阅读说明：本技术 制备左乙拉西坦的方法 (Process for the preparation of levetiracetam ) 是由 王波 侯奇伟 康璐 于 2019-11-19 设计创作，主要内容包括：本发明涉及制备左乙拉西坦的方法,其包括如下步骤：使氨基丁酸在低级醇和氯化亚砜反应得到中间体I；加入氨水继续反应,加入盐酸调节pH至约3使成盐,得成盐的中间体II精制品；使中间体II在催化剂和二氯甲烷中在KOH存在下反应,接着添加4-氯丁酰氯继续反应；加水使水解后用稀盐酸调节至弱碱性,结晶后得到左乙拉西坦粗品；在乙酸乙酯中脱色并结晶,得到左乙拉西坦的精制品。本发明还涉及由此制得的左乙拉西坦,以及它们的制药用途,例如可用于治疗或预防癫痫、帕金森氏病、运动障碍、偏头痛、震颤、特发性震颤、双相性精神障碍、慢性疼痛、神经性疼痛、或者支气管、哮喘或者过敏病症。(The invention relates to a method for preparing levetiracetam, which comprises the following steps: reacting aminobutyric acid in lower alcohol and thionyl chloride to obtain an intermediate I; adding ammonia water for continuous reaction, adding hydrochloric acid to adjust the pH value to about 3 to salify, and obtaining a salified intermediate II refined product; reacting the intermediate II in a catalyst and dichloromethane in the presence of KOH, and then adding 4-chlorobutyryl chloride to continue the reaction; adding water to hydrolyze, adjusting to alkalescence by using dilute hydrochloric acid, and crystallizing to obtain a levetiracetam crude product; decoloring and crystallizing in ethyl acetate to obtain a refined levetiracetam product. The invention also relates to levetiracetam thus prepared and to the pharmaceutical use thereof, for example for the treatment or prophylaxis of epilepsy, Parkinson's disease, dyskinesias, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic conditions.)

1. A process for preparing levetiracetam comprising the steps of:

(1) suspending 0.5mol of (S) -2-aminobutyric acid in 10-15 equivalents of lower alcohol in a reaction bottle, dropwise adding 1-1.5 equivalents of reaction solvent thionyl chloride at the temperature of 20-30 ℃, slowly heating to 40-50 ℃ after dropwise adding, keeping warm and stirring for 4 hours to remove the solvent after reaction, concentrating under reduced pressure at 40-50 ℃ to evaporate the solvent, adding 2 equivalents of reaction solvent after the product is viscous, and stirring and cooling to-5 ℃ to form a suspension;

(2) slowly adding 6-10 equivalents of cold (0 ℃) ammonia water into a reaction bottle of the suspension obtained in the previous step, stirring to react for 5-7 hours, heating to 15-25 ℃, continuously stirring for 3-4 hours to finish the reaction, adding 0.2 equivalent of ethanol, distilling the ammonia water under reduced pressure at 85 ℃ until a large amount of products are separated out, then adding 6 equivalents of methanol, stirring and heating to reflux, adding hydrochloric acid to adjust the pH value to 3.0-3.5, continuously heating to clarify the materials, stirring for 2-3 hours at a constant temperature to form salt, then distilling under reduced pressure to remove the methanol, adding 1.5 equivalents of ethyl acetate (or petroleum ether, toluene and isopropyl ether) when a large amount of white products are separated out, stirring for 2 hours at 50 ℃, centrifuging, washing a solid product with ethyl acetate, filtering, and drying a filter cake under reduced pressure at 60-80 ℃ to obtain a refined salt-formed intermediate II product;

(3) sequentially adding 0.5mol of the intermediate II, 0.02-0.1 equivalent of catalyst and 20 equivalents of dichloromethane into a reaction bottle, and cooling to-10 ℃ by using circulating cooling liquid; slowly adding 3 equivalents of KOH under rapid stirring, naturally heating to 20-30 ℃, and stirring for reacting for 45-60 min; cooling to below-5 ℃, slowly dropping a mixed solution prepared from 1-1.2 equivalents of 4-chlorobutyryl chloride and 3.5 equivalents of dichloromethane, and continuously stirring at 0 +/-5 ℃ for 2-3 hours after the addition; continuously cooling to-15-10 ℃, slowly adding 1 equivalent of KOH, reacting at 0 +/-5 ℃ for 2-3 hours after the addition is finished, quickly filtering the reaction liquid by using a filter, fully washing filter residues by using 0.5 equivalent of dichloromethane, and combining washing filtrate;

(4) adding 0.5 equivalent of purified water into the washing filtrate, stirring and hydrolyzing for 30-60 min, adjusting the pH value to be alkalescent with the pH value of 7-9 by using dilute hydrochloric acid, standing and layering, and separating liquid to obtain an organic layer; adding dichloromethane into the water layer for extraction; mixing the dichloromethane of the extract liquid and dichloromethane obtained by separating liquid, adding anhydrous sodium sulfate for drying, then filtering by using a filter, fully washing filter residues by using dichloromethane, mixing washing filtrate (namely mixed solution of the filtrate and washing liquid), adding acetone with the weight of 2 times, stirring and crystallizing at 50 ℃ for 1h, cooling to-10 ℃, then stirring and crystallizing for 2-3 h, carrying out suction filtration, and washing a crystallized product by using cold (-10 ℃) ethyl acetate to obtain a crude product of levetiracetam;

(5) adding the levetiracetam crude product into a reaction bottle, adding 3 times of ethyl acetate by weight, heating and refluxing to clarify, adding 0.5-1 w/v% of medicinal carbon, refluxing, stirring and decoloring for 0.5-1 h, filtering while hot, concentrating the filtrate at 40-50 ℃ under reduced pressure until a large amount of white solid is separated out, cooling to-10 ℃, stirring and crystallizing for 2-3 h, centrifuging, collecting a crystallized product, and drying at 45-50 ℃ to obtain the levetiracetam refined product.

