and the purity can reach 99.6 percent.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing a medicine for treating epilepsy by using L-2-aminobutanamide hydrochloride.
Background
Epilepsy is a chronic recurrent transient brain dysfunction syndrome caused by various causes, and the long-term recurrent attacks of the disease seriously affect the life quality and social work capacity of patients, thus causing great harm to individuals and society.
The levetiracetam has the chemical name of (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide, is a novel antiepileptic drug developed by UCB company in Belgium, has the characteristics of high therapeutic index, high safety index, capability of being used for independent treatment, no interaction with other antiepileptic drugs, slight side effect, good tolerance, excellent indexes of each pharmacokinetic item and the like, and is the only antiepileptic drug with unique performance for preventing epileptogenesis reported at present. The chemical structural formula of levetiracetam is as follows:
the synthesis report of levetiracetam in the prior art mainly comprises the following technical routes:
route one: US 4696943 discloses a synthesis method using 2-pyrrolidone as a starting material, which comprises the steps of synthesizing levetiracetam acid, resolving, converting into mixed anhydride to activate carboxyl, and finally obtaining levetiracetam. The route is a synthesis method for early obtaining of levetiracetam, has long reaction steps, harsh reaction conditions and large resolution loss, and is not suitable for industrial production.
Route two: EP 1806339A discloses a synthesis method using chiral 2-bromobutyramide as a raw material to avoid subsequent resolution, but strong alkali sodium methoxide is used in the reaction, so racemization is unavoidable in the nucleophilic substitution reaction process, the product purity is insufficient, further purification treatment is required, the yield is only 40%, and the cost is increased, so that the method is not suitable for industrial production.
Route three: WO 0164637A1 discloses a synthesis method using methyl 2-oxobutyrate as a raw material, wherein methyl 2-oxobutyrate and 2-pyrrolidone are reacted to generate methyl 2- (2-oxo-pyrrolidine) -2-butenoate, and then ammonified to obtain 2- (2-oxo-pyrrolidine) -2-butenamide, and finally the levetiracetam is obtained through hydrogenation reduction under the catalysis of rhodium or ruthenium complex with chiral phosphine as a ligand. However, the route uses the chiral metal catalyst rhodium or ruthenium with high price, has high cost, also uses an autoclave, has high reaction safety requirement and is not suitable for industrial production.
Route four: CN 102558012a discloses a synthesis method using (S) -2-aminobutyric acid as raw material, which comprises the steps of firstly, carrying out alkylation reaction on (S) -2-aminobutyric acid and 4-chlorobutyryl chloride to obtain an acylated product, then carrying out acylation reaction to obtain mixed anhydride, then carrying out ammonolysis to obtain chlorobutyramide, and finally closing a ring to obtain a target product levetiracetam. The route can generate partial racemization in the ammonolysis process, and finally strong alkali is needed for ring closure, and racemization can be caused, so that the purity of a target product is lower, the reaction steps are longer, and the method is not suitable for industrial production.
Route five: CN101550100a discloses a synthesis method using L-threonine as raw material, which prepares levetiracetam through the processes of esterification, halogenation, catalytic reduction, ammonolysis, cyclization, etc. Wherein, the sulfoxide halide is used in the esterification and halogenation processes, and Raney nickel, palladium carbon, rhodium carbon or supported platinum oxide is used in the catalytic reduction process. The method has high corrosiveness and tear resistance, is a chemical reagent controlled by public security departments, can be easily hydrolyzed into sulfur dioxide and hydrogen chloride when meeting water, and has great influence on the environment. International regulations on the use of thionyl chloride are also more stringent, e.g. ACGIH (American society of government Industrial Cookies) prescribes that the time threshold of thionyl chloride in workshops should not exceed 4.9mg/m 3 . Therefore, this method is not suitable for industrial production.
