Preparation method of emedastine fumarate

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of emedastine fumarate. The preparation method comprises the following steps: enabling SM1 and SM2 to react to obtain Int1, enabling Int1 to react with SM3 to obtain Int2, and salifying Int2 and fumaric acid to obtain emedastine fumarate. The purity and the yield of the emedastine fumarate obtained by the preparation method are relatively high, and a remarkable effect is achieved in the aspect of single impurity control.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing emedastine fumarate. Background Art

[0002] Emedastine fumarate, chemical name 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole disodium fumarate, belongs to histamine H 1 Compared with other drugs of the same type, emedastine fumarate has the advantages of high selectivity, rapid onset of action and few side effects. Emedastine fumarate was jointly developed by Kannebo-Kowa of Japan and launched in Japan in 1993 for the treatment of allergic rhinitis and chronic urticaria in the form of capsules. It was launched by the FDA in 1997 for the treatment of seasonal allergic conjunctivitis in the form of eye drops.

[0003] A variety of preparation methods of emedastine are disclosed in the prior art, among which Chinese patents CN107043355B and CN112778279B report the synthesis of compound I and compound II (emedastine), respectively, as shown in Route 1. This method uses o-phenylenediamine as the starting material, and synthesizes compound I through Boc protection, substitution, de-Boc protection, cyclization, etc., and then reacts with N-methyl homopiperazine to obtain emedastine. The reaction operation is cumbersome and difficult to industrialize; and sodium acetate borohydride is used, which is easy to produce over-reduction impurities, which has a great impact on product quality; at the same time, when preparing compound I, the total yield is about 25%, the yield is low, and the cost is high; the high temperature reaction of 150°C is used, which has high requirements for production equipment and is difficult to industrialize; when preparing compound II from compound I, the reaction conversion rate is low, the reproducibility is poor, and the product quality cannot be guaranteed. In addition, when compound I and N-methyl homopiperazine are subjected to condensation reaction, a byproduct impurity 1 is easily produced, which cannot be refined and removed in subsequent reactions, affecting product quality.

[0004]

[0005] Document 1 (Yang Jinsong, et al., Synthesis of a new antihistamine drug, Emedastine fumarate, Chinese Journal of Medicinal Chemistry. 2003, Vol. 13 (Issue 2), p104-105, DOI: 10.3969 / j.issn.1005-0108.2003.02.012) uses 2-chlorobenzimidazole to react with 2-bromoethyl ethyl ether under the action of potassium carbonate for solid-liquid reaction, and the obtained compound III is further reacted with N-methyl homopiperazine for solid-liquid reaction, and emedastine fumarate is obtained after post-treatment, as shown in the following route 2. This reaction is a solid-liquid two-phase reaction when 2-chlorobenzimidazole reacts with 2-bromoethyl ethyl ether to generate compound III, and the reaction conversion rate is low, and the production cost is high; when compound III is used to prepare compound II, it is also a solid-liquid two-phase reaction, and column chromatography is used for purification, which is difficult in terms of industrialization; at the same time, the total yield of the three-step reaction is about 18%, which is a low yield. Moreover, this route is prone to produce an intramolecular substitution product impurity 2 in the first step of the reaction, and further reaction produces impurity 3, which has a significant impact on the product.

[0006]

[0007] Document 2 (Li Yanqin, et al., Improvement of the Synthesis Process and Structural Characterization of Emedastine Fumarate API, Applied Chemistry. 2013, Vol. 30 (Issue 11), p1285-1288, DOI: 10.3724 / SP.J.1095.2013.20601) has been improved on the basis of route 2, and a phase transfer catalyst has been added to react to obtain Emedastine Fumarate. However, even if a phase transfer catalyst is added to this route, the reaction system is still in a solid-liquid suspension state, and the conversion rate is improved, but still low; and when preparing compound II from compound III, DMF is refluxed for 12 hours, which consumes a lot of energy and is not conducive to industrial production. Even if route 2 is improved, this route still produces more impurities 2 and impurities 3.

[0008] The structural formulas of the impurities 1, 2 and 3 mentioned above are as follows:

[0009]

[0010] As described above, the synthesis process of emedastine in the prior art mostly adopts heterogeneous reaction, which leads to low reaction efficiency and incomplete reaction, complex post-processing, difficulty in removing related substances and low yield, etc., and produces a large amount of impurities 1, impurity 2 and impurity 3, which brings the risk of excessive impurities to the quality of the raw material drug.

