A method for preparing high purity levetiracetam

Abstract

This invention relates to the preparation of high-purity levetiracetam (S)-2-(2-oxo-1-pyrrolidine)butyramide. The preparation of the high-purity levetiracetam begins with 2-(2-oxopyrrolidine-1-yl)butyric acid as the starting material. Through esterification and ammonolysis, a racemic levetiracetam is obtained, which is then resolved by R-mandelic acid to yield high-purity levetiracetam with a chiral content of over 99.9%, a chiral isomer content of less than 0.05%, and no chloride detected. The chiral isomer (R)-2-(2-oxo-1-pyrrolidine)butyramide recovered after resolution can be racemed and further resolved by R-mandelic acid for the preparation of levetiracetam, achieving a total yield of over 90%. The recovered R-mandelic acid can be reused repeatedly, significantly reducing the consumption of resolving agent. This reaction has a short procedure, is easy to operate, and has a stable yield, which significantly reduces the cost of preparing levetiracetam. In addition, it has a very high chiral content, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical drug synthesis technology, and specifically to the synthesis of high-purity levetiracetam. Background Technology

[0002] Levetiracetam, chemically named (S)-2-(2-oxo-1-pyrrolidine)butyramide, is an antiepileptic drug developed by UBC Pharmaceuticals in Belgium. Clinically, it is mainly used as adjunctive therapy for partial seizures in adults and children aged 4 years and older with epilepsy. Its molecular formula is C8H2O. 14 N2O2, with a molecular weight of 170.21, has the following structural formula:

[0003] .

[0004] Levetiracetam was initially marketed in Europe and the United States in 1999 for the treatment of partial-onset seizures in adults. In June 2005, its oral tablets and injectable formulations were approved for marketing, primarily for adjunctive treatment of partial-onset seizures in adults and children aged 4 years and older with epilepsy. In March 2007, levetiracetam was launched in China under the brand name Keppra.

[0005] Levetiracetam, as an antiepileptic drug, has a low plasma protein binding rate, making it less likely to cause significant clinical interactions due to competition with other drugs for protein binding sites. Levetiracetam has more ideal pharmacokinetics than other antiepileptic drugs, and due to its easy absorption, high bioavailability, low toxicity, and good tolerability, it occupies a pivotal position in the current antiepileptic drug series. Furthermore, levetiracetam is currently the only antiepileptic drug that can prevent epileptic seizures.

[0006] Regarding the preparation of levetiracetam, there are currently several publicly reported synthetic routes, mainly including chemical resolution, non-synthetic synthesis, enzymatic hydrolysis, and synthesis methods using aminobutyramide as a starting material. However, these methods generally have disadvantages such as low overall yield, high environmental pollution, high raw material cost, low chiral content, and / or long synthesis steps, resulting in the current high price of levetiracetam.

[0007] The original research company, UBC Pharmaceuticals in Belgium, synthesized levetiracetam using a chemical resolution method. Starting with racemic 2-(2-oxo-1-pyrrolidine)butyric acid, chiral resolution was performed in pure benzene using R-α-methylbenzylamine as a resolving agent to obtain the methylbenzylamine salt of (S)-2-(2-oxo-1-pyrrolidine)butyric acid. This salt was then dissociated under strongly alkaline conditions, reacted with ethyl chloroformate, and subsequently subjected to ammonolysis with ammonia to generate levetiracetam. This method uses pure benzene as the resolution solvent, which is highly toxic and environmentally unfriendly. Furthermore, the chiral isomer (R)-2-(2-oxo-1-pyrrolidine)butyric acid is discarded as organic waste. The reaction process is lengthy, resulting in a relatively low overall yield.

[0008] US Patent (Publication No.: US20050182262A) discloses a synthetic route using S-2-aminobutyrate as a starting material. The route involves reacting with thionyl chloride in methanol to form an acyl chloride, followed by esterification with methanol to obtain S-2-aminobutyrate methyl hydrochloride. The S-2-aminobutyrate methyl hydrochloride undergoes ammonolysis in ammonia to give S-2-aminobutyramide hydrochloride, which then undergoes a condensation reaction with 4-chlorobutyryl chloride. Finally, it is cyclized in potassium hydroxide to obtain levetiracetam. This synthetic route is relatively long, and the chlorinating agents used are thionyl chloride, phosphorus pentachloride, or oxalyl chloride, all of which have high toxicity or corrosiveness and cause significant environmental pollution. Chinese patent (publication number: CN104860863A) reports a one-pot synthesis of levetiracetam using S-2-aminobutyramide and 4-chlorobutyryl chloride as starting materials. This is essentially the same route reported in US patent (publication number: US20050182262A) and lacks originality. The synthetic routes reported in Chinese patents CN85105301 and CN03130585.7 are also largely consistent with those reported in US patent (publication number: US20050182262A) and Chinese patent (publication number: CN104860863A), with only minor adjustments and modifications to specific details of the synthesis process.