In the process of synthesizing antiepileptic drug levetiracetam, L-2-aminobutanamide hydrochloride is an important intermediate, and is mainly prepared by a traditional chiral salifying free method at present, a large amount of D-configuration byproducts are generated in the preparation process, so that the cost is greatly increased, the antiepileptic drug levetiracetam is not environment-friendly, and the L-2-aminobutanamide hydrochloride can also be prepared by an asymmetric synthesis method, and the preparation method mainly comprises the following synthetic routes:
(1) 2-Bromobutyric acid/2-Bromobutyric acid methyl ester route
CN102020584a reports that 2-bromobutyric acid is taken as a starting material, firstly reacts with thionyl chloride to generate 2-bromobutyryl chloride, reacts with ammonia water to obtain racemic 2-aminobutanamide, and is resolved by L-tartaric acid and salified.
CN102898324a reports that methyl 2-bromobutyrate is taken as a starting material, and reacts with ammonia water to obtain racemic 2-aminobutanamide in one step, and the racemic 2-aminobutanamide is resolved by L-tartaric acid and then salified.
The patent reports that the synthesis yield is higher, the reaction steps are short, the operation is simple, but the price of 2-bromobutyric acid/methyl 2-bromobutyrate is expensive, the cost of raw materials is high, the price of the product is not dominant, and a large amount of wastewater is generated in the production process, so that the environmental protection is not facilitated.
(2) Hydantoin route
The method comprises the steps of reacting n-propanal serving as a raw material with ammonium bicarbonate and sodium cyanide to generate hydantoin, hydrolyzing under the condition of pressurization and alkalinity to obtain sodium 2-aminobutyric acid, and regulating the pH value to an equivalent point by hydrochloric acid to obtain the 2-aminobutyric acid. The method comprises the steps of resolving 2-aminobutyric acid by L-tartaric acid to obtain L-2-aminobutyric acid, acylating the L-2-aminobutyric acid to obtain an L-2-aminobutyric acid compound, and obtaining L-2-aminobutyric acid amide under the condition of ammonia water. The reaction releases a large amount of ammonia gas, and meanwhile, the desalting cost is higher, and the theoretical yield is only 50%.
(3) N-propanal route
CN101928229a discloses that n-propionaldehyde is taken as a raw material, and is subjected to stoneley reaction with ammonia, ammonium chloride and sodium cyanide aqueous solution to obtain 2-aminobutyric acid, the 2-aminobutyric acid is obtained through normal pressure hydrolysis under alkaline conditions, and finally, the L-2-aminobutyric acid hydrochloride is obtained through resolution into salt. The method has the advantages of simple operation, no high-temperature high-pressure reaction, high product yield and good quality. However, the sodium cyanide which is a highly toxic substance is used, and the improper operation of the sodium cyanide in the charging and weighing stage can cause poisoning and even death of people, so that the health hazard to operators is great. In addition, the reaction produces a large amount of wastewater containing ammonium chloride and excessive sodium cyanide, the treatment cost is high, and the potential safety hazards limit the industrial popularization of the processes.
Disclosure of Invention
The present invention aims to provide a method for synthesizing a drug for treating epilepsy by using L-2-aminobutanamide hydrochloride, so as to solve the problems in the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a method for synthesizing a medicament for treating epilepsy by using L-2-aminobutanamide hydrochloride, wherein the medicament for treating epilepsy is levetiracetam;
the method is characterized in that L-2-aminobutanamide hydrochloride and 4-chlorobutyrate are added into isopropanol under the protection of nitrogen, nucleophilic substitution reaction and ring closure reaction are carried out under the action of alkaline substances and catalysts by heating and refluxing, and the medicine for treating epilepsy is obtained, wherein the specific chemical reaction formula is as follows:
wherein R is methyl or ethyl.
