A kind of preparation method of clonazepam

Abstract

The invention discloses a preparation method of clonazepam, comprising the following steps: using 2-amino-2'-chloro-5-nitrobenzophenone as raw material, oximation with hydroxylamine hydrochloride to obtain 2-amino-2'-chloro-5-nitrobenzophenone oxime; successively reacting with chloroacetyl chloride, closing the ring in acetic acid to obtain 2-chloromethyl-4-(2-chlorophenyl)-6-nitroquinazoline-3-oxide; ring expansion under the action of sodium hydroxide to obtain 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide; finally deoxidation under the action of phosphorus trichloride to obtain clonazepam. The preparation method of the present invention avoids the use of dangerous reagents such as sodium azide, triphenylphosphine, ammonia; reagents such as urotropine are not used in the preparation process, there is no problem of complex process reaction, and more impurities are generated; the preparation process does not need to purify the intermediate, the yield is high, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmacy, and more specifically, to a method for preparing clonazepam. Background Art

[0002] Clonazepam belongs to the benzodiazepine class of drugs. It was approved for marketing by the U.S. Food and Drug Administration (FDA) in 1975. Its effects are similar to those of diazepam or nitrazepam, but its anticonvulsant effect is about 5 times stronger than that of diazepam or nitrazepam. It has obvious and rapid effects in hypnosis, anti-anxiety, epilepsy, and anticonvulsant. Clonazepam is suitable for controlling epilepsy of various types, and has good effects on absence seizures, infantile spasms, myoclonic and akinetic seizures. It is a broad-spectrum antiepileptic drug.

[0003] Chinese patent document CN113072508A discloses a method of obtaining clonazepam by sequentially reacting 2-bromoacetamido-2'-chloro-5-nitrobenzophenone with bromoacetyl bromide under alkaline conditions, then reacting with sodium azide for azidation, and then reacting with triphenylphosphine for intramolecular condensation. This route is complex, has a long reaction process, a low yield, and uses dangerous reagents such as sodium azide and triphenylphosphine in the reaction process, which is not suitable for industrial production.

[0004]

[0005] Chinese patent document CN113149915A discloses a method of reacting 2-amino-2'-chloro-5-nitrobenzophenone with bromoacetyl bromide (chloroacetyl chloride) for acylation to obtain 2-bromo(chloro)acetamido-2'-chloro-5-nitrobenzophenone; and reacting with ammonia reagents for ammonolysis, condensation and other reactions to obtain clonazepam. Regarding the steps of ammonolysis, condensation and the like, in the embodiment, the intermediate of the reaction of freshly prepared ammonia methanol saturated solution with amide is carried out at 80°C under the condition of sealed tube reaction, the reaction temperature exceeds the boiling point of the solvent methanol by nearly 20°C, and ammonia volatilizes in large quantities at a high temperature of 80°C, resulting in a high internal pressure in the system. The ammonolysis and condensation steps of the process are complicated, and it is easy to introduce process impurities into the product, and there is a large safety risk in the reaction production control, which is not conducive to application in industrial production.

[0006]

[0007] Indian patent document IN2011MU01345A discloses a process for obtaining clonazepam product by reflux reaction of 2-chloroacetamido-2'-chloro-5-nitrobenzophenone and urotropine in isopropanol, reflux reaction in methanol and ammonium chloride aqueous solution, and refining and purifying in ethyl acetate. The process reaction is complex and will also introduce process impurities into the final product, thus affecting the product quality; at the same time, the yield is low, only 51% to 53%.

[0008] The document "Development of a Commercially Viable Clonazepam Process" (Organic Process Research & Development, 1997, 1, 268-272) discloses a process for preparing clonazepam using 2-amino-2'-chloro-5-nitrobenzophenone as a starting material through aminoacylation, halogen exchange, aminolysis and salt formation, intramolecular Schiff base cyclization reaction, and purification. This process requires the use of ammonia in the aminolysis reaction step, which is not conducive to industrial production. In addition, while preparing the target intermediate primary amine product, it is easy to generate impurities such as secondary amines and even tertiary amines, thereby affecting the quality of the intermediate and the finished product.

