Preparation method of high-purity levetiracetam

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of high-purity levetiracetam. According to the method, (S)-2-aminobutanamide hydrochloride and 4-chlorobutyryl chloride are used as raw materials, and high-purity levetiracetam is prepared through an acylation reaction, a cyclization reaction and a specific crystallization process. The preparation method of the levetiracetam is simple and convenient, simple to operate and low in cost, and also effectively avoids the risk of introducing a toxic impurity tetrabutylammonium bromide. By utilizing the method disclosed by the invention, the problems of low purity and yield of a product and high cost caused by the fact that tetrabutylammonium bromide is required to be added in a method for synthesizing levetiracetam in the prior art are effectively solved.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing high-purity levetiracetam. Background Art

[0002] Levetiracetam, chemical name is (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide, molecular formula is C 8 H 14 N 2 O 2 , molecular weight is 170.21, CAS number is 102767-28-2, and its structural formula is as follows:

[0003] Levetiracetam is a new type of anti-epileptic drug. Clinical results show that levetiracetam has a unique drug metabolism mechanism, which makes its efficacy fully exerted. It is suitable for a variety of different types of epileptic seizures, and has the characteristics of rapid onset, high safety, and strong tolerance. It not only has excellent efficacy, but also has high safety in the clinical treatment process, fewer side effects, and small antagonism with other drugs. When used in combination, it does not affect the efficacy of other drugs. There are two main methods for synthesizing levetiracetam. One is to use (S)-2-aminobutanamide hydrochloride and 4-chlorobutyryl chloride as raw materials, and under the catalytic action of tetrabutylammonium bromide, the target product levetiracetam is obtained by synchronous reaction of amidation and intramolecular cyclization. The other is to use (S)-2-aminobutanamide hydrochloride and 4-chlorobutyryl chloride as starting materials, and obtain an intermediate through acylation reaction; then use tetrabutylammonium bromide as a catalyst, and react the intermediate with a strong base to obtain levetiracetam through cyclization. Regardless of the method, tetrabutylammonium bromide is required as a catalyst, which will result in the risk of tetrabutylammonium bromide remaining in the final product, which may affect the product quality. Moreover, tetrabutylammonium bromide is irritating to the eyes, skin and respiratory tract, and can cause adverse symptoms such as redness, swelling or pain after contact, seriously endangering the personal safety of the operator.

[0004] Therefore, developing a method for preparing levetiracetam that is high-purity, safe and non-toxic has important practical significance. Summary of the invention

[0005] The methods for synthesizing levetiracetam in the prior art all require the addition of tetrabutylammonium bromide, which will result in low purity and yield of the product, resulting in the problem of increased cost. The present invention provides a preparation method of high-purity levetiracetam, which can not only obtain levetiracetam with higher yield and purity, but also avoid the risk of introducing toxic impurity tetrabutylammonium bromide, effectively ensuring the personal safety of operators.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions: The first aspect of the present invention provides a method for preparing high-purity levetiracetam, comprising the following steps: Step 1, using (S)-2-aminobutanamide hydrochloride and 4-chlorobutyryl chloride as raw materials for acylation reaction to obtain an acylation reaction solution; concentrating the acylation reaction solution to a mass volume ratio of 1g:9mL to 1g:12mL with the (S)-2-aminobutanamide hydrochloride to obtain an intermediate concentrated solution; crystallizing the intermediate concentrated solution to obtain a levetiracetam intermediate; Step 2, dispersing the levetiracetam intermediate and the water absorbent in a low boiling point organic solvent, adding a strong base in batches, performing a cyclization reaction, and obtaining a cyclization product; dissolving the cyclization product in a recrystallization solvent, crystallizing, and obtaining a crude levetiracetam; Step 3, dissolving the crude levetiracetam in a recrystallization solvent, and crystallizing to obtain levetiracetam; Wherein, in step 1, crystallization is performed by cooling to 0-10°C, heating to 20-35°C, and then cooling to 0-10°C; In step 2 and step 3, crystallization is performed by heating under reflux and gradually cooling to 0-10°C.

