Preparation method of oxiracetam impurity B

Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of an oxiracetam impurity B. The preparation method of the oxiracetam impurity B comprises the following step: reacting 4-halo-3-hydroxy-butyrate as shown in a formula (2) with glycyl glycinamide halogen acid salt as shown in a formula (3) to obtain the oxiracetam impurity B as shown in a formula (1). The target product oxiracetam impurity B can be prepared in one step by reacting 4-halo-3-hydroxy-butyrate with glycyl glycinamide halogen acid salt, and the synthetic route is short in time consumption, high in product yield and low in cost. The synthesized oxiracetam impurity B can be used as a contrast for oxiracetam detection, and is used for controlling the quality of commercially available oxiracetam drugs.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a method for preparing an oxiracetam impurity B. Background Art

[0002] Oxiracetam is a drug that improves brain metabolism and nourishes brain nerves. It is currently widely used in clinical practice, mainly for the treatment of brain dysfunction, memory impairment, senile dementia, cerebral infarction, brain trauma, cerebral ischemia, etc. Oxiracetam can improve the memory, attention, and orientation of patients with dementia, thereby improving the patient's neurological function and daily living ability. Clinically, it has a good therapeutic effect on mild and moderate senile dementia and other senile encephalopathy, and its toxicity is very low.

[0003] N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxotetrahydropyrrol-1-yl)acetamide (codenamed Oxiracetam impurity B, its structural formula is shown below) is one of the impurities in the inspection of Oxiracetam-related substances. It is difficult to purchase, so it is crucial to optimize the simple synthesis of this substance for testing the quality of Oxiracetam.

[0004] Summary of the invention

[0005] The object of the present invention is to provide a novel preparation method for oxiracetam impurity B, using 4-halo-3-hydroxy-butyrate as a starting material, reacting with glycyl glycinamide hydrohalide to directly synthesize oxiracetam impurity B, wherein oxiracetam impurity B is the code name of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxotetrahydropyrrol-1-yl)acetamide, and the synthesis route of the present invention is short in time consumption, high in product purity and high in yield.

[0006] The present invention provides a method for preparing an oxiracetam impurity B, comprising reacting a 4-halo-3-hydroxy-butyrate ester represented by formula (2) and a glycyl glycinamide hydrohalide represented by formula (3) to obtain an oxiracetam impurity B represented by formula (1), wherein the reaction formula is as follows:

[0007]

[0008] Among them, X in formula (2) 1 is selected from halogen atoms, preferably chlorine or bromine, and R in formula (2) is selected from hydrogen, substituted or unsubstituted C 1-3 Alkyl, X in formula (3) 2 is selected from halogen atoms, preferably chlorine or bromine.

[0009] The invention uses 4-halo-3-hydroxy-butyric acid ester and glycyl glycinamide hydrohalide to react, so as to prepare the target product oxiracetam impurity B in one step. The synthesis route of the invention has short time consumption, high product yield and low cost.

[0010] In one embodiment, in order to make the reaction of 4-halo-3-hydroxy-butyrate and glycyl glycinamide hydrohalide more thorough, the molar amount of glycyl glycinamide hydrohalide represented by formula (3) is not less than the molar amount of 4-halo-3-hydroxy-butyrate represented by formula (2), thereby increasing the yield of the target product oxiracetam impurity B;

[0011] Preferably, the molar ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the glycyl glycinamide hydrohalide represented by formula (3) is 1.0:(1.0-1.4), and the molar ratio can specifically be 1.0:1.0, 1.0:1.05, 1.0:1.1, 1.0:1.15, 1.0:1.2, 1.0:1.25, 1.0:1.3, 1.0:1.35, 1.0:1.4, or a point value between any two of the above;

[0012] More preferably, the molar ratio of the 4-halogeno-3-hydroxy-butyrate represented by formula (2) to the glycyl glycinamide hydrohalide represented by formula (3) is greater than 1.0:1.2 and less than or equal to 1:1.4. Further controlling the molar ratio of the 4-halogeno-3-hydroxy-butyrate represented by formula (2) to the glycyl glycinamide hydrohalide represented by formula (3) can further improve the yield of the target product oxiracetam impurity B, and further increasing the glycyl glycinamide hydrohalide represented by formula (3) will cause the formation of impurities.

