A method for the purification of oxazepam

Abstract

This invention discloses a method for purifying oxazepam. Crude oxazepam is added to an amide-based dipolar proton-dependent solvent, kept at a constant temperature until dissolved, then activated carbon is added for decolorization, and the mixture is filtered to obtain a filtrate. Water is added dropwise to the filtrate at 45–55°C, the temperature is lowered after addition, and the mixture is kept at 20–25°C. The mixture is then filtered to obtain a primary purified wet oxazepam product. This primary purified wet oxazepam product is added to a ketone solvent, heated, and kept at 40–50°C. After cooling and crystallization, the product is filtered to obtain the purified oxazepam product. The purity of the obtained oxazepam product is not less than 99.95%, and the content of the impurity 6-chloro-4-phenylquinoline-2-carboxaldehyde in the product does not exceed 0.02%. The method of this invention significantly reduces the amount and consumption of refining solvents, greatly increases the capacity of refining equipment, reduces preparation costs, and achieves a refining yield of over 90%, which is more than 20 percentage points higher than the yield of the prior art (70%).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for purifying oxazepam. Background Technology

[0002] Oxazepam belongs to the benzodiazepine class of sedative-hypnotic drugs. It has significant sedative and anti-anxiety effects, as well as good muscle relaxant and anticonvulsant effects. It can relieve symptoms such as anxiety, tension, and insomnia in patients with neurosis. It is used as an adjunct treatment for neurosis, insomnia, and epilepsy, and is suitable for the elderly or those with renal insufficiency. The 2015 edition of the Chinese Pharmacopoeia specifies two known impurities in the related substances test of oxazepam raw materials and tablets: (3RS)-7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine-3-acetic acid ester (referred to as impurity I) and 6-chloro-4-phenylquinoline-2-carboxaldehyde (referred to as impurity II). Impurity I is an intermediate in the preparation process of oxazepam; impurity II is the main degradation product of oxazepam. The literature "Inspection of related substances in oxazepam raw materials and tablets" (Journal of Pharmaceutical Analysis, 2008, 28(4), 562-566) reported that oxazepam is unstable under acid, alkali, light, oxygen and heating conditions, and impurity II is easily generated in all of them.

[0003]

[0004] The "National Compendium of Active Pharmaceutical Ingredient Processes" describes the preparation process of oxazepam. The refining process involves dissolving the crude product under reflux in ethanol at a volume ratio of 50:1, followed by direct cooling to crystallize. The resulting oxazepam product contains more than 0.12% impurity II, which is the largest single impurity under the related substances test for oxazepam active pharmaceutical ingredient. While the impurity II levels obtained by existing refining methods meet pharmacopoeia standards, it is difficult to control impurity II to below 0.1% and total impurities to below 0.2%. Oxazepam has poor solubility in various organic solvents such as ethanol, methanol, ethyl acetate, acetone, dichloromethane, and chloroform, requiring a large amount of solvent in the refining process (the crude product and...). The high mass-to-volume ratio of ethanol (1:50) severely restricts the production capacity of refining equipment. Oxazepam contains an unstable seven-membered ring structure, which easily generates degradation impurities (impurity II is the main degradation impurity) under various conditions, including heating. Existing preparation technologies, to avoid prolonged exposure of the material to high temperatures (ethanol reflux temperature 78-80℃), not only strictly control the reflux decolorization time, but also employ direct cooling crystallization instead of a prolonged concentration and solvent removal process to ensure that the product's related substances meet requirements. However, the presence of a large amount of crystallization solvent during the crystallization process results in a oxazepam refining yield of only about 70%. Furthermore, the inability to reuse the refining solvent further increases production costs. Therefore, it is necessary to adopt a new technical solution for the refining of oxazepam. Summary of the Invention

[0005] To address the problems existing in the prior art, the present invention aims to provide a purification method for oxazepam. This purification method can effectively reduce the content of impurity II (6-chloro-4-phenylquinoline-2-carboxaldehyde) in oxazepam, enabling oxazepam to meet stricter quality standards. The technical solution of this invention can obtain high-purity oxazepam with low production cost and high yield, making it suitable for industrial production.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] A method for refining oxazepam includes the following steps:

[0008] (1) Add crude oxazepam to an amide-based dipolar proton solvent, keep warm to dissolve, add activated carbon for decolorization, and filter to obtain the filtrate;

[0009] (2) Add purified water dropwise to the filtrate at 45-55℃, cool down after adding, keep warm at 20-25℃, and filter to obtain oxazepam primary purified wet product.

[0010] (3) Add the primary refined wet product of oxazepam to a ketone solvent and heat it. Keep it at 40-50°C, cool and crystallize, and filter to obtain the refined oxazepam product.

[0011] Preferably, the amide-based dipolar proton solvent in step (1) is at least one of N,N-dimethylformamide and N,N-dimethylacetamide.

[0012] Preferably, the temperature for heat preservation and dissolution in step (1) is 45-55°C.