Further, the L-2-aminobutanamide hydrochloride is prepared by adding 2-aminobutanamide into a solvent, adding an inducer glyceraldehyde and a resolving agent L-tartaric acid, heating for asymmetric resolution, filtering, adding the obtained double salt into concentrated hydrochloric acid for separation, and dripping ethanol for precipitation, wherein the specific chemical reaction formula is as follows:
further, the molar ratio of the 2-aminobutanamide, glyceraldehyde and L-tartaric acid is 1:0.3 to 0.8:1 to 1.2;
the weight-volume ratio of the 2-aminobutanamide to the solvent is 1g: 5-10 mL;
the molar ratio of the 2-aminobutanamide to the concentrated hydrochloric acid is 1:1.1 to 1.3;
the concentration of the concentrated hydrochloric acid is 30-36 wt%.
Further, the asymmetric splitting temperature is 60-80 ℃ and the time is 5-8 h;
the separation temperature is room temperature and the separation time is 1-2 h.
Further, the solvent is ethanol, n-propanol or isopropanol.
Further, the molar ratio of the 4-chlorobutyrate to the L-2-aminobutanamide hydrochloride is 1.0 to 2.0:1.
further, the molar ratio of the alkaline substance to the L-2-aminobutanamide hydrochloride is 2-4: 1.
further, the molar ratio of the catalyst to the L-2-aminobutanamide hydrochloride is 0.1 to 0.3:1.
further, the catalyst is sodium iodide or potassium iodide.
Further, the alkaline substance is sodium bicarbonate, potassium carbonate, sodium carbonate or triethylamine.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts a milder alkaline substance and synthesizes levetiracetam by a one-pot method, the operation is simple, the levetiracetam can be prepared without post-treatment in the middle, the levetiracetam obtained by the invention has low impurity content and high chemical purity, the yield can reach more than 83.43 percent, and the purity reaches 99.6 percent;
the L-2-aminobutanamide hydrochloride is prepared by adopting an asymmetric resolution method, glyceraldehyde is adopted as an inducer, L-tartaric acid is adopted as a resolution agent, D-aminobutanamide which is required to be removed in the prior art can be converted into L-aminobutanamide, the resolution rate can reach more than 95.53%, compared with the theoretical conversion rate of 50% in the prior art, the resolution rate is doubled, the impurity content of the obtained L-2-aminobutanamide hydrochloride is low, the chemical purity is high, the raw material cost is greatly reduced compared with the prior art, the reaction process is mild, the environment is friendly, and the danger in the production process is avoided.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Embodiment one:
the method for synthesizing the drug for treating epilepsy by using L-2-aminobutanamide hydrochloride comprises the following synthesis steps:
one) resolution of L-2-aminobutanamide hydrochloride
10.2g (0.1 mol) of 2-aminobutanamide is put into a 100mL three-necked flask, 60mL of ethanol is added, stirring and dispersing are carried out, 4.5g (0.05 mol) of inducer glyceraldehyde and 15.0g (0.1 mol) of resolving agent L-tartaric acid are added, heating is carried out to 70 ℃, asymmetric resolving is carried out at 70 ℃, stirring reaction is carried out for 6 hours, filtration and washing with a small amount of ethanol are carried out, and the L-2-aminobutanamide L-tartaric acid double salt is obtained (the next reaction is directly carried out without drying).
