Process for the synthesis of n-acetyloxazepam

Abstract

The present application relates to a preparation method of zopiclone related substance N-acetyl zopiclone, which takes N-desmethyl zopiclone or a salt thereof as a raw material, disperses or dissolves in a solvent, and refluxes in the presence of an alkaline catalyst and by adding an acetylating agent. The synthesis method of the present application realizes the goal of judging the reaction endpoint by visually observing the solution clarity, high purity of the crude product, high yield, mild reaction conditions, low impurity content of the product, and can be suitable for production scale-up and product use as a zopiclone impurity standard.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing N-acetylzopiclone, a related substance of zopiclone. Background Technology

[0002] Abnormal sleep volume and unusual behaviors during sleep are manifestations of disruption of the normal rhythmic alternation of sleep and wakefulness, which can be caused by various factors and is often related to physical illnesses. Research on sleep and sleep disorders can be traced back to the 19th century. Studies have shown that the locus coeruleus and raphe nuclei in the pons are related to the occurrence of REM (rapid eye movement) sleep, while the raphe nuclei in the midbrain may be related to NREM (non-rapid eye movement) sleep. The raphe nuclei contain serotonergic neurons, and the locus coeruleus contains noradrenergic neurons. Chemically increasing or decreasing serotonin levels can facilitate or inhibit NREM and REM. Therefore, the central pathway of serotonergic neurons may be related to the maintenance of NREM and the activation of REM, while the central pathway of noradrenergic neurons may be related to the maintenance of REM and wakefulness.

[0003] Cyclopyrrolidones are a newly discovered class of compounds with sedative-hypnotic activity. A representative compound is zopiclone (chemical name 6-(5-chloropyridin-2-yl)-7-[(4-methylpiperazin-1-yl)formyloxy]-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one), developed by Rhône-Plunk in France and launched in France in 1988 (now a Sanofi product). This compound is an inhibitory neurotransmitter γ-aminobutyric acid (GABA) receptor agonist and has been marketed as a representative sedative-hypnotic drug in this class in more than 80 countries and regions worldwide. The structure of zopiclone is shown below:

[0004]

[0005] Although zopiclone has a different structure from benzodiazepines, it can bind to benzodiazepine receptors and has the same pharmacological effects as benzodiazepines, making it the first non-benzodiazepine sedative-hypnotic drug. Zopiclone is a GABAA receptor agonist that enhances the inhibitory effect of GABA, possessing sedative, hypnotic, muscle relaxant, anticonvulsant, and anti-anxiety effects. Its half-life in vivo is only 5 hours. After administration, it effectively shortens the sleep latency, increases total sleep time, reduces the number of nighttime awakenings, and does not cause side effects such as memory impairment upon waking. This drug is non-addictive, and the resulting sequelae and adverse reactions are much weaker than those of benzodiazepines. Clinically, it is used to treat severe sleep disorders, including transient and short-term insomnia, and is therefore considered a representative of the third generation of sedative-hypnotic drugs. Zopiclone is a fast-acting hypnotic drug with a high safety profile due to its rapid absorption, quick onset of action, and absorption that is not affected by the timing of administration, repeated doses, or gender. It was launched in China in 1989, is covered by the National Medical Insurance Program, and is included in the National Essential Medicines List. Currently, domestically produced zopiclone has captured a major share of the domestic market.

[0006] Zopiclone can generate various impurities during production and storage. According to domestic and international reports, approximately nine related substances of zopiclone have been identified so far. These impurities are introduced during the synthesis of zopiclone or generated during its degradation, and have a significant impact on the safety and efficacy of the drug. Their chemical structures are as follows:

[0007]

[0008]

[0009] During long-term synthesis and research of zopiclone, the applicant discovered and isolated an impurity present in the active pharmaceutical ingredient that had not previously attracted the attention of those skilled in the art: 6-(5-chloropyridin-2-yl)-7-[(4-acetylpiperazin-1-yl)carbonyloxy]-5,6-dihydropyrrole[3,4-b]pyrazin-5-one, hereinafter referred to as N-acetylzopiclone, with the following structure:

[0010] N-acetylzopiclone

[0011] Currently, there are no detailed research reports on this impurity. In 2007, US Patent US7456173B2 (Compositions comprising zopiclone derivatives and methods of making and using the same) listed two corresponding isomers of N-acetylzopiclone when listing a series of zopiclone analogs, with the following structures.