[0009] US Patent (US4696943) discloses a synthetic route using α-pyrrolidone as a starting material. First, levetiracetam acid is synthesized, then resolved using R-α-phenylethylamine to obtain S-type levetiracetam acid. Following esterification and ammonolysis, levetiracetam is finally obtained. This synthetic route represents an early process for obtaining levetiracetam, but it involves lengthy reaction steps, low overall yield, and significant difficulties in recovering and reusing the resolving agent, resulting in high resolving agent costs, making it unsuitable for large-scale industrial production.

[0010] A Chinese literature report (Yang Yan et al., A new method for process optimization of the antiepileptic drug levetiracetam, Journal of East China University of Science and Technology (Natural Science Edition), 2013, 39(3): 307) publicly reported a method for preparing levetiracetam using S-α-ethyl-2-oxo-1-pyrrolidineacetic acid as the starting material in a one-pot process. This synthetic route is relatively short and has a high overall yield, but the starting material S-α-ethyl-2-oxo-1-pyrrolidineacetic acid is expensive and difficult to purchase. Furthermore, the known impurity S-α-ethyl-2-oxo-1-pyrrolidineacetic acid in the levetiracetam obtained by this synthetic method cannot meet the pharmacopoeia's impurity limit requirement of 0.05%, requiring multiple purifications.

[0011] Chinese patent (publication number: CN101550100A) discloses a process for preparing levetiracetam from L-threonine as a starting material via esterification, chlorination, catalytic reduction, ammonolysis, and cyclization. This process has a long synthetic route, the thionyl chloride used in the chlorination reaction is highly corrosive and has lachrymatory properties, causing significant environmental pollution, and the metal catalysts such as palladium on carbon and rhodium on carbon used in the reduction reaction are very expensive, greatly increasing the overall cost.

[0012] Currently known synthetic processes for levetiracetam generally suffer from drawbacks such as high cost, long synthetic routes, low overall yield, significant environmental pollution, and / or excessive impurities. There is an urgent need for a new synthetic process to address these problems. Summary of the Invention

[0013] This invention addresses the numerous problems existing in the above-mentioned existing synthesis processes by providing a novel process for the synthesis of high-purity levetiracetam.

[0014] To achieve the above objectives, the present invention provides the following synthetic technology solution:

[0015] A method for preparing high-purity levetiracetam, an anti-epileptic drug, using 2-(2-oxopyrrolidone-1-yl)butyric acid (compound II) as a starting material includes the following steps:

[0016] Step 1: Add 2-(2-oxopyrrolidone-1-yl)butyric acid (compound II) to an alcohol, then add concentrated sulfuric acid as a catalyst to undergo esterification, yielding compound III. Then, pass ammonia gas through the solution to carry out ammonolysis, yielding the racemic levetiracetam (compound IV). The chemical reaction formula is as follows:

[0017] .

[0018] Step 2: Add the racemic levetiracetam (compound IV) obtained in the previous step to chloroform until completely dissolved. Then add R-mandelic acid (compound V), heat the reaction, cool to crystallize, and filter to obtain the R-mandelic acid salt of (S)-2-(2-oxo-1-pyrrolidine)butyramide (compound VI). Recover (R)-2-(2-oxo-1-pyrrolidine)butyramide (devetiracetam, compound VII) from the filtrate. After racemization, it can be further resolved with R-mandelic acid to prepare levetiracetam. The chemical reaction formula is as follows:

[0019] .

[0020] Step 3: Dissolve the R-mandelic acid salt of (S)-2-(2-oxo-1-pyrrolidine)butyramide (compound VI) in chloroform, then add potassium hydroxide for solid dissociation, filter, recover R-mandelic acid from the filter cake, evaporate the chloroform from the filtrate under reduced pressure, and then add acetone to crystallize, thus obtaining high-purity (S)-2-(2-oxo-1-pyrrolidine)butyramide (levetiracetam), with a chiral content >99.9% and no detected chloride. The chemical reaction formula is as follows:

[0021] .