Adding the obtained L-2-aminobutanamide L-tartaric acid double salt into 11.6mL of concentrated hydrochloric acid with concentration of 30wt% (molar ratio of 2-aminobutanamide to hydrochloric acid is 1:1.1), stirring at room temperature, separating reaction for 1.5h until the solution is completely clarified, slowly dripping ethanol for crystallization, cooling to 0 ℃ for crystallization for 4h after a small amount of crystals are separated out, filtering, and vacuum drying to obtain 13.33g of L-2-aminobutanamide hydrochloride with yield 96.18%, purity 99.6%, ee value of 99.76%, wherein the specific chemical reaction formula is as follows:
preparation of two) levetiracetam
Under the protection of nitrogen, 9.7g (0.07 mol) of L-2-aminobutanamide hydrochloride, 12g (0.0879 mol) of 4-chlorobutyrate methyl ester, 36g (0.260 mol) of potassium carbonate and 1.2g (0.007 mol) of potassium iodide are added to 100mL of isopropanol, the mixture is heated to reflux reaction for 24 hours, after the reaction is finished, the mixture is filtered while the mixture is hot, the filtrate is evaporated to dryness under reduced pressure, 60mL of acetone and 1g of active carbon are added into the obtained residue, the mixture is heated again to reflux for 2 hours, the active carbon is filtered while the mixture is hot, the mixture is slowly cooled to 0 ℃, the temperature is maintained for crystallization for 4 hours, the mixture is filtered, 10.11g of levetiracetam is obtained, the yield 84.87%, the HPLC purity is 99.8%, and the ee value is 99.92%, and the specific chemical reaction formula is as follows:
embodiment two:
the method for synthesizing the drug for treating epilepsy by using L-2-aminobutanamide hydrochloride comprises the following synthesis steps:
one) resolution of L-2-aminobutanamide hydrochloride
10.2g (0.1 mol) of 2-aminobutanamide is put into a 100mL three-necked flask, 51mL of normal propyl alcohol is added, stirring and dispersing are carried out, 2.7g (0.03 mol) of inducer glyceraldehyde and 16.5g (0.11 mol) of resolving agent L-tartaric acid are added, heating is carried out to 80 ℃, the temperature is maintained to 80 ℃ for asymmetric resolution, stirring reaction is carried out for 5 hours, filtering and washing with a small amount of ethanol are carried out, and the L-2-aminobutanamide L-tartaric acid double salt (the next reaction is directly carried out without drying) is obtained.
Adding the obtained L-2-aminobutanamide L-tartaric acid double salt into 11.8mL of concentrated hydrochloric acid with concentration of 32wt% (molar ratio of 2-aminobutanamide to hydrochloric acid is 1:1.2), stirring at room temperature, separating to react for 1.5h until the solution is completely clarified, slowly dropwise adding ethanol to perform crystallization, dropwise adding a small amount of crystals to separate out, cooling to 4 ℃ to perform crystallization for 6h, filtering, and vacuum drying to obtain 13.31g of L-2-aminobutanamide hydrochloride with yield 96.03%, purity of 99.5% and ee value of 99.64%.
Preparation of two) levetiracetam
Under the protection of nitrogen, 9.7g (0.07 mol) of L-2-aminobutanamide hydrochloride, 21.09g (0.14 mol) of ethyl 4-chlorobutyrate, 23.52g (0.28 mol) of sodium bicarbonate and 3.15g (0.021 mol) of sodium iodide are added to 120mL of isopropanol, the mixture is heated to reflux reaction for 22h, after the reaction is finished, the mixture is filtered and evaporated to dryness under reduced pressure, 60mL of acetone and 1g of active carbon are added to the obtained residue, the mixture is heated and refluxed for 2h again, the active carbon is removed by filtration while the mixture is hot, the mixture is slowly cooled to 5 ℃, the temperature is maintained at 5 ℃ for crystallization for 6h, and the mixture is filtered to obtain 10.28g of levetiracetam, the yield is 86.28%, the purity measured by HPLC is 99.7%, and the ee value is 99.89%.
Embodiment III:
the method for synthesizing the drug for treating epilepsy by using L-2-aminobutanamide hydrochloride comprises the following synthesis steps:
one) resolution of L-2-aminobutanamide hydrochloride
10.2g (0.1 mol) of 2-aminobutanamide is put into a 250mL three-necked flask, 80mL of isopropanol is added, stirring and dispersing are carried out, 3.6g (0.04 mol) of inducer glyceraldehyde and 18.0g (0.12 mol) of resolving agent L-tartaric acid are added, heating is carried out to 65 ℃, asymmetric resolving is carried out at 65 ℃, stirring reaction is carried out for 8 hours, filtration and washing with a small amount of ethanol are carried out, and the L-2-aminobutanamide L-tartaric acid double salt (the next reaction is directly carried out without drying) is obtained.