[0012]

[0013] Although the US7456173B2 specification does not provide a detailed study of the two substances, it does provide a synthetic process route for compounds with the above-mentioned structure or similar structures.

[0014] Through practical exploration, the applicant repeated the procedures described in the literature and discovered that the synthetic routes recorded in the prior art had unsatisfactory problems:

[0015] Route 1: The route for the condensation reaction of hydroxyl compounds with 4-acetylpiperazine-1-formyl chloride under alkaline conditions;

[0016]

[0017] This method is a heterogeneous reaction, which takes a long time, and the raw material 4-acetylpiperazine-1-formyl chloride is not easy to obtain. Using DMAP as a catalyst introduces other impurities.

[0018] Route 2: N-Demethylzopiclone undergoes an acylation reaction with acetic anhydride under acetic acid conditions to generate N-acetylzopiclone.

[0019]

[0020] Route 2, while yielding the target product, also produces an impurity with extremely similar polarity that is difficult to separate: 6-(5-chloropyridin-2-yl)-5-hydroxy-7-carbonyl-5,6-dihydropyrrole[3,4-b]pyrazine, commonly known as the "hydroxy compound." This compound is a starting material for the synthesis of zopiclone and a degradation product of zopiclone; it is also the starting material for the reaction in Route 1. Further studies have shown that N-acetylzopiclone is unstable under acidic conditions, and the CO bond readily breaks to form the "hydroxy compound," the structure of which is shown in the following formula:

[0021] Hydroxy compounds

[0022] Route 3: Similar to Route 2, N-demethylzopiclone is reacted with anhydrides of acyl chloride or mixed formic acid (or acetic acid).

[0023]

[0024] A comprehensive analysis of zopiclone's related substances provides a basis for drug quality control and process optimization, and lays the foundation for drug safety and efficacy. Using N-acetylzopiclone as a related substance for purity control of zopiclone is highly significant. Therefore, it is still necessary to explore a synthetic method for obtaining N-acetylzopiclone with high purity (>99%), mild reaction conditions, and suitability for large-scale production. Summary of the Invention

[0025] The purpose of this invention is to provide a method for preparing N-acetylzopiclone, a zopiclone-related substance.

[0026] The technical solution of this invention is a method for preparing N-acetylzopiclone, which is obtained through the following steps:

[0027] The reaction is carried out by dispersing or dissolving N-demethylzopiclone or its salt in a solvent and adding an acetylation reagent in the presence of a basic catalyst, as shown in the following reaction formula.

[0028]

[0029] According to the present invention, the key point is that the catalyst used must be a basic catalyst, which differs from the use of acidic environments or reaction reagents in the prior art and is an indispensable condition for achieving the core objective of the present invention. The use of a basic catalyst is a key improvement of the present invention. By using a basic catalyst, the present invention avoids problems such as the generation of difficult-to-separate byproducts that occur when the reaction is carried out in an acidic system.

[0030] The most preferred alkaline catalyst used in this invention is a weakly basic organic reagent, such as triethylamine or pyridine, followed by 4-dimethylaminopyridine (DMAP) or ammonia. Experiments have shown that the reaction can also be carried out using solid sodium hydroxide or potassium hydroxide, or a solution of sodium hydroxide or potassium hydroxide (e.g., a 10% concentration solution).

[0031] According to the present invention, the amount of alkaline catalyst can be selected according to the actual reaction environment. Preferably, the mass of alkaline catalyst is 0.1-1.25 times the mass of the raw material N-demethylzopiclone or its salt, for example, 0.15 times, 0.19 times, 0.2 times, 0.25 times, 0.3 times, 0.35 times, 0.4 times, 0.45 times, 0.5 times, 0.55 times, 0.6 times, 0.65 times, 0.7 times, 0.75 times, 0.8 times, 0.85 times, 0.9 times, 0.95 times, 1.0 times, 1.1 times, 1.2 times, etc., preferably 0.2-0.5 times.

