Key intermediate of oxiracetam and optical isomer of oxiracetam as well as preparation method and application of key intermediate

Abstract

The invention discloses oxiracetam, a key intermediate of an optical isomer of oxiracetam and a preparation method and application of the key intermediate, and relates to the technical field of drug synthesis, and the optical isomer is (S)-oxiracetam or (R)-oxiracetam. The key intermediate of the oxiracetam, the key intermediate of the (S)-oxiracetam or the key intermediate of the (R)-oxiracetam are respectively 2-(4-hydroxy-2-oxopyrrolidine-1-yl) diphenyl methyl acetate, 2-((S)-4-hydroxy-2-oxopyrrolidine-1-yl) diphenyl methyl acetate or 2-((R)-4-hydroxy-2-oxopyrrolidine-1-yl) diphenyl methyl acetate; according to the key intermediate, the quality control of the intermediate is easier in the process of synthesizing oxiracetam and optical isomers (S)-oxiracetam and (R)-oxiracetam, and the purity of the final product can be improved and the separation and purification difficulty of the final product can be reduced by separating and purifying the intermediate.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a key intermediate of oxiracetam and its optical isomers, and a preparation method and application thereof. Background Art

[0002] Oxiracetam is a nootropic drug synthesized by Italian company ISF in 1974. Its chemical name is 4-hydroxy-2-oxo-1-pyrrolidineacetamide. It is a racemic compound composed of R-oxiracetam and S-oxiracetam. The drug is a β-hydroxy derivative of piracetam and a cyclic derivative of hydroxyaminobutyric acid (GABOB). Animal experiments and clinical trials have shown that it can improve the thinking, memory and learning ability of subjects. Under normal and hypoxic conditions, oxiracetam can increase the level of ATP in the brain by stimulating the conversion of adenosine diphosphate to adenosine triphosphate (ATP), accelerate the metabolism of brain phospholipids, stimulate the synthesis of brain ribonucleic acid and protein, enhance the tolerance of the cerebral cortex to hypoxia, reduce cerebrovascular resistance, increase cerebral blood flow, prevent the occurrence of secondary lesions, and play a certain role in strengthening memory and restoring brain cell function. There are many foreign data reporting that it can improve brain dysfunction in patients with dementia and post-concussion syndrome. Oxiracetam is clinically used for mild to moderate vascular dementia, senile dementia, and memory and intellectual impairment caused by brain trauma. Currently, racemic oxiracetam is used clinically, and data show that S-oxiracetam is more effective than R-oxiracetam. Experiments have shown that compared with racemic oxiracetam, S-oxiracetam can more significantly improve the learning and memory impairment of mice caused by scopolamine.

[0003] There are many reports on the synthesis method of racemic oxiracetam. Patent CN102134212A discloses a method for preparing oxiracetam, comprising the following steps: (1) using 4-chloroacetoacetate as a raw material, and using ammonia water to ammonolyze to obtain 4-chloroacetoacetamide, (2) cyclizing 4-chloroacetoacetamide under alkaline conditions of pH 7-12 to obtain pyrrolidine-2,4-dione, (3) condensing pyrrolidine-2,4-dione with chloroacetate or bromoacetate to obtain ethyl 2-(2,4-dioxopyrrolidine-1-yl)acetate, (4) reducing the 4-keto group of 2-(2,4-dioxopyrrolidine-1-yl)acetate to obtain ethyl 2-(4-hydroxy-2-oxopyrrolidine-1-yl)acetate, and (5) reducing the 4-keto group to 2-(4-hydroxy-2-oxopyrrolidine-1-yl)acetate and subjecting it to ammonolysis to obtain oxiracetam. This method has many reaction steps and the intermediates need to be purified, which is not conducive to industrial production.

[0004] Patent CN02137846.0 discloses a method for preparing oxiracetam, which uses ethyl 4-chloroacetoacetate as the starting material, condenses with sodium azide to obtain ethyl 4-azidoacetoacetate, reduces to obtain 4-amino-3-hydroxybutyric acid, and then cyclizes to obtain 4-hydroxy-2-pyrrolidone, condenses with ethyl chloroacetate to obtain ethyl 2-(4-hydroxy-2-oxopyrrolidine-1-yl)acetate, and finally aminolyzes to obtain oxiracetam. The raw material sodium azide used in this synthesis method is expensive and explosive; when the intermediate 4-hydroxy-2-pyrrolidone is condensed with ethyl chloroacetate without protecting the hydroxyl group, it is inevitable that O-hydrocarbonated byproducts will be produced, and the impurities produced by the subsequent aminolysis reaction will enter the final product, affecting the quality of oxiracetam.