[0011] In view of the above situation, the present invention has developed a preparation method of emedastine fumarate which has simple process operation, few side reactions, low impurity content, good quality, high yield and is suitable for large-scale production through experiments. Summary of the invention

[0012] An object of the present invention is to provide a method for preparing high-purity emedastine fumarate.

[0013] The method for preparing high-purity emedastine fumarate according to the present invention is characterized in that the chemical reaction equation of the method is as follows:

[0014]

[0015] The method comprises the following steps:

[0016] Step 1): SM1 is added to N,N-dimethylformamide to dissolve, and then an organic base is added for activation to obtain an activated solution; SM2 is added to N,N-dimethylformamide, and then a catalyst is added and stirred, and then the activated solution is added dropwise and kept warm for reaction, and Int1 is obtained after post-treatment;

[0017] Step 2): Int1 is added to an alkaline reagent and stirred under controlled temperature, and then SM3 is added and kept warm for reaction, and Int2 is obtained after post-treatment;

[0018] Step 3): Add fumaric acid to a mixed solvent and heat to dissolve, add Int2 ethanol solution dropwise and keep warm to react, cool to crystallize, filter and dry to obtain emedastine fumarate.

[0019] In the above chemical reaction equation and reaction steps, SM1 is 2-chlorobenzimidazole, SM2 is 2-bromoethyl ether, and SM3 is N-methyl homopiperazine.

[0020] In one embodiment, in the above-mentioned preparation method, in step 1), the organic base can be selected from one or more of 2,6-lutidine, diethylamine, 1-methylimidazole, 4-methylpyridine, and quinoline; the catalyst can be selected from one or more of sodium molybdate, sodium tungstate, sodium vanadate, and sodium chromate.

[0021] In the above-described preparation method, in step 1), the molar ratio of organic base: catalyst: SM2: SM1 is (1.05-2.5): (0.05-0.3): (1.1-2.5): 1; preferably, the molar ratio of organic base: catalyst: SM2: SM1 is (1.05-2.0): (0.05-0.3): (1.1-1.8): 1.

[0022] In the above-mentioned preparation method, in step 1), the temperature of the insulation reaction is 50-80° C., and the reaction time is 2-10 h; preferably, the temperature of the insulation reaction is 65° C., and the reaction time is 5 h.

[0023] In the above-mentioned preparation method, in step 1), the post-treatment method is that after the reaction liquid is kept warm, the reaction liquid is cooled and added to water, extracted with ethyl acetate, and the ethyl acetate phase is dried and concentrated to dryness to obtain Int1.

[0024] In the above-mentioned preparation method, in step 2), the alkaline reagent is selected from one or more of tetramethylguanidine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

[0025] In the above-described preparation method, in step 2), the molar ratio of the alkaline reagent: SM3: Int1 is (3-5): (1.05-2): 1; preferably, the molar ratio of the alkaline reagent: SM3: Int1 is (3.5-4.5): (1.05-1.5): 1.

[0026] In the above-mentioned preparation method, in step 2), the insulation temperature is 60-100° C., and the reaction time is 4-10 h; preferably, the insulation temperature is 80° C., and the reaction time is 7 h.

[0027] In the above-mentioned preparation method, in step 2), the post-treatment method is to add the reaction solution to water for quenching, extract with ethyl acetate, add water to the ethyl acetate phase, and adjust the solution pH to 1-3, separate the liquids, adjust the pH of the aqueous phase to 10-13, extract with ethyl acetate and separate the liquids, and dry the organic phase and concentrate to dryness.

[0028] Generally, the operation of drying the organic phase described in the present invention refers to using a desiccant to absorb a small amount of moisture in the organic phase, and commonly used desiccant includes anhydrous calcium chloride, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous potassium carbonate, etc. The desiccant is usually added to the organic solution and stirred or placed for a period of time before filtering. During filtering, a small amount of organic solvent can be used to rinse the desiccant to reduce the product yield loss caused by the solution containing the target product remaining on the desiccant. When selecting a desiccant, it is necessary to consider whether it reacts chemically with the organic matter, whether it is dissolved in the organic liquid, the drying speed and the water absorption, and anhydrous magnesium sulfate is preferably used to dry in the present invention.