Adding the obtained L-2-aminobutanamide L-tartaric acid double salt into 11.9mL of concentrated hydrochloric acid with the concentration of 33wt% (the molar ratio of 2-aminobutanamide to hydrochloric acid is 1:1.25), stirring at room temperature, separating and reacting for 2h until the solution is completely clear, slowly dripping ethanol for crystallization, dripping a small amount of crystals for crystallization, cooling to 1 ℃ for 5h, filtering, and vacuum drying to obtain 13.29g of L-2-aminobutanamide hydrochloride with the yield of 95.89%, the purity of 99.7% and the ee value of 99.73%.
Preparation of two) levetiracetam
Under the protection of nitrogen, 9.7g (0.07 mol) of L-2-aminobutanamide hydrochloride, 9.56g (0.07 mol) of 4-chlorobutyrate methyl ester, 14.84g (0.14 mol) of sodium carbonate and 1.16g (0.007 mol) of potassium iodide are added to 80mL of isopropanol, the mixture is heated to reflux reaction for 26 hours, after the reaction is finished, the mixture is filtered and evaporated to dryness under reduced pressure, 50mL of acetone and 1g of active carbon are added to the obtained residue, the mixture is heated and refluxed for 3 hours again, the active carbon is removed by filtration while the mixture is hot, the mixture is cooled slowly to 2 ℃, the temperature is maintained at 2 ℃ for crystallization for 5 hours, the mixture is filtered, 9.94g of levetiracetam is obtained, the yield is 83.43%, the purity measured by HPLC is 99.7%, and the ee value is 99.89%.
Embodiment four:
the method for synthesizing the drug for treating epilepsy by using L-2-aminobutanamide hydrochloride comprises the following synthesis steps:
one) resolution of L-2-aminobutanamide hydrochloride
10.2g (0.1 mol) of 2-aminobutanamide is put into a 250mL three-necked flask, 90mL of ethanol is added, stirring and dispersing are carried out, 4.5g (0.05 mol) of inducer glyceraldehyde and 15.0g (0.1 mol) of resolving agent L-tartaric acid are added, heating is carried out to 75 ℃, the temperature is maintained at 75 ℃ for asymmetric resolution, stirring reaction is carried out for 7h, filtration and washing with a small amount of ethanol are carried out, and the L-2-aminobutanamide L-tartaric acid double salt is obtained (the next reaction is directly carried out without drying).
Adding the obtained L-2-aminobutanamide L-tartaric acid double salt into 11.6mL of concentrated hydrochloric acid with concentration of 30wt% (molar ratio of 2-aminobutanamide to hydrochloric acid is 1:1.1), stirring at room temperature, separating to react for 1h until the solution is completely clear, slowly dropwise adding ethanol to perform crystallization, dropwise adding a small amount of crystals to precipitate, cooling to 3 ℃ to perform crystallization for 5.5h, filtering, and vacuum drying to obtain 13.24g of L-2-aminobutanamide hydrochloride with yield of 95.53%, purity of 99.5% and ee value of 99.81%.
Preparation of two) levetiracetam
Under the protection of nitrogen, 9.7g (0.07 mol) of L-2-aminobutanamide hydrochloride, 15.06g (0.1 mol) of ethyl 4-chlorobutyrate, 23.52g (0.2 mol) of triethylamine, 2.25g (0.015 mol) of sodium iodide are added to 100mL of isopropanol, the mixture is heated to reflux reaction for 20h, after the reaction is finished, the mixture is filtered and evaporated to dryness under reduced pressure, 60mL of acetone and 0.8g of active carbon are added to the obtained residue, the mixture is heated and refluxed for 2h again, the active carbon is removed by filtration while the mixture is hot, the mixture is slowly cooled to 3 ℃, the temperature is maintained at 3 ℃ for 4h, 10.13g of levetiracetam is obtained by filtration, the yield is 85.02%, the purity measured by HPLC is 99.8%, and the ee value is 99.93%.