[0005] There are few reports in the literature on the preparation method of (R)-oxiracetam.

[0006] At present, there are many reports on the synthesis route of (S)-oxiracetam. Patents CN106349145, CN106631962, CN108358825, and CN105968024 respectively use 2-oxiranyl acetate isobutyl ester, 2-oxiranyl acetamide, S-4-methyl-2-oxotetrahydrofuran, and S-4-amino-3-hydroxybutyric acid as raw materials for synthesis. At present, these four raw materials are not available for large-scale industrialization, and the price of reagents is very expensive. The price of some raw materials even far exceeds the price of the product, and there is no industrial value.

[0007] The document Tetrahedron: Asymmetry Vol. 3, No. 11, pp. 1431-1440, 1992 uses natural chiral malic acid as a raw material to prepare S-oxiracetam. Although the raw material is cheap and easily available, the route involves 8 steps of reaction and the synthesis route is long. Many steps of reaction require column chromatography purification and have no industrial value.

[0008] Patent CN106349144 uses a chiral resolution agent to perform chiral resolution on the racemic oxiracetam synthetic intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid to obtain 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, which is then subjected to esterification and aminolysis to obtain the target product. However, the intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid is not easy to prepare by crystallization. In addition, obtaining a single-configuration compound by resolution will cause waste of another configuration part. The total resolution yield is only 30%-40%, which greatly increases the cost and is not suitable for industrial production.

[0009] At present, the synthetic route with industrial prospects mainly uses S-4-chloro-3-hydroxybutyric acid ethyl ester as the raw material. Since this raw material is also the starting material of the bulk drug atorvastatin, there is a large amount of industrial supply, and it is cheap and easy to obtain. There are currently three schemes using this as the starting material:

[0010] 1. The technology disclosed in patent CN102060744 is to react (S)-4-chloro-3-hydroxybutyric acid ethyl ester with glycinamide under alkaline conditions to obtain the target compound in a "one-pot method". This preparation scheme only obtains the product through one-step reaction, which seems simple, but cannot meet the basic requirements of GMP for quality control of pharmaceutical intermediates. There is no clear quality control point for intermediates, resulting in uncontrollable drug quality. Patent CN114621128A reports an improved scheme, which uses tert-butyldimethylchlorosilane to protect the hydroxyl group of S-oxiracetam, thereby converting S-oxiracetam into 2-((S)-4-tert-butyldimethylchlorosilylhydroxy-2-oxopyrrolidin-1-yl)acetamide, and the hydroxyl protected product can be crystallized, thereby increasing the intermediate quality control point of the 2-((S)-4-tert-butyldimethylchlorosilylhydroxy-2-oxopyrrolidin-1-yl)acetamide crystals, and then purifying the 2-((S)-4-tert-butyldimethylchlorosilylhydroxy-2-oxopyrrolidin-1-yl)acetamide and removing the protecting group to obtain the product. Patent CN106397294 adopts a similar idea, in which tert-butyloxycarbonyl is used to connect the 4-hydroxyl group in 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid to form a crystallizable derivative. Although this idea adds a quality control point and can perform a crystallization purification operation on a synthetic intermediate of the route, it meets the relevant requirements for quality control in drug registration and declaration to a certain extent. However, the operation of protecting and then deprotecting the hydroxyl group on the reaction intermediate leads to an unnecessary increase in the length of the synthetic route, and also increases the preparation cost.