[0009] Chinese patent document CN114702452A discloses a method of preparing 2-amino-N-(2-(2-chlorobenzoyl)-4-nitrophenyl)acetamide hydrochloride by reacting 2-bromoacetamido-2'-chloro-5-nitrobenzophenone with urotropine and hydrochloric acid-ethanol solution, and then reacting the 2-amino-N-(2-(2-chlorobenzoyl)-4-nitrophenyl)acetamide hydrochloride with sodium acetate aqueous solution in anhydrous ethanol as solvent to prepare clonazepam. The process effectively avoids the generation of compound A impurity, but fails to avoid the generation of compound B impurity and compound C impurity by cyclization reaction with urotropine.

[0010]

[0011] The above-mentioned clonazepam preparation methods all have their own limitations: in the intramolecular condensation step, dangerous reagents such as sodium azide and triphenylphosphine are either used; or ammonia is involved in the reaction under sealed tube conditions, which poses a great safety risk; or the one-pot reaction with urotropine is used for preparation, which not only requires long-term high-temperature reflux, but also has a relatively low selectivity of the reaction and a low purity of the final product; or the clonazepam product is prepared by reacting with urotropine, hydrochloric acid-ethanol solution, and sodium acetate aqueous solution in sequence, which can reduce the generation of compound A impurities, but fails to avoid compound B impurities and compound C impurities generated by the cyclization reaction with urotropine. Summary of the invention

[0012] In view of this, the present invention provides a method for preparing clonazepam, which solves the defects of the above prior art methods for preparing clonazepam by redesigning the reaction circuit.

[0013] Based on this, the technical solution of the present invention is as follows:

[0014] A method for preparing clonazepam, comprising the steps of:

[0015] S1. 2-amino-2'-chloro-5-nitrobenzophenone and hydroxylamine hydrochloride are subjected to oximation reaction in an organic solvent and an alkaline solution. After the reaction is completed, 2-amino-2'-chloro-5-nitrobenzophenone oxime is prepared by post-treatment;

[0016] S2. reacting 2-amino-2'-chloro-5-nitrobenzophenone oxime with chloroacetyl chloride in a mixed solution of glacial acetic acid, potassium permanganate and a ketone solvent, and adding a mixed solution of sodium hydroxide, water and ethanol to the residue after concentration to react, thereby preparing 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide;

[0017] S3.7-Nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide reacts with phosphorus trichloride in a solvent. After the reaction, the pH is adjusted to 7-8, the aqueous layer is extracted, the organic layers are combined and dehydrated, the mixture is stirred at room temperature, filtered, the filtrate is concentrated under reduced pressure, a solvent is added, and clonazepam is obtained by freezing, filtering and drying.

[0018] Furthermore, in step S1, the organic solvent is ethanol, the base is sodium hydroxide or potassium hydroxide, and the oximation reaction temperature is 75°C to 80°C.

[0019] Preferably, in step S1, the ratio of 2-amino-2'-chloro-5-nitrobenzophenone: ethanol: base: hydroxylamine hydrochloride is 1 g: (12-18) mL: (2.8-3.2) g: (2.5-3.0) g.

[0020] Furthermore, the post-treatment described in step S1 is to cool the reaction to 50-55° C. after completion of the reaction, add acid to adjust the pH to 6-7, remove the solvent, add water to crystallize, filter, wash with water, and dry to obtain 2-amino-2'-chloro-5-nitrobenzophenone oxime.

[0021] Furthermore, in step S2, the reaction temperature with chloroacetyl chloride is 25-35° C., and the ketone solvent is acetone or butanone; the ratio of 2-amino-2'-chloro-5-nitrobenzophenone oxime: glacial acetic acid: potassium permanganate: ketone solvent: chloroacetyl chloride is 1 g: (0.3-0.5) mL: (0.001-0.002) g: (2.5-3.0) mL: (0.7-1.0) g.

[0022] Furthermore, the reaction temperature of the mixed solution formed with sodium hydroxide, water and ethanol in step S2 is 20-30° C.; the ratio of 2-amino-2'-chloro-5-nitrobenzophenone oxime: sodium hydroxide: water: industrial ethanol is 1 g: (0.9-1.2) g: (0.9-1.2) mL: (7-9) mL.

[0023] Furthermore, the reaction temperature with phosphorus trichloride in step S3 is 35-45° C.; the ratio of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide: trichloromethane: phosphorus trichloride is 1 g: (9-12) mL: (1-1.5) g.