2. The process according to claim 1, wherein in step (1), the lower alcohol is selected from the group consisting of methanol, ethanol, isopropanol; methanol is preferred.

3. The process according to claim 1, wherein in the step (1), 0.5mol of (S) -2-aminobutyric acid is suspended in 12 equivalents of the lower alcohol.

4. The process according to claim 1, wherein in the step (1), 1.2 equivalents of thionyl chloride as a reaction solvent is added dropwise.

5. The process according to claim 1, wherein in step (3), the catalyst is selected from the group consisting of: tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride and benzyltriethylammonium chloride.

6. The process according to claim 1, wherein in step (3), the amount of the catalyst is 0.05 equivalent.

7. The process according to claim 1, wherein the amount of the 4-chlorobutyryl chloride in step (3) is 1 equivalent.

8. The method according to claim 1, wherein in the step (2), 0.2 to 0.3 equivalent of oleic acid is added simultaneously with the addition of the cold ammonia water; and/or, in the step (3), 0.1 to 0.2 equivalent of chlorobutanol is added at the same time of adding 4-chlorobutyryl chloride.

9. Levetiracetam prepared according to a process comprising the steps of:

(1) suspending 0.5mol of (S) -2-aminobutyric acid in 10-15 equivalents of lower alcohol in a reaction bottle, dropwise adding 1-1.5 equivalents of reaction solvent thionyl chloride at the temperature of 20-30 ℃, slowly heating to 40-50 ℃ after dropwise adding, keeping warm and stirring for 4 hours to remove the solvent after reaction, concentrating under reduced pressure at 40-50 ℃ to evaporate the solvent, adding 2 equivalents of reaction solvent after the product is viscous, and stirring and cooling to-5 ℃ to form a suspension;

(2) slowly adding 6-10 equivalents of cold (0 ℃) ammonia water into a reaction bottle of the suspension obtained in the previous step, stirring to react for 5-7 hours, heating to 15-25 ℃, continuously stirring for 3-4 hours to finish the reaction, adding 0.2 equivalent of ethanol, distilling the ammonia water under reduced pressure at 85 ℃ until a large amount of products are separated out, then adding 6 equivalents of methanol, stirring and heating to reflux, adding hydrochloric acid to adjust the pH value to 3.0-3.5, continuously heating to clarify the materials, stirring for 2-3 hours at a constant temperature to form salt, then distilling under reduced pressure to remove the methanol, adding 1.5 equivalents of ethyl acetate (or petroleum ether, toluene and isopropyl ether) when a large amount of white products are separated out, stirring for 2 hours at 50 ℃, centrifuging, washing a solid product with ethyl acetate, filtering, and drying a filter cake under reduced pressure at 60-80 ℃ to obtain a refined salt-formed intermediate II product;

(3) sequentially adding 0.5mol of the intermediate II, 0.02-0.1 equivalent of catalyst and 20 equivalents of dichloromethane into a reaction bottle, and cooling to-10 ℃ by using circulating cooling liquid; slowly adding 3 equivalents of KOH under rapid stirring, naturally heating to 20-30 ℃, and stirring for reacting for 45-60 min; cooling to below-5 ℃, slowly dropping a mixed solution prepared from 1-1.2 equivalents of 4-chlorobutyryl chloride and 3.5 equivalents of dichloromethane, and continuously stirring at 0 +/-5 ℃ for 2-3 hours after the addition; continuously cooling to-15-10 ℃, slowly adding 1 equivalent of KOH, reacting at 0 +/-5 ℃ for 2-3 hours after the addition is finished, quickly filtering the reaction liquid by using a filter, fully washing filter residues by using 0.5 equivalent of dichloromethane, and combining washing filtrate;

(4) adding 0.5 equivalent of purified water into the washing filtrate, stirring and hydrolyzing for 30-60 min, adjusting the pH value to be alkalescent with the pH value of 7-9 by using dilute hydrochloric acid, standing and layering, and separating liquid to obtain an organic layer; adding dichloromethane into the water layer for extraction; mixing the dichloromethane of the extract liquid and dichloromethane obtained by separating liquid, adding anhydrous sodium sulfate for drying, then filtering by using a filter, fully washing filter residues by using dichloromethane, mixing washing filtrate (namely mixed solution of the filtrate and washing liquid), adding acetone with the weight of 2 times, stirring and crystallizing at 50 ℃ for 1h, cooling to-10 ℃, then stirring and crystallizing for 2-3 h, carrying out suction filtration, and washing a crystallized product by using cold (-10 ℃) ethyl acetate to obtain a crude product of levetiracetam;

(5) adding the levetiracetam crude product into a reaction bottle, adding 3 times of ethyl acetate by weight, heating and refluxing to clarify, adding 0.5-1 w/v% of medicinal carbon, refluxing, stirring and decoloring for 0.5-1 h, filtering while hot, concentrating the filtrate at 40-50 ℃ under reduced pressure until a large amount of white solid is separated out, cooling to-10 ℃, stirring and crystallizing for 2-3 h, centrifuging, collecting a crystallized product, and drying at 45-50 ℃ to obtain the levetiracetam refined product.