[0011] 2. Chinese Journal of New Drugs, 2011, 20(19), 1920 reported a synthetic route using glycine and S-4-chloro-3-hydroxybutyrate as raw materials for condensation and then esterification and aminolysis. The route adjusted the preparation method of the target product obtained by the "one-pot method" reported in CN102060744 to first form 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, then ethyl esterify with ethanol in the presence of sulfuric acid under reflux and water separation, and finally aminolysis with ammonia water. Objectively, two intermediate quality control points may be formed. However, when repeating the scheme reported in the literature, the inventor found that the reaction required glycine and S-4-chloro-3-hydroxybutyrate to be mixed and reacted, while glycine The common salts thereof are insoluble in most conventional organic solvents, so water can only be used as a solvent for the reaction. The product 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid is extremely water-soluble and cannot be crystallized in an aqueous solvent. At the same time, due to its high water solubility, it is impossible to extract it from the water phase system using an organic solvent, resulting in difficulty in purification and separation from the salt substances in the reaction system. After further ethylation to form ethyl 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetate, the product is an oily substance and cannot be crystallized and purified. Therefore, the scheme cannot provide a clear intermediate quality control point in actual operation, cannot meet the requirements for drug registration and declaration, and is not suitable for industrial production.

[0012] 3. WO2005 / 115978 reports that (S)-4-chloro-3-hydroxybutyric acid ethyl ester and glycine ethyl ester are reacted under alkaline conditions to prepare ethyl 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetate. However, ethyl 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetate does not have crystallinity, and also cannot provide quality control points, cannot meet the requirements for drug registration, and is not suitable for industrial production.

[0013] Therefore, the current synthesis schemes for racemic oxiracetam, or its optical isomers S-oxiracetam and R-oxiracetam have obvious defects and cannot meet the GMP requirements for quality control of drugs and drug intermediates. It is urgent to find a clear intermediate quality control point without increasing the synthesis route and preparation cost to meet the GMP requirements for industrial production of drugs. Summary of the invention

[0014] Based on the problem that the current synthesis scheme of racemic oxiracetam or its optical isomers S-oxiracetam and R-oxiracetam cannot meet the requirements of GMP for quality control of drugs and drug intermediates, the object of the present invention is to provide a key intermediate of oxiracetam and its optical isomers and a preparation method and application thereof. The key intermediate of oxiracetam and its optical isomers (S)-oxiracetam and (R)-oxiracetam can be crystallized from a water-containing reaction system in the form of a monohydrate due to its unique spatial structure, so it is easy to separate and purify, making it easier to control the quality of the intermediate during the synthesis of oxiracetam and its optical isomers (S)-oxiracetam and (R)-oxiracetam, and by separating and purifying the intermediate, the purity of the final product can be improved, the difficulty of separation and purification of the final product can be reduced, and the relevant quality requirements for drug registration and industrial production can be met.

[0015] The present invention is achieved through the following technical solutions:

[0016] In the first aspect, the present application provides a key intermediate of oxiracetam and its optical isomers, wherein the optical isomer is (S)-oxiracetam or (R)-oxiracetam; the key intermediates of oxiracetam, (S)-oxiracetam, and (R)-oxiracetam are respectively 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester as shown in formula (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester as shown in formula (II), and 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester as shown in formula (III), wherein:

[0017]

[0018] In a second aspect, the present application provides a method for preparing a key intermediate of oxiracetam and its optical isomers, comprising the following steps:

[0019] (1) using 4-halo-3-hydroxybutyric acid ethyl ester, (S)-4-halo-3-hydroxybutyric acid ethyl ester or (R)-4-halo-3-hydroxybutyric acid ethyl ester as starting materials, reacting with glycine in the presence of a base to obtain 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid;

[0020] (2) reacting the 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) with diphenyldiazomethane to obtain the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III);

[0021] (3) The obtained key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III) is precipitated from the reaction system in the form of a monohydrate.

[0022] Furthermore, in step (1),

[0023] The 4-halogeno-3-hydroxybutyric acid ethyl ester includes 4-chloro-3-hydroxybutyric acid ethyl ester or 4-bromo-3-hydroxybutyric acid ethyl ester;

[0024] The (S)-4-halo-3-hydroxybutyric acid ethyl ester includes (S)-4-chloro-3-hydroxybutyric acid ethyl ester or (S)-4-bromo-3-hydroxybutyric acid ethyl ester;

[0025] The (R)-4-halo-3-hydroxybutyric acid ethyl ester includes (R)-4-chloro-3-hydroxybutyric acid ethyl ester or (R)-4-bromo-3-hydroxybutyric acid ethyl ester.