[0022] In step one, compound II undergoes an esterification reaction in methanol, ethanol, or isopropanol, where the carboxylic acid and the hydroxyl group of the alcohol are catalyzed by concentrated sulfuric acid to generate the corresponding ester. Methanol is preferred as the alcohol used here, and the reaction temperature is 20-40℃, preferably 28-32℃.

[0023] In step two, the solvent used for the salt separation of compound IV and compound V is one or more of chloroform, dichloroethane, and dichloromethane in any ratio, preferably chloroform. The weight ratio of compound IV to chloroform is 1:8~15, preferably 1:10. The molar ratio of compound IV to compound V is 1:0.4-0.6, preferably 1:0.5. The mandelic acid salt of levetiracetam is obtained after separation. The mother liquor is concentrated to dryness and then recovered to obtain (R)-2-(2-oxo-1-pyrrolidine)butyramide (compound VII). Racemization in ethyl acetate and hydrochloric acid yields compound IV, which can be further separated with R-mandelic acid to obtain levetiracetam.

[0024] In step three, the dissociation solvent for compound VI can be chloroform, dichloroethane, dichloromethane, or any combination thereof, with chloroform being preferred. The base used for dissociation can be sodium hydroxide, potassium hydroxide, potassium carbonate, etc., with potassium hydroxide being preferred. After dissociation, R-mandelic acid is first recovered by filtration, which can then be used for the resolution of compound IV to prepare levetiracetam. After the filtrate is concentrated to dryness, acetone is added to induce crystallization, yielding high-purity levetiracetam. Detailed Implementation

[0025] The present invention will be further illustrated by the following examples, but they are not intended to limit the present invention.

[0026] Example 1 Preparation of Compound IV

[0027] 1500g methanol, 20g concentrated sulfuric acid, and 100g 2-(2-oxopyrrolidone-1-yl)butyric acid were added to a 3000ml three-necked flask. The mixture was stirred at 30℃±2℃ for 8 hours. Liquid chromatography analysis showed that the residual 2-(2-oxopyrrolidone-1-yl)butyric acid was less than 0.3%, at which point the reaction was stopped, yielding methyl 2-(2-oxopyrrolidone-1-yl)butyrate. The reaction system was then cooled to 0-5℃, and ammonia gas was introduced for 3 hours. Liquid chromatography analysis showed that the residual methyl 2-(2-oxopyrrolidone-1-yl)butyrate was <0.2%, at which point ammonia introduction was stopped. The mixture was then distilled under reduced pressure at a water bath temperature of 30-35℃ to recover methanol. The residue was compound IV, with a dry weight of approximately 96.5g, yielding 97.1%.

[0028] Example 2 Preparation of Compound IV

[0029] 1500g ethanol, 20g concentrated sulfuric acid, and 100g 2-(2-oxopyrrolidone-1-yl)butyric acid were added to a 3000ml three-necked flask. The mixture was stirred at 30℃±2℃ for 8 hours. Liquid chromatography analysis showed that the residual 2-(2-oxopyrrolidone-1-yl)butyric acid was less than 0.3%, at which point the reaction was stopped, yielding ethyl 2-(2-oxopyrrolidone-1-yl)butyrate. The reaction system was then cooled to 0-5℃, and ammonia gas was introduced for 3 hours. Liquid chromatography analysis showed that the residual ethyl 2-(2-oxopyrrolidone-1-yl)butyrate was <0.2%, at which point ammonia introduction was stopped. The mixture was then distilled under reduced pressure at a water bath temperature of 30-35℃ to recover methanol. The residue was compound IV, with a dry weight of approximately 95.8g, yielding 96.4%.

[0030] Example 3 Preparation of Compound VI

[0031] Add 50g of 2-(2-oxopyrrolidone-1-yl)butyramide and 500g of chloroform to a 1000ml three-necked flask. Heat to about 50℃. The 2-(2-oxopyrrolidone-1-yl)butyramide is completely dissolved. Add 22g of R-mandelic acid. Continue stirring at about 50℃ for 2 hours. Then slowly cool down. After about 2 hours, the temperature drops below ℃. Crystallize at 0-5℃ for 4 hours. Filter. Dry the filter cake under reduced pressure at 40℃ for 5 hours to obtain 45g of compound VI, with a yield of 47.8%.