[0032] According to the present invention, the acetylation reagent used is a conventional reagent that provides acylation, such as anhydride or acyl chloride. The preferred acetylation reagent of the present invention is acetic anhydride. Preferably, the mass of the acetylation reagent is 0.1-2 times the mass of the raw material N-demethylzopiclone or its salt, for example, 0.15 times, 0.2 times, 0.25 times, 0.3 times, 0.35 times, 0.4 times, 0.45 times, 0.5 times, 0.55 times, 0.6 times, 0.65 times, 0.7 times, 0.75 times, 0.8 times, 0.85 times, 0.9 times, 0.95 times, 1.0 times, 1.1 times, 1.15 times, 1.2 times, 1.25 times, 1.3 times, 1.35 times, 1.4 times, 1.45 times, 1.5 times, 1.55 times, 1.6 times, 1.65 times, 1.7 times, 1.75 times, 1.8 times, 1.85 times, 1.9 times, 1.95 times, etc., preferably 0.3-1 times. The preferred method is to use acetic anhydride in an amount of 0.3-1 times the mass of the raw material N-demethylzopiclone or its salt for the reaction.

[0033] According to the present invention, the selected solvent can be a conventional solvent that can satisfy the dispersion of the two raw materials for the reaction. However, alkaline solvents, such as N,N-dimethylformamide (DMF), are not recommended as the dispersion system. This is because when using alkaline solvents, the amount of solvent used is much greater than that of the catalyst, and when the raw material is an acidic salt, it may easily dissolve in alkaline organic solvents. This makes endpoint determination difficult when using DMF-type alkaline solvents as reaction reagents. Furthermore, solvents with relatively low boiling points are preferred. For example, DMF itself has a high boiling point, requiring a 135°C oil bath to evaporate the solvent, and high temperatures may lead to an increase in byproducts. Therefore, solvents more suitable for the present invention are non-alkaline solvents or solvents with a boiling point below 130°C, especially solvents that simultaneously satisfy the requirements of being non-alkaline and having a boiling point below 130°C. For example, solvents selected from one or more of ethyl acetate, toluene, acetonitrile, ethanol, and dichloromethane are preferred, with the most preferred solvents selected from one or more of acetonitrile, ethanol, and dichloromethane. The amount of solvent used is generally related to the reaction environment, the amount of raw materials, and the amount of product, with the aim of ensuring sufficient dissolution of the reaction product. In this invention, the volume of solvent used is preferably 10-50 times (in liters) the mass of the raw material N-demethylzopiclone or its salt (in kilograms), and more preferably 15-25 times.

[0034] According to the present invention, in order to accelerate the reaction rate, the reaction system can be heated. Preferably, the reaction temperature is controlled at a level that allows the reaction solvent to reflux. The specific temperature used depends on the type of solvent, with the aim of achieving reflux of the solution.

[0035] According to the present invention, when using a salt of N-desmethylzopiclone as a raw material, the salts that can be used include, but are not limited to, its inorganic or organic acid salts, such as hydrochloride, sulfate, or nitrate. In some embodiments of the present invention, N-desmethylzopiclone hydrochloride is used.

[0036] According to the method of this invention, the product is free of hydroxyl compounds, has high purity, complete reaction, and high yield. Furthermore, by selecting a more suitable solvent, the reaction endpoint can be determined very easily. Those skilled in the art can determine the completion of the reaction by observing the change in the reaction system from cloudy to clear. Therefore, the reaction endpoint is very easy to observe and control according to the method of this invention, which is very significant for actual production processes. The reaction endpoint can be controlled visually, allowing the reaction to be stopped immediately after the system has been clarified by reflux, the solvent to be evaporated, and subsequent processing steps to be carried out. This avoids problems such as excessively long reaction times, high energy consumption, and increased byproduct generation. Based on previous research, the synthesis and preparation according to the method of this invention results in a fast reaction rate. Laboratory-level reactions typically reach the endpoint in about 3-10 minutes.

[0037] According to the method of the present invention, after the reaction is completed, conventional purification can be performed. For example, conventionally, the solvent can be evaporated under reduced pressure, the residue can be washed (e.g., with water), filtered, and dried. In one embodiment of the present invention, the solvent is evaporated under reduced pressure, water is added, the residue is filtered, the filter residue is washed with water until neutral, and then dried.