[0026] Furthermore, in step (1),

[0027] Glycine and a base are added to water and stirred until completely dissolved, and then heated to react with ethyl 4-halo-3-hydroxybutyrate, ethyl (S)-4-halo-3-hydroxybutyrate or ethyl (R)-4-halo-3-hydroxybutyrate, and then cooled to room temperature and pH is adjusted with an acid to obtain a reaction solution containing 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid.

[0028] Furthermore, the pH value is adjusted to 3-4 with acid.

[0029] Furthermore, the base in step (1) includes sodium hydroxide or potassium hydroxide.

[0030] Furthermore, in step (2),

[0031] The reaction solution of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) is directly reacted with diphenyldiazomethane without separation and purification to obtain the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III).

[0032] In a third aspect, the present application provides the key intermediate of oxiracetam or its optical isomers or the use of the key intermediate of oxiracetam or its optical isomers prepared by the above-mentioned preparation method, including use in the preparation of oxiracetam, (S)-oxiracetam or (R)-oxiracetam.

[0033] Wherein, the preparation method of oxiracetam comprises the following steps:

[0034] (1) using 4-halo-3-hydroxybutyric acid ethyl ester as a starting material and reacting with glycine in the presence of a base to obtain 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid;

[0035] (2) reacting the 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) with diphenyldiazomethane to obtain the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) and precipitating the monohydrate of (I) from the reaction system;

[0036] (3) The key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) is subjected to aminolysis reaction to obtain the target product oxiracetam.

[0037] The reaction equation is as follows:

[0038]

[0039] Wherein, X represents Cl or Br.

[0040] Wherein, the preparation method of (S)-oxiracetam comprises the following steps:

[0041] (1) using (S)-4-halo-3-hydroxybutyric acid ethyl ester as a starting material and reacting with glycine in the presence of a base to obtain 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid;

[0042] (2) reacting the 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) with diphenyldiazomethane to obtain the key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) and precipitating the monohydrate form of II from the reaction system;

[0043] (3) The key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) is subjected to aminolysis reaction to obtain the target product (S)-oxiracetam.

[0044] The reaction equation is as follows:

[0045]

[0046] Wherein, X represents Cl or Br.

[0047] Wherein, the preparation method of (R)-oxiracetam comprises the following steps:

[0048] (1) using (R)-4-halo-3-hydroxybutyric acid ethyl ester as a starting material and reacting with glycine in the presence of a base to obtain 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid;

[0049] (2) reacting the 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) with diphenyldiazomethane to obtain the key intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III), and precipitating the monohydrate form of III from the reaction system;

[0050] (3) The key intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III) is subjected to aminolysis reaction to obtain the target product (R)-oxiracetam.

[0051] The reaction equation is as follows:

[0052]

[0053] Wherein, X represents Cl or Br.

[0054] Furthermore, when preparing oxiracetam, (S)-oxiracetam or (R)-oxiracetam, the aminolysis reaction is carried out in a methanol-ammonia solution or aqueous ammonia.

[0055] The inventors found during the research and development process that most of the esters formed by 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid are not crystalline, such as methyl ester, ethyl ester, isopropyl ester, n-propyl ester, n-butyl ester. On the other hand, the solution of increasing the volume of the group forming the ester with 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid in order to increase its crystallization possibility also has difficulties, because with the increase of the volume of the ester-forming group, on the one hand, the difficulty of the esterification reaction increases rapidly, and the conventional relatively cheap acid-catalyzed esterification conditions with water and dehydration by a dehydrating agent cannot complete the large position. The esterification reaction of the hindered group, with long-term high-temperature esterification or strong dehydration conditions, the raw materials 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid will undergo obvious degradation to generate impurities. If expensive condensation reagents such as DCC / HOBT, EDCI / HOBT, HATU, etc. are used for esterification, the synthesis cost will increase rapidly. On the other hand, the difficulty of aminolysis will also increase accordingly. The difficulty of aminolysis of phenyl ester, benzyl ester, triphenylmethyl ester, isobutyl ester, tert-butyl ester to form the product oxiracetam, S-oxiracetam or R-oxiracetam increases rapidly, and usually requires high temperature, high pressure and long-term aminolysis reaction. For example, tert-butyl ester basically does not react with ammonia methanol system and ammonia water system under conventional aminolysis conditions.