[0013] Preferably, the ratio of crude oxazepam to amide-based dipolar proton solvent in step (1) is 1 g: 3-4 mL.

[0014] Preferably, the ratio of crude oxazepam to activated carbon in step (1) is 1g:0.04-0.05g.

[0015] Preferably, the heat preservation time in step (2) is 30 minutes.

[0016] Preferably, the ratio of the ketone solvent to crude oxazepam in step (3) is 4-5 mL: 1 g.

[0017] Preferably, the heat preservation time in step (3) is 30 minutes.

[0018] Preferably, the cooling crystallization temperature in step (3) is -5 to 10°C, and the time is 1 hour; more preferably, the cooling crystallization temperature is 0 to 5°C.

[0019] Preferably, the ketone solvent in step (3) is at least one of acetone and butanone.

[0020] During extensive experimentation, the applicant accidentally discovered that, under different solvents and the same dissolution temperature, the purity and impurity II quality indicators of crude oxazepam obtained by crystallization in N,N-dimethylformamide were the most ideal. The significant increase in impurity II in the crystallized product obtained after heating at higher temperatures for longer periods in other solvents did not occur. Through further exploration, the applicant found that recrystallization of crude oxazepam using N,N-dimethylacetamide also achieved similar results in terms of product purity and impurity II quality indicators. To ensure the purification yield of oxazepam, after decolorization in N,N-dimethylformamide or N,N-dimethylacetamide, a water precipitation post-treatment method was adopted. Comparative experiments showed that adding water droplets to the filtrate at higher temperatures was more effective in removing other single impurities than the usual low-temperature water precipitation method. Furthermore, adding water droplets to the filtrate was more effective than adding the filtrate droplets to water. The dropping temperature and the order of material addition played a crucial role in the water precipitation post-treatment process. Subsequent pulping with ketone solvents helps to shorten the product drying time and ensure the quality stability of the product during the drying process.

[0021] Compared with the prior art, the beneficial effects of the present invention include:

[0022] This invention provides a method for purifying oxazepam, yielding a product with a purity of not less than 99.95% and an impurity content of 6-chloro-4-phenylquinoline-2-carboxaldehyde not exceeding 0.02%. This method significantly reduces the amount and consumption of refining solvents, greatly increases the capacity of refining equipment, lowers preparation costs, and achieves a refining yield of over 90%, which is more than 20 percentage points higher than the yield of existing technologies (70%). In summary, the method of this invention has advantages such as low production cost, high yield, high purity of the prepared oxazepam product, and suitability for industrial production. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0024] The crude oxazepam described in the examples and comparative examples was prepared according to the method recorded in the "National Compendium of Pharmaceutical Raw Material Processes" (State Pharmaceutical Administration, 1980).

[0025] Example 1

[0026] A method for refining oxazepam, comprising the following steps:

[0027] Add 20g of crude oxazepam and 60mL of N,N-dimethylformamide to a reaction flask, stir and heat, and stir at 50-55℃ for 10 minutes to dissolve. Add 1g of activated carbon, and continue to stir at 50-55℃ for 30 minutes. Filter, add 300mL of purified water dropwise to the filtrate at 50-55℃, cool down, and keep warm at 20-25℃ for 30 minutes. Filter to obtain the first-stage purified wet oxazepam.

[0028] The total amount of the purified wet oxazepam obtained in the previous step and 80 mL of acetone were added to a reaction flask, stirred and heated, and kept at 40-45°C for 30 minutes. The temperature was then lowered to 0-5°C to allow crystallization, which was carried out for 1 hour. After filtration and drying, 18.2 g of oxazepam product was obtained, with an HPLC purity of 99.978% and an impurity content of 0.012% for 6-chloro-4-phenylquinoline-2-carboxaldehyde. The yield was 91%.

[0029] Example 2

[0030] A method for refining oxazepam, comprising the following steps:

[0031] Add 50g of crude oxazepam and 200mL of N,N-dimethylacetamide to a reaction flask, stir and heat, and stir at 45-50℃ for 10 minutes until dissolved. Add 2.5g of activated carbon, and continue to stir at 45-50℃ for 30 minutes. Filter, add 1000mL of purified water dropwise to the filtrate at 45-50℃, cool down, and keep at 20-25℃ for 30 minutes. Filter to obtain primary purified wet oxazepam.

[0032] The total amount of the purified wet oxazepam obtained in the previous step and 250 mL of butanone were added to a reaction flask, stirred and heated, and kept at 45-50℃ for 30 minutes. The temperature was then lowered to 0-5℃ to crystallize, and crystallization was allowed to occur for 1 hour. After filtration and drying, 45.8 g of oxazepam product was obtained, with an HPLC purity of 99.969% and an impurity content of 0.013% for 6-chloro-4-phenylquinoline-2-carboxaldehyde. The yield was 91.6%.