[0013] In one embodiment, the reaction solvent of the reaction is selected from any one of anhydrous ethanol and anhydrous methanol, or a combination of the two;

[0014] Preferably, the mass ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the reaction solvent is 1.0:(1.5-2.5), and the mass ratio can specifically be 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3, 1.0:2.4, 1.0:2.5, or a point value between any two of the above. In the present invention, further controlling the mass ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the reaction solvent can improve the yield and purity of the reaction product.

[0015] In one embodiment, the method further comprises adding a base to the reaction; preferably, the base is an anhydrous base; preferably, the anhydrous base is selected from any one of anhydrous potassium bicarbonate, anhydrous potassium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate, or a combination of at least two thereof;

[0016] Preferably, the mass ratio of the glycyl glycinamide hydrohalide salt shown in formula (3) to the base is 6.0:(1.0-3.0), and the mass ratio can specifically be 6.0:1.0, 6.0:1.1, 6.0:1.2, 6.0:1.3, 6.0:1.4, 6.0:1.5, 6.0:1.6, 6.0:1.7, 6.0:1.8, 6.0:1.9, 6.0:2.0, 6. 0:2.1, 6.0:2.2, 6.0:2.3, 6.0:2.4, 6.0:2.5, 6.0:2.6, 6.0:2.7, 6.0:2.8, 6.0:2.9, 6.0:3.0, or a point value between any two of the above. The present invention can promote the reaction to proceed to a positive reaction, reduce the generation of impurities, and improve the yield by controlling the mass ratio of glycylglycinamide hydrohalide to the base.

[0017] In one embodiment, the method further comprises adding a ruthenium metal catalyst to the reaction; preferably, the ruthenium metal catalyst is selected from any one of RuO2, RuCl3, and ruthenium hydroxide, or a combination of at least two thereof. Adding a ruthenium metal catalyst to the reaction can further improve the yield of the product;

[0018] Preferably, the molar ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by the formula (2) to the ruthenium metal catalyst is 1.0:(0.1-0.65), and the molar ratio can specifically be 1.0:0.1, 1.0:0.15, 1.0:0.2, 1.0:0.25, 1.0:0.3, 1.0:0.35, 1.0:0.4, 1.0:0.45, 1.0:0.5, 1.0:0.55, 1.0:0.6, 1.0:0.65, or any point value between any two of the above.

[0019] In one embodiment, the reaction is carried out in an anhydrous system.

[0020] Under the synthetic route provided by the present invention, by maintaining the reaction system as an anhydrous reaction system, the reaction rate can be increased and the decomposition of the reaction product and the generation of by-products can be reduced, thereby further improving the reaction yield, improving the purity of the crude product, and reducing the pressure of subsequent purification.

[0021] In one embodiment, the method further comprises adding a dehydrating agent to the reaction; preferably, the dehydrating agent is selected from any one of 3A molecular sieve and 4A molecular sieve, or a combination of two thereof;

[0022] Preferably, the mass ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the water removing agent is 1.0:(0.5-1.5).

[0023] In one embodiment, the reaction temperature of the reaction is 75-85°C, and the reaction temperature can be 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85°C, or any value between the above two. The reaction time of the reaction is 3-6h, and the reaction time can be 3, 3.5, 4, 4.5, 5, 5.5, 6h, or any value between the above two.

[0024] In one embodiment, after the reaction is completed, post-treatment is performed, and the post-treatment includes filtering, beating and drying;

[0025] Preferably, the crystallization solvent for pulping is any one of methanol, ethanol, n-propanol or isopropanol, or a combination of at least two thereof; preferably, the crystallization solvent is a mixed solvent of ethanol and isopropanol; preferably, the mass ratio of ethanol to isopropanol is 5.0:(1.5-2.5), and the specific mass ratio can be 5.0:1.5, 5.0:1.6, 5.0:1.7, 5.0:1.8, 5.0:1.9, 5.0:2.0, 5.0:2.1, 5.0:2.2, 5.0:2.3, 5.0:2.4, 5.0:2.5, 5.0:2.6, 5.0:2.7, 5.0:2.8, 5.0:2.9, 5.0:2.10, 5.0:2.11, 5.0:2.12, 5.0:2.13, 5.0:2.14, 5.0:2.15, 5.0:2.26, 5.0:2.27, 5.0:2.38, 5.0:2.49, 5.0:2.5 .0:2.2, 5.0:2.3, 5.0:2.4, 5.0:2.5, or any point value between the above two; preferably, the mass ratio of the 4-halogeno-3-hydroxy-butyrate represented by the formula (2) to the crystallization solvent is 1.0:(1-1.5), and the mass ratio can specifically be 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, or any point value between the above two;

[0026] Preferably, the beating temperature is 70-90°C. By controlling the beating temperature, impurities can be removed more effectively and the purity can be improved. The beating time is 20-40 minutes.