[0056] In the present invention, the inventors unexpectedly discovered during the experiment of optimizing the synthesis route of oxiracetam, S-oxiracetam or R-oxiracetam that diphenyldiazomethane can be used as a raw material to form diphenylmethyl ester with 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid. The reaction process is different from the general esterification reaction. It undergoes a highly active carbene intermediate process and can quickly complete the esterification reaction of large steric hindered groups in an aqueous solution at room temperature, so that the esterification process that generally requires anhydrous conditions to complete can be carried out in water. This feature is exactly the same as 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)- The 4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid has strong water solubility and cannot be separated and purified from the aqueous phase system generated in the previous step of the reaction. The esterification reaction can be directly carried out in the aqueous phase system without purification. More importantly, the special spatial structure and physical properties of the key intermediate can form a monohydrate with water, while the formed monohydrate is insoluble in water and can be directly precipitated from the aqueous solution system of the reaction. The precipitated crystals have high purity and controllable quality. More surprisingly, the key intermediate is used as a raw material to carry out aminolysis in a methanol ammonia solution or ammonia water. The aminolysis reaction speed is faster and more thorough than that of methyl ester and ethyl ester, and the target product oxiracetam, S-oxiracetam or R-oxiracetam can be easily obtained with high purity.

[0057] The key intermediate of the present invention is unique in that its special spatial structure and physical properties can form a monohydrate with water, and the monohydrate formed is insoluble in water, and can be directly precipitated from the aqueous solution system of the reaction. This feature solves a major pain point in the synthesis route of oxiracetam and its optical isomers (S)-oxiracetam and (R)-oxiracetam, namely: the entire preparation process does not have a key intermediate with controllable quality, and cannot meet the relevant requirements of GMP for the quality control of intermediates in the drug synthesis route, making it difficult to register and declare drugs. At the same time, the intermediate also solves the problem of salt substances that are difficult to effectively remove in ordinary solutions, without the need for complex silica gel column chromatography and ion exchange column chromatography processes, and thoroughly solves the current situation that the synthesis route intermediates and salt substances of oxiracetam and its optical isomers (S)-oxiracetam and (R)-oxiracetam are difficult to separate and purify, saving a large number of purification operations and reducing preparation costs.

[0058] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0059] (1) The key intermediate prepared by the present invention simplifies the synthesis process of the entire oxiracetam and its optical isomers (S)-oxiracetam and (R)-oxiracetam. The esterification reaction of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid is carried out in water, without the need to esterify the 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in the previous step. The reaction liquid of 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid can be directly reacted after purification, and the product can be directly precipitated from the aqueous solution system of the reaction in the form of a monohydrate, and the salt substances that are difficult to effectively remove in the conventional scheme are dissolved in water and completely removed, without the need for complex silica gel column chromatography and ion exchange column chromatography processes, and the current situation that it is difficult to separate and purify the intermediates and salt substances in the synthesis route of oxiracetam and its optical isomers (S)-oxiracetam and (R)-oxiracetam is completely solved, a large amount of purification operations are saved, and the preparation cost is reduced;

[0060] (2) The esterification reaction of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid is a necessary step for preparing oxiracetam, (S)-oxiracetam or (R)-oxiracetam by this route, and the generation of the intermediate of the present invention does not require additional synthetic reaction steps;

[0061] (3) The present invention forms a key intermediate with controllable quality, which can meet the relevant requirements of GMP for the quality control of intermediates in the drug synthesis route. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. In the drawings:

[0063] Figure 1 The key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 1 of the present invention 1 H NMR spectrum;

[0064] Figure 2The DSC spectrum of the key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 1 of the present invention;

[0065] Figure 3 This is the TGA spectrum of the key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 1 of the present invention;

[0066] Figure 4 This is the XRD spectrum of the key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 1 of the present invention.

[0067] Figure 5 The key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 5 of the present invention 1 H NMR spectrum;

[0068] Figure 6 This is the DSC spectrum of the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 5 of the present invention;

[0069] Figure 7 This is the TGA spectrum of the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 5 of the present invention;

[0070] Figure 8 This is the XRD spectrum of the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 5 of the present invention.