10. Use of levetiracetam prepared by the process of any one of claims 1-8 or levetiracetam of claim 9 in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: epileptogenic diseases, seizure disorders, convulsions, Parkinson's disease, dyskinesias induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs, Huntington's chorea and other neurological disorders including bipolar disorder, mania, depression, anxiety, attention deficit disorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmias, myotonia, ***e abuse, stroke, myoclonus, tremor, essential tremor, simple or complex tics, tourette's syndrome, restless leg syndrome and other movement disorders, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthma persistence and allergic bronchitis, asthma syndrome, bronchial hyperresponsiveness and bronchospatic syndromes, as well as allergic and vasomotor rhinitis and rhinoconjunctivitis; in particular for the preparation of a medicament for the treatment or prevention of a disease or condition selected from: epilepsy, Parkinson's disease, movement disorders, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic conditions.

Technical Field

The present invention relates to a novel process for the preparation of levetiracetam having the excellent properties as described herein.

Background

European patent EP0162036B discloses a levorotatory compound Levetiracetam (Levetiracetam) with chemical name of (S) - (-) - [ alpha ] -ethyl-2-oxo-1-pyrrolidineacetamide, (-) - (S) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide. Molecular formula C8H14N2O2, molecular weight 170.21, and chemical structural formula as follows:

levetiracetam is a white to off-white crystalline powder that is readily soluble in water (1.04g/mL), chloroform (653mg/mL) and methanol (536mg/mL), soluble in ethanol (165mg/mL), slightly soluble in acetonitrile (57 mg/mL).

Levetiracetam is a cholinergic agonist. The drug is very effective on an animal model of epileptic seizure induced by ignition and chemistry, but is ineffective in an animal model of superstrong electric shock and pentaerythrine seizure, suggesting that the action mechanism is different from other effective AEDs. The exact mechanism of action of levetiracetam is unknown and studies suggest that it binds specifically to a site on the central nervous system cell membrane and is thought to be associated with its antiepileptic effects. The medicine can be used as protective agent for treating and preventing central nervous system hypoxia and local blood group attack. The compounds are effective in the treatment of epilepsy for which the dextro enantiomer (R) - (-) - [ alpha ] -ethyl-2-oxo-1-pyrrolidineacetamide has been shown to be completely inactive (AJ. Gowe et al, Eur. J. Pharmacol., 222, 1992, 193-203).

Levetiracetam is a pyrrolidone derivative, and the chemical structure of levetiracetam is unrelated to the chemical structure of the existing antiepileptic drugs. The anti-epileptic effect of levetiracetam was evaluated in a number of anti-epileptic animal models. Levetiracetam has no inhibitory effect on simple seizures induced by maximal stimulation with electric current or multiple startling agents and shows only weak activity in sub-maximal stimulation and threshold tests. Protection was observed against systemic seizures secondary to pilocarpine and monarda amino acid-induced focal seizures, and these two chemical convulsants mimic the characteristics of some people's complex partial seizures with secondary systemic seizures. Levetiracetam has inhibitory effects on both the light-off process and the light-off status of the rat light-off model with complex partial seizures. The predictive value of these animal models for a particular type of epilepsy in the human body is not clear.

In vivo and in vitro experiments show that levetiracetam inhibits hippocampal epileptiform abrupt discharge without affecting normal neuronal excitability, and suggest that levetiracetam may selectively inhibit epileptiform abrupt discharge supersynchrony and epileptic seizure propagation.

Levetiracetam has no affinity for a variety of known receptors, such as benzodiazepines, GABA, glycine, NMDA, reuptake sites and second messenger systems, at concentrations up to 10 μ M. In vitro experiments showed that levetiracetam had no effect on neuronal voltage-gated sodium ion channels or T-type calcium currents. Levetiracetam does not directly facilitate gabaergic neurotransmission, but studies have shown an antagonistic effect on GABA and glycine gated current negative regulator activity in cultured neurons. The saturable and stereoselective neuronal binding site of levetiracetam is found in rat brain tissue, but the identity and function of this binding site is currently unclear.

① acts with synaptophysin 2A widely distributed in central neurons, regulates the exocytosis function of synaptophysin and the release of presynaptic neurotransmitters, animal experiments show that SV2A knockout mice exhibit restricted growth, increased neuronal excitability and severe convulsive susceptibility, levetiracetam has high affinity in the brain and is closely related to inhibition of epileptic discharge, ② antagonizes gamma-aminobutyric acid receptor blockers, thereby indirectly enhancing the effects of gamma-aminobutyric acid receptors, inhibiting the activity of neuronal excitants at the CA3 region, etc. the activation of N ③ inhibitory high-voltage ion channels of hippocampus, and the like, thus, the activation of calcium channels of levetiracetam, and the like, are related to the stimulation of neuronal excitant genes, thus, the activation of calcium channels of hippocampal, and the like, are related to the stimulation of gamma-aminobutyric acid receptors, and the stimulation of gamma-aminobutyric acid neuroleptic neurotransmitters, thus, the stimulation of gamma-aminobutyric acid receptors, inhibition of hippocampal neurons, and the like, and the stimulation of calcium channels, thus, the stimulation of gamma-aminobutyric acid receptors, and the activation of hippocampal neurons, and the like, can be related to the study on the level of excitatory genes.