[0038] According to the method of the present invention, the yield of the target product in the current experiments can reach at least 81.3%, and the purity can reach at least 95%. Research has found that the crude product obtained in one experiment had a purity of 99.307% and a maximum single impurity content of 0.515%, which was identified as zopiclone, introduced from the raw material N-demethylzopiclone. This is highly advantageous for using N-acetylzopiclone as a standard for zopiclone testing. Therefore, it is foreseeable that further control of zopiclone residues in the raw materials will further improve the purity of the product of the present invention.

[0039] In one embodiment of the present invention, the synthesis method provided by the present invention is to synthesize under alkaline conditions (preferably pyridine catalysis), using N-demethylzopiclone as a starting material and acetic anhydride as an acetylation agent, under reflux in a suitable solvent (preferably acetonitrile):

[0040]

[0041] According to the present invention, high-purity N-acetylzopiclone that meets detection requirements can be obtained through the above reaction. The present invention has several beneficial effects:

[0042] 1. There are no commercially available standards for N-acetylzopiclone. The method of this invention allows for the large-scale synthesis of standards to provide reference materials for various levels of testing departments. The method of this invention allows for easy synthesis at scales exceeding 10g under laboratory conditions, with crude product purity >95%, yield >80%, and mild reaction conditions, making it suitable for production scale-up. This invention provides samples for the study and prevention of the safety and environmental hazards of zopiclone after use, and is of significant value.

[0043] 2. The product prepared according to the method of this invention is superior to the synthetic routes provided in the prior art in terms of single impurity, total impurities, and number of impurities. Specifically, this is reflected in:

[0044] (1) N-acetylzopiclone does not contain hydroxyl groups, making it more suitable for use as a standard.

[0045] (2) The post-reaction processing of the product is more convenient, requiring only simple water washing and drying to meet the requirements;

[0046] (3) The N-demethylzopiclone reaction of the raw material is complete, and the yield is high;

[0047] (4) The reaction endpoint is easy to determine. After the reaction starts, the system will gradually change from turbid to clear. When the solution is clear, the reaction has been completed and the reaction can be terminated.

[0048] (5) Comparison revealed that the product obtained by the synthetic route of the present invention has high purity and high yield. Attached Figure Description

[0049] Figure 1 HPLC chromatogram of the synthetic product of Comparative Example 1 (patent US7456173B2 route)

[0050] Figure 2 HPLC chromatogram of the synthetic product of Comparative Example 2 (patent US7456173B2 route)

[0051] Figure 3 Mass spectrum of the product in Example 1

[0052] Figure 4 HPLC chromatogram of the product in Example 1

[0053] Figure 5 1H NMR spectrum of the product in Example 1

[0054] Figure 6 Carbon spectrum of the product in Example 1

[0055] Figure 7 HPLC chromatogram of the product in Example 2

[0056] Figure 8HPLC chromatogram of the product in Example 3 Detailed Implementation

[0057] HPLC testing method

[0058] Liquid chromatography conditions: Perform the test according to the high performance liquid chromatography method (Chinese Pharmacopoeia, Part IV, General Chapter 0512), using octadecylsilane-bonded silica gel as the packing material (Waters Shield RP18, 4.6 mm × 250 mm, 5 μm or equivalent column).

[0059] Dissolve 8.1g sodium dodecyl sulfate and 1.6g sodium dihydrogen phosphate in 1000ml of water. Adjust the pH to 3.7 with phosphoric acid to form a phosphate solution. Prepare a 2:3 acetonitrile solution as the mobile phase. The detection wavelength is 303nm.

[0060] Sample preparation: Take approximately 10 mg of sample and place it in a 10 ml volumetric flask. Add mobile phase and sonicate to dissolve the sample and dilute to the mark. Shake well to obtain the test solution. Inject 20 μl of the test solution into the liquid chromatograph. Adjust the mobile phase ratio to ensure the retention time of the main component peak is 27–31 minutes. Calculate the percentage concentration of each peak using the area normalization method.

[0061] Comparative Example 1

[0062] In a 250 mL two-necked flask, add 5 g (12.2 mmol) of N-desmethylzopiclone hydrochloride, 60 mL of acetonitrile, and 6 g (100 mmol) of acetic acid. Heat under reflux at 82 °C for 20 minutes, then add 5 g (45 mmol) of acetic anhydride dropwise. Continue reflux for 10 minutes until the system is completely clear. Evaporate the solvent by rotary evaporation, add 200 mL of purified water, stir for 5 minutes, and filter. Wash the filter cake three times with purified water. Dry under reduced pressure at 60 °C to obtain 4.57 g of N-acetylzopiclone, yield 88.6%, purity 97.324%, and hydroxyl impurity content 1.840%.

[0063] The above product, N-acetylzopiclone, was subjected to HPLC analysis. The results are shown in the appendix. Figure 1 As can be seen from the spectrum, the peak at RT4.4 min is the product N-acetylzopiclone, and the peak at RT4.2 min is the impurity hydroxyl compound (the same applies to subsequent spectra).

[0064] Comparative Example 2

[0065] Add 5 g (12.2 mmol) of N-desmethylzopiclone hydrochloride, 60 ml of acetonitrile, and 6 g (100 mmol) of acetic acid to a 250 ml two-necked flask. Heat under reflux at 82 °C for 20 minutes, then add 5 g (45 mmol) of acetic anhydride dropwise. Continue reflux for 70 minutes. Evaporate the solvent by rotary evaporation, add 200 ml of purified water, and discard the aqueous layer that forms at the bottom of the flask. Dry under reduced pressure at 60 °C. Analyze the solid content; the purity of N-acetylzopiclone is 53.719%, and the content of hydroxyl impurities is 33.393%.

[0066] The above product, N-acetylzopiclone, was subjected to HPLC analysis. The results are shown in the appendix. Figure 2 .

[0067] Example 1

[0068] In a 250 mL two-necked flask, add 5.0 g (12.2 mmol) of N-desmethylzopiclone hydrochloride, 80 mL of acetonitrile, and 1.5 g (19 mmol) of pyridine. Heat under reflux at 82 °C for 20 minutes, then add 5.0 g (49 mmol) of acetic anhydride dropwise. Continue reflux for 5 minutes until the system is completely clear. Evaporate the solvent by rotary evaporation, add 200 mL of purified water, stir for 5 minutes, and filter. Wash the filter cake three times with purified water. Dry under reduced pressure at 60 °C to obtain 4.72 g of N-acetylzopiclone, yield 93.2%, purity 99.307%.

[0069] Mass spectrum of the product from Example 1 (with sodium ion M+Na) + The target compound has a molecular weight M of 416, M+Na + =439), see results below. Figure 3 Simultaneously, HPLC analysis of the product was performed, and the results are shown in the appendix. Figure 4 The structure was confirmed by 500M 1H and 1C NMR spectra; the test results are attached. Figure 5 , 6.

[0070] Example 2

[0071] In a 250 mL two-necked flask, add 4 g (9.7 mmol) of N-desmethylzopiclone hydrochloride, 100 mL of dichloromethane, and 2 g (126.6 mmol) of triethylamine. Heat under reflux at 40 °C for 5 minutes, then add 3 g (29.4 mmol) of acetic anhydride dropwise. Continue reflux for 3 minutes until the system becomes completely clear. Evaporate the solvent by rotary evaporation, add 100 mL of purified water, and stir for 10 minutes until a viscous solid gradually forms. Filter under vacuum. Wash the filter cake three times with purified water. Dry under reduced pressure at 60 °C to obtain 3.43 g of N-acetylzopiclone, yield 85%, purity 98.716%.

[0072] The HPLC test results of the product in Example 2 are shown in the appendix. Figure 7 .

[0073] Example 3

[0074] 4 g (9.7 mmol) of N-desmethylzopiclone hydrochloride and 100 ml of DMF were added to a 250 ml two-necked flask. The mixture was heated under reflux at 110 °C for 30 seconds until the system became completely clear. 3 g (29.4 mmol) of acetic anhydride was added dropwise. The mixture was heated for another 3 minutes, and the solvent was evaporated by rotary evaporation (oil bath 140 °C). 100 ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was then filtered. The filter cake was washed three times with purified water. The cake was dried under reduced pressure at 60 °C to obtain 3.37 g of N-acetylzopiclone, with a yield of 83.5%, a purity of 88.548%, and a hydroxyl impurity content of 9.469%.

[0075] The HPLC test of the product in Example 3 was performed, and the test results are shown in the appendix. Figure 8 .

[0076] Examples 4 to 11

[0077] Add N-demethylzopiclone hydrochloride, solvent, and basic catalyst to a 250 ml two-necked flask, heat to reflux, and add acetic anhydride dropwise. Continue refluxing until the system becomes completely clear; if it does not become clear, stop heating after refluxing for 30 minutes. Purify according to the method in Example 1. See the table below for specific reaction conditions.

[0078] Table 1 Preparation conditions of Examples 4-11

[0079]

[0080] As can be seen from Examples 1 to 11, the product can be successfully synthesized when the amount of catalyst is 0.2-1.25 times the mass of the raw material and the amount of acetic anhydride is 0.3-1 times the mass of the raw material.

[0081] When using toluene and ethyl acetate as solvents, the reaction system remains turbid if the amount of solvent is insufficient, as both the raw materials and products have low solubility in the solvent. This makes it difficult to determine the reaction endpoint.

[0082] However, when NaOH is used as a catalyst, the reaction phenomena are quite different from those of organic bases. Furthermore, the post-reaction processing is difficult to handle due to the viscous substance adhering to the bottom of the flask, so it is not considered a preferred solution in this invention.

[0083] Example 12 Impurity Comparison Determination

[0084] The purity of the products from Example 1 and Comparative Examples 1 and 2 was determined using the aforementioned HPLC method. The results are shown in the table below.

[0085] Table 2 Comparison of Purity and Impurity Determination

[0086]

[0087] The test results above show that the product obtained by the preparation method of this invention has a much higher purity than the synthetic route of the prior art. Furthermore, because the reaction endpoint of the comparative example cannot be determined, the impurities in the comparative example increase continuously with the extension of reaction time. Therefore, regardless of single impurities, total impurities, or the number of impurities, the product obtained by the preparation method of this invention has much lower purity than that of the prior art, meeting the application requirements of the compound as a raw material for standards and other applications.

[0088] Example 13 Product Quality Measurement

[0089] The purity and yield of the synthesis reactions in Examples 1-11 were determined, and the results are shown in the table below.

[0090] Table 3 Purity of Products from Embodiments of the Invention

[0091]

[0092] The test results above show that, except for Example 3, the purity and yield of the products obtained in the preparation method of this invention meet the actual requirements. The main impurity in the products is zopiclone, and the products meet the requirements for use as zopiclone related substance standards. Example 3 selected an alkaline solvent such as N,N-dimethylformamide (DMF) as the dispersion system. Because an alkaline solvent is used, the amount used is much larger than that of the catalyst. Moreover, DMF itself has a high boiling point, requiring a 135°C oil bath to evaporate the solvent, and the high temperature will inevitably lead to an increase in by-products. Therefore, it is not recommended to use an alkaline solvent such as N,N-dimethylformamide (DMF) as the dispersion system.

[0093] Obviously, the described embodiments are only a part of the embodiments of this application, not all of them. Therefore, all other embodiments obtained based on the claims of this application are within the scope of protection of this application.

Claims

1. A method for preparing N-acetylzopiclone, characterized in that, The reaction is carried out by dispersing or dissolving N-demethylzopiclone or its salt in a solvent, adding acetylation reagent acetic anhydride in the presence of a basic catalyst, wherein the basic catalyst is selected from one or more of 4-dimethylaminopyridine, triethylamine, and pyridine, the solvent is acetonitrile, and the reaction is carried out under reflux. The reaction is complete when the reaction solution becomes clear. The amount of alkaline catalyst used is 0.2-0.5 times the mass of the raw material N-demethylzopiclone; The amount of acetylation reagent used is 0.3-1 times the mass of N-desmethylzopiclone; The volume of the solvent is 15-30 times the mass of N-demethylzopiclone.

2. The preparation method according to claim 1, characterized in that, After the reaction was completed, the solvent was evaporated under reduced pressure, water was added and filtered, the filter residue was washed with water until neutral, and then dried.

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