[0027] In one embodiment, the post-treatment further comprises cooling the pulp to 0-25°C.

[0028] Based on the above, compared with the prior art, the present invention has at least one of the following beneficial technical effects:

[0029] (1) The present invention uses 4-halo-3-hydroxy-butyric acid ester and glycyl glycinamide hydrohalide to react to obtain the target product oxiracetam impurity B in one step. The synthetic route of the present invention is time-consuming, has a high product yield and low cost.

[0030] (2) The oxiracetam impurity B synthesized by the present invention can be used as a control for oxiracetam detection and used to control the quality of commercially available oxiracetam drugs.

[0031] Other features and beneficial effects of the present invention will be described in the following description, and partly become apparent from the description, or understood by practicing the present invention. The purpose and other beneficial effects of the present invention can be realized and obtained by the structures particularly pointed out in the description, claims and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is a high performance liquid chromatogram of the oxiracetam impurity B obtained in Example 1;

[0033] Figure 2 is the infrared spectrum of Oxiracetam impurity B obtained in Example 1;

[0034] Figure 3 is the hydrogen spectrum of Oxiracetam impurity B prepared in Example 1;

[0035] Figure 4 This is the carbon spectrum of the oxiracetam impurity B obtained in Example 1. DETAILED DESCRIPTION

[0036] 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 part of the embodiments of the present invention, rather than all the embodiments; the technical features designed in different implementation modes of the present invention described below can be combined with each other as long as they do not conflict with each other; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0037] The 4-halo-3-hydroxy-butyric acid ester represented by formula (2) and the glycyl glycinamide hydrohalide represented by formula (3) used in the present invention can adopt relevant commercial products. For example, the glycyl glycinamide hydrohalide represented by formula (3) can adopt the commercially available compound glycyl glycinamide hydrobromide (CAS: 3479-49-0).

[0038] The HPLC detection parameters are as follows:

[0039] Reagents: acetonitrile (HPLC grade), phosphoric acid (AR grade), ammonia (AR grade)

[0040] High performance liquid chromatograph: Agilent 1260 liquid chromatograph or Thermo Fisher Ultmate 3000 with UV detector; Chromatographic column: 25cm*4.6mm, 5μm stainless steel inner filling L8;

[0041] HPLC conditions: injection volume: 20 μL; running time: 20 min; flow rate: 1.0 ml / min; detection wavelength: 205 nm; mobile phase: pH 6.0 phosphoric acid aqueous solution-acetonitrile (25:75);

[0042] HPLC test method:

[0043] (1) Solution preparation: Use mobile phase as diluent;

[0044] (2) Preparation of test solution: Prepare a sample solution with a concentration of 1.0 mg / ml using a diluent and prepare two replicates in parallel;

[0045] (3) After the instrument is stable, inject samples separately: ≥1 injection - blank solution, double sample single injection - sample solution;

[0046] (4) Calculation of results: Based on the relative retention time, the chromatographic purity and the content of related substances were calculated by the area normalization method. The relative retention time of oxiracetam impurity B, RRT = 1.20.

[0047] Example 1

[0048] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0049]

[0050] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, and 20g of anhydrous ethanol were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and the filtered mother liquor was concentrated to dryness. Then, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then cooled to 25°C for crystallization for 4 hours. Filter and dry to obtain 5.18g of white crystals, i.e., Oxiracetam impurity B. The purity of Oxiracetam impurity B in the solid is 99.2% (reference Figure 1 ), with a yield of 50.2%.

[0051] The obtained Oxiracetam impurity B was subjected to infrared, hydrogen and carbon spectrum detection, and the results were as follows:

[0052] (1) Infrared absorption spectrum scanning characteristic absorption peak:

[0053] 1622cm -1 , 1651cm -1 , 1666cm -1 ,3211cm -1 , 3313cm -1 , 3406cm -1 (refer to Figure 2 );

[0054] (2) 1 H-NMR (400MHz, D2O), δ (ppm):

[0055] 2.40-2.45; 2.88-2.94; 3.43-3.46; 3.85-3.96; 4.08-4.21; 4.59-4.63; (Reference Figure 3 );

[0056] (3) 13 C-NMR (400MHz, D2O), δ (ppm):

[0057] 39.83; 41.99; 45.52; 57.41; 64.01; 170.60; 174.03; 176.79 (reference Figure 4 ).