CN109134341A (application No. 201811099818.8, treasure island) discloses a preparation method of levetiracetam, which comprises the following steps: step 1: taking L-2-aminobutyric acid as a starting material, and carrying out esterification with thionyl chloride to obtain (S) -2-aminobutyric acid methyl ester hydrochloride; step 2: carrying out aminolysis reaction on (S) -2-aminobutyrate methyl ester hydrochloride and ammonia water to generate (S) -2-aminobutanamide hydrochloride; and step 3: performing acylation reaction on (S) -2-aminobutanamide hydrochloride and a mixed solution of 4-chlorobutyryl chloride and dichloromethane in the presence of dichloromethane, tetrabutylammonium bromide, anhydrous sodium sulfate and an acid-binding agent to generate (S) -N- [1 (aminocarbonyl) propyl ] -4-bromobutanamide; and 4, step 4: (S) -N- [1 (aminocarbonyl) propyl ] -4-bromobutanamide, dichloromethane and tetrabutylammonium bromide are subjected to ring closure reaction under the conditions of anhydrous sodium sulfate and potassium hydroxide to obtain a crude product of levetiracetam; and 5: and recrystallizing the crude levetiracetam to generate levetiracetam. It is believed that the preparation method uses readily available starting materials, ensures good reproducibility of the synthetic route, simple unit operation, and economic accounting. The reaction in each step is easy to purify, the quality is controllable, and the reaction yield is greatly improved.

CN107915667A (application No. 201610881679.9, Fukanren) discloses an improved method of a levetiracetam synthesis process, which takes (S) -2-aminobutanamide (I) as an initial raw material, firstly obtains (S) -N- [1 (aminocarbonyl) propyl ] -4-bromobutanamide (II) with 4-bromobutyryl bromide under the action of sodium bicarbonate, and then cyclizes under the action of potassium carbonate to obtain levetiracetam (III); the method achieves the effects of mild reaction conditions, safe operation, effective control of single impurity (especially enantiomer) and the like by adjusting the starting raw materials and the alkali, and the ee of the method is more than or equal to 99.6 percent.

CN109053528A (application number: 201811107027.5, Macrocrown) relates to a synthetic process of levetiracetam, which is characterized in that: the synthetic route is as follows: the method comprises the following specific steps: the first step is as follows: synthesizing (S) -2- (4-chlorobutanamide) butanamide, adding a solvent into a reaction bottle, adding (S) -2- (4-chlorobutanamide) butyric acid under stirring, adding (Boc)2O after stirring and dissolving, controlling the temperature in a reaction system to be 20-30 ℃, slowly dropwise adding pyridine into the reaction system for 20 minutes, and stirring and reacting for 30 minutes after the addition is finished; adding ammonium salt into the reaction system, and stirring and reacting for 5-8 hours at the temperature of 20-30 ℃; after the reaction is finished, filtering to remove insoluble substances in the system, and concentrating the filtrate under reduced pressure to dryness; adding the concentrate into acetone, heating to 60-70 ℃ to dissolve the concentrate until the concentrate is completely dissolved, cooling to 10-20 ℃, stirring and crystallizing for 2-3 hours; filtering, drying under reduced pressure to obtain (S) -2- (4-chlorobutanamide) butanamide; the second step is that: synthesis of levetiracetam, adding a solvent into a reaction bottle, adding (S) -2- (4-chlorobutanamide) butanamide under stirring, and cooling a system to 0-5 ℃ after stirring and dissolving; adding alkali in batches, and continuously stirring for 3-4 hours at 0-5 ℃; after the reaction is finished, adjusting the pH value of the system to 6-7 by using 4N hydrochloric acid; concentrating under reduced pressure to remove solvent, adding dichloromethane and purified water, separating liquid, extracting, and extracting water phase with dichloromethane; and combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering and concentrating the organic phases, and recrystallizing the obtained crude product by using a refined solvent to obtain a pure levetiracetam. The process is believed to be free of chemical resolution, free of highly toxic or strongly corrosive chemical reagents, simple to operate, mild in conditions, environment-friendly, high in finished product quality and suitable for industrial production.

CN101885696A (application No. 200910051155.7, Waals Bionics) relates to a method for preparing levetiracetam, comprising the following steps: (A) performing ammoniation on (S) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid under the action of an activating agent and an acid-binding agent to prepare a levetiracetam crude product; (B) and recrystallizing the crude levetiracetam in ethyl acetate containing organic amine to obtain the high-purity levetiracetam.

CN102863370A (application No. 201210387420.0, Hua Liang biol.) discloses a new synthesis method of an antiepileptic drug levetiracetam, which comprises the following steps: (A) the (S) -alpha-ethyl-oxo-1-pyrrolidine acetic acid dissolved in the solvent is used for preparing a reaction active intermediate under the action of a catalyst. (B) And performing ammoniation reaction on the reactive intermediate and ammonia gas, and recrystallizing to obtain the high-purity levetiracetam. The method is believed to be simple to operate, few in byproducts and high in yield, and is suitable for industrial large-scale production in factories.