[0032] Example 4 Preparation of Compound VI

[0033] 80g of 2-(2-oxopyrrolidone-1-yl)butyramide and 720g of dichloroethane were added to a 1000ml three-necked flask. The temperature was raised to about 60℃, and the 2-(2-oxopyrrolidone-1-yl)butyramide was completely dissolved. 35.2g of R-mandelic acid was added, and the temperature was maintained at about 60℃ and stirred for 2 hours. Then the temperature was slowly lowered, and after about 2 hours, the temperature dropped to below 5℃. Crystallization was carried out at 0-5℃ for 4 hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 40℃ for 5 hours to obtain 71.5g of compound VI (dry product), with a yield of 47.5%.

[0034] Example 5: Recovery of Compound IV

[0035] 500g of the chloroform mother liquor from the preparation of levetiracetam R-mandelic acid was evaporated to dryness under reduced pressure at 40°C. The chloroform was recovered, and the residue was (R)-2-(2-oxo-1-pyrrolidine)butyramide (compound VII). 300g of ethyl acetate and 30g of hydrochloric acid were added to the residue, and the mixture was stirred at 25°C for 24 hours. 450g of water was added, and the pH was adjusted to 6.5-7 with saturated sodium carbonate. The mixture separated into layers; the aqueous layer was discarded, and the ethyl acetate layer was concentrated to dryness under reduced pressure. The residue was the recovered compound IV, which can be directly resolved by R-mandelic acid for the preparation of levetiracetam.

[0036] Example 6 Preparation of Compound VI

[0037] 50g of recovered racemic 2-(2-oxopyrrolidone-1-yl)butyramide (compound IV) and 500g of chloroform were added to a 1000ml three-necked flask. The temperature was raised to about 50℃, and the 2-(2-oxopyrrolidone-1-yl)butyramide was completely dissolved. 22g of recovered R-mandelic acid was added, and the temperature was maintained at about 50℃ and stirred for 2 hours. Then the temperature was slowly lowered, and after about 2 hours, the temperature dropped to below 5℃. Crystallization was carried out at 0-5℃ for 4 hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 40℃ for 5 hours to obtain 44.5g of compound VI, with a yield of 47.3%.

[0038] Example 7 Preparation of Compound VI

[0039] 80g of recovered racemic 2-(2-oxopyrrolidone-1-yl)butyramide (compound IV) and 720g of dichloroethane were added to a 1000ml three-necked flask. The temperature was raised to about 60℃, and the 2-(2-oxopyrrolidone-1-yl)butyramide was completely dissolved. 35.2g of recovered R-mandelic acid was added, and the temperature was maintained at about 60℃ and stirred for 2 hours. Then the temperature was slowly lowered, and after about 2 hours, the temperature dropped to below 5℃. Crystallization was carried out at 0-5℃ for 4 hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 40℃ for 5 hours to obtain 70.8g of compound VI (dry product), with a yield of 47.0%.

[0040] Example 8 Preparation of Compound I

[0041] 1000g of chloroform and 100g of levetiracetam R-mandelic acid salt (compound VI) were dissolved in a 2000ml three-necked flask by stirring at approximately 25°C. Then, 16g of potassium hydroxide was added, and the mixture was stirred at 25°C for 1 hour. A solid slowly precipitated out. The mixture was filtered, and the insoluble residue was the recovered R-mandelic acid. The filtrate was evaporated to dryness under reduced pressure at 30°C to recover the chloroform. 400g of acetone was added to the residue, and the mixture was cooled to 0-5°C to allow crystals to crystallize for 2 hours. The residue was filtered, and the filter cake was the levetiracetam. The mixture was dried under reduced pressure at 50°C for 4 hours to obtain 51.5g of compound I (dry product), with a yield of 97%, a chiral content of 99.92%, and no chloride detected.

[0042] Example 9 Preparation of Compound I

[0043] 1200g of dichloroethane and 100g of levetiracetam R-mandelic acid salt (compound VI) were dissolved in a 2000ml three-necked flask by stirring at approximately 25°C. Then, 16g of potassium hydroxide was added, and the mixture was stirred at 25°C for 1 hour. A solid slowly precipitated out. The mixture was filtered, and the insoluble residue was the recovered R-mandelic acid. The filtrate was evaporated to dryness under reduced pressure at 30°C to recover dichloroethane. 400g of acetone was added to the residue, and the mixture was cooled to 0-5°C to crystallize for 2 hours. The residue was filtered, and the filter cake was the levetiracetam. The mixture was dried under reduced pressure at 50°C for 4 hours to obtain 51g of compound I (dry product), with a yield of 96.1%, a chiral content of 99.95%, and no chloride detected.