[0058] Example 2

[0059] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0060]

[0061] 10.13g of 4-bromo-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, and 20g of anhydrous ethanol were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and the filtered mother liquor was concentrated to dryness, and 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then cooled to 25°C for crystallization for 4 hours. Filter and dry to obtain 6.20g of white crystals, i.e., Oxiracetam impurity B. The purity of Oxiracetam impurity B in the solid was 99.3%, and the yield was 55.6%.

[0062] Example 3

[0063] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0064]

[0065] 9.49g of 4-bromo-3-hydroxy-butyric acid methyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, and 20g of anhydrous ethanol were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and the filtered mother liquor was concentrated to dryness, and 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then cooled to 25°C for crystallization for 4 hours. Filter and dry to obtain 5.96g of white crystals, i.e., Oxiracetam impurity B. The purity of Oxiracetam impurity B in the solid was 99.2%, and the yield was 53.3%.

[0066] Example 4

[0067] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0068]

[0069] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, 20g of anhydrous ethanol and 4g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 3A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then dropped to 25°C for crystallization for 4 hours. Filtered and dried to obtain 7.41g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.6%, and the yield was 72.2%.

[0070] Example 5

[0071] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0072]

[0073] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, 1.0g of RuCl3 and 20g of anhydrous ethanol were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and the filtered mother liquor was concentrated to dryness, and 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then cooled to 25°C for crystallization for 4 hours. Filter and dry to obtain 8.10g of white crystals, i.e., Oxiracetam impurity B. The purity of Oxiracetam impurity B in the solid was 99.5%, and the yield was 78.3%.

[0074] Example 6

[0075] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0076]

[0077] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, 1.0g of RuCl3, 20g of anhydrous ethanol and 4g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 3A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then dropped to 25°C for crystallization for 4 hours. Filtered and dried to obtain 8.50g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.8%, and the yield was 82.3%.

[0078] Example 7

[0079] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0080]

[0081] 10.13g of 4-bromo-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, 1.0g of RuCl3, 20g of anhydrous ethanol and 8.1g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 3A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then dropped to 25°C for crystallization for 4 hours. Filtered and dried to obtain 9.04g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.3%, and the yield was 80.8%.

[0082] Example 8

[0083] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0084]

[0085] 9.49g of 4-bromo-3-hydroxy-butyric acid methyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, 1.0g of RuCl3, 20g of anhydrous ethanol and 7.6g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 3A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then dropped to 25°C for crystallization for 4 hours. Filtered and dried to obtain 9.16g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.6%, and the yield was 81.9%.

[0086] Example 9

[0087] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0088]

[0089] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium carbonate, 2.0g of RuCl3, 20g of anhydrous ethanol and 8g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 3A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then dropped to 25°C for crystallization for 4 hours. Filtered and dried to obtain 8.54g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.8%, and the yield was 82.7%.

[0090] Example 10

[0091] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0092]

[0093] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 12.21g of glycyl glycinamide hydrobromide, 6.1g of anhydrous sodium bicarbonate, 3.2g of RuO2, 20g of anhydrous ethanol and 12g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 3A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then crystallized at 25°C for 4 hours. Filtered and dried to obtain 8.40g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.8%, and the yield was 81.4%.

[0094] Embodiment 11

[0095] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0096]

[0097] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 10.18g of glycyl glycinamide hydrobromide, 2.0g of anhydrous potassium carbonate, 4.75g of ruthenium hydroxide, 12g of anhydrous methanol and 4g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 4A) were added to a 50ml three-necked flask and mixed, and reacted at 75°C for 6 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 8g of methanol-n-propanol (the mass ratio of methanol to n-propanol was 5:1.5) mixed solvent was added and heated at 70°C for 20min, and then dropped to 15°C for crystallization for 3 hours. Filtered and dried to obtain 8.33g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.8%, and the yield was 80.6%.

[0098] Example 12

[0099] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0100]

[0101] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 13.24g of glycyl glycinamide hydrobromide, 5.3g of anhydrous potassium bicarbonate, 3.0g of RuCl3, 16g of anhydrous methanol and 8g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 4A) were added to a 50ml three-necked flask and mixed, and reacted at 85°C for 4 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 10.4g of ethanol-n-propanol (the mass ratio of ethanol to n-propanol was 5:2.5) mixed solvent was added and heated at 90°C for 40min, and then dropped to 5°C for crystallization for 2 hours. Filtered and dried to obtain 8.57g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.8%, and the yield was 83.0%.

[0102] Embodiment 13

[0103] The preparation of N-(2-amino-2-oxoethyl)-2-(4-hydroxy-2-oxopyrrol-1-yl)acetamide is as follows:

[0104]

[0105] 8g of 4-chloro-3-hydroxy-butyric acid ethyl ester, 11.27g of glycyl glycinamide hydrochloride, 5.6g of anhydrous sodium carbonate, 2.0g of RuCl3, 20g of anhydrous ethanol and 12g of molecular sieve (Jiangxi Chengyu Ceramics Co., Ltd., pore size 4A) were added to a 50ml three-necked flask and mixed, and reacted at 80°C for 3 hours. After the reaction, the mixture was filtered, and after the filtered mother liquor was concentrated to dryness, 12g of ethanol-isopropanol (the mass ratio of ethanol to isopropanol was 5:2) mixed solvent was added and heated at 80°C for 30min, and then dropped to 0°C for crystallization for 1 hour. Filter and dry to obtain 8.61g of white crystals, i.e., oxiracetam impurity B. The purity of oxiracetam impurity B in the solid was 99.8%, and the yield was 83.3%.

[0106] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an oxiracetam impurity B, characterized in that: The method comprises reacting a 4-halo-3-hydroxy-butyric acid ester represented by formula (2) and a glycyl glycinamide hydrohalide represented by formula (3) to obtain an oxiracetam impurity B represented by formula (1). The reaction formula of the reaction is shown as follows: Among them, X in formula (2) 1 is selected from halogen atoms, preferably chlorine or bromine, and R in formula (2) is selected from hydrogen, substituted or unsubstituted C 1-3 Alkyl, X in formula (3) 2 is selected from halogen atoms, preferably chlorine or bromine.

2. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The molar amount of the glycyl glycinamide hydrohalide salt represented by formula (3) is not less than the molar amount of the 4-halo-3-hydroxy-butyrate represented by formula (2); Preferably, the molar ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the glycyl glycinamide hydrohalide represented by formula (3) is 1.0:(1.0-1.4).

3. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The reaction solvent of the reaction is selected from any one of anhydrous ethanol and anhydrous methanol or a combination of the two; Preferably, the mass ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the reaction solvent is 1.0:(1.5-2.5).

4. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The method further comprises adding a base to the reaction; Preferably, the base is an anhydrous base; Preferably, the anhydrous base is selected from any one of anhydrous potassium bicarbonate, anhydrous potassium carbonate, anhydrous sodium bicarbonate, anhydrous sodium carbonate, or a combination of at least two thereof; Preferably, the mass ratio of the glycyl glycinamide hydrohalide salt represented by formula (3) to the base is 6.0:(1.0-3.0).

5. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The method further comprises adding a ruthenium metal catalyst to the reaction; preferably, the ruthenium metal catalyst is selected from any one of RuO2, RuCl3, and ruthenium hydroxide, or a combination of at least two thereof; Preferably, the molar ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the ruthenium metal catalyst is 1.0:(0.1-0.65).

6. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The reaction is carried out in an anhydrous system.

7. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The method further comprises adding a water removal agent to the reaction; Preferably, the dehydrating agent is selected from any one of 3A molecular sieve and 4A molecular sieve, or a combination of the two; Preferably, the mass ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the water removing agent is 1.0:(0.5-1.5).

8. The method for preparing oxiracetam impurity B according to claim 1, characterized in that: The reaction temperature of the reaction is 75-85° C., and the reaction time of the reaction is 3-6 h.

9. The method for preparing the oxiracetam impurity B according to any one of claims 1 to 8, characterized in that: After the reaction is completed, post-treatment is performed, and the post-treatment includes filtering, beating and drying; Preferably, the crystallization solvent used for pulping is any one of methanol, ethanol, n-propanol or isopropanol, or a combination of at least two thereof; Preferably, the crystallization solvent is a mixed solvent of ethanol and isopropanol; Preferably, the mass ratio of ethanol to isopropanol is 5.0:(1.5-2.5); Preferably, the mass ratio of the 4-halogeno-3-hydroxy-butyric acid ester represented by formula (2) to the crystallization solvent is 1.0:(1.0-1.5); Preferably, the beating temperature is 70-90°C, and the beating time is 20-40 min.

10. The method for preparing oxiracetam impurity B according to claim 9, characterized in that: The post-treatment also includes cooling the pulp to 0-25°C.

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