Fifth embodiment:
the method for synthesizing the drug for treating epilepsy by using L-2-aminobutanamide hydrochloride comprises the following synthesis steps:
one) resolution of L-2-aminobutanamide hydrochloride
10.2g (0.1 mol) of 2-aminobutanamide is put into a 250mL three-necked flask, 102mL of ethanol is added, stirring and dispersing are carried out, 3.2g (0.36 mol) of inducer glyceraldehyde and 17.3g (0.115 mol) of resolving agent L-tartaric acid are added, heating is carried out to 70 ℃, asymmetric resolution is carried out at 70 ℃, stirring reaction is carried out for 7.5h, filtration and washing with a small amount of ethanol are carried out, and the L-2-aminobutanamide L-tartaric acid double salt (the next reaction is directly carried out without drying) is obtained.
Adding the obtained L-2-aminobutanamide L-tartaric acid double salt into 11.2mL of concentrated hydrochloric acid with the concentration of 36wt% (the molar ratio of 2-aminobutanamide to hydrochloric acid is 1:1.3), stirring at room temperature, separating to react for 1.8h until the solution is completely clarified, slowly dropwise adding ethanol to perform crystallization, cooling to 3 ℃ to perform crystallization for 4.5h after a small amount of crystals are separated out, filtering, and vacuum drying to obtain 13.26g of L-2-aminobutanamide hydrochloride with the yield of 95.67%, the purity of 99.6% and the ee value of 99.69%.
Preparation of two) levetiracetam
Under the protection of nitrogen, 9.7g (0.07 mol) of L-2-aminobutanamide hydrochloride, 12.29g (0.09 mol) of 4-chlorobutyrate methyl ester, 24.88g (0.18 mol) of potassium carbonate and 3.32g (0.02 mol) of sodium iodide are added to 100mL of isopropanol, the mixture is heated to reflux reaction for 23h, after the reaction is finished, the mixture is filtered and evaporated to dryness under reduced pressure, 55mL of acetone and 1.2g of active carbon are added to the obtained residue, the mixture is heated and refluxed for 2.5h again, the active carbon is removed by filtration while the mixture is still hot, the temperature is slowly reduced to 0 ℃, the mixture is maintained at 0 ℃ for crystallization for 4h, and the mixture is filtered to obtain 10.08g of levetiracetam, the yield is 84.60%, the purity measured by HPLC is 99.8%, and the ee value is 99.92%.
Example six:
the method for synthesizing the drug for treating epilepsy by using L-2-aminobutanamide hydrochloride comprises the following synthesis steps:
one) resolution of L-2-aminobutanamide hydrochloride
10.2g (0.1 mol) of 2-aminobutanamide is put into a 100mL three-necked flask, 65mL of ethanol is added, stirring and dispersing are carried out, 4.1g (0.046 mol) of inducer glyceraldehyde and 15.8g (0.105 mol) of resolving agent L-tartaric acid are added, heating is carried out to 60 ℃, the temperature is maintained to be 60 ℃ for asymmetric resolution, stirring reaction is carried out for 6.5h, filtering and washing with a small amount of ethanol are carried out, and the L-2-aminobutanamide L-tartaric acid double salt (the next reaction is directly carried out without drying) is obtained.