[0029] In the preparation method described above, in step 3), the mixed solvent is ethanol and N,N-dimethylformamide; the temperature is 55-75°C; the volume ratio of ethanol and N,N-dimethylformamide in the mixed solvent is 16:1, and the mass volume ratio (m / V, i.e., mass / volume) of fumaric acid to the mixed solvent is 1:10; the mass volume ratio (m / V, mass / volume) of Int2 to ethanol in the Int2 ethanol solution is 1:3; the molar ratio of fumaric acid to Int2 is 2:1.

[0030] The pH value mentioned in the present invention can be obtained by testing with pH test paper or pH meter. Generally, when the pH value is a specific value, it does not mean that the pH value of the solution is strictly equal to the value, but means that the pH value of the solution is within a smaller range near the value, and the specific size of this range depends on the accuracy and reliability of the measurement method and instrument used. The pH value described in the present invention is preferably tested with a pH meter, and the range of pH value generally does not exceed ±0.1, that is, when the pH value is 5, it means that the pH value obtained by the test is between 4.9 and 5.1; preferably, the range of pH value does not exceed ±0.05, that is, when the pH value is 5, it means that the pH value obtained by the test is between 4.95 and 5.05.

[0031] Furthermore, the preparation method of high-purity emedastine fumarate of the present invention is characterized in that the chemical reaction equation of the method is as follows:

[0032]

[0033] The method comprises the following steps:

[0034] Step 1): SM1 is added to N,N-dimethylformamide to dissolve, and then an organic base is added for activation to obtain an activated solution; SM2 is added to N,N-dimethylformamide, and then a catalyst is added and stirred, and then the activated solution is added dropwise and kept warm for reaction, and Int1 is obtained after post-treatment;

[0035] The organic base is selected from one or more of 2,6-lutidine, diethylamine, 1-methylimidazole, 4-methylpyridine, and quinoline; the catalyst is selected from one or more of sodium molybdate, sodium tungstate, sodium vanadate, and sodium chromate;

[0036] The molar ratio of the organic base: catalyst: SM2: SM1 is (1.05-2.0): (0.05-0.3): (1.1-1.8): 1;

[0037] The temperature of the insulation reaction is 65°C and the reaction time is 5h;

[0038] The post-treatment method is as follows: after the reaction liquid is kept warm for reaction, the reaction liquid is cooled and added dropwise to water, extracted with ethyl acetate, and the ethyl acetate phase is dried and concentrated to dryness to obtain Int1.

[0039] Step 2): Int1 is added to an alkaline reagent and stirred at a temperature of 60-100°C, and then SM3 is added and kept warm for reaction, and Int2 is obtained after post-treatment;

[0040] The alkaline reagent is selected from one or more of tetramethylguanidine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene);

[0041] The molar ratio of the alkaline reagent: SM3: Int1 is (3.5-4.5): (1.05-1.5): 1;

[0042] The insulation temperature is 80°C and the reaction time is 7h;

[0043] The post-treatment method comprises the following steps: adding the reaction solution to water for quenching, extracting with ethyl acetate, adding water to the ethyl acetate phase, adjusting the solution pH to 1-3 with a hydrochloric acid solution, separating the phases, adjusting the aqueous phase pH to 10-13 with a sodium hydroxide solution, extracting with ethyl acetate, drying the organic phase with anhydrous magnesium sulfate, and concentrating to dryness.

[0044] Step 3): Add fumaric acid to a mixed solvent and heat to dissolve, add Int2 ethanol solution dropwise to keep warm for reaction, cool to crystallize, filter and dry to obtain emedastine fumarate;

[0045] The mixed solvent is ethanol and N,N-dimethylformamide; the reaction temperature is 55-75°C;

[0046] The volume ratio of ethanol to N,N-dimethylformamide in the mixed solvent is 16:1, and the mass volume ratio (m / V, mass / volume) of fumaric acid to the mixed solvent is 1:10;

[0047] The mass volume ratio (m / V, mass / volume) of Int2 to ethanol in the Int2 ethanol solution is 1:3;

[0048] The molar ratio of fumaric acid to Int2 is 2:1.