[0007] Compared to prior art, the present invention designs a kind of preparation method of high-purity levetiracetam, first with (S) -2- aminobutanamide hydrochloride and 4- chlorobutyryl chloride as raw materials for acylation reaction, obtain acylation reaction liquid, but the inventor finds through a large number of creative experiments, in the process of acylation reaction liquid reduced pressure concentration, a large amount of paste solids will be produced, it is impossible to stir, and it is necessary to add a large amount of anhydrous ether for dispersing the paste solid generated, resulting in crystallization process operation complexity, the intermediate quality obtained deteriorates. Based on this, the present invention is concentrated to a certain degree when reduced pressure concentration reaction solution just starts to carry out cooling crystallization process, after gradually separating out a large amount of pastes, concentrated solution is warming up to room temperature, the paste separated out can gradually change into the better solid of state, and then be reduced to a certain temperature to carry out crystallization process, can obtain better state and higher quality levetiracetam intermediate. This operation avoids adding a large amount of anhydrous ether for processing, saves preparation cost, saves crystallization time.

[0008] Moreover, the present invention does not need to add tetrabutylammonium bromide as a phase transfer catalyst during the cyclization reaction, and crystallization is performed by heating reflux and gradually cooling the crystallization method, so that a levetiracetam drug with high yield and good purity can be obtained, and the introduction of toxic impurity tetrabutylammonium bromide is effectively avoided, and the personal safety of the operator is guaranteed. The technical solution of the present invention effectively solves the problem that the method for synthesizing levetiracetam in the prior art needs to add tetrabutylammonium bromide, which will result in low purity and yield of the product, resulting in increased costs.

[0009] Preferably, in step one, crystallization is carried out by cooling to 0-5°C, heating to 25-30°C and then cooling to 0-5°C; in step two and step three, crystallization is carried out by heating under reflux and gradually cooling to 0-5°C.

[0010] Further preferably, in step one, the specific operation of crystallization comprises the following steps: cooling the intermediate concentrated solution to 0-5°C, stirring at this temperature for 50-70 minutes, then heating to 25-30°C, stirring at this temperature for 50-70 minutes, and finally cooling to 0-5°C, stirring at this temperature for 100-150 minutes.

[0011] Further preferably, in step 2, the specific operation steps of the crystallization are as follows: dissolving the cyclization product in a recrystallization solvent, reflux, keeping warm and stirring for 25min~35min, cooling to 20℃~30℃, keeping warm and stirring for 50min~70min, then cooling to 0~5℃, keeping warm and stirring for 100min~150min.

[0012] Further preferably, in step three, the crystallization process also includes a decolorization treatment, specifically comprising the following steps: dissolving the crude levetiracetam in a recrystallization solvent, refluxing, adding a decolorizing agent under reflux for decolorization for 20 min to 40 min, continuing to keep warm for 10 min to 20 min, filtering, cooling the filtrate to 20 ° C to 30 ° C, keeping warm and stirring for 50 min to 70 min, then cooling to 0 ~ 5 ° C, keeping warm and stirring for 100 min to 200 min.

[0013] More preferably, in step three, the decolorizing agent is medicinal charcoal.

[0014] More preferably, in step three, the amount of the decolorizing agent added is 2% to 5% of the quality of the crude levetiracetam.

[0015] Preferably, the recrystallization solvent is any one of ethyl acetate, acetone or ethanol.

[0016] Preferably, in step 1, the molar ratio of the (S)-2-aminobutanamide hydrochloride to the 4-chlorobutyryl chloride is 1:1.2 to 1:2.2.

[0017] Preferably, in step 1, the raw materials for the acylation reaction further include an acid binding agent, and the molar ratio of the (S)-2-aminobutanamide hydrochloride to the acid binding agent is 1:2 to 1:3.5.

[0018] Further preferably, in step 1, the acid binding agent is finely powdered potassium carbonate.

[0019] Preferably, in step 2, the water absorbing agent is anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0020] Preferably, in step 2, the molar ratio of the levetiracetam intermediate to the strong base is 1:1.5~1:2.