[0044] Example 10 Preparation of Compound I

[0045] 1000g of chloroform and 100g of levetiracetam R-mandelic acid salt (compound VI) were dissolved in a 2000ml three-necked flask by stirring at approximately 25°C. Then, 11.5g of sodium hydroxide was added, and the mixture was stirred at 25°C for 1 hour. A solid slowly precipitated out. The mixture was filtered, and the insoluble residue was the recovered R-mandelic acid. The filtrate was evaporated to dryness under reduced pressure at 30°C to recover the chloroform. 400g of acetone was added to the residue, and the mixture was cooled to 0-5°C to crystallize for 2 hours. The residue was filtered, and the filter cake was the levetiracetam. The mixture was dried under reduced pressure at 50°C for 4 hours to obtain 51.2g of compound I (dry product), with a yield of 96.4%, a chiral content of 99.93%, and no chloride detected.

[0046] Example 11 Preparation of Compound I

[0047] 1200g of dichloroethane and 100g of levetiracetam R-mandelic acid salt (compound VI) were dissolved in a 2000ml three-necked flask by stirring at approximately 25°C. Then, 11.4g of sodium hydroxide was added, and the mixture was stirred at 25°C for 1 hour. A solid slowly precipitated out. The mixture was filtered, and the insoluble residue was the recovered R-mandelic acid. The filtrate was evaporated to dryness under reduced pressure at 30°C to recover dichloroethane. 400g of acetone was added to the residue, and the mixture was cooled to 0-5°C to crystallize for 2 hours. The residue was filtered, and the filter cake was the levetiracetam. The levetiracetam was dried under reduced pressure at 50°C for 4 hours to obtain 50.5g of dried levetiracetam, with a yield of 95.1%, a chiral content of 99.96%, and no chloride detected.

Claims

1. A process for the preparation of high purity (S)-2-(2-oxo-l-pyrrolidine)butanamide (I) ###0001### (I) characterized in that The target compound is prepared by the following route: ； The synthesis steps are as follows: 1) 2-(2-oxopyrrolidin-1-yl)butyric acid (II) is subjected to esterification reaction in methanol solvent under the catalysis of concentrated sulfuric acid to obtain 2-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (III); wherein R is methyl, and the solvent used is methanol; 2) 2-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (III) is subjected to ammonolysis reaction in methanol solvent by passing in ammonia to obtain racemic 2-(2-oxo-1-pyrrolidine)butyramide (IV); after the ammonolysis reaction is completed, the solvent is evaporated and dried, chloroform is added, and the next step reaction is directly performed; the weight ratio of compound IV to chloroform is 1:8-15; 3) racemic 2-(2-oxo-1-pyrrolidine)butyramide (IV) is subjected to resolution into a salt by adding resolution agent R-mandelic acid (V) in chloroalkane to obtain (S)-2-(2-oxo-1-pyrrolidine)butyramide R-mandelate (VI); the weight ratio of compound IV to compound V is 1:0.4-0.6; the solvent used is one or more of chloroform, dichloromethane and dichloroethane in any ratio; 4) (S)-2-(2-oxo-1-pyrrolidine)butyramide R-mandelate (VI) is subjected to dissociation by adding potassium hydroxide in chloroform solvent to obtain high-purity levetiracetam (S)-2-(2-oxo-1-pyrrolidine)butyramide (I); The dissociation of compound VI is performed by using one or more of chloroform, dichloromethane and dichloroethane in any ratio as the solvent.

2. The method of claim 1, wherein: In preparation step 4), the base used for dissociation is sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate.

3. The method of claim 1, wherein: In preparation step 3), (R)-2-(2-oxo-1-pyrrolidine)butyramide (compound VII) recovered after resolution can be racemized to obtain compound IV in ethyl acetate solvent under the action of hydrochloric acid, and then subjected to re-resolution to prepare compound I.

4. The preparation method according to claim 1, characterized in that, In preparation step 4), compound V recovered after the dissociation of compound VI is continuously used for resolution to prepare compound VI.

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