[0049] The test of the single impurity content in emedastine fumarate can be carried out by referring to the test method for the content in the corresponding quality standard included in the European Pharmacopoeia EP11.0 or the test method optimized thereon.

[0050] It will be appreciated by those skilled in the art that the impurities 1, 2 and 3 listed above in the present invention are only a few specific process impurities, not all impurities. In the field of organic synthesis, ensuring the purity and yield of the product is a complex and delicate process, which involves consideration and control in many aspects, such as the selection of raw materials, reagents and catalysts, the optimization of reaction conditions (ratio, temperature, time, etc.), post-processing process, etc. Generally speaking, organic synthesis reactions may bring various known or unknown impurities due to factors such as raw materials, reagents, reaction conditions, etc. In the organic synthesis process, the complexity of the reaction often causes the purity of the product to be affected. In addition, whether the reaction conditions and post-processing process are appropriate also has a huge impact on the yield and purity of the product. For example, when two or more different molecules participate in the reaction, intermediate molecules may be formed, resulting in the formation of by-products. These by-products may be known or unknown, depending on the conditions of the reaction and the properties of the substances involved in the reaction. In organic synthesis reactions, due to the influence of various factors such as raw materials, reagents, reaction conditions, unexpected products or impurities may be produced, which may have an important impact on the purity and final use of the product.

[0051] The preparation method of emedastine fumarate of the present invention controls each step of the reaction through process control and combines a specific post-treatment method to improve the yield of each step of the reaction while controlling the single impurities and total impurities of each step of the reaction at a relatively low level.

[0052] The purity and yield of the emedastine fumarate obtained by the preparation method of the present invention are relatively high, especially in terms of the control of single impurities. The present invention also conducts a stability study on the prepared emedastine fumarate, and the results show that the emedastine fumarate obtained by the preparation method of the present invention shows a more stable trend in terms of quality such as single impurities and purity in the stability study.

[0053] The method of the present invention, in which 2-chlorobenzimidazole, 2-bromoethyl ethyl ether and N-methyl homopiperazine are used as starting materials for reacting to prepare emedastine fumarate, has the following advantages:

[0054] 1) The reaction processes of Int1 and Int2 are both homogeneous, which is not easy to produce product encapsulation, and can effectively avoid the large by-products caused by heterogeneous reactions, greatly improving the reaction conversion rate and yield;

[0055] 2) The reaction conditions are mild, the operation is simple, the power cost is greatly reduced, and it is suitable for industrial production;

[0056] 3) The obtained emedastine fumarate has reliable process and stable quality;

[0057] 4) The purity of the obtained product is above 99.9%, with less impurities, which is higher than the European Pharmacopoeia standard;

[0058] 5) The obtained product has good stability and is not easy to degrade. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 : The 1H-NMR diagram of emedastine fumarate in Example 1;

[0060] Figure 2 : MS graph of emedastine fumarate in Example 1; DETAILED DESCRIPTION

[0061] The technical solution of the present invention is now further described in conjunction with specific embodiments. These embodiments are only typical embodiments of the present invention and do not constitute any limitation to the scope of the present invention. For those skilled in the art, it is not necessary and impossible to list all the embodiments exhaustively. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements fall within the scope of protection of the present invention. The experimental methods for which specific experimental conditions are not indicated in the following examples are usually carried out under conventional conditions or under the conditions recommended by the manufacturer.

[0062] Embodiment 1:

[0063] SM1 (10.0 g, 0.066 mol) was added to N, N-dimethylformamide (30 ml) to dissolve, and then 2,6-dimethylpyridine (10.5 g, 0.098 mol) was added, and the mixture was stirred at 65°C for 2 h to obtain an activated product solution. SM2 (15.0 g, 0.098 mol) was added to N, N-dimethylformamide (45 ml), and then sodium molybdate (2.7 g, 0.013 mol) was added, and the mixture was stirred at 65°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 65°C and stirred for 5 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int1 (13.65 g), with a yield of 92.7%.