[0021] Preferably, in step 2, the mass ratio of the levetiracetam intermediate to the low-boiling point organic solvent is 1:9 to 1:15.

[0022] Preferably, in step 2, the mass ratio of the levetiracetam intermediate to the water absorbent is 1:1.0 to 1:2.0.

[0023] Preferably, in step 2, the low boiling point organic solvent is dichloromethane.

[0024] Preferably, in step three, the mass ratio of the crude levetiracetam to the recrystallization solvent is 1:1.5~1:7.5.

[0025] Preferably, in step 1, the temperature of the acylation reaction is 0-20° C., and the time of the acylation reaction is 3 h-6 h.

[0026] Preferably, in step 2, the temperature of the cyclization reaction is -5°C to 10°C, and the time of the cyclization reaction is 2h to 5h.

[0027] In summary, the present invention uses (S)-2-aminobutanamide hydrochloride and 4-chlorobutyryl chloride as raw materials, and synthesizes a high-purity levetiracetam through acylation reaction, cyclization reaction and unique crystallization process. The preparation method can not only obtain levetiracetam with better yield and purity, but also avoids the risk of introducing toxic impurity tetrabutylammonium bromide, and the technical solution of the present invention effectively solves the problem that the method for synthesizing levetiracetam in the prior art needs to add tetrabutylammonium bromide, which will lead to the problem of low purity and yield of the product and increased cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the H NMR spectrum of levetiracetam obtained in Example 1; Figure 2 This is the NMR carbon spectrum of levetiracetam obtained in Example 1; Figure 3 The mass spectrum of levetiracetam obtained in Example 1 is shown in FIG. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Example 1 This embodiment provides a method for preparing high-purity levetiracetam, which specifically includes the following contents: Step 1: Add 4.0 kg (S) -2-aminobutyramide hydrochloride and 72.0 kg acetonitrile to a 100L double-layer glass reactor, mix well, add 8.0 kg of fine powder potassium carbonate at 25 ° C, stir for 30 min, cool to 3 ° C, add 6.1 kg 4-chlorobutyryl chloride acetonitrile solution, wherein the mass percentage of 4-chlorobutyryl chloride is 55wt%, and carry out acylation reaction at 5 ° C for 5h. Filter, wash the solid filtrate twice with acetonitrile, 2 kg each time, combine the washing liquid and the filtrate to obtain an acylation reaction liquid; concentrate the acylation reaction liquid under reduced pressure to 45 L to obtain an intermediate concentrated liquid; crystallize the intermediate concentrated liquid, first cool it to 3°C, keep it warm and stir for 60 min, then heat it to 28°C, keep it warm and stir for 60 min, then cool it to 3°C, keep it warm and stir for 120 min, centrifuge, wash the filter cake with 1 kg of acetonitrile, vacuum dry the solid filtrate at 45°C for 5 h, and obtain 5.11 kg of levetiracetam intermediate, with a yield of 85.6% and a purity of 99.1%; Step 2, add 5.0kg of the levetiracetam intermediate and 5.0kg of anhydrous sodium sulfate to a 100L stainless steel reactor, suspend in 50.0kg of dichloromethane, stir at 28°C and 350rpm for 30min, cool to -3°C, add 2.5kg of potassium hydroxide in 5 batches, each with an interval of 30min, keep the reaction solution temperature no more than 10°C during addition, and after the addition is completed, carry out the cyclization reaction at 8°C for 3.5h, filter, and wash the solid filtrate twice with dichloromethane, 5.0kg each time, combine the filtrate and the washing liquid to obtain a cyclization reaction liquid; concentrate the cyclization reaction liquid, remove the solvent, add 25.0kg of acetone, heat to reflux, keep warm and stir for 30min, cool to 25°C, stir and crystallize for 60min, then cool to 2°C, stir and crystallize for 120min. Filter, wash the solid filtrate with 2 kg of acetone, and then vacuum dry the solid filtrate at 45° C. for 3 h to obtain 3.65 kg of crude levetiracetam, with a yield of 88.6%; Step 3, add 3.5kg of crude levetiracetam and 5.95kg of anhydrous ethanol to a 10L double-layer glass reactor, heat to reflux, insulate and stir for 30min, add 0.105kg of medicinal charcoal, insulate and stir for 30min under reflux, filter, transfer the filtrate to a 10L crystallization kettle, cool to 25°C, stir and crystallize for 60min, then cool to 3°C, stir and crystallize for 180min. Filter, wash the solid filtrate with 1.4kg of acetone, and then vacuum dry the solid filtrate at 45°C for 3h to obtain 2.76kg of levetiracetam. It is calculated that the yield is 78.9%, and the purity is 99.9% after testing, and no isomers are detected.