Adding the obtained L-2-aminobutanamide L-tartaric acid double salt into 10.6mL of concentrated hydrochloric acid with the concentration of 34wt% (the molar ratio of 2-aminobutanamide to hydrochloric acid is 1:1.15), stirring at room temperature, separating to react for 1.3h until the solution is completely clarified, slowly dropwise adding ethanol to perform crystallization, dropwise adding a small amount of crystals to separate out, cooling to 0 ℃ to perform crystallization for 5h, filtering, and vacuum drying to obtain 13.30g of L-2-aminobutanamide hydrochloride, wherein the yield is 95.96%, the purity is 99.6%, and the ee value is 99.72%.
Preparation of two) levetiracetam
Under the protection of nitrogen, 9.7g (0.07 mol) of L-2-aminobutanamide hydrochloride, 15.02g (0.11 mol) of 4-chlorobutyrate methyl ester, 22.26g (0.21 mol) of sodium carbonate and 2.99g (0.018 mol) of potassium iodide are added to 100mL of isopropanol, the mixture is heated to reflux reaction for 24 hours, after the reaction is finished, the mixture is filtered and evaporated to dryness under reduced pressure, 50mL of acetone and 0.8g of active carbon are added into the obtained residue, the mixture is heated and refluxed again for 2 hours, the active carbon is removed by filtration while the mixture is still hot, the temperature is slowly reduced to 4 ℃, the temperature is maintained at 4 ℃ for crystallization for 5 hours, and the mixture is filtered to obtain 10.01g of levetiracetam, and the yield is 84.01%, the purity measured by HPLC (high performance liquid chromatography) is 99.6%, and the ee value is 99.90%.
Comparative example one:
the product L-2-aminobutanamide hydrochloride commonly found in the market is purchased, and the resolution ratio of the product is 35.4% and the purity is 98.2%.
The resolution and purity of L-2-aminobutanamide hydrochloride of examples one to six were compared with the product yield and purity of the comparative example, and the comparison results thereof are shown in Table 1:
as can be seen from Table 1, the resolution and purity of the obtained L-2-aminobutanamide hydrochloride are higher than those of products sold in the market by adopting an asymmetric resolution method.
TABLE 1
| Project | Resolution (%) | Purity (%) |
| Example 1 | 96.18 | 99.6 |
| Example two | 96.03 | 99.5 |
| Example III | 95.89 | 99.7 |
| Example IV | 95.53 | 99.5 |
| Example five | 95.67 | 99.6 |
| Example six | 95.96 | 99.6 |
| Comparative example one | 35.4 | 98.2 |
Comparative example two:
the yield of the product levetiracetam is 35.4% and the purity is 98.2% as the product commonly found on the market is purchased.
The yields and purities of levetiracetam of examples one to six were compared with those of the comparative examples, and the comparison results are shown in table 1:
as can be seen from Table 2, the yield and purity of levetiracetam produced by the method for synthesizing the medicament for treating epilepsy by using L-2-aminobutanamide hydrochloride are higher than those of products sold in the market.