[0064] Add Int1 (10.0 g, 0.045 mol) to tetramethylguanidine (20.5 g, 0.178 mol) and stir at 80°C. Then add SM3 (6.6 g, 0.058 mol) and keep the mixture at 80°C for 7 h. The reaction solution was cooled to 0-10°C and added dropwise to 0-10°C water (100 ml). The mixture was extracted with ethyl acetate (100 ml x 2). The ethyl acetate phases were combined and water (100 ml) was added. The pH was adjusted to 2 with 10% hydrochloric acid solution, and the phases were separated. The ethyl acetate phase was discarded. The aqueous phase was adjusted to pH 12 with 10% sodium hydroxide solution, and ethyl acetate (300 ml) was added for extraction. The phases were separated, and the ethyl acetate phase was dried over anhydrous magnesium sulfate. Activated carbon (0.5 g) was added, and the mixture was filtered. The filtrate was concentrated to dryness at 50°C to obtain a light yellow oily substance Int2 (11.95 g) with a yield of 88.8%.

[0065] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N, N-dimethylformamide (5 ml), dissolved at 65 ° C to obtain a fumaric acid solution. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml), dissolved at 65 ° C, and added dropwise to the fumaric acid solution, stirred at this temperature for 2 h, cooled to 20-30 ° C and stirred for 1 h. Filtered, the filter cake was vacuum dried at 50 ° C to obtain an off-white solid emedastine fumarate (15.78 g), with a yield of 89.3%. Its H NMR spectrum is: 1 H NMR (400 MHz, D 2 O): δ7.53-7.35ppm(m,4H), δ6.56ppm(s,4H), δ4.42-4.39ppm(m,2H), δ4.11ppm(s,2H), δ3.90ppm(s,2H), δ3.86-3.83ppm(m,2H), δ3.66ppm(s,2H), δ3.42-3.40ppm(m,2H), δ3.38-3.37ppm(m,2H), δppm2.95(s,3H), δ2.34-2.31ppm(m,2H), δ0.95-0.91ppm(s,3H). Its mass spectrum is: molecular ion peak [M+1] + The molecular weight of emedastine is 303.15 (after deducting fumaric acid, the exact molecular weight of emedastine is 302.21).

[0066] Embodiment 2:

[0067] SM1 (10.0 g, 0.066 mol) was added to 30 ml N, N-dimethylformamide (30 ml) to dissolve, and then diethylamine (5.034 g, 0.069 mol) was added, and the mixture was stirred at 50°C for 2 h to obtain an activated product solution. SM2 (11.032 g, 0.072 mol) was added to N, N-dimethylformamide (45 ml), and sodium tungstate (0.963 g, 0.005 mol) was added, and the mixture was stirred at 50°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 50°C and stirred for 10 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int1 (13.52 g), with a yield of 91.8%.

[0068] Int1 (10.0 g, 0.045 mol) was added to DBU (23.715 g, 0.156 mol) and stirred at 60°C. Then SM3 (5.34 g, 0.047 mol) was added and the mixture was kept at 60°C for 10 h. The reaction solution was cooled to 0-10°C and added dropwise to 0-10°C water (100 ml), extracted with ethyl acetate (100 ml×2), the ethyl acetate phases were combined, and water (100 ml) was added. The pH was adjusted to 1 with 10% hydrochloric acid solution, the phases were separated, the ethyl acetate phase was discarded, the aqueous phase was adjusted to pH 10 with 10% sodium hydroxide solution, and ethyl acetate (300 ml) was added for extraction, the phases were separated, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and 0.5 g of activated carbon was added, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int2 (11.78 g) with a yield of 87.5%.

[0069] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N,N-dimethylformamide (5 ml) and dissolved at 55°C. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml) and dissolved at 55°C, and then added dropwise to the fumaric acid solution. The mixture was stirred at this temperature for 2 hours, and then cooled to 20-30°C and stirred for 1 hour. The mixture was filtered and the filter cake was dried under vacuum at 50°C to obtain off-white solid emedastine fumarate (15.65 g) with a yield of 88.5%.

[0070] Embodiment 3:

[0071] SM1 (10.0 g, 0.066 mol) was added to N, N-dimethylformamide (30 ml) to dissolve, and then 1-methylimidazole (10.762 g, 0.125 mol) was added, and the mixture was stirred at 80°C for 2 h to obtain an activated product solution. SM2 (18.052 g, 0.118 mol) was added to N, N-dimethylformamide (45 ml), and then sodium vanadate (3.615 g, 0.020 mol) was added, and the mixture was stirred at 80°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 80°C and stirred for 2 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int1 (13.40 g), with a yield of 91.0%.