CN1802352A (application No. 200480008875.0, teva) relates to a process for the preparation of optically and chemically pure levetiracetam and to levetiracetam prepared by such process, the process for the preparation of (S) - α -ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) comprising reacting (S) -2-amino-butanamide hydrochloride and 4-chlorobutyryl chloride in a solvent selected from acetonitrile and methyl tert-butyl ether in the presence of a strong base and recovering the crude levetiracetam.

CN102558012A (application No. 201210069026.2, Zhiqing chemical) discloses a synthetic method of levetiracetam, which comprises the following steps: A. alkylation reaction: taking (S) -2-aminobutyric acid (I) as a raw material, carrying out alkylation reaction with 4-chlorobutyryl chloride (II) in the presence of an alkaline reagent, and carrying out post-treatment after the alkylation reaction is finished to obtain (S) -2- (4-chlorobutyrylamide) butyric acid (III); B. acylation reaction: in the presence of an acid binding agent, carrying out acylation reaction on the (S) -2- (4-chlorobutanamide) butyric acid obtained in the step A and ethyl chloroformate or methyl chloroformate to obtain a mixed anhydride (IV) reaction solution, wherein R in the formula (IV) is methyl or ethyl; the obtained mixed acid anhydride reaction liquid directly enters the next reaction without treatment; C. ammonolysis reaction: adding an ammoniation reagent into the obtained mixed acid anhydride reaction solution for ammonolysis reaction to obtain chlorobutanamide (V); D. and (3) cyclization reaction: and C, in the presence of a phase transfer catalyst and alkali, adding the chlorobutanamide obtained in the step C into an organic solvent for cyclization reaction to obtain levetiracetam (VI). The invention is believed to solve the technical problems of great environmental pollution, complex splitting process and unfavorable production in the prior art that thionyl chloride is used as a raw material or benzene is used for the splitting process, and provides a levetiracetam synthesis method which comprises the steps of taking (S) -2-aminobutyric acid as a raw material to carry out alkylation reaction with 4-chlorobutyryl chloride, then carrying out acylation reaction with an acylating agent, and then carrying out cyclization reaction in the presence of a phase transfer catalyst through ammonolysis to obtain levetiracetam. The invention is believed to provide a brand new levetiracetam synthesis method, which does not need a splitting process, and avoids the problem of using benzene as a splitting agent; a thionyl chloride reagent is not adopted, so that the harm to a human body and the pollution to the environment are reduced; the product has high yield and quality, the total molar yield is more than 81%, the HPLC purity is more than 98%, and the optical purity is more than 99.0%.

However, the method for preparing levetiracetam in the prior art has the defects of complex process, low step yield, poor product purity, especially chromatographic purity and the like, so that the method for preparing levetiracetam by providing a new method can overcome one or more defects, and still is expected by the technical personnel in the field.

Disclosure of Invention

The invention aims to prepare levetiracetam, and the method is expected to have the advantages of simple process, higher step yield, higher product purity, particularly higher chromatographic purity and the like in one or more aspects. It has been surprisingly found that one or more of the above technical effects can be achieved using the process of the present invention for preparing levetiracetam. The present invention has been completed based on this finding.

To this end, the invention provides in a first aspect a process for the preparation of levetiracetam comprising the steps of:

(1) suspending 0.5mol of (S) -2-aminobutyric acid in 10-15 equivalents of lower alcohol in a reaction bottle, dropwise adding 1-1.5 equivalents of reaction solvent thionyl chloride at the temperature of 20-30 ℃, slowly heating to 40-50 ℃ after dropwise adding, keeping warm and stirring for 4 hours to remove the solvent after reaction, concentrating under reduced pressure at 40-50 ℃ to evaporate the solvent, adding 2 equivalents of reaction solvent after the product is viscous, and stirring and cooling to-5 ℃ to form a suspension;

(2) slowly adding 6-10 equivalents of cold (0 ℃) ammonia water into a reaction bottle of the suspension obtained in the previous step, stirring to react for 5-7 hours, heating to 15-25 ℃, continuously stirring for 3-4 hours to finish the reaction, adding 0.2 equivalent of ethanol, distilling the ammonia water under reduced pressure at 85 ℃ until a large amount of products are separated out, then adding 6 equivalents of methanol, stirring and heating to reflux, adding hydrochloric acid to adjust the pH value to 3.0-3.5, continuously heating to clarify the materials, stirring for 2-3 hours at a constant temperature to form salt, then distilling under reduced pressure to remove the methanol, adding 1.5 equivalents of ethyl acetate (or petroleum ether, toluene and isopropyl ether) when a large amount of white products are separated out, stirring for 2 hours at 50 ℃, centrifuging, washing the solid products with ethyl acetate, filtering, and drying the filter cake under reduced pressure at 60-80 ℃ to obtain a refined salt-formed intermediate II product.