[0033] Example 3

[0034] A method for refining oxazepam, comprising the following steps:

[0035] Add 50g of crude oxazepam and 180mL of N,N-dimethylformamide to a reaction flask, stir and heat, and stir at 45-50℃ for 10 minutes until dissolved. Add 2.0g of activated carbon, and continue to stir at 45-50℃ for 30 minutes. Filter, add 900mL of purified water dropwise to the filtrate at 45-50℃, cool down, and keep warm at 20-25℃ for 30 minutes. Filter to obtain primary purified wet oxazepam.

[0036] The total amount of the purified wet oxazepam obtained in the previous step and 225 mL of acetone were added to a reaction flask, stirred and heated, and kept at 40-45℃ for 30 minutes. The temperature was then lowered to 0-5℃ to allow crystallization, which was carried out for 1 hour. After filtration and drying, 45.2 g of oxazepam product was obtained, with an HPLC purity of 99.970% and an impurity content of 0.013% for 6-chloro-4-phenylquinoline-2-carboxaldehyde. The yield was 90.4%.

[0037] Comparative Example 1

[0038] 50g of crude oxazepam and 2000mL of ethanol were added to a reaction flask, stirred and heated to 78-80℃ for 30 minutes until dissolved. 2g of activated carbon was added, and the mixture was kept at 78-80℃ and stirred for another 30 minutes. The mixture was filtered, and the filtrate was cooled and kept at 0-5℃ for 1 hour. After filtration and drying, 35.2g of oxazepam product was obtained with an HPLC purity of 99.315% and an impurity content of 0.127% for 6-chloro-4-phenylquinoline-2-carboxaldehyde. The yield was 70.4%.

[0039] Comparative Example 2

[0040] 50g of crude oxazepam and 2000mL of ethanol were added to a reaction flask, stirred and heated to 78-80℃ for 30 minutes until dissolved. 2g of activated carbon was added, and the mixture was kept at 78-80℃ with stirring for another 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The solution was then cooled to 0-5℃ and kept at that temperature for 1 hour. After filtration and drying, 41.3g of oxazepam product was obtained, with an HPLC purity of 99.192% and an impurity content of 0.211% for 6-chloro-4-phenylquinoline-2-carboxaldehyde. The yield was 82.6%.

[0041] Comparative Example 3

[0042] Add 50g of crude oxazepam and 180mL of N,N-dimethylformamide to a reaction flask, stir and heat, and stir for 10 minutes at 45-50℃ until dissolved. Add 2.0g of activated carbon, and continue stirring at 45-50℃ for 30 minutes. Filter, and cool the filtrate to 20-25℃ for later use. Add the filtrate cooled to 20-25℃ to 900mL of purified water, and keep at 20-25℃ for 30 minutes. Filter to obtain primary purified wet oxazepam.

[0043] The total amount of the purified wet oxazepam obtained in the previous step and 225 mL of acetone were added to a reaction flask, stirred and heated, and kept at 40-45°C for 30 minutes. The temperature was then lowered to 0-5°C to allow crystallization, which was carried out for 1 hour. After filtration and drying, 45.1 g of oxazepam product was obtained, with an HPLC purity of 99.519% and an impurity of 0.086% 6-chloro-4-phenylquinoline-2-carboxaldehyde. The yield was 90.2%.

[0044] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for refining oxazepam, characterized in that, Includes the following steps: (1) Add crude oxazepam to an amide-based dipolar proton solvent, keep warm to dissolve, add activated carbon for decolorization, and filter to obtain the filtrate; The amide-based dipolar proton solvent mentioned in step (1) is at least one of N,N-dimethylformamide and N,N-dimethylacetamide; (2) Add purified water dropwise to the filtrate at 45-55℃, cool down after adding, keep warm at 20-25℃, and filter to obtain oxazepam primary purified wet product; (3) Add the primary refined wet product of oxazepam to a ketone solvent and heat it. Keep it at 40-50°C, cool and crystallize, and filter to obtain the refined oxazepam product. The ketone solvent in step (3) is at least one of acetone and butanone.

2. The method for refining oxazepam according to claim 1, characterized in that, In step (1), the ratio of crude oxazepam to amide-based dipolar proton solvent is 1 g: 3-4 mL.

3. The method for refining oxazepam according to claim 2, characterized in that, The ratio of crude oxazepam to activated carbon in step (1) is 1g: 0.04-0.05g.

4. A method for refining oxazepam according to any one of claims 1 to 3, characterized in that, In step (3), the ratio of the ketone solvent to crude oxazepam is 4-5 mL: 1 g.

5. The method for refining oxazepam according to claim 4, characterized in that, The temperature for heat preservation and dissolution in step (1) is 45-55℃.

6. A method for refining oxazepam according to any one of claims 1 to 3, characterized in that, The heat preservation time in step (2) is 30 minutes; the heat preservation time in step (3) is 30 minutes.

7. The method for refining oxazepam according to claim 6, characterized in that, The cooling and crystallization temperature in step (3) is -5 to 10°C, and the time is 1 hour.

8. The method for refining oxazepam according to claim 7, characterized in that, The cooling and crystallization temperature is 0–5°C.

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