[0072] Int1 (10.0 g, 0.045 mol) was added to DBU (30.490 g, 0.200 mol) and stirred at 100°C. SM3 (7.623 g, 0.067 mol) was then added and the mixture was kept at 100°C for 4 h. The reaction solution was cooled to 0-10°C and added dropwise to 0-10°C water (100 ml), extracted with ethyl acetate (100 ml×2), the ethyl acetate phases were combined, and water (100 ml) was added. The pH was adjusted to 3 with 10% hydrochloric acid solution, the phases were separated, the ethyl acetate phase was discarded, the pH of the aqueous phase was adjusted to 13 with 10% sodium hydroxide solution, and ethyl acetate (300 ml) was added for extraction, the phases were separated, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and activated carbon (0.5 g) was added, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int2 (11.91 g) with a yield of 88.5%.

[0073] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N,N-dimethylformamide (5 ml), dissolved at 75°C to obtain a fumaric acid solution. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml), dissolved at 75°C, and added dropwise to the fumaric acid solution. The mixture was stirred at this temperature for 2 h, cooled to 20-30°C, and stirred for 1 h. Filtered, the filter cake was vacuum dried at 50°C, and an off-white solid emedastine fumarate (15.73 g) was obtained, with a yield of 89.0%.

[0074] Embodiment 4:

[0075] SM1 (10.0 g, 0.066 mol) was dissolved in N, N-dimethylformamide (30 ml), and then 4-methylpyridine (9.156 g, 0.098 mol) was added, and the mixture was stirred at 65°C for 2 h to obtain an activated product solution. SM2 (15.0 g, 0.098 mol) was added to N, N-dimethylformamide (45 ml), and then sodium chromate (2.123 g, 0.013 mol) was added, and the mixture was stirred at 65°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 65°C and stirred for 5 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int1 (13.51 g), with a yield of 91.7%.

[0076] Int1 (10.0 g, 0.045 mol) was added to tetramethylguanidine (20.5 g, 0.178 mol) and stirred at 80°C. Then SM3 (6.6 g, 0.058 mol) was added and the mixture was kept at 80°C for 7 h. The reaction solution was cooled to 0-10°C and added dropwise to 0-10°C water (100 ml), extracted with ethyl acetate (100 ml×2), the ethyl acetate phases were combined, and water (100 ml) was added. The pH was adjusted to 2 with 10% hydrochloric acid solution, the phases were separated, the ethyl acetate phase was discarded, the aqueous phase was adjusted to pH 12 with 10% sodium hydroxide solution, and ethyl acetate (300 ml) was added for extraction, the phases were separated, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and activated carbon (0.5 g) was added, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int2 (11.88 g) with a yield of 88.3%.

[0077] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N,N-dimethylformamide (5 ml) and dissolved at 65°C. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml) and dissolved at 65°C, then added dropwise to the fumaric acid solution, stirred at this temperature for 2 h, cooled to 20-30°C and stirred for 1 h. Filtered, the filter cake was dried under vacuum at 50°C to obtain off-white solid emedastine fumarate (15.68 g), with a yield of 88.7%.

[0078] Embodiment 5:

[0079] SM1 (10.0 g, 0.066 mol) was added to N, N-dimethylformamide (30 ml) to dissolve, and then quinoline (12.698 g, 0.098 mol) was added, and the mixture was stirred at 65°C for 2 h to obtain an activated product solution. SM2 (15.0 g, 0.098 mol) was added to N, N-dimethylformamide (45 ml), and sodium molybdate (2.7 g, 0.013 mol) was added, and the mixture was stirred at 65°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 65°C and stirred for 5 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int1 (13.45 g), with a yield of 91.3%.