(3) Sequentially adding 0.5mol of the intermediate II, 0.02-0.1 equivalent of catalyst and 20 equivalents of dichloromethane into a reaction bottle, and cooling to-10 ℃ by using circulating cooling liquid; slowly adding 3 equivalents of KOH under rapid stirring, naturally heating to 20-30 ℃, and stirring for reacting for 45-60 min; cooling to below-5 ℃, slowly dropping a mixed solution prepared from 1-1.2 equivalents of 4-chlorobutyryl chloride and 3.5 equivalents of dichloromethane, and continuously stirring at 0 +/-5 ℃ for 2-3 hours after the addition; and continuously cooling to-15 to-10 ℃, slowly adding 1 equivalent of KOH, reacting at 0 +/-5 ℃ for 2 to 3 hours after the addition is finished, quickly filtering the reaction liquid by using a filter, fully washing filter residues by using 0.5 equivalent of dichloromethane, and combining the washing filtrates.

(4) Adding 0.5 equivalent of purified water into the washing filtrate, stirring and hydrolyzing for 30-60 min, adjusting the pH value to be alkalescent with the pH value of 7-9 by using dilute hydrochloric acid, standing and layering, and separating liquid to obtain an organic layer; adding dichloromethane into the water layer for extraction; mixing the dichloromethane of the extract liquid and dichloromethane obtained by separating liquid, adding anhydrous sodium sulfate for drying, then filtering by using a filter, fully washing filter residues by using dichloromethane, mixing washing filtrate (namely mixed solution of the filtrate and washing liquid), adding acetone with the weight of 2 times, stirring and crystallizing at 50 ℃ for 1h, cooling to-10 ℃, then stirring and crystallizing for 2-3 h, carrying out suction filtration, and washing a crystallized product by using cold (-10 ℃) ethyl acetate to obtain a crude product of levetiracetam;

(5) adding the levetiracetam crude product into a reaction bottle, adding 3 times of ethyl acetate by weight, heating and refluxing to clarify, adding 0.5-1 w/v% of medicinal carbon, refluxing, stirring and decoloring for 0.5-1 h, filtering while hot, concentrating the filtrate at 40-50 ℃ under reduced pressure until a large amount of white solid is separated out, cooling to-10 ℃, stirring and crystallizing for 2-3 h, centrifuging, collecting a crystallized product, and drying at 45-50 ℃ to obtain the levetiracetam refined product.

The process according to any one of the first aspect of the present invention, wherein in step (1), the lower alcohol is selected from methanol, ethanol, isopropanol.

The process according to any one of the first aspect of the present invention, wherein in step (1), 0.5mol of (S) -2-aminobutyric acid is suspended in 12 equivalents of a lower alcohol.

The process according to any one of the first aspect of the present invention, wherein in step (1), the lower alcohol is methanol.

The process according to any one of the first aspect of the present invention, wherein in the step (1), 1.2 equivalents of thionyl chloride as a reaction solvent is added dropwise.

The process according to any one of the first aspect of the invention, wherein in step (3), the catalyst is selected from: tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride and benzyltriethylammonium chloride.

The process according to any one of the first aspect of the present invention, wherein in step (3), the amount of the catalyst is 0.05 equivalent.

The process according to any one of the first aspect of the present invention, wherein the amount of 4-chlorobutyryl chloride in step (3) is 1 equivalent.

The method according to any one of the first aspect of the present invention, wherein in the step (2), 0.2 to 0.3 equivalent of oleic acid is added simultaneously with the addition of the cold aqueous ammonia. It has been surprisingly found that the yield of the reaction product can be greatly improved by the addition of oleic acid.

The method according to the first aspect of the present invention, wherein in the step (3), 0.1 to 0.2 equivalent of chlorobutanol is added simultaneously with the addition of 4-chlorobutyryl chloride. It has been surprisingly found that the content of key impurities in the final product can be greatly reduced by the addition of chlorobutanol.

Further, the second aspect of the present invention provides levetiracetam, which is prepared according to a method comprising the following steps:

(1) suspending 0.5mol of (S) -2-aminobutyric acid in 10-15 equivalents of lower alcohol in a reaction bottle, dropwise adding 1-1.5 equivalents of reaction solvent thionyl chloride at the temperature of 20-30 ℃, slowly heating to 40-50 ℃ after dropwise adding, keeping warm and stirring for 4 hours to remove the solvent after reaction, concentrating under reduced pressure at 40-50 ℃ to evaporate the solvent, adding 2 equivalents of reaction solvent after the product is viscous, and stirring and cooling to-5 ℃ to form a suspension;

(2) slowly adding 6-10 equivalents of cold (0 ℃) ammonia water into a reaction bottle of the suspension obtained in the previous step, stirring to react for 5-7 hours, heating to 15-25 ℃, continuously stirring for 3-4 hours to finish the reaction, adding 0.2 equivalent of ethanol, distilling the ammonia water under reduced pressure at 85 ℃ until a large amount of products are separated out, then adding 6 equivalents of methanol, stirring and heating to reflux, adding hydrochloric acid to adjust the pH value to 3.0-3.5, continuously heating to clarify the materials, stirring for 2-3 hours at a constant temperature to form salt, then distilling under reduced pressure to remove the methanol, adding 1.5 equivalents of ethyl acetate (or petroleum ether, toluene and isopropyl ether) when a large amount of white products are separated out, stirring for 2 hours at 50 ℃, centrifuging, washing the solid products with ethyl acetate, filtering, and drying the filter cake under reduced pressure at 60-80 ℃ to obtain a refined salt-formed intermediate II product.