[0024] Furthermore, the solvent in step S3 is an ethanol / petroleum ether mixed solvent system, or an ethanol / isopropyl ether mixed solvent system.

[0025] Preferably, the volume ratio of ethanol to petroleum ether in the mixed solvent system of the solvent in step S3 is 2:1 to 3:1.

[0026] Preferably, the volume ratio of ethanol to isopropyl ether in the mixed solvent system of the solvent in step S3 is 3:1 to 4:1.

[0027] The beneficial effects of the present invention are:

[0028] 1. The method for preparing clonazepam provided by the present invention avoids the use of dangerous reagents such as sodium azide, triphenylphosphine, and ammonia by oximating 2-amino-2'-chloro-5-nitrobenzophenone, reacting it with chloroacetyl chloride, and then closing the ring in acetic acid, followed by ring expansion and deoxygenation. In addition, reagents such as urotropine are not used in the preparation process, thereby avoiding the problems of complex reactions and the generation of more impurities.

[0029] 2. The preparation method of clonazepam provided by the present invention has mild conditions, readily available raw materials, no need to purify the intermediates, high product yield, and is suitable for industrial production. DETAILED DESCRIPTION

[0030] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0031] In the field of chemical pharmaceuticals, the drug synthesis route not only needs to consider the quality of the product, such as product purity and yield, but also the intermediate process reaction parameters, raw material properties and possible impurities in the middle. Therefore, when studying a new preparation route, it is often limited by various factors. However, the replacement of raw materials or the adjustment of reaction conditions alone cannot guarantee the quality of the product. On the other hand, although the basic chemical reaction principles are well known to those skilled in the art, the design of the reaction route based on the product and the initial raw material is blind, and the feasibility of the route and the solution of technical problems need to be taken into account. Therefore, different from the above-mentioned preparation routes of the prior art, based on different reaction principles, the design of a new route is realized as a creative process by obtaining different intermediates.

[0032] The present invention designs a new preparation route to solve the limitations of the prior art clonazepam preparation method in terms of raw material safety, reliability, purity and yield of the target product.

[0033] In an embodiment of the present invention, a method for preparing clonazepam is provided, the steps comprising:

[0034] S1. 2-amino-2'-chloro-5-nitrobenzophenone and hydroxylamine hydrochloride are subjected to oximation reaction in an organic solvent and an alkaline solution. After the reaction is completed, 2-amino-2'-chloro-5-nitrobenzophenone oxime is prepared by post-treatment;

[0035] S2. reacting 2-amino-2'-chloro-5-nitrobenzophenone oxime with chloroacetyl chloride in a mixed solution of glacial acetic acid, potassium permanganate and a ketone solvent, and adding a mixed solution of sodium hydroxide, water and ethanol to the residue after concentration to react, thereby preparing 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide;

[0036] S3.7-Nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide reacts with phosphorus trichloride in a solvent. After the reaction, the pH is adjusted to 7-8, the aqueous layer is extracted, the organic layers are combined and dehydrated, the mixture is stirred at room temperature, filtered, the filtrate is concentrated under reduced pressure, a solvent is added, and clonazepam is obtained by freezing, filtering and drying.

[0037] The specific reaction route is as follows:

[0038]

[0039] The preparation method avoids the use of dangerous reagents such as sodium azide, triphenylphosphine, and ammonia by oximating 2-amino-2'-chloro-5-nitrobenzophenone, reacting it with chloroacetyl chloride, and then closing the ring in acetic acid, followed by ring expansion and reduction. In addition, reagents such as urotropine are not used in the preparation process, thereby avoiding the problems of complex reactions and the generation of more impurities.

[0040] In an embodiment of the present invention, in step S1: the organic solvent is ethanol, the alkali is sodium hydroxide or potassium hydroxide, and the oximation reaction temperature is 75°C to 80°C. The selection of solvents considers solubility on the one hand and cost and recyclability on the other. In order to improve the quality of the reaction product, the ratio of 2-amino-2'-chloro-5-nitrobenzophenone: ethanol: alkali: hydroxylamine hydrochloride is 1g: (12-18) mL: (2.8-3.2) g: (2.5-3.0) g. Preferably, the post-treatment described in step S1 is to cool to 50-55°C after the reaction is completed, add acid to adjust the pH to 6-7, remove the solvent, add water for crystallization, filter, wash with water, and dry to prepare 2-amino-2'-chloro-5-nitrobenzophenone oxime. The yield of 2-amino-2'-chloro-5-nitrobenzophenone oxime obtained in the above process reaches more than 97%. Among them, 2-amino-2'-chloro-5-nitrobenzophenone oxime exists in two isomers, cis and trans, both of which are target products. The sum of the purity of the isomers is the total purity, which is above 98%.