[0080] Int1 (10.0 g, 0.045 mol) was added to tetramethylguanidine (20.5 g, 0.178 mol) and stirred at 80°C. Then SM3 (6.6 g, 0.058 mol) was added and the mixture was kept at 80°C for 7 h. The reaction solution was cooled to 0-10°C and added dropwise to 0-10°C water (100 ml), extracted with ethyl acetate (100 ml×2), the ethyl acetate phases were combined, and water (100 ml) was added. The pH was adjusted to 2 with 10% hydrochloric acid solution, the phases were separated, the ethyl acetate phase was discarded, the aqueous phase was adjusted to pH 12 with 10% sodium hydroxide solution, and ethyl acetate (300 ml) was added for extraction, the phases were separated, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and activated carbon (0.5 g) was added, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int2 (12.05 g) with a yield of 89.5%.

[0081] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N,N-dimethylformamide (5 ml), dissolved at 65°C to obtain a fumaric acid solution. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml), dissolved at 65°C, and added dropwise to the fumaric acid solution. The mixture was stirred at this temperature for 2 h, cooled to 20-30°C, and stirred for 1 h. The mixture was filtered and the filter cake was dried under vacuum at 50°C to obtain an off-white solid emedastine fumarate (15.80 g) with a yield of 89.4%.

[0082] Embodiment 6:

[0083] SM1 (10.0 g, 0.066 mol) was added to N, N-dimethylformamide (30 ml) to dissolve, and potassium carbonate (13.683 g, 0.099 mol) was added, and the mixture was stirred at 65°C for 1 h to obtain an activated product solution. SM2 (15.0 g, 0.098 mol) was added to N, N-dimethylformamide (45 ml), and the mixture was stirred at 65°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 65°C and stirred for 5 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a red oily substance Int1 (10.05 g), with a yield of 68.2%.

[0084] Int1 (10.0 g, 0.045 mol) was added to N, N-dimethylformamide (30 ml), and potassium carbonate (24.6 g, 0.178 mol) was added, and the mixture was stirred at 80 ° C. SM3 (6.6 g, 0.058 mol) was added, and the mixture was kept at 120 ° C for 7 h. The reaction solution was cooled to 0-10 ° C, and then added dropwise to 0-10 ° C water (100 ml), and extracted with ethyl acetate (100 ml × 2). The ethyl acetate phase was combined, and water (100 ml) was added. 10% hydrochloric acid solution was used to adjust the pH to 5, and the liquid was separated. The ethyl acetate phase was discarded, and the aqueous phase was adjusted to pH 12 with 10% sodium hydroxide solution. Ethyl acetate (300 ml) was added for extraction, and the liquid was separated. The ethyl acetate phase was dried over anhydrous magnesium sulfate, and activated carbon (0.5 g) was added, filtered, and the filtrate was concentrated to dryness at 50 ° C to obtain a brown oil Int2 (8.24 g), with a yield of 61.2%.

[0085] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N,N-dimethylformamide (5 ml), dissolved at 65°C to obtain a fumaric acid solution. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml), dissolved at 65°C, and added dropwise to the fumaric acid solution. The mixture was stirred at this temperature for 2 h, cooled to 20-30°C, and stirred for 1 h. Filtered, the filter cake was dried under vacuum at 50°C, and an off-white solid emedastine fumarate (12.39 g) was obtained, with a yield of 70.1%.

[0086] Embodiment 7:

[0087] SM1 (10.0 g, 0.066 mol) was added to N, N-dimethylformamide (30 ml) to dissolve, and then 4-methylpyridine (9.156 g, 0.098 mol) was added, and the mixture was stirred at 45°C for 12 h to obtain an activated product solution. SM2 (15.0 g, 0.098 mol) was added to N, N-dimethylformamide (45 ml), and then sodium chromate (0.21 g, 0.0013 mol) was added, and the mixture was stirred at 65°C for 0.5 h. The activated product solution was added dropwise, and after the addition was completed, the mixture was kept at 65°C and stirred for 5 h. The reaction solution was cooled to 0-10°C, and added dropwise to 0-10°C water (150 ml), and extracted with ethyl acetate (80 ml × 3). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int1 (11.62 g), with a yield of 78.9%.