[0031] ESI-MS (m / z): 171.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 6.66 (br, 1H), 6.12 (br, 1H), 4.47-4.51 (m, 1H), 3.36-3.51 (m, 2H), 2.35 -2.48(m,2H), 1.89-2.11(m,3H), 1.61-1.72(m,1H), 0.87-0.92(t,3H). 13 C NMR (400 MHz, CDCl 3 ): 176.03, 172.66, 56.01, 43.85, 31.11, 21.22, 18.17, 10.56.

[0032] Example 2 This embodiment provides a method for preparing high-purity levetiracetam, which specifically includes the following contents: Step 1: Add 4.0 kg (S) -2-aminobutyramide hydrochloride and 72.0 kg acetonitrile to a 100L double-layer glass reactor, mix well, add 10.2 kg of fine powder potassium carbonate at 20 ° C, stir for 30 min, cool to 15 ° C, add 6.5 kg 4-chlorobutyryl chloride acetonitrile solution, wherein the mass percentage of 4-chlorobutyryl chloride is 55wt%, and carry out acylation reaction at 18 ° C for 4h. Filter, wash the solid filtrate twice with acetonitrile, 2 kg each time, combine the washing liquid and the filtrate to obtain an acylation reaction liquid; concentrate the acylation reaction liquid under reduced pressure to 48 L to obtain an intermediate concentrated liquid; crystallize the intermediate concentrated liquid, first cool to 8°C, keep warm and stir for 55 min, then heat to 27°C, keep warm and stir for 65 min, then cool to 5°C, keep warm and stir for 130 min, centrifuge, filter, wash the filter cake with 1 kg of acetonitrile, vacuum dry the solid filtrate at 45°C for 5 h, and obtain 4.98 kg of levetiracetam intermediate, with a yield of 83.4% and a purity of 99.1%; Step 2, add 4.9kg of the levetiracetam intermediate and 5.5kg of anhydrous magnesium sulfate to a 100L stainless steel reactor, suspend in 49.0kg of dichloromethane, stir for 30min at 22°C and 350rpm, cool to -3°C, add 2.6kg of potassium hydroxide in 5 batches, each with an interval of 30min, keep the reaction solution temperature no more than 10°C during addition, after the addition is completed, carry out cyclization reaction at 3°C ​​for 4h, filter, and wash the solid filtrate twice with dichloromethane. 5.0 kg each time, combining the filtrate and the washing liquid to obtain a cyclization reaction liquid; concentrating the cyclization reaction liquid, removing the solvent, adding 24.0 kg of ethyl acetate, heating to reflux, keeping warm and stirring for 30 minutes, cooling to 21°C, stirring and crystallizing for 60 minutes, cooling to 5°C, stirring and crystallizing for 120 minutes, filtering, washing the solid filtrate with 2 kg of ethyl acetate, and then vacuum drying the solid filtrate at 45°C for 3 hours to obtain 3.53 kg of crude levetiracetam, with a yield of 87.6%; Step 3, add 3.5kg of crude levetiracetam and 17kg of acetone to a 10L double-layer glass reactor, heat to reflux, keep warm and stir for 30min, add 0.11kg of medicinal charcoal, keep warm and stir for 40min under reflux, filter, transfer the filtrate to a 10L crystallization kettle, cool to 25°C, stir and crystallize for 70min, cool to 3°C, stir and crystallize for 150min, filter, wash the solid filtrate with 1.5kg of acetone, and then vacuum dry the solid filtrate at 45°C for 3h to obtain 2.90kg of levetiracetam. It is calculated that the yield is 82.9%, and the purity is 99.9% after testing, and no isomers are detected.