[0041] In an embodiment of the present invention, in step S2: the reaction temperature with chloroacetyl chloride is 25-35°C, the ketone solvent is acetone or butanone; the ratio of 2-amino-2'-chloro-5-nitrobenzophenone oxime: glacial acetic acid: potassium permanganate: ketone solvent: chloroacetyl chloride is 1g: (0.3-0.5) mL: (0.001-0.002) g: (2.5-3.0) mL: (0.7-1.0) g. Preferably, the reaction temperature of the mixed solution formed with sodium hydroxide, water and ethanol in step S2 is 20-30°C; the ratio of 2-amino-2'-chloro-5-nitrobenzophenone oxime: sodium hydroxide: water: industrial ethanol is 1g: (0.9-1.2) g: (0.9-1.2) mL: (7-9) mL. The yield of the intermediate product 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide obtained in the above process is more than 91%, and the purity is more than 99%.

[0042] In an embodiment of the present invention, in step S3: the reaction temperature with phosphorus trichloride is 35-45°C; the ratio of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide: chloroform: phosphorus trichloride is 1g: (9-12)mL: (1-1.5)g. Preferably, the solvent is an ethanol / petroleum ether mixed solvent system, and the volume ratio of ethanol to petroleum ether is 2:1-3:1; or an ethanol / isopropyl ether mixed solvent system is selected, and the volume ratio of ethanol to isopropyl ether is 3:1-4:1. The above process obtains the target product clonazepam with an HPLC purity of 99.8% and a yield of more than 91.8%.

[0043] In the embodiment of the present invention, the extraction of the water layer and the dehydration of the organic layer in step S3 are both common separation operations. The extraction can select a common extraction agent such as chloroform, and the dehydration of the organic layer can select charcoal and anhydrous sodium sulfate treatment.

[0044] The final product obtained by the above-mentioned clonazepam preparation method is identified as follows according to the identification method provided in the Pharmacopoeia:

[0045] 1) Color reaction: Take 10 mg of the product, add 1 ml of dilute hydrochloric acid to dissolve it, add potassium bismuth iodide test solution dropwise, and an orange-red precipitate will be produced. After standing, the color of the precipitate becomes darker;

[0046] 2) Maximum absorption wavelength: Take the target product, add 0.5% sulfuric acid ethanol solution to make a solution containing about 10 μg per 1 ml, and measure it by UV-visible spectrophotometry. The maximum absorption is at wavelengths of 252nm and 307nm.

[0047] 3) Infrared absorption spectroscopy: The target product was taken and an infrared absorption spectrometer was used to obtain an infrared absorption spectrum. The results obtained were consistent with those described in the pharmacopoeia spectrum.

[0048] The results obtained by the above identification method can verify that the structure of the product obtained by the preparation method of this scheme is consistent with clonazepam.

[0049] The following are preferred embodiments of the present invention, which are used to verify the technical solutions and effects of the invention.

[0050] In the embodiments, the raw materials involved are all commercially available industrial raw materials, the standards are industrial grade, and the purity of the same raw materials is the same.

[0051] Example 1

[0052] 1. Preparation of compound 2-amino-2'-chloro-5-nitrobenzophenone oxime

[0053] Add 100g of 2-amino-2'-chloro-5-nitrobenzophenone, 250g of hydroxylamine hydrochloride, and 1200ml of industrial ethanol to the reaction bottle, heat to 50°C, and drip a solution of 280g of potassium hydroxide dissolved in 550ml of water, and control the dripping temperature to 50°C to 65°C. After the addition, heat to 75°C to 80°C for ketoxime insulation reaction for 10 hours. After the reaction is completed, cool to 50°C to 55°C, drip a mass percentage concentration of ≥18% hydrochloric acid aqueous solution to adjust the pH to 6 to 7, distill to remove the solvent, add 1000ml of water and cool to 10°C to 20°C for crystallization, filter and dry to obtain 103g of 2-amino-2'-chloro-5-nitrobenzophenone oxime, HPLC purity is 98.67%, and the yield is 97.72%.

[0054] 2. Preparation of compound 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide

[0055] Add 30ml of glacial acetic acid, 300ml of acetone and 0.1g of potassium permanganate to the reaction bottle and stir for 15 minutes. Then add 100g of 2-amino-2'-chloro-5-nitrobenzophenone oxime and drop 70g of chloroacetyl chloride, and control the temperature of chloroacetyl chloride dropwise to 25℃~35℃. After the addition, stir and react at 25℃~35℃ for 2 hours. Concentrate under reduced pressure to remove the organic solvent, add a mixed solution prepared in advance by 90g of sodium hydroxide, 90ml of water and 700ml of industrial ethanol to the residue remaining under reduced pressure and concentration under stirring, and stir at 20℃~30℃ for 1 hour. Cool to 10℃, add 18% mass percent hydrochloric acid aqueous solution to adjust the pH to 3~4. Water was added for further separation, the mixture was filtered, washed with water, and dried to obtain 103.5 g of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide with a HPLC purity of 99.31% and a yield of 91.03%.

[0056] 3. Preparation of Clonazepam

[0057] Add 100g of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide and 900ml of chloroform to the reaction bottle, cool to 5°C, and drop 100g of phosphorus trichloride, controlling the drop temperature at 5°C to 15°C. After the addition, heat to 35°C to 45°C and keep the reaction for 1.5 hours. After the reaction is completed, the temperature is lowered to 5°C to 10°C, 5% sodium carbonate aqueous solution is added dropwise to adjust the pH to 7-8, the aqueous layer is extracted with chloroform, the organic layers are combined, and washed with saturated sodium chloride aqueous solution until neutral, 10g activated carbon and 15g anhydrous sodium sulfate are added to the organic layer, the temperature is raised to reflux and stirred for 1 hour, filtered while hot, the filtrate is concentrated under reduced pressure, a mixed solution of 80ml ethanol and 20ml isopropyl ether is added, the temperature is lowered to 0°C to 5°C, filtered and dried to obtain 87.6g of the final product, HPLC purity is 99.82%, and the yield is 92.04%, which is identified as clonazepam by the identification method in the "Pharmacopoeia".

[0058] Example 2

[0059] 1. Preparation of compound 2-amino-2'-chloro-5-nitrobenzophenone oxime

[0060] Add 100g of 2-amino-2'-chloro-5-nitrobenzophenone, 300g of hydroxylamine hydrochloride, and 1800ml of industrial ethanol to the reaction bottle, heat to 50°C, and drip a solution of 320g of sodium hydroxide dissolved in 600ml of water, and control the dripping temperature to 50°C to 65°C. After the addition, heat to 75°C to 80°C for ketoxime insulation reaction for 9 hours. After the reaction is completed, cool to 50°C to 55°C, drip a mass percentage concentration of ≥18% hydrochloric acid aqueous solution to adjust the pH to 6 to 7, distill to remove the solvent, add 1600ml of water and cool to 10°C to 20°C for crystallization, filter and dry to obtain 103.5g of 2-amino-2'-chloro-5-nitrobenzophenone oxime, HPLC purity is 98.81%, and the yield is 98.20%.

[0061] 2. Preparation of compound 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide

[0062] Add 50ml of glacial acetic acid, 250ml of butanone and 0.2g of potassium permanganate to the reaction bottle and stir for 15 minutes. Then add 100g of 2-amino-2'-chloro-5-nitrobenzophenone oxime, add 100g of chloroacetyl chloride dropwise, and control the temperature of chloroacetyl chloride addition to 25℃~35℃. After addition, stir and react at 25℃~35℃ for 1.5 hours. Concentrate under reduced pressure to remove the organic solvent, add a mixed solution prepared in advance by 120g of sodium hydroxide, 120ml of water and 900ml of industrial ethanol to the residue remaining after concentration under reduced pressure with stirring, and stir at 20℃~30℃ for 1 hour. Cool to 10℃, add 18% hydrochloric acid aqueous solution by mass percentage concentration to adjust the pH to 3~4. Water was added for further separation, the mixture was filtered, washed with water, and dried to obtain 104.2 g of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide with a HPLC purity of 99.14% and a yield of 91.64%.

[0063] 3. Preparation of Clonazepam

[0064] Add 100g of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide and 1200ml of chloroform to the reaction bottle, cool to 5°C, and drop 150g of phosphorus trichloride, controlling the drop temperature at 5°C to 15°C. After the addition, heat to 35°C to 45°C and keep the temperature for reaction for 1 hour. After the reaction is completed, the temperature is lowered to 5°C to 10°C, a 5% sodium carbonate aqueous solution is added dropwise to adjust the pH to 7 to 8, the aqueous layer is extracted with chloroform, the organic layers are combined, and washed with a saturated sodium chloride aqueous solution until neutral, 10g of activated carbon and 15g of anhydrous sodium sulfate are added to the organic layer, the temperature is raised to reflux and stirred for 1 hour, filtered while hot, the filtrate is concentrated under reduced pressure, a mixed solution of 60ml of ethanol and 20ml of petroleum ether is added, the temperature is lowered to 0°C to 5°C, filtered, and dried to obtain 87.4g of the final product, the HPLC purity is 99.84%, the yield is 91.83%, and it is identified as clonazepam by the identification method in the Pharmacopoeia.

[0065] Example 3

[0066] 1. Preparation of compound 2-amino-2'-chloro-5-nitrobenzophenone oxime

[0067] Add 100g of 2-amino-2'-chloro-5-nitrobenzophenone, 270g of hydroxylamine hydrochloride, and 1500ml of industrial ethanol to the reaction bottle, heat to 50°C, and drip a solution of 300g of sodium hydroxide dissolved in 580ml of water, and control the dripping temperature to 50°C to 65°C. After the addition, heat to 75°C to 80°C for ketoxime insulation reaction for 10 hours. After the reaction is completed, cool to 50°C to 55°C, drip a mass percentage concentration of ≥18% hydrochloric acid aqueous solution to adjust the pH to 6 to 7, distill to remove the solvent, add 1300ml of water and cool to 10°C to 20°C for crystallization, filter and dry to obtain 103.3g of 2-amino-2'-chloro-5-nitrobenzophenone oxime, HPLC purity is 98.73%, and the yield is 98.00%.

[0068] 2. Preparation of compound 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide

[0069] Add 40ml of glacial acetic acid, 280ml of acetone and 0.1g of potassium permanganate to the reaction bottle and stir for 15 minutes. Then add 100g of 2-amino-2'-chloro-5-nitrobenzophenone oxime and drop 80g of chloroacetyl chloride, and control the temperature of chloroacetyl chloride dropwise at 25℃~35℃. After the addition, stir and react at 25℃~35℃ for 2 hours. Concentrate under reduced pressure to remove the organic solvent, add a mixed solution prepared in advance by 100g of sodium hydroxide, 100ml of water and 800ml of industrial ethanol to the residue remaining under reduced pressure and concentration, and stir at 20℃~30℃ for 1 hour. Cool to 10℃, add 18% mass percent hydrochloric acid aqueous solution to adjust the pH to 3~4. Water was added for further separation, the mixture was filtered, washed with water, and dried to obtain 103.7 g of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide with a HPLC purity of 99.21% and a yield of 91.20%.

[0070] 3. Preparation of Clonazepam

[0071] Add 100g of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide and 1000ml of chloroform to the reaction bottle, cool to 5°C, and drop 120g of phosphorus trichloride, controlling the drop temperature at 5°C to 15°C. After the addition, heat to 35°C to 45°C and keep the temperature for 1 hour. After the reaction is completed, the temperature is lowered to 5°C to 10°C, 5% sodium carbonate aqueous solution is added dropwise to adjust the pH to 7-8, the aqueous layer is extracted with chloroform, the organic layers are combined, and washed with saturated sodium chloride aqueous solution until neutral, 10g activated carbon and 15g anhydrous sodium sulfate are added to the organic layer, the temperature is raised to reflux and stirred for 1 hour, filtered while hot, the filtrate is concentrated under reduced pressure, a mixed solution of 60ml ethanol and 30ml petroleum ether is added, the temperature is lowered to 0°C to 5°C, filtered, and dried to obtain 87.8g of the final product, the HPLC purity is 99.87%, the yield is 92.25%, and it is identified as clonazepam by the identification method in the "Pharmacopoeia".

[0072] Finally, a few points should be explained. Although the present invention has been described in detail above with general descriptions and specific embodiments, on the basis of the present invention, the above embodiments are only used to illustrate the technical solution of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, ordinary technicians in this field should understand that they can still modify the technical solutions recorded in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing clonazepam, characterized in that the steps include: S1. 2-amino-2'-chloro-5-nitrobenzophenone and hydroxylamine hydrochloride are subjected to oximation reaction in an organic solvent and an alkaline solution. After the reaction is completed, 2-amino-2'-chloro-5-nitrobenzophenone oxime is prepared by post-treatment; S2. reacting 2-amino-2'-chloro-5-nitrobenzophenone oxime with chloroacetyl chloride in a mixed solution of glacial acetic acid, potassium permanganate and a ketone solvent, and adding a mixed solution of sodium hydroxide, water and ethanol to the residue after concentration to react, thereby preparing 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide; S3.7-Nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide reacts with phosphorus trichloride in a solvent. After the reaction, the pH is adjusted to 7-8, the aqueous layer is extracted, the organic layers are combined and dehydrated, the mixture is stirred at room temperature, filtered, the filtrate is concentrated under reduced pressure, a solvent is added, and clonazepam is obtained by freezing, filtering and drying.

2. The method for preparing clonazepam according to claim 1, characterized in that: In step S1, the organic solvent is ethanol, the base is sodium hydroxide or potassium hydroxide, and the oximation reaction temperature is 75°C to 80°C.

3. The method for preparing clonazepam according to claim 2, characterized in that: In step S1, the ratio of 2-amino-2'-chloro-5-nitrobenzophenone: ethanol: base: hydroxylamine hydrochloride is 1 g: (12-18) mL: (2.8-3.2) g: (2.5-3.0) g.

4. The method for preparing clonazepam according to claim 1, characterized in that: The post-treatment in step S1 is as follows: after the reaction is completed, the temperature is lowered to 50-55° C., acid is added to adjust the pH to 6-7, the solvent is removed, water is added for crystallization, and 2-amino-2'-chloro-5-nitrobenzophenone oxime is prepared by filtering, washing with water, and drying.

5. The method for preparing clonazepam according to claim 1, characterized in that: The reaction temperature with chloroacetyl chloride in step S2 is 25-35° C., and the ketone solvent is acetone or butanone; the ratio of 2-amino-2'-chloro-5-nitrobenzophenone oxime: glacial acetic acid: potassium permanganate: ketone solvent: chloroacetyl chloride is 1 g: (0.3-0.5) mL: (0.001-0.002) g: (2.5-3.0) mL: (0.7-1.0) g.

6. The method for preparing clonazepam according to claim 1, characterized in that: The reaction temperature of the mixed solution formed by sodium hydroxide, water and ethanol in step S2 is 20-30° C.; the ethanol is industrial ethanol; the ratio of 2-amino-2'-chloro-5-nitrobenzophenone oxime: sodium hydroxide: water: industrial ethanol is 1 g: (0.9-1.2) g: (0.9-1.2) mL: (7-9) mL.

7. The method for preparing clonazepam according to claim 1, characterized in that: The reaction temperature with phosphorus trichloride in step S3 is 35-45° C.; the solvent is chloroform; the ratio of 7-nitro-2-oxo-5-(2-chlorophenyl)-1,4-benzodiazepine-4-oxide: chloroform: phosphorus trichloride is 1 g: (9-12) mL: (1-1.5) g.

8. The method for preparing clonazepam according to claim 1, characterized in that: The solvent in step S3 is an ethanol / petroleum ether mixed solvent system, or an ethanol / isopropyl ether mixed solvent system.

9. The method for preparing clonazepam according to claim 8, characterized in that: The volume ratio of ethanol to petroleum ether in the mixed solvent system of the solvent in step S3 is 2:1 to 3:

1.

10. The method for preparing clonazepam according to claim 8, characterized in that: The volume ratio of ethanol to isopropyl ether in the mixed solvent system of the solvent in step S3 is 3:1 to 4:1.

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