[0088] Int1 (10.0 g, 0.045 mol) was added to tetramethylguanidine (10 g, 0.087 mol) and stirred at 55°C. Then SM3 (6.6 g, 0.058 mol) was added and the mixture was kept at 55°C for 12 h. The reaction solution was cooled to 0-10°C and added dropwise to 0-10°C water (100 ml), extracted with ethyl acetate (100 ml×2), the ethyl acetate phases were combined, and water (100 ml) was added. The pH was adjusted to 4 with 10% hydrochloric acid solution, the phases were separated, the ethyl acetate phase was discarded, the pH of the aqueous phase was adjusted to 14 with 10% sodium hydroxide solution, and ethyl acetate (300 ml) was added for extraction, the phases were separated, the ethyl acetate phase was dried over anhydrous magnesium sulfate, and activated carbon (0.5 g) was added, filtered, and the filtrate was concentrated to dryness at 50°C to obtain a light yellow oil Int2 (10.19 g) with a yield of 75.7%.

[0089] Fumaric acid (8.44 g, 0.073 mol) was added to anhydrous ethanol (80 ml) and N,N-dimethylformamide (5 ml) and dissolved at 65°C. Int2 (10.0 g, 0.033 mol) was added to anhydrous ethanol (30 ml) and dissolved at 65°C, then added dropwise to the fumaric acid solution, stirred at this temperature for 2 h, cooled to 20-30°C and stirred for 1 h. Filtered, the filter cake was dried under vacuum at 50°C to obtain off-white solid emedastine fumarate (12.85 g), with a yield of 72.7%.

[0090] Comparative Example 1 (prepared with reference to document 2):

[0091] 24.0 g 2-chlorobenzimidazole, 26.0 g 2-bromoethyl ethyl ether, 72 ml N,N-dimethylformamide, 32.4 g potassium carbonate and 1.0 g tetrabutylammonium bromide were stirred and heated to 60-70°C, and the temperature was kept for 12 hours. Water was added, and 3×100 ml ethyl acetate was used for extraction. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 22.3 g of brown oil Int1, with a yield of 63.1%.

[0092] 24.0g Int1, 13.0g N-methyl homopiperazine, 72ml N,N-dimethylformamide, 30.0g potassium carbonate and 1.0g tetrabutylammonium bromide were refluxed for 12h. The mixture was cooled to 40°C, the pH was adjusted to 10 with 5% sodium hydroxide aqueous solution, and 3×100ml ethyl acetate was used for extraction. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 22.2g of dark yellow oily substance Int2, with a yield of 68.7%.

[0093] 12.1 g of Int2 was dissolved in 4 times of anhydrous ethanol, 9.3 g of fumaric acid was added, and the mixture was heated to dissolve. The mixture was cooled and crystallized to obtain 13.8 g of off-white powder emedastine fumarate, with a yield of 64.5%.

[0094] Test Example 1: The products prepared in Examples 1-5 and Comparative Example 1 were tested, and the test results are shown in the following table:

[0095]

[0096] Test Example 2: The stability of emedastine fumarate obtained in Examples 1-5 and Comparative Example 1 was studied, and the test results are shown in the following table (stability study conditions are 40°C ± 2°C, RH 75% ± 5%):

[0097]

Claims

1. A method for preparing emedastine fumarate, characterized in that: The chemical reaction equation of the method is as follows: The method comprises the following steps: Step 1): SM1 is added to N,N-dimethylformamide to dissolve, and then an organic base is added for activation to obtain an activated solution; SM2 is added to N,N-dimethylformamide, and then a catalyst is added and stirred, and then the activated solution is added dropwise and kept warm for reaction, and Int1 is obtained after post-treatment; Step 2): Int1 is added to an alkaline reagent and stirred under controlled temperature, and then SM3 is added and kept warm for reaction, and Int2 is obtained after post-treatment; Step 3): Add fumaric acid to a mixed solvent and heat to dissolve, add Int2 ethanol solution dropwise and keep warm to react, cool to crystallize, filter and dry to obtain emedastine fumarate.

2. The preparation method according to claim 1, characterized in that: In the step 1), the organic base is selected from one or more of 2,6-lutidine, diethylamine, 1-methylimidazole, 4-methylpyridine, and quinoline; and the catalyst is selected from one or more of sodium molybdate, sodium tungstate, sodium vanadate, and sodium chromate.

3. The preparation method according to any one of claims 1-2, characterized in that: In the step 1), the molar ratio of organic base: catalyst: SM2: SM1 is (1.05-2.5): (0.05-0.3): (1.1-2.5): 1; preferably, the molar ratio of organic