(3) Sequentially adding 0.5mol of the intermediate II, 0.02-0.1 equivalent of catalyst and 20 equivalents of dichloromethane into a reaction bottle, and cooling to-10 ℃ by using circulating cooling liquid; slowly adding 3 equivalents of KOH under rapid stirring, naturally heating to 20-30 ℃, and stirring for reacting for 45-60 min; cooling to below-5 ℃, slowly dropping a mixed solution prepared from 1-1.2 equivalents of 4-chlorobutyryl chloride and 3.5 equivalents of dichloromethane, and continuously stirring at 0 +/-5 ℃ for 2-3 hours after the addition; and continuously cooling to-15 to-10 ℃, slowly adding 1 equivalent of KOH, reacting at 0 +/-5 ℃ for 2 to 3 hours after the addition is finished, quickly filtering the reaction liquid by using a filter, fully washing filter residues by using 0.5 equivalent of dichloromethane, and combining the washing filtrates.

(4) Adding 0.5 equivalent of purified water into the washing filtrate, stirring and hydrolyzing for 30-60 min, adjusting the pH value to be alkalescent with the pH value of 7-9 by using dilute hydrochloric acid, standing and layering, and separating liquid to obtain an organic layer; adding dichloromethane into the water layer for extraction; mixing the dichloromethane of the extract liquid and dichloromethane obtained by separating liquid, adding anhydrous sodium sulfate for drying, then filtering by using a filter, fully washing filter residues by using dichloromethane, mixing washing filtrate (namely mixed solution of the filtrate and washing liquid), adding acetone with the weight of 2 times, stirring and crystallizing at 50 ℃ for 1h, cooling to-10 ℃, then stirring and crystallizing for 2-3 h, carrying out suction filtration, and washing a crystallized product by using cold (-10 ℃) ethyl acetate to obtain a crude product of levetiracetam;

(5) adding the levetiracetam crude product into a reaction bottle, adding 3 times of ethyl acetate by weight, heating and refluxing to clarify, adding 0.5-1 w/v% of medicinal carbon, refluxing, stirring and decoloring for 0.5-1 h, filtering while hot, concentrating the filtrate at 40-50 ℃ under reduced pressure until a large amount of white solid is separated out, cooling to-10 ℃, stirring and crystallizing for 2-3 h, centrifuging, collecting a crystallized product, and drying at 45-50 ℃ to obtain the levetiracetam refined product.

Levetiracetam according to any of the second aspects of the invention, wherein in step (1) the lower alcohol is selected from methanol, ethanol, isopropanol.

Levetiracetam according to any of the second aspects of the invention, wherein in step (1) (S) -2-aminobutyric acid 0.5mol is suspended in 12 equivalents of lower alcohol.

Levetiracetam according to any of the second aspects of the invention, wherein in step (1) the lower alcohol is methanol.

Levetiracetam according to any of the second aspects of the invention, wherein in step (1), 1.2 equivalents of thionyl chloride, a reaction solvent, are added dropwise.

Levetiracetam according to any of the second aspects of the invention, wherein in step (3) the catalyst is selected from: tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride and benzyltriethylammonium chloride.

The levetiracetam according to any of the second aspects of the invention, wherein in step (3) the amount of catalyst is 0.05 equivalents.

The levetiracetam according to any of the second aspects of the invention, wherein in step (3), the amount of 4-chlorobutyryl chloride is 1 equivalent.

The levetiracetam according to any of the second aspects of the invention, wherein in step (2), 0.2-0.3 equivalent of oleic acid is added at the same time as the cold ammonia water is added. It has been surprisingly found that the yield of the reaction product can be greatly improved by the addition of oleic acid.

The levetiracetam according to any of the second aspects of the invention, wherein 0.1-0.2 equivalent of chlorobutanol is added at the same time as the 4-chlorobutyryl chloride in step (3). It has been surprisingly found that the content of key impurities in the final product can be greatly reduced by the addition of chlorobutanol.

Further, a third aspect of the present invention relates to the use of levetiracetam prepared by the process according to any of the embodiments of the first aspect of the present invention or levetiracetam according to the second aspect of the present invention for the preparation of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: epileptogenic diseases, seizure disorders, convulsions, Parkinson's disease, dyskinesias induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs, Huntington's chorea and other neurological disorders including bipolar disorder, mania, depression, anxiety, attention deficit disorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmias, myotonia, ***e abuse, stroke, myoclonus, tremor, essential tremor, simple or complex tics, tourette's syndrome, restless leg syndrome and other movement disorders, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthma persistence and allergic bronchitis, asthma syndrome, bronchial hyperresponsiveness and bronchospatic syndromes, as well as allergic and vasomotor rhinitis and rhinoconjunctivitis; in particular for the preparation of a medicament for the treatment or prevention of a disease or condition selected from: epilepsy, Parkinson's disease, movement disorders, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic conditions.

In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

The present invention has surprisingly found that the process of the present invention has advantageous properties in one or more of the following areas, such as simple process, high product yield, low impurities, etc.

Detailed Description

The following examples are provided for illustrative purposes only and are not intended to, nor should they be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications can be made to the following embodiments without departing from the spirit or scope of the invention.

The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.