[0071] Fig. 9 This is the DSC spectrum of the key intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 7 of the present invention;

[0072] Fig.10 This is the TGA spectrum of the key intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester monohydrate in Example 7 of the present invention. DETAILED DESCRIPTION

[0073] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments.

[0074] Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. 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.

[0075] Example 1

[0076] This example provides a synthesis of a key intermediate of olatan (I), which is prepared by the following method:

[0077] S1. Preparation of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid

[0078] Take 50 g of glycine and 50 g of sodium hydroxide as raw materials, add them into 500 mL of water and stir until they are completely dissolved, add 25 g of ethyl 4-chloro-3-hydroxybutyrate dropwise, raise the temperature to reflux for reaction for 3 hours after the addition is complete, cool to room temperature, and adjust the pH to 3 with dilute hydrochloric acid to obtain a reaction solution containing 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid.

[0079] S2. Preparation of key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (Ⅰ)

[0080] A 250 ml chloroform solution containing 50 g of diphenyldiazomethane was added dropwise into the aqueous solution of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step S1, and the mixture was stirred at room temperature for 5 hours. The chloroform was concentrated to remove a large amount of solid precipitated, and the intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) was obtained by filtration. The monohydrate thereof was 42.7 g, with a yield of 83%. The purity of the solid according to HPLC was 99.9%.

[0081] Key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (Ⅰ) monohydrate 1 HNMR spectrum Figure 5 As shown, 1 H NMR (400MHz, CDCl3) δ7.42–7.22(m,10H),6.90(s,1H),4.51–4.40(m,1H),4.26–4.08(m,2H),3.72(dd,J=1 0.5,5.4Hz,1H),3.32(dd,J=10.5,1.6Hz,1H),2.69(dd,J=17.5,6.4Hz,1H),2.40(dd,J=17.4,2.0Hz,1H).

[0082] The key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) monohydrate1 HNMR, DSC, TGA, and XRD spectra are shown in Figure 1 , 2, 3, and 4, the spectra show that the monohydrated state of the obtained crystal form and its unique lattice morphology can be determined.

[0083] Example 2

[0084] This example provides a method for preparing oxiracetam using the key intermediate (I) of oxiracetam prepared in Example 1, which is prepared by the following method:

[0085] 42.7 g of the intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) monohydrate prepared in Example 1 was dissolved in 500 mL of 20% ammonia methanol solution, stirred at room temperature for 2 hours, the reaction was stopped, and the methanol was concentrated to remove a large amount of solid precipitated. 100 mL of ethanol was added for slurrying, filtered, and dried to obtain 18.4 g of the product oxiracetam, with a yield of 93%. HPLC showed a purity of 99.9%.

[0086] Example 3

[0087] This example shows the synthesis of a key intermediate of olatan (I), which is prepared by the following method:

[0088] S1. Preparation of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid

[0089] Take 50 g of glycine and 50 g of sodium hydroxide as raw materials, add them into 500 ml of water and stir until they are completely dissolved, add 21.1 g of ethyl 4-bromo-3-hydroxybutyrate dropwise, raise the temperature to reflux for reaction for 3 hours after the addition is complete, cool to room temperature, and adjust the pH to 3 with dilute hydrochloric acid to obtain a reaction solution containing 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid.

[0090] S2. Preparation of key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (Ⅰ)

[0091] A solution of 50 g of diphenyldiazomethane in 250 ml of tetrahydrofuran was added dropwise into the aqueous solution of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step S1, and the mixture was stirred at room temperature for 5 hours. The tetrahydrofuran was concentrated to remove the tetrahydrofuran, and a large amount of solid precipitated. The intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) was obtained by filtration as its monohydrate, 28.8 g, with a yield of 84%, and a purity of 99.9% as shown by HPLC.

[0092] Example 4

[0093] This example provides a method for preparing oxiracetam using the oxiracetam key intermediate (I) prepared in Example 3, which is prepared by the following method:

[0094] 28.8 g of the intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I) monohydrate prepared in Example 3 was dissolved in 500 ml of 25% ammonia water, stirred at room temperature for 2 hours, the reaction was stopped, and the water was removed by concentration. A large amount of solid precipitated, 100 mL of ethanol was added for slurrying, filtered, and dried to obtain 12.6 g of the product oxiracetam, with a yield of 95%. HPLC showed a purity of 99.9%.

[0095] Example 5

[0096] This example is a synthesis of a key intermediate (II) of S-oxiracetam, prepared by the following method:

[0097] S1. Preparation of 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid

[0098] Take 50 g of glycine and 50 g of sodium hydroxide as raw materials, add them into 500 ml of water and stir until they are completely dissolved, add 25 g of ethyl S-4-chloro-3-hydroxybutyrate dropwise, and after the addition is complete, heat the mixture to reflux for reaction for 3 hours, cool the mixture to room temperature, and adjust the pH to 3-4 with dilute hydrochloric acid to obtain a reaction solution containing 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid.

[0099] S2. Preparation of key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II)

[0100] A 250 ml dichloromethane solution containing 50 g of diphenyldiazomethane was added dropwise into the aqueous solution of 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step S1, and the mixture was stirred at room temperature for 5 hours. The dichloromethane was removed by concentration, and a large amount of solid precipitated. The intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) was obtained by filtration as its monohydrate, 43.8 g, with a yield of 85%. The purity of HPLC was 99.9%.

[0101] Key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) monohydrate 1 HNMR spectrum Figure 1 As shown, 1HNMR (400MHz, DMSO) δ7.49–7.20(m,10H),6.82(s,1H),5.24(d,J=3.8Hz,1H),4.33(dd,J=5.8,2.6Hz,1H),4.19(dd,J=42.8,17. 6Hz, 2H), 3.60 (dd, J = 10.1, 5.6Hz, 1H), 3.22 (dd, J = 10.1, 2.2Hz, 1H), 2.55 (dd, J = 17.1, 6.7Hz, 1H), 2.10 (dd, J = 16.4, 3.3Hz, 1H).

[0102] The key intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) monohydrate 1 H NMR, DSC, TGA, and XRD spectra are shown in Figure 5 , 6, 7, and 8, the spectra show that the monohydrated state of the obtained crystal form and its unique lattice morphology can be determined.

[0103] Example 6

[0104] This example provides a method for preparing oxiracetam using the key intermediate (II) of S-oxiracetam prepared in Example 5, which is prepared by the following method:

[0105] 43.8 g of the intermediate 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) monohydrate prepared in Example 5 was dissolved in 500 ml of 15% ammonia methanol solution, stirred at room temperature for 2 hours, the reaction was stopped, and the methanol was concentrated to remove a large amount of solid precipitated. 100 mL of ethanol was added for slurrying, filtered, and dried to obtain 19.2 g of product S-oxiracetam with a yield of 95%. HPLC showed a purity of 99.9%.

[0106] Example 7

[0107] This example is a synthesis of a key intermediate (III) of R-oxiracetam, prepared by the following method:

[0108] S1. Preparation of 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid

[0109] Take 50 g of glycine and 50 g of sodium hydroxide as raw materials, add them into 500 ml of water and stir until they are completely dissolved, add 25 g of ethyl R-4-chloro-3-hydroxybutyrate dropwise, and after the addition is complete, heat the mixture to reflux for reaction for 3 hours, cool the mixture to room temperature, and adjust the pH to 3-4 with dilute hydrochloric acid to obtain a reaction solution containing 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid.

[0110] S2. Preparation of key intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III)

[0111] A 250 ml dichloromethane solution containing 50 g of diphenyldiazomethane was added dropwise into the aqueous solution of 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step S1, and the mixture was stirred at room temperature for 5 hours. The dichloromethane was removed by concentration, and a large amount of solid precipitated. The intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III) was obtained by filtration, which was 44.7 g of its monohydrate with a yield of 87%. The purity of HPLC was 99.9%.

[0112] The DSC and TGA spectra of the key intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III) monohydrate are as follows: Fig. 9 , as shown in 10, the spectrum shows that the monohydrated state of the obtained crystal form and its unique lattice morphology can be determined.

[0113] Example 8

[0114] This embodiment provides a method for preparing oxiracetam using the R-oxiracetam key intermediate (III) prepared in Example 7, which is prepared by the following method:

[0115] 44.7 g of the intermediate 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III) monohydrate obtained in step S2 of Example 7 was dissolved in 500 ml of 20% ammonia methanol solution, stirred at room temperature for 2 hours, the reaction was stopped, and the methanol was concentrated to remove a large amount of solid precipitated. 100 ml of ethanol was added for pulping, filtered, and dried to obtain 20.6 g of product S-oxiracetam with a yield of 94%. HPLC showed a purity of 99.9%.

[0116] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A key intermediate of oxiracetam and its optical isomers, characterized in that: The optical isomer is (S)-oxiracetam or (R)-oxiracetam; the key intermediates of oxiracetam, (S)-oxiracetam and (R)-oxiracetam are 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester having a structural formula as shown in formula (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester having a structural formula as shown in formula (II), and 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester having a structural formula as shown in formula (III), wherein:

2. A method for preparing the key intermediate of oxiracetam and its optical isomers according to claim 1, characterized in that: The steps include: (1) using 4-halo-3-hydroxybutyric acid ethyl ester, (S)-4-halo-3-hydroxybutyric acid ethyl ester or (R)-4-halo-3-hydroxybutyric acid ethyl ester as starting materials, reacting with glycine in the presence of a base to obtain 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid; (2) reacting the 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) with diphenyldiazomethane to obtain the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III); (3) The obtained key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III) is precipitated from the reaction system in the form of a monohydrate.

3. The method for preparing the key intermediate of oxiracetam and its optical isomers according to claim 2, characterized in that: In step (1), The 4-halogeno-3-hydroxybutyric acid ethyl ester includes 4-chloro-3-hydroxybutyric acid ethyl ester or 4-bromo-3-hydroxybutyric acid ethyl ester; The (S)-4-halo-3-hydroxybutyric acid ethyl ester includes (S)-4-chloro-3-hydroxybutyric acid ethyl ester or (S)-4-bromo-3-hydroxybutyric acid ethyl ester; The (R)-4-halo-3-hydroxybutyric acid ethyl ester includes (R)-4-chloro-3-hydroxybutyric acid ethyl ester or (R)-4-bromo-3-hydroxybutyric acid ethyl ester.

4. The method for preparing the key intermediate of oxiracetam and its optical isomers according to claim 2, characterized in that: In step (1), Glycine and a base are added to water and stirred until completely dissolved, and then heated to react with ethyl 4-halo-3-hydroxybutyrate, ethyl (S)-4-halo-3-hydroxybutyrate or ethyl (R)-4-halo-3-hydroxybutyrate, and then cooled to room temperature and pH is adjusted with an acid to obtain a reaction solution containing 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid.

5. The method for preparing the key intermediate of oxiracetam and its optical isomers according to claim 4, characterized in that: Adjust the pH to 3-4 with acid.

6. The method for preparing the key intermediate of oxiracetam and its optical isomers according to claim 2, characterized in that: The alkali described in step (1) includes sodium hydroxide or potassium hydroxide.

7. The method for preparing the key intermediate of oxiracetam and its optical isomers according to claim 2, characterized in that: In step (2), The reaction solution of 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid, 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid obtained in step (1) is directly reacted with diphenyldiazomethane without separation and purification to obtain the key intermediate 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid diphenylmethyl ester (III).

8. Use of the key intermediate of oxiracetam and its optical isomers according to claim 1 or the key intermediate of oxiracetam or its optical isomers prepared by the preparation method according to any one of claims 2 to 7, characterized in that: The invention also includes a method for preparing oxiracetam, (S)-oxiracetam or (R)-oxiracetam.

9. The use of the key intermediate of oxiracetam and its optical isomers according to claim 8, characterized in that: The preparation method of the oxiracetam, (S)-oxiracetam or (R)-oxiracetam is: The key intermediates 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid benzhydryl ester (I), 2-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid benzhydryl ester (II) or 2-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)acetic acid benzhydryl ester (III) are subjected to aminolysis reaction respectively to obtain the target product oxiracetam, (S)-oxiracetam or (R)-oxiracetam.

10. The use of the key intermediate of oxiracetam and its optical isomers according to claim 9, characterized in that: When the ammonolysis reaction is carried out, it is carried out in a methanol ammonia solution or in aqueous ammonia.

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