[0033] Example 3 This embodiment provides a method for preparing high-purity levetiracetam, which specifically includes the following steps: Step 1: Add 4.0 kg of (S)-2-aminobutyramide hydrochloride and 72.0 kg of acetonitrile to a 100 L double-layer glass reactor, mix evenly, add 6.0 kg of fine powder potassium carbonate at 20 °C, stir for 30 min, cool down to 8 °C, and add a 55 wt% acetonitrile solution of 5.3 kg of 4-chlorobutyryl chloride. Carry out an acylation reaction at 10 °C for 6 h, filter, wash the solid filter cake with acetonitrile twice, 2 kg each time, combine the washing liquid and the filtrate to obtain an acylation reaction solution; concentrate the acylation reaction solution under reduced pressure to 38 L to obtain an intermediate concentrate; crystallize the intermediate concentrate, first cool down to 7 °C, keep stirring for 65 min, then heat up to 30 °C, keep stirring for 50 min, then cool down to 2 °C, keep stirring for 130 min, centrifuge, filter, wash the filter cake with 1 kg of acetonitrile, and carry out vacuum drying on the solid filter cake at 45 °C for 5 h to obtain 5.15 kg of levetiracetam intermediate, with a yield of 86.3% and a purity of 99.2%. Step 2: Add 5.0 kg of the levetiracetam intermediate and 4.5 kg of anhydrous sodium sulfate to a 100 L stainless steel reactor, dissolve them in 50.0 kg of dichloromethane, stir at 26 °C and 350 rpm for 30 min, cool down to 0 °C, add 2.3 kg of potassium hydroxide in 5 batches, with an interval of 30 min each time, and keep the reaction solution temperature not exceeding 10 °C during the addition. After the addition is completed, carry out a cyclization reaction at 6 °C for 3.5 h, filter, wash the solid filter cake with dichloromethane twice, 5.0 kg each time, combine the filtrate and the washing liquid to obtain a cyclization reaction solution; concentrate the cyclization reaction solution to remove the solvent, add 23.0 kg of acetone, heat to reflux, keep stirring for 28 min, cool down to 22 °C, stir and crystallize for 58 min, then cool down to 1 °C, stir and crystallize for 150 min, filter, wash the solid filter cake with 2 kg of acetone, and then carry out vacuum drying on the solid filter cake at 45 °C for 3 h to obtain 3.55 kg of crude levetiracetam, with a yield of 86.2%. Step 3: Add 3.5 kg of crude levetiracetam and 19.5 kg of acetone to a 10 L double-layer glass reactor, heat to reflux, keep stirring for 30 min, add 0.14 kg of medicinal charcoal, keep stirring at reflux for 35 min, filter, transfer the filtrate to a 10 L crystallization kettle, cool down to 26 °C, stir and crystallize for 62 min, then cool down to 3 °C, stir and crystallize for 150 min, filter, wash the solid filter cake with 1.5 kg of acetone, and then carry out vacuum drying on the solid filter cake at 45 °C for 3 h to obtain 2.87 kg of levetiracetam. After calculation, the yield is 82.0%. After testing, the purity is 99.9%, and no isomers are detected.

[0034] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing high-purity levetiracetam, characterized in that: The steps include: Step 1, using (S)-2-aminobutanamide hydrochloride and 4-chlorobutyryl chloride as raw materials for acylation reaction to obtain an acylation reaction solution; concentrating the acylation reaction solution to a mass volume ratio of 1g:9mL to 1g:12mL with the (S)-2-aminobutanamide hydrochloride to obtain an intermediate concentrated solution; crystallizing the intermediate concentrated solution to obtain a levetiracetam intermediate; Step 2, dispersing the levetiracetam intermediate and the water absorbent in a low boiling point organic solvent, adding a strong base in batches, performing a cyclization reaction, and obtaining a cyclization product; dissolving the cyclization product in a recrystallization solvent, crystallizing, and obtaining a crude levetiracetam; Step 3, dissolving the crude levetiracetam in a recrystallization solvent, and crystallizing to obtain levetiracetam; Wherein, in step 1, crystallization is performed by cooling to 0-10°C, heating to 20-35°C, and then cooling to 0-10°C; In step 2 and step 3, crystallization is performed by heating under reflux and gradually cooling to 0-10°C.