Detection method example 1: high performance liquid chromatography for determining levetiracetam content and impurity levetiracetam acid content

Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; mixing acetonitrile and dipotassium hydrogen phosphate solution in a volume ratio of 5: 95 is a mobile phase, the dipotassium phosphate solution is prepared by dissolving 2g of dipotassium phosphate with 1000ml of water, and trace triethylamine is added into the mobile phase, the pH value of the mobile phase is adjusted to 6.0 by using 10% phosphoric acid solution, and the addition amount of the triethylamine accounts for 0.2 w/v% of the mobile phase; the detection wavelength is 245 nm; weighing levetiracetam and levetiracetam acid reference substances, 10mg respectively, placing the levetiracetam and levetiracetam acid reference substances into a 100ml measuring flask, adding a mobile phase for dissolving and diluting to a scale, injecting the solution serving as a system applicability solution into a liquid chromatograph, wherein the separation degree of levetiracetam acid and levetiracetam peak is not less than 3.0;

content determination: precisely weighing a proper amount of fine powder containing levetiracetam 10mg, placing the fine powder into a 50ml measuring flask, adding a mobile phase for dissolving, diluting to a scale, shaking uniformly, and filtering; precisely measuring 5ml of the subsequent filtrate, placing the subsequent filtrate in a 50ml measuring flask, and adding a mobile phase to dilute the subsequent filtrate to a scale to obtain a sample solution; taking a proper amount of levetiracetam as a reference substance, precisely weighing, adding a mobile phase for dissolving, and quantitatively diluting to prepare a solution containing about 0.5mg of levetiracetam per 1ml as a reference substance solution; precisely measuring 20 mul of reference substance and sample solution, respectively, injecting into a liquid chromatograph, and recording chromatogram; calculating the content of levetiracetam in the detection object by peak area according to an external standard method;

and (3) related substance determination: precisely weighing a proper amount of fine powder containing levetiracetam 10mg, placing the fine powder into a 20ml measuring flask, adding a mobile phase for dissolving, and diluting to a scale to obtain a test solution; accurately weighing a proper amount of levetiracetam acid (S) -2- (2-Oxypyrrolidin-1-yl) butanoid acid reference substance, adding a mobile phase for dissolving and diluting to prepare a solution containing 4.0 mu g of levetiracetam acid per 1ml as a levetiracetam acid reference substance solution; accurately weighing appropriate amount of levetiracetam reference substance, and dissolving with mobile phase to obtain reference solution containing levetiracetam 0.01mg per 1 ml; precisely measuring 20 μ l of the reference solution, injecting into a liquid chromatograph, and adjusting detection sensitivity to make the peak height of the main component chromatographic peak about 20% of the full range; precisely measuring 20 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram; if a chromatographic peak with the same retention time as levetiracetam acid exists in a chromatogram of a test solution, calculating the percentage content of impurity levetiracetam acid in a detection object relative to active ingredient levetiracetam by a peak area according to an external standard method; optionally, deducting a solvent peak in a chromatogram of the test solution, comparing peak areas of other single unknown impurities with a main peak area of a control solution, and respectively calculating the percentage content of the other single unknown impurities relative to the active ingredient levetiracetam.

Generally, less than 0.3% of levetiracetam acid is required for the impurity in levetiracetam, and less than 0.1% of each of the other individual unknown impurity levels, the total amount of impurities having to exceed 1.0%, these specifications requiring, for example, the specifications set forth in the united states pharmacopeia 38 edition on levetiracetam quality standards.

In addition, the peak area of other single unknown impurities is not larger than 0.1 times (0.1%) of the main peak area of the control solution by deducting the solvent peak in the chromatogram of the test solution.

When the method is used for measuring various materials related to the invention, the HPLC method is found to be ideal, for example, the separation degree of levetiracetam acid and levetiracetam peak is more than 3.0, the number of levetiracetam theoretical plates reaches more than 5000, and the precision of levetiracetam measurement is excellent; for the impurity levetiracetam acid appearing in the test solution, for the same test solution, sample introduction is repeated for 6 times, the peak area of the impurity levetiracetam acid is read, and the relative standard deviation RSD of the 6 times of measurement data is calculated, and the result shows that the RSD is in the range of 0.08-0.16% and is far lower than the standard requirement in the field that the common requirement is less than 1%.

Detection method example 2: levetiracetam R-isomer examination

The R-isomer is present as an impurity in levetiracetam and its amount needs to be controlled, and the HPLC method below this experimental example can be used to detect the content of this R-isomer (the percentage of the R-isomer peak area to the main peak area) in the product.

Chromatographic conditions are as follows:

a chromatographic column: chiral chromatography column (Chiralpak AD-H, 4.6 x 250mm),

column temperature: at a temperature of 20 c,

mobile phase: n-hexane-ethanol (4: 1),

flow rate: 1.0ml/min of the mixture is added,

a detector: UV detection (wavelength 215nm),

the system adaptability is as follows:

during measurement, a sample is prepared by using a mobile phase, the peak appearance sequence of a system chromatogram is sequentially an R-isomer and a levetiracetam peak, and the separation degree is not less than 4.0.

In the following examples, example 1, etc., levetiracetam was prepared in three main stages, the reaction scheme is as follows:

synthesis of intermediate I:

synthesis of intermediate II:

synthesizing levetiracetam: