A preparation method and application of high-purity azelastine hydrochloride

Abstract

The invention discloses a preparation method of azelastine hydrochloride, using N-methyl hexahydroazepine-4-one hydrochloride, benzoyl hydrazide and 2-(p-chlorophenylacetyl) benzoic acid as raw materials, and obtaining through condensation reduction, concentrated hydrochloric acid hydrolysis, cyclization reaction and salt-forming reaction steps, wherein in the cyclization reaction process, a mixed solvent of methanol and water is selected as a reaction solvent, and a cyclization reaction is performed after heat preservation treatment, so that azelastine free base can be precipitated in a solid form, is easy to filter, and has high quality. The present invention prepares azelastine hydrochloride, has high yield, high product purity, small solvent residue and good stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis and relates to a method for preparing a raw material drug, in particular to a method for preparing high-purity azelastine hydrochloride. Background Art

[0002] Azelastine hydrochloride (CAS: 79307-93-0), also known as 4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1-(2H)-phthalazine hydrochloride, is a white to off-white crystalline powder, slightly soluble in water, and its structural formula is as follows:

[0003]

[0004] Azelastine hydrochloride was researched and developed by Germany's Asta-Werker AG and Japan's Eisai Co., Ltd. It is an antihistamine that can be prepared into different dosage forms clinically for the treatment of chronic urticaria and bronchial asthma, allergic rhinitis or allergic conjunctivitis and other diseases. Commonly used dosage forms in clinical practice include tablets (specifications 1mg / 2mg), nasal spray and eye drops.

[0005] Based on the consideration of production cost and process difficulty, the current industrial production method of azelastine hydrochloride usually adopts: using N-methylhexahydroazepine-4-one hydrochloride as raw material, reacting with benzoylhydrazide to form acylhydrazone, and then reducing and hydrolyzing with hydrochloric acid to carry out cyclization reaction with 2-(p-chlorophenylacetyl)benzoic acid to obtain a reaction solution containing azelastine free base, and then post-processing to obtain azelastine free base, and then salifying with hydrochloric acid to obtain azelastine hydrochloride product. The reaction route is basically as follows:

[0006]

[0007] Among them, most of the intermediates after condensation reduction and hydrochloric acid hydrolysis are in oily state, and the intermediate free base azelastine obtained by further cyclization is also mostly in oily state. For the industrial production of bulk drugs, the intermediate is an oily substance, which is difficult to formulate quality standard monitoring and has an important impact on production operability. Specifically for the preparation of azelastine hydrochloride, since the free base is relatively close to the finished product, the free base is in an oily state and is easy to wrap the solvent, and the risk of impurities being introduced into the finished product is relatively large. It is necessary to purify the free base through cumbersome processes, otherwise it is difficult to find suitable salt-forming conditions; on the other hand, the stability of the intermediate in the oily state is generally not high (strong hygroscopicity, etc.), and it is not easy to store. In the actual production process, the intermediate in the oily state is generally required to complete the subsequent reaction as soon as possible, and the production operation space is small. Therefore, how to avoid cumbersome post-processing purification steps, obtain azelastine free base with better quality, especially obtain solid free base, and then obtain azelastine hydrochloride products, is a problem that needs to be solved urgently in industrial production.

[0008] The main reports on the synthesis of azelastine hydrochloride are as follows:

[0009] In the domestic patent CN102391253A, N-methylhexahydroazepine-4-one hydrochloride is used as a raw material, reacted with benzoylhydrazide to form an acylhydrazone, then reduced by sodium borohydride, and finally reacted with 2-(p-chlorophenylacetyl)benzoic acid to prepare a free base azelastine. In the above patent, the solvent used for the cyclization reaction is water, and the product generated during the reaction is insoluble in water and deposited at the bottom of the reactor as an oily substance. The subsequent processing process is very difficult and it is difficult to convert it into solid particles, which is not conducive to industrial production, and is more obvious in the amplification reaction. The free base post-processing process and crystallization process of this method are complicated and cumbersome, and the yield is not high. The purity of the product obtained after two recrystallizations is only 99.1%, which fails to meet the requirements for the use of high-end preparations.

[0010] Cao Rihui et al. reported (see the document Synthesis of Azelastine Hydrochloride. Chinese Journal of Pharmaceutical Industry 34.1 (2003): 1-3.) that methanol was used as a reaction solvent in the cyclization reaction, but after the reaction was completed, the solvent still needed to be removed before alkalization to obtain the free base of Azelastine. The document did not record the properties of the obtained free base of Azelastine. During the development process, the applicant found that when excessive methanol was used as the reaction solvent, the precipitated Azelastine became flocculent and difficult to filter, which was not conducive to industrial production.

[0011] In domestic patent CN113045547A, N-methylhexahydroazepine-4-one hydrochloride is used as raw material, reacted with benzoyl hydrazide to form acylhydrazone, and then reduced with potassium borohydride, and then reacted with organic acid (fumaric acid, etc.) to form an intermediate, and the oily intermediate is solidified and then acidified to form a hydrochloride, and then reacted with 2-(p-chlorophenylacetyl)benzoic acid cyclization reaction. The free base azelastine obtained by the cyclization reaction of this patent scheme is an oily liquid; the subsequent azelastine hydrochloride is precipitated finely after salt formation, which is not conducive to filtering. At the same time, the method uses toluene industry unfriendly reagents for salt formation, and increases the reaction step with organic acid, which will increase the production cost. For large-scale production, it is a suboptimal choice.

[0012] In the international application WO2009080744A1, N-methylhexahydroazepine-4-one hydrochloride, benzoyl hydrazide and 2-(p-chlorophenylacetyl)benzoic acid are used as the main raw materials to synthesize solid azelastine free base, and further prepare anhydrous and crystalline forms of azelastine free base. This process method requires the use of isobutyl methyl ketone reagent, which is less friendly to the environment and human body, and obtains solid free base azelastine with good purity (HPLC purity: 99.8%) through cumbersome process such as extraction, decolorization, cooling and washing. Comprehensively considering the whole process of this process, there is still a large room for optimization.

[0013] In addition, the prior art pays little attention to the impact of the quality of azelastine hydrochloride API on the preparation process and application. For example, in the preparation of liquid preparations, the dissolution time of the API has an important impact on the process production. It is well known in the art that based on factors such as the process, the API may cause instability during the preparation application process. In order to reduce the risks brought by the process, it is very important to improve the stability and quality of the API itself.

[0014] In summary, the prior art has many steps in the synthesis of azelastine hydrochloride, and the post-processing process is cumbersome, the yield is low, the production cost is high, and the quality of the free base azelastine is ignored on the quality of the azelastine hydrochloride product after salt formation and the production operation. Therefore, in order to obtain high-quality azelastine hydrochloride products, the prior art preparation method is improved to provide a method for preparing azelastine hydrochloride with simple operation, mild reaction conditions, high yield, small impurities and good stability. Summary of the invention

[0015] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for large-scale industrial production of azelastine hydrochloride, which is safe, simple, has good process reproducibility, mild reaction conditions and is suitable for large-scale industrial production. The synthetic route of the present invention is safe and efficient, has high product yield, high product purity, low solvent residue and good stability.

[0016] The purpose of the present invention is achieved by the following technical solution: A method for preparing azelastine hydrochloride comprises the following steps:

[0017] (1) dissolving benzoyl hydrazide in an organic solvent, adding N-methylhexahydroazepine-4-one hydrochloride at 0-5° C. and stirring, dropping an alkali solution, adding a reducing agent, and heating to carry out a reduction reaction; after the reaction is completed, extracting and concentrating to obtain compound 1;

[0018] (2) adding concentrated hydrochloric acid to compound 1 under stirring, and heating to carry out a hydrolysis reaction; after the reaction is completed, cooling and concentrating to obtain compound 2;

[0019] (3) First, compound 2 is dissolved in a reaction solvent mixed with methanol and water, the pH is adjusted and the mixture is kept warm, and then compound 3 is added and the temperature is raised to carry out a cyclization reaction; after the reaction is completed, an alkali solution is directly added to adjust the pH to 9-10 without removing the solvent, and a solid is precipitated, which is a crude product of azelastine free base; the obtained crude product is post-treated and dried to obtain a solid compound 4, i.e., azelastine free base;

[0020] (4) Compound 4 is added to a salt-forming solvent and heated to dissolve; concentrated hydrochloric acid is added to adjust the pH to 1 to 3, the mixture is stirred at room temperature, cooled and crystallized to obtain a solid, which is filtered and dried to obtain Compound 5, i.e., azelastine hydrochloride;

[0021] in:

[0022] In step 1, the molar ratio of benzoyl hydrazide to N-methylhexahydroazepine-4-one hydrochloride is 1:1.1-2.0;

[0023] In step 2, the mass volume ratio (g / ml) of compound 1 to concentrated hydrochloric acid is 1:2-5;

[0024] In step 3, the volume ratio of water to methanol is 1:0.5-2; the mass volume ratio (g / ml) of compound 2 to reaction solvent is 1:5-8.

[0025] The reaction route is as follows:

[0026]

[0027] Among them, compound 1 is N-(1-methyl-hexahydroazepine-4-yl-)benzoyl hydrazide; compound 2 is 1-methylhexahydroazepine-4-hydrazide hydrochloride; compound 3 is 2-(p-chlorophenylacetyl)benzoic acid; compound 4 is azelastine free base; and compound 5 is azelastine hydrochloride.

[0028] In step 1, the organic solvent is selected from any one of methanol, ethanol or isopropanol or a mixture thereof with water, preferably methanol.

[0029] In step 1, the molar ratio of benzoyl hydrazide to N-methylhexahydroazepine-4-one hydrochloride is preferably 1:1.2-1.4, specifically about 1:1.3.

[0030] In step 1, the alkaline solution is selected from an aqueous solution of potassium hydroxide or sodium hydroxide.

[0031] In step 1, to ensure complete reduction reaction, the molar amount of the reducing agent is 3-6 times, preferably 4-5 times, of the starting material benzoyl hydrazide.

[0032] In step 1, the reducing agent is sodium borohydride or potassium borohydride, preferably potassium borohydride.

[0033] In step 1, the reduction reaction temperature is 40-60° C., preferably 45-55° C., which is conducive to complete reduction reaction and ensuring the reaction selectivity of the reducing agent. The lower the reduction reaction temperature, the longer the reaction time, and the higher the reduction reaction temperature, the lower the reaction conversion rate.

[0034] In step 1, the reduction reaction time is 0.5 to 3 hours, preferably 1 to 2.5 hours, specifically 1.5 hours or 2 hours.

[0035] Preferably, the specific process of step 1 comprises: dissolving benzoyl hydrazide in methanol, adding N-methylhexahydroazepine-4-one hydrochloride at 0-5°C, stirring for 10-20 minutes, dropping KOH aqueous solution, adding potassium borohydride, heating to 45-55°C for 1-2.5 hours. After the reaction is completed, extract once, retain the oil phase, and concentrate under reduced pressure to obtain compound 1. After the reaction is completed, the extractant added for extraction is selected from ethyl acetate or dichloromethane, preferably ethyl acetate.

[0036] In step 2, there is no particular regulation on the amount of concentrated hydrochloric acid used, as long as it can fully dissolve compound 2 and ensure the reaction. Preferably, the mass volume ratio (g / ml) of compound 1 to concentrated hydrochloric acid is 1:2-5; more preferably 1:3-4.

[0037] In step 2, the reaction temperature is 100-130° C., preferably 110-120° C., which can ensure complete reaction. Both low and high reaction temperatures are not conducive to the hydrolysis reaction; and high reaction temperatures tend to accelerate the volatilization of concentrated hydrochloric acid.

[0038] In step 2, the reaction time is 1 to 4 hours, preferably 2 to 3 hours, which can ensure complete reaction.

[0039] Preferably, the specific process of step 2 comprises: slowly adding concentrated hydrochloric acid to compound 1 under stirring, heating to 110-130° C., reacting for 2-3 hours. After the reaction is completed, cooling to 70-80° C., and concentrating under reduced pressure to obtain compound 2.

[0040] In the method for preparing azelastine hydrochloride of the present invention, the compound 2 obtained in step 2 does not need to be purified and can be directly used in the next cyclization reaction.

[0041] In the preparation method of azelastine hydrochloride of the present invention, in the step 3, the selection of the reaction solvent is one of the key technologies for realizing the precipitation of azelastine free base. In the step 3, in the generation of azelastine by the cyclization reaction, the reaction solvent has an important influence on the precipitation of the azelastine product. In the prior art, it is recorded that a single methanol or water is used as a reaction solvent. However, azelastine obtained by using a single methanol as a solvent is mostly in an oily state, and it is difficult to precipitate free base azelastine with better properties after one-step alkalization; it needs to be purified after multiple post-treatments before it can be used in the next step of salt formation reaction; and using a single water as a reaction solvent, as mentioned above, the amplified process reaction is prone to the crude product in the form of oil being deposited at the bottom of the reactor, and there is a problem of difficulty in post-treatment, and it is also difficult to convert it into solid particles by one-step alkalization to precipitate azelastine. At the same time, the prior art uses a single solvent for the cyclization reaction, and the quality requirements of the intermediate compound 2 are relatively high, and it is necessary to purify and improve the quality of compound 2, such as using ether solvent for desolventization, extraction and washing, etc., and the process is cumbersome. Especially when ether solvent is used in industrial production, ether is very volatile and has anesthetic effect, which can easily cause explosion or fire or cause dizziness in production personnel.

[0042] After many experiments, the applicant surprisingly found that using a mixture of methanol and a specific proportion of water or tetrahydrofuran or 1,4-butylene oxide as a reaction solvent can not only overcome the problem of the reaction product settling to the bottom, but also directly add alkaline water to alkalize after the reaction is completed without removing the solvent, so that solid particles of azelastine free base can be precipitated. The obtained product is of suitable size and easy to filter.

[0043] Considering the reaction selectivity and solvent residue, the preferred solvent in the cyclization reaction of this application is methanol and water. Furthermore, the applicant found through experimental comparison that too little or too much methanol has an impact on the reaction selectivity and the precipitation of free alkali. When the volume ratio of water to methanol in the mixed solvent is 1:0.5-2, the reaction can be fully carried out, preferably 1:0.8-1.5; more specifically, it can be 1:1, which can ensure that the material does not agglomerate or sink to the bottom during the reaction, the reaction degree and yield are better, and solid particles can be precipitated after one-step alkalization.

[0044] Furthermore, to ensure the reaction effect of the present invention, in step 3, the mass volume ratio (g / ml) of the compound 2 to the reaction solvent is 1:5-8, preferably 1:5.5-7.5; more preferably 1:6-7.

[0045] In the preparation method of azelastine hydrochloride of the present invention, in the step 3, firstly heat-insulating the solvent containing compound 2 is one of the key technologies for obtaining the precipitation of high-purity azelastine free base. In step 3, the prior art generally adds compound 2 and compound 3 reaction materials, dissolves and reacts directly. The technicians found that even if methanol and water are selected as reaction reagents, although the yield and purity of azelastine obtained meet the requirements, after simple post-treatment, the final purity of free base azelastine is only about 98%, which is difficult to improve. The technicians found through various experiments that after heat-insulating compound 2 for a certain period of time, compound 3 is added to react, which can improve the purity of the obtained azelastine free base. Specifically, the heat-insulating process is: first, compound 2 is added to a reaction solvent mixed with methanol and water, alkali is added to adjust the pH to 7-8, heat-insulating and stirring for a period of time, and then compound 3 is added and heated to react. Among them, the insulation temperature and time need to be controlled within a specific range. If the insulation temperature is too high or the insulation time is too long, the components in compound 2 may decompose or other side reactions may occur, resulting in a decrease in the conversion rate of the cyclization reaction in step 3 and a significant increase in impurities; if the insulation temperature is too low or the insulation time is too short, the effect on product quality optimization is not obvious. Preferably, the insulation temperature is 35-50°C and the insulation time is 20-50min; preferably, the insulation temperature is 40-45°C and the insulation time is 30-40min, which can improve the degree of reaction in step 3 and further improve the purity of azelastine. After simple post-treatment, the purity of the free base azelastine can be increased to more than 99.5%, which is conducive to obtaining high-quality azelastine hydrochloride after the next step of salt formation. In step 3, the heat preservation treatment can optimize the quality of azelastine products and improve the yield. The reason is speculated to be that in the cyclization reaction in step 3, compound 2 reacts with compound 3 as a nucleophilic reagent containing a nitrogen atom. Heat preservation treatment of compound 2 in a solvent at a pH of 7-8 is beneficial to activate the nitrogen atom in compound 2 to a certain extent before reacting with compound 3, thereby increasing the reaction selectivity and reducing the occurrence of side reactions.

[0046] Further, in step 3, in order to ensure that the reaction is fully carried out, the molar ratio of compound 2 and compound 3 is 1:0.8-1.4; preferably 1:0.9~1.3; more preferably 1:1.0~1.2. Among them, compound 2 obtained in the present application does not need to be purified, and the compound 2 obtained by steps 1 and 2 has a good conversion rate and yield. In the actual production process, for the convenience of calculation, the obtained compound 2 can also be calculated according to the amount of benzoyl hydrazide, which has no substantial effect on the effect of the reaction in this step 3, that is, the molar ratio of benzoyl hydrazide and compound 3 is 1:0.8-1.4; preferably 1:0.9~1.3; more preferably 1:1.0~1.2.

[0047] Furthermore, in step 3, after adding compound 3, in order to ensure that the reaction materials are fully dissolved and the reaction proceeds, the temperature needs to be raised to reflux for reaction, specifically, the temperature can be raised to 55-75°C, preferably 60-70°C.

[0048] Furthermore, in step 3, after adding compound 3, the reaction time is 0.5 to 3.5 h; preferably 1.0 to 3.0 h, and more preferably 1.5 to 2.5 h.

[0049] Preferably, the specific process in step 3 includes: dissolving compound 2 in a mixed solvent of methanol and water, adjusting the pH to 7-8, heating to 40-45°C and stirring for 30-40 minutes, then adding compound 3, and then heating to 60-70°C and reflux reaction for 1.5-2.5 hours.

[0050] In step 3, the obtained crude free base azelastine can be improved to a purity greater than 99.5% after simple post-treatment. Specifically, the post-treatment refers to: adding the precipitated crude free base solid to ethyl acetate and water, stirring and adding 10% hydrochloric acid to adjust the pH to 1-2, separating the layers, and retaining the water layer; adding 20% ​​NaOH solution to adjust the pH to ≥12; precipitating the azelastine free base solid, and filtering to obtain it.

[0051] Further, in step 3, the specific process in step 3 also includes: after the reaction is completed, without removing the solvent, directly adding 0.02%-0.05% NaOH solution to adjust the pH to 9-10, and the solid is precipitated, which is the crude product of azelastine free base; the solid is added to ethyl acetate and water, stirred and added with 10% hydrochloric acid to adjust the pH to 1-2, separated and the water layer is retained; 20% NaOH solution is added to adjust the pH ≥ 12; the solid is precipitated, stirred for 0.5-1h, filtered, and dried to obtain compound 4, which is azelastine free base.

[0052] In step 4, the salt-forming solvent and dosage are one of the important factors for achieving the technical effect of the azelastine hydrochloride product with better properties. The selection of the salt-forming solvent is based on the ability to fully dissolve the free base azelastine, combined with the quality of the precipitated product. The salt-forming solvent is selected from acetone, methanol, ethanol and isopropanol, one or more combinations in any proportion, preferably anhydrous ethanol. In terms of dosage, when the salt-forming solvent is too little, the crude product is not well dissolved, and the azelastine in the solution is unevenly distributed, which reduces the degree of salt formation; the amount of the salt-forming solvent is too much, which affects the subsequent precipitation amount and reduces the yield.

[0053] Specifically, in step 4, the mass volume ratio of azelastine free base (compound 4) to anhydrous ethanol is 1:4-9, preferably 1:5-7.

[0054] In step 4, after the addition of hydrochloric acid in the salt formation process is completed, the temperature and time of heat preservation and crystallization are also important factors. Appropriate heat preservation and crystallization conditions are conducive to the salt formation reaction and the formation of good crystals of the product. Specifically, in the salt formation process in step 4, the heat preservation temperature is 40 to 60°C, preferably 45 to 55°C; the heat preservation time is 1 to 2 hours; preferably 1.2 to 1.6 hours.

[0055] Further, the mixture is cooled to a crystallization temperature of 15 to 30° C. and stirred for crystallization for 1 to 3 hours. More specifically, the crystallization temperature is 20 to 25° C. (room temperature) and stirred for crystallization for 1.5 to 2.5 hours.

[0056] In step 4, in order to reduce the residual solvent and fully remove the solvent, the drying temperature is 95-140° C., preferably 100-120° C. If the drying temperature is too low, the residual solvent in the obtained product is large, and after long-term storage, the stability is poor and does not meet the product quality standards; if the drying temperature is too high, the impurities increase, the product properties and color become darker, and the product quality decreases.

[0057] Preferably, the specific process in step 4 includes: adding compound 4 to anhydrous ethanol, heating to 45-55°C, stirring to fully dissolve it, adding concentrated hydrochloric acid to adjust the pH to 1-3, and continuing to keep warm and stir for 1.2-1.6 hours; naturally cooling to 20-25°C, keeping warm and stirring for crystallization for 1.5-2.5 hours. Filtering, and vacuum drying the solid at 100-120°C to obtain azelastine hydrochloride.

[0058] In a preferred embodiment, the preparation of azelastine hydrochloride according to the present invention comprises the following steps:

[0059] (1) Benzoyl hydrazide was dissolved in methanol, N-methylhexahydroazepine-4-one hydrochloride was added at 0-5°C, and after stirring for 10-20 minutes, KOH aqueous solution was added dropwise, and potassium borohydride was added, and the temperature was raised to 45-55°C for 1-2.5 hours. After the reaction was completed, extraction was performed once, and the oil phase was retained and concentrated under reduced pressure to obtain compound 1.

[0060] (2) Slowly add concentrated hydrochloric acid to compound 1 under stirring, raise the temperature to 110-130°C, and react for 2-3 hours. After the reaction is completed, reduce the temperature to 70-80°C, and concentrate under reduced pressure to obtain compound 2.

[0061] (3) Compound 2 was dissolved in a mixed solvent of methanol and water, the pH was adjusted to 7-8, the temperature was raised to 40-45°C and stirred for 30-40 min, then compound 3 was added, and the temperature was raised to 60-70°C for reflux reaction for 1.5-2.5 h; after the reaction was completed, 0.02%-0.05% NaOH solution was directly added for alkali adjustment to pH 9-10, and solid was precipitated; the solid was added to ethyl acetate and water, stirred and 10% hydrochloric acid was added to adjust the pH to 1-2, the layers were separated, and the water layer was retained; 20% NaOH solution was added to adjust the pH ≥ 12; the solid was precipitated, stirred for 0.5-1 h, filtered, and dried to obtain compound 4.

[0062] (4) Compound 4 was added to anhydrous ethanol, heated to 45-55°C, stirred to fully dissolve, and concentrated hydrochloric acid was added to adjust the pH to 1-3, and the mixture was kept warm and stirred for 1.2-1.6 hours; the mixture was naturally cooled to 20-25°C, and kept warm and stirred for crystallization for 1.5-2.5 hours. The mixture was filtered, and the solid was dried in vacuum at 100-120°C to obtain azelastine hydrochloride.

[0063] The concentration of concentrated hydrochloric acid in the present application is 25%-36%. Considering the reaction efficiency and industrial production safety, 36% is preferred.

[0064] The reduced pressure concentration described in this application is a conventional operation in the art, and the concentration operation will not have a substantial impact on the effect of the present invention. The degree of concentration is in line with the common knowledge of those skilled in the art, and is generally understood to be concentrated until there is no fraction.

[0065] The azelastine hydrochloride obtained by the technical solution of the present application has improved product purity and quality, with an HPLC purity of >99.9%, a maximum single impurity of the product controlled within 0.1%, a single impurity content of <0.05%, and a small amount of residual solvent.

[0066] The azelastine hydrochloride obtained by the technical solution of the present application has uniform powder, crystal characteristics, good stability, can meet the needs of preparations, can be used in the preparation of azelastine hydrochloride tablets, sprays or eye drops, and can reduce the risks brought by the preparation process.

[0067] The preparation method of azelastine hydrochloride of the present application does not require high vacuum distillation and column chromatography purification operations in the entire process, and the product does not need to be refined. The operation is simple and suitable for industrial production.

[0068] In general, the present invention has the following advantages and beneficial effects compared with the prior art:

[0069] 1. The present invention optimizes the cyclization reaction process, ensures that the free base azelastine is precipitated as solid particles through heat preservation treatment and selection of a mixed solvent of methanol and water, and the obtained azelastine has high purity and good uniformity, avoiding the salt-forming reaction refining and impurity removal process.

[0070] 2. The whole process has a reasonable overall design, is easy to operate, uses safe and green solvents, has readily available raw materials, and is easy to realize industrial production.

[0071] 3. The azelastine hydrochloride obtained by the present invention has an HPLC purity of >99.9%, a small amount of residual solvent, uniform product powder properties, good stability, and can meet the needs of liquid and solid preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 HPLC spectrum of azelastine free base prepared in Example 1.

[0073] Figure 2 HPLC spectrum of azelastine hydrochloride prepared in Example 11.

[0074] Figure 3 XRD spectrum of azelastine hydrochloride prepared in Example 11.

[0075] Figure 4 HPLC spectrum of azelastine hydrochloride prepared in Comparative Example 10.

[0076] Figure 5 Appearance diagram of the azelastine free base product prepared by the present invention.

[0077] Figure 6 Appearance diagram of the azelastine hydrochloride product prepared by the present invention. DETAILED DESCRIPTION

[0078] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0079] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principle of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention. Unless otherwise specified, the drugs and reagents used in the present invention can be purchased from the market.

[0080] Example 1

[0081] Azelastine free base (Compound 4) was prepared by the following steps:

[0082] Dissolve 20.4g of benzoyl hydrazide in 80ml of methanol, cool to 0-5°C, add 32.7g of N-methylhexahydroazepine-4-one hydrochloride, stir and react for 10-20min, then drop 200ml of 1mol / L KOH aqueous solution, add 36.7g of potassium borohydride, heat to 50°C and react for 2h. After the reaction, add 400ml of ethyl acetate for extraction, and retain the ethyl acetate phase. Concentrate under reduced pressure to obtain 36.9g of oily substance as compound 1.

[0083] Under stirring, 130 ml of 36% concentrated hydrochloric acid was slowly added to the obtained compound 1, and the temperature was raised to 115°C for reaction for 2.5 hours. After the reaction was completed, the temperature was lowered to 70-80°C and concentrated under reduced pressure to obtain 26.7 g of an oily substance, which was compound 2.

[0084] The obtained compound 2 was dissolved in a mixed solvent of methanol (90 ml) and water (90 ml), and the pH was adjusted to 8 with 30% NaOH solution. After heating to 42°C and stirring for 35 minutes, 41.2g of compound 3 was added, and the temperature was raised to 65°C for reaction for 2 hours. After the reaction was completed, there was no need to remove the solvent, and 0.05% NaOH solution was directly added to adjust the pH to 10 with alkali, and stirred. A white to off-white solid precipitated, and the solid was collected by filtration. The solid was added to 400ml of ethyl acetate and 400ml of water, and 10% hydrochloric acid was added to adjust the pH to 1.5 with stirring. The layers were separated and the water layer was retained; 20% NaOH solution was added to adjust the pH to 12; the solid precipitated, stirred for 0.5h, filtered, and dried to obtain 53.3g of off-white solid, which was compound 4 (azelastine free state), with an HPLC purity of 99.87%. Its HPLC detection spectrum is shown as follows Figure 1 shown.

[0085] Example 2

[0086] Azelastine free base (Compound 4) was prepared by the following steps:

[0087] Dissolve 20.4g of benzoyl hydrazide in 80ml of methanol, cool to 0-5°C, add 32.7g of N-methylhexahydroazepine-4-one hydrochloride, stir and react for 10-20min, then drop 200ml of 1mol / L KOH aqueous solution, add 25.7g of sodium borohydride, heat to 50°C and react for 2h. After the reaction, add 400ml of ethyl acetate for extraction, and retain the ethyl acetate phase. Concentrate under reduced pressure to obtain 36.6g of oily substance, which is compound 1.

[0088] Under stirring, 130 ml of 36% concentrated hydrochloric acid was slowly added to the obtained compound 1, and the temperature was raised to 115°C for reaction for 2.5 hours. After the reaction was completed, the temperature was lowered to 70-80°C and concentrated under reduced pressure to obtain 26.4 g of an oily substance, which was compound 2.

[0089] The obtained compound 2 was dissolved in a mixed solvent of methanol (90 ml) and water (90 ml), and the pH was adjusted to 8 with 30% NaOH solution. After heating to 42°C and stirring for 35 minutes, 41.2g of compound 3 was added, and the temperature was raised to 65°C for reaction for 2 hours. After the reaction was completed, 0.05% NaOH solution was directly added to adjust the pH to 9.5, and a white to off-white solid was precipitated by stirring, and the solid was collected by filtration. The solid was added to 400ml ethyl acetate and 400ml water, and 10% hydrochloric acid was added to adjust the pH to 2 after stirring, and the layers were separated, and the water layer was retained; 20% NaOH solution was added to adjust the pH to 13; the solid precipitated, stirred for 0.5h, filtered, and dried to obtain 52.8g of off-white solid, which was compound 4, i.e., azelastine free state, with an HPLC purity of 99.56%.

[0090] Example 3

[0091] Azelastine free base (Compound 4) was prepared by the following steps:

[0092] Dissolve 477g of benzoyl hydrazide in 1.8L of methanol, cool to 0-5°C, add 753g of N-methylhexahydroazepine-4-one hydrochloride, stir and react for 10-20min, then drop 5L of 1mol / L KOH aqueous solution, add 852g of potassium borohydride, heat to 50°C and react for 2h. After the reaction is completed, add 8L of ethyl acetate for extraction, and retain the ethyl acetate phase. Concentrate under reduced pressure to obtain 831g of oily substance, which is compound 1.

[0093] Under stirring, 3L of 36% concentrated hydrochloric acid was slowly added to the obtained compound 1, and the temperature was raised to 115°C for reaction for 2.5h. After the reaction was completed, the temperature was lowered to 70-80°C and concentrated under reduced pressure to obtain 593g of an oily substance, which was compound 2.

[0094] The obtained compound 2 was dissolved in a mixed solvent of methanol (2L) and water (2L), and the pH was adjusted to 8.5 with 30% NaOH solution. After heating to 42°C (±2°C) and stirring for 35min, 989g of compound 3 was added, and the temperature was raised to 65°C for reaction for 2h. After the reaction was completed, 0.05% NaOH solution was directly added to adjust the pH to 9.5, and solids were precipitated by stirring. The solids were collected by filtration. The solids were added to 8L ethyl acetate and 8L water, and 10% hydrochloric acid was added to adjust the pH to 1.5 by stirring, and the layers were separated, and the water layer was retained; 20% NaOH solution was added to adjust the pH to 13; the solids precipitated, stirred for 0.5h, filtered, and dried to obtain 1188g of off-white solids, which were compound 4, i.e., azelastine free state, with an HPLC purity of 99.51%.

[0095] Examples 4-6 and Comparative Examples 1-6

[0096] In order to analyze the effect of the solvent type of the cyclization reaction on the free base azelastine product, the azelastine free base was prepared by referring to the synthesis step of Example 1, wherein the feeding amounts of compound 2 and compound 3 were 18.3 g (0.1 mol) and 30.2 g (0.11 mol), respectively, and the solvent types used in the cyclization reaction process are shown in the following table:

[0097] Table 1: Effect of solvent type on cyclization reaction

[0098]

[0099] It can be seen from Examples 4-6 in Table 1 above that in the cyclization reaction process, a specific ratio of methanol and water / tetrahydrofuran is selected as a mixed solvent for the reaction. After the reaction is completed, no solvent removal operation is required. After adding an alkaline solution to adjust the pH, a free base azelastine solid with better quality can be precipitated, and after simple post-treatment, the purity can reach more than 99.5%, which is conducive to the subsequent salt-forming reaction and improves the quality of the finished azelastine hydrochloride product.

[0100] In Comparative Example 1, methanol was used as the solvent, and the solid precipitated after alkali adjustment was flocculent and difficult to filter; in Comparative Example 2, the amount of methanol used was low, which was not conducive to the precipitation of free alkali solids, and the precipitated solids were a paste and solid mixture.

[0101] In Comparative Examples 3-6, under the same conditions, methanol was used as a mixed solvent with acetonitrile, dichloromethane, acetone and ethyl acetate respectively. After the reaction was completed, direct alkali adjustment could not make the free base azelastine solid stable and fully precipitated.

[0102] In general, methanol and water / tetrahydrofuran are selected as mixed solvents for the cyclization reaction. When the volume ratio of methanol to water / tetrahydrofuran is 0.5-2:1, and the optimal situation is when the volume ratio of methanol to water is 1:1, after the reaction is completed, there is no need to remove the solvent. After directly adding alkali for adjustment, the free base azelastine can be precipitated as a solid with high purity; and the properties are better and easy to filter, which is conducive to industrial production.

[0103] Examples 7-10 and Comparative Examples 7-9

[0104] In order to analyze the effect of the heat preservation treatment of the cyclization reaction on the obtained azelastine free base product, the azelastine free base was prepared by referring to the synthesis steps of Example 1, wherein the feeding amounts of compound 2 and compound 3 were 18.3 g (0.1 mol) and 30.2 g (0.11 mol), respectively, the reaction solvent was methanol (60 ml) + water (60 ml), and the heat preservation conditions were shown in the following table:

[0105] Table 2: Effect of insulation treatment temperature and time

[0106] Insulation temperature Insulation time purity Yield Example 7 42℃ 30min 99.71％ 96.6％ Example 8 42℃ 40min 99.58％ 94.5％ Example 9 35℃ 35min 99.61％ 93.2％ Example 10 50℃ 35min 99.53％ 91.4％ Comparative Example 7 60℃ 30min 91.69％ 69.3％ Comparative Example 8 35℃ 60min 90.52％ 70.3％ Comparative Example 9 / 0 98.27％ 85.4％

[0107] Analysis of the results in Table 2 above shows that whether or not to use heat preservation treatment has a significant effect on the purity and reaction yield of azelastine, specifically:

[0108] In Examples 7-10, the insulation temperature and insulation time are controlled within the scope of the present application, and the purity of the obtained azelastine is greater than 99.5%; and the reaction yield is greater than 91%.

[0109] In Comparative Example 7, the holding temperature was too high and in Comparative Example 8, the holding time was too long, and the quality of the obtained azelastine product was reduced, with a purity of only 90-98%, and the yield was also significantly reduced to about 70-85%.

[0110] In Comparative Example 9, the heat preservation treatment was not used, and the purity of the obtained azelastine was 98.2%, and the yield was 85.3%, which was worse than that of Examples 7-9. Although the purity and yield barely met the requirements, the azelastine hydrochloride obtained after the subsequent salt formation still needed additional impurity removal treatment to meet the purity requirements of high-quality pharmaceutical raw materials (>99%).

[0111] In general, the insulation temperature and time need to be controlled within a specific range, that is, the insulation time is 35-50°C and the insulation time is 30-40 minutes, which can improve the purity and reaction yield of azelastine.

[0112] Example 11 Preparation of Azelastine Hydrochloride

[0113] 300 ml of anhydrous ethanol was added to 53.3 g of azelastine free base obtained in Example 1 above, the temperature was raised to 50°C, stirred to dissolve, and then 36% concentrated hydrochloric acid was added to adjust the pH to 1.5, and the mixture was kept warm and stirred for 1.5 hours; the mixture was naturally cooled to room temperature (about 25°C), and the mixture was kept warm and stirred for crystallization for 2 hours. The solid was filtered and the filter cake was washed once with anhydrous ethanol and dried in vacuo at 100-120°C to obtain 55.6 g of azelastine hydrochloride, which was a white to off-white powder with an HPLC purity of 99.94%. The HPLC detection spectrum of the product was as follows: Figure 2 As shown; the product has crystal characteristics, and its XRD spectrum is as follows Figure 3 shown.

[0114] Example 12 Preparation of Azelastine Hydrochloride

[0115] 300 ml of anhydrous ethanol was added to 52.8 g of azelastine free base obtained in Example 2 above, the temperature was raised to 50°C, stirred to dissolve, concentrated hydrochloric acid was added to adjust the pH to 2, and the stirring was continued for 1.5 hours; the mixture was naturally cooled to room temperature (about 25°C), and the mixture was stirred for crystallization for 2 hours. The solid was filtered and the filter cake was washed once with anhydrous ethanol and dried in vacuo at 100-120°C to obtain 54.4 g of azelastine hydrochloride, a white to off-white powder with an HPLC purity of 99.95%, which had the same XRD spectrum characteristics as the product obtained in Example 11.

[0116] Example 13 Preparation of Azelastine Hydrochloride

[0117] 6.5L of anhydrous ethanol was added to 1188g of azelastine free base obtained in Example 3 above, the temperature was raised to 50°C, stirred to dissolve, concentrated hydrochloric acid was added to adjust the pH to 2, and the stirring was continued for 1.5h; the mixture was naturally cooled to room temperature (about 25°C), and the mixture was stirred for crystallization for 2h. The solid was filtered and the filter cake was washed once with anhydrous ethanol and vacuum dried at 100-120°C to obtain 1209.0g of azelastine hydrochloride, which was a white to off-white powder with an HPLC purity of 99.94%. Its XRD characteristic peaks were consistent with those of the product obtained in Example 11.

[0118] Comparative Example 10 Preparation of Azelastine Hydrochloride

[0119] 180 ml of anhydrous ethanol was added to 32.6 g of azelastine free base prepared in the above comparative example 9, the temperature was raised to 50°C, stirred to dissolve, concentrated hydrochloric acid was added to adjust the pH to 1.5, and the mixture was kept warm and stirred for 1.5 hours; the mixture was naturally cooled to room temperature (20-25°C), and the mixture was kept warm and stirred for crystallization for 2 hours. The solid obtained by filtration was grayish in color when observed with the naked eye. Anhydrous ethanol was used for recrystallization once, and vacuum dried at 100-120°C to obtain 25.9 g of azelastine hydrochloride, an off-white solid powder, with an HPLC purity of 99.24%. The HPLC detection spectrum was as shown in FIG. Figure 4 shown.

[0120] Comparative Example 11 Preparation of Azelastine Hydrochloride

[0121] Referring to the prior art, such as patent CN102391253A, the cyclization reaction uses water as a solvent for synthesis, and the specific operation is as follows:

[0122] At room temperature, 18g of compound 2 and 30.2g of compound 3 were added to 600ml of water and stirred to disperse; 20% NaOH solution was added to adjust the pH to 7; the temperature was raised to 110°C, the materials were fully dissolved, and the reaction was refluxed with stirring for 3h (TLC monitoring), and cooled to room temperature under stirring. The system became turbid, but no obvious solid precipitation was observed; the temperature was continued to be cooled to 0-5°C, and a paste-like solid was precipitated on the wall; the pH was adjusted to 9 with 20% NaOH solution, and solid was precipitated by stirring. The mixture was allowed to stand and filtered to obtain a solid (slightly sticky), which was dried to obtain 27.9g of a dark gray solid. Add 150 ml of acetone to the solid, heat to dissolve, add an appropriate amount of activated carbon, stir and reflux for 1 hour, filter while hot, and adjust the pH of the filtrate to 1-2 with an isopropanol solution containing HCl while cooling and stirring; cool to room temperature and stir for 2 hours, filter to obtain a light yellow solid, wash twice with ice acetone, drain, and recrystallize once with acetone and ethanol respectively, and dry to obtain a white to off-white solid, which is 24.6 g of azelastine hydrochloride with HPLC purity of 99.92%.

[0123] Test 1 Azelastine Hydrochloride Product Stability

[0124] The stability of the azelastine hydrochloride raw material was investigated under high temperature, high humidity and light, and the samples before and after placement were tested and analyzed. The results are shown in Table 3 below.

[0125] Table 3: Stability study of azelastine hydrochloride raw materials

[0126]

[0127] Analysis of the data in Table 3 above shows that the azelastine hydrochloride prepared in the present application has good compound stability. After being placed at high temperature, high humidity and light for 10 days, the product purity changes by only 0.01-0.02%, and the purity remains almost unchanged, indicating that the product is not easily degraded to produce impurities, has good stability, and has better stability relative to the comparative example. In addition, the azelastine hydrochloride product crystal form prepared in the present application was not found to be crystallized after being placed at high temperature, high humidity and light, which is conducive to its stable presence in solid preparations and reduces the risk of instability of the raw material drug due to the process.

[0128] Experiment 2 Investigation of the dissolution properties of azelastine hydrochloride

[0129] At a rotation speed of 500 rpm, 0.5 g of azelastine hydrochloride was dissolved in 40 ml of water for injection (concentration 12.5 mg / ml), and the dissolution and cooling conditions were observed. The results are summarized in Table 4.

[0130] Table 4: Investigation of predissolution conditions for APIs

[0131]

[0132] It can be seen from the results in Table 4 above that, under the same conditions, the solubility of the azelastine hydrochloride product obtained in the present application is improved, and no precipitation occurs after cooling and placement, and the solution remains clear. Specifically:

[0133] At 35°C, the raw material of Example 13 obtained by the technical solution of the present application can be completely dissolved in about 13 minutes, while the raw material obtained in Comparative Example 11 still has a small amount of solid that has not dissolved after 30 minutes; the dissolution time is shorter than that of commercially available raw materials.

[0134] At 40-50°C, the solubility of azelastine hydrochloride increases. Although Example 13, Comparative Example 11 and commercially available raw materials can be completely dissolved, the solution of Comparative Example 11 was observed to become turbid after being cooled and placed. At the same time, the raw material dissolution time of Example 13 is shorter, which can save the preparation time in production and reduce the risk of instability of the raw material due to process factors such as long-term stirring.

[0135] Test 3 Application of azelastine hydrochloride in solid preparations

[0136] Azelastine hydrochloride tablets with a specification of 2 mg were prepared by wet granulation and the obtained tablets were analyzed. 2 g of azelastine hydrochloride, 18 g of microcrystalline cellulose, 12 g of corn starch, 14 g of anhydrous lactose, and 16 g of hydroxypropyl cellulose were granulated in a wet granulator by a conventional method, dried, and granulated. Finally, 0.6 g of magnesium stearate was added and tablets were obtained.

[0137] Table 5: Long-term stability study of tablets

[0138] sample Long-term stability (3M) Total impurities % Example 13 0.04％ Comparative Example 11 0.10％

[0139] From the data in Table 5 above, it can be seen that the azelastine hydrochloride prepared in this scheme has good stability in the preparation of solid tablets, the total impurities do not change much after long-term storage, the long-term stability is good, and it is slightly better than the product of Comparative Example 11.

[0140] In summary, the present invention optimizes the process route to first prepare azelastine free base with better quality, which is solid and has higher purity. The appearance of the product before drying is shown in Figure 5At the same time, by regulating the reaction conditions such as the content of the reaction substrate and the solvent in each step, a high-purity azepine hydrochloride product is further obtained, which can be used as a medicinal azepine hydrochloride raw material in preparations. The purity is as high as 99.9% or more, and the product uniformity is good. The product appearance is shown in Figure 6 .

[0141] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for preparing azelastine hydrochloride, comprising the following steps: (1) dissolving benzoyl hydrazide in an organic solvent, adding N-methylhexahydroazepine-4-one hydrochloride at 0-5° C. and stirring, dropping an alkali solution, adding a reducing agent, and heating to carry out a reduction reaction; after the reaction is completed, extracting and concentrating to obtain compound 1, wherein compound 1 is N-(1-methyl-hexahydroazepine-4-yl-)benzoyl hydrazide; (2) adding concentrated hydrochloric acid to compound 1 under stirring, and heating to carry out a hydrolysis reaction; after the reaction is completed, cooling and concentrating to obtain compound 2, wherein compound 2 is 1-methylhexahydroazepine-4-hydrazine hydrochloride; (3) First, compound 2 is dissolved in a reaction solvent mixed with methanol and water, the pH is adjusted and the mixture is kept warm, and then compound 3 is added and the temperature is raised to carry out a cyclization reaction; after the reaction, an alkali solution is directly added to adjust the pH to 9-10 without removing the solvent, and a solid is precipitated, which is a crude product of azelastine free base; the obtained crude product is post-treated and dried to obtain a solid compound 4, wherein the compound 3 is 2-(p-chlorophenylacetyl)benzoic acid, and the compound 4 is a free base of azelastine; wherein the post-treatment comprises adding the precipitated crude free base solid to ethyl acetate and water, stirring, adding 10% hydrochloric acid to adjust the pH to 1-2, separating the layers, and retaining the water layer; Add 20% NaOH solution to adjust the pH to ≥ 12; precipitate the azelastine free base solid; (4) Compound 4 is added to a salt-forming solvent and heated to dissolve; concentrated hydrochloric acid is added to adjust the pH to 1 to 3, the mixture is stirred at room temperature, cooled and crystallized to obtain a solid, which is filtered and dried to obtain Compound 5, i.e., azelastine hydrochloride; Characterized in that, in step 1, the molar ratio of benzoyl hydrazide to N-methylhexahydroazepine-4-one hydrochloride is 1:1.1-2.0; In step 2, the mass volume ratio (g / ml) of compound 1 to concentrated hydrochloric acid is 1:2-5; In step 3, the volume ratio of water to methanol is 1:0.5-2; the mass volume ratio of compound 2 to reaction solvent is 1:5-8; the feeding molar ratio of compound 2 to compound 3 is 1:0.8-1.4; the insulation temperature of the insulation treatment is 35-50°C, and the insulation time is 20-50min.

2. The preparation method according to claim 1, characterized in that: In step 3, the molar ratio of compound 2 to compound 3 is 1:0.9-1.

3.

3. The preparation method according to claim 1, characterized in that: In step 3, the heat preservation treatment temperature is 40-45°C.

4. The preparation method according to claim 1, characterized in that: In step 3, the heat preservation treatment time is 30 to 40 minutes.

5. The preparation method according to claim 1, characterized in that: In step 4, the salt-forming solvent is anhydrous ethanol.

6. The preparation method according to claim 1, characterized in that: In step 4, the drying temperature is 95-140°C.

7. A method for preparing high-purity azelastine hydrochloride, comprising the following steps: (1) dissolving benzoyl hydrazide in methanol, adding N-methylhexahydroazepine-4-one hydrochloride at 0-5°C, stirring for 10-20 minutes, adding KOH aqueous solution dropwise, adding potassium borohydride, heating to 45-55°C, reacting for 1-2.5 hours; after the reaction, extracting once, retaining the oil phase, and concentrating under reduced pressure to obtain compound 1, wherein compound 1 is N-(1-methyl-hexahydroazepine-4-yl-)benzoyl hydrazide; (2) Slowly adding concentrated hydrochloric acid to compound 1 under stirring, raising the temperature to 110-130° C., and reacting for 2-3 hours; after the reaction, lowering the temperature to 70-80° C., and concentrating under reduced pressure to obtain compound 2, wherein compound 2 is 1-methylhexahydroazepine-4-hydrazine hydrochloride; (3) Compound 2 is dissolved in a mixed solvent of methanol and water, the pH is adjusted to 7-8, the temperature is raised to 40-45°C and stirred for 30-40 minutes, and then compound 3 is added, and the temperature is raised to 60-70°C and refluxed for reaction for 1.5-2.5 hours; after the reaction is completed, 0.02%-0.05% NaOH solution is directly added to adjust the pH to 9-10, solid is precipitated, and the solid is collected by filtration; the solid is added to ethyl acetate and water, 10% hydrochloric acid is added to adjust the pH to 1-2 with stirring, the layers are separated, and the water layer is retained; 20% NaOH solution is added to adjust the pH to ≥12; the solid is precipitated, stirred for 0.5-1 hour, filtered, and dried to obtain compound 4, wherein the compound 3 is 2-(p-chlorophenylacetyl)benzoic acid, and the compound 4 is azelastine free base; (4) Compound 4 is added to anhydrous ethanol, heated to 45-55°C, stirred to fully dissolve, and then concentrated hydrochloric acid is added to adjust the pH to 1-3, and the stirring is continued for 1.2-1.6 hours; the mixture is naturally cooled to room temperature, stirred and crystallized for 1.5-2.5 hours; filtered, and the solid is vacuum dried at 100-120°C to obtain azelastine hydrochloride.

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