2. The method for preparing high-purity levetiracetam according to claim 1, characterized in that: In step 1, crystallization is performed by cooling to 0-5°C, heating to 25-30°C and then cooling to 0-5°C; in step 2 and step 3, crystallization is performed by heating under reflux and gradually cooling to 0-5°C.

3. The method for preparing high-purity levetiracetam as claimed in claim 2, characterized in that: In step 1, the specific operation of the crystallization includes the following steps: cooling the intermediate concentrated solution to 0-5°C, stirring at this temperature for 50-70 minutes, then heating it to 25-30°C, stirring at this temperature for 50-70 minutes, and finally cooling it to 0-5°C, stirring at this temperature for 100-150 minutes.

4. The method for preparing high-purity levetiracetam according to claim 2, characterized in that: In step 2, the specific operation steps of the crystallization are as follows: dissolve the cyclization product in a recrystallization solvent, reflux, keep warm and stir for 25min~35min, cool to 20℃~30℃, keep warm and stir for 50min~70min, cool to 0~5℃, keep warm and stir for 100min~150min.

5. The method for preparing high-purity levetiracetam according to claim 2, characterized in that: In step three, the crystallization process also includes a decolorization treatment, which specifically includes the following steps: dissolving the crude levetiracetam in a recrystallization solvent, refluxing, adding a decolorizing agent under reflux for decolorization for 20 min to 40 min, continuing to keep warm for 10 min to 20 min, filtering, cooling the filtrate to 20 ° C to 30 ° C, keeping warm and stirring for 50 min to 70 min, then cooling to 0 ~ 5 ° C, keeping warm and stirring for 100 min to 200 min.

6. The method for preparing high-purity levetiracetam according to claim 5, characterized in that: In step 3, the decolorizing agent is medicinal charcoal; and / or In step 3, the amount of the decolorizing agent added is 2% to 5% of the quality of the crude levetiracetam.

7. The method for preparing high-purity levetiracetam according to claim 1 or 3, characterized in that: The recrystallization solvent is any one of ethyl acetate, acetone or ethanol.

8. The method for preparing high-purity levetiracetam according to claim 1, characterized in that: In step 1, the molar ratio of the (S)-2-aminobutanamide hydrochloride to the 4-chlorobutyryl chloride is 1:1.2 to 1:2.2; and / or In step 1, the raw materials for the acylation reaction also include an acid binding agent, and the molar ratio of the (S)-2-aminobutanamide hydrochloride to the acid binding agent is 1:2 to 1:3.

5.

9. The method for preparing high-purity levetiracetam according to claim 1, characterized in that: In step 2, the water absorbing agent is anhydrous sodium sulfate or anhydrous magnesium sulfate; and / or In step 2, the molar ratio of the levetiracetam intermediate to the strong base is 1:1.5 to 1:2; and / or In step 2, the mass ratio of the levetiracetam intermediate to the low boiling point organic solvent is 1:9 to 1:15; and / or In step 2, the mass ratio of the levetiracetam intermediate to the water absorbing agent is 1:1.0 to 1:2.0; and / or In step 3, the mass ratio of the crude levetiracetam to the recrystallization solvent is 1:1.5~1:7.

5.

10. The method for preparing high-purity levetiracetam according to claim 1, characterized in that: In step 1, the temperature of the acylation reaction is 0-20° C., and the time of the acylation reaction is 3 h-6 h; and / or In step 2, the temperature of the cyclization reaction is -5°C to 10°C, and the time of the cyclization reaction is 2h to 5h.

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