TABLE 2
| Project | Yield (%) | Purity (%) |
| Example 1 | 84.87 | 99.8 |
| Example two | 86.28 | 99.7 |
| Example III | 83.43 | 99.7 |
| Example IV | 85.02 | 99.8 |
| Example five | 84.60 | 99.8 |
| Example six | 84.01 | 99.6 |
| Comparative example | 60.8 | 98.2 |
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (3)
1. A method for synthesizing a medicament for treating epilepsy by using L-2-aminobutanamide hydrochloride, which is characterized by comprising the following steps of: the medicine for treating epilepsy is levetiracetam;
the method is characterized in that L-2-aminobutanamide hydrochloride and 4-chlorobutyrate are added into isopropanol under the protection of nitrogen, nucleophilic substitution reaction and ring closure reaction are carried out under the action of alkaline substances and catalysts by heating and refluxing, and the medicine for treating epilepsy is obtained, wherein the specific chemical reaction formula is as follows:
wherein R is methyl or ethyl,
the L-2-aminobutanamide hydrochloride is prepared by adding 2-aminobutanamide into a solvent, adding an inducer glyceraldehyde and a resolving agent L-tartaric acid, heating for asymmetric resolution, filtering, adding the obtained double salt into 30-36 wt% of concentrated hydrochloric acid for separation, and dripping ethanol for precipitation, wherein the specific chemical reaction formula is as follows:
the temperature of the asymmetric splitting is 60-80 ℃ and the time is 5-8 h;
the separation temperature is room temperature and the separation time is 1-2 hours,
the molar ratio of the 2-aminobutanamide, glyceraldehyde and L-tartaric acid is 1:0.3 to 0.8:1 to 1.2;
the weight-volume ratio of the 2-aminobutanamide to the solvent is 1g: 5-10 mL;
the molar ratio of the 2-aminobutanamide to the concentrated hydrochloric acid is 1:1.1 to 1.3 percent of the total weight of the composite,
the molar ratio of the 4-chlorobutyrate to the L-2-aminobutanamide hydrochloride is 1.0-2.0: 1,
the molar ratio of the alkaline substance to the L-2-aminobutanamide hydrochloride is 2-4: 1,
the molar ratio of the catalyst to the L-2-aminobutanamide hydrochloride is 0.1-0.3: 1,
the alkaline substance is sodium bicarbonate.
2. The method for synthesizing a medicament for treating epilepsy by using L-2-aminobutanamide hydrochloride according to claim 1, wherein: the solvent is ethanol, n-propanol or isopropanol.
3. The method for synthesizing a medicament for treating epilepsy by using L-2-aminobutanamide hydrochloride according to claim 1, wherein: the catalyst is sodium iodide or potassium iodide.
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| JP2002253294A (en) * | 2001-03-02 | 2002-09-10 | Mitsubishi Gas Chem Co Inc | Method for producing optically active aliphatic amino acid amide |
| CN1288133C (en) * | 2003-08-20 | 2006-12-06 | 天津泰普药品科技发展有限公司 | Synthesis of (S)-alpha-ethyl-2-oxi-1-pentazane acetamide |
| EP1879861A2 (en) * | 2005-04-01 | 2008-01-23 | Rubamin Laboratories Limited | Process for preparing levetiracetam and racemization of (r)- and (s)-2-amino butynamide and the corresponding acid derivatives |
| JP2007191470A (en) * | 2005-12-19 | 2007-08-02 | Nippon Shokubai Co Ltd | Method for producing optically active 2-aminobutanamide or its salt |
| CN101955439A (en) * | 2009-07-14 | 2011-01-26 | 华东理工大学 | Method for resolving alpha-substituted-2-amino acetamide |
| CN102382027B (en) * | 2011-09-20 | 2013-11-13 | 浙江江北药业有限公司 | Method for preparing levetiracetam |
| CN102584622B (en) * | 2012-02-15 | 2013-08-14 | 雅本化学股份有限公司 | Preparation method of L-2-aminobutanamide hydrochloride |
| CN108239016A (en) * | 2016-12-23 | 2018-07-03 | 上虞京新药业有限公司 | A kind of method for preparing Levetiracetam |
| CN109678752B (en) * | 2018-12-27 | 2021-11-16 | 南京红杉生物科技有限公司 | Method for synthesizing L-2-aminobutanamide hydrochloride by asymmetric transformation |
| CN109503408B (en) * | 2019-01-07 | 2021-12-21 | 宁波赜军医药科技有限公司 | Resolution method of (S) - (+) -2-aminobutanamide hydrochloride |
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Denomination of invention: Method for synthesizing drugs for treating epilepsy using L-2-aminobutylamide hydrochloride Effective date of registration: 20230913 Granted publication date: 20230606 Pledgee: Industrial and Commercial Bank of China Limited Cangzhou Bohai New Area Branch Pledgor: CANGZHOU SENARY CHEMICAL SCIENCE-TEC CO.,LTD. Registration number: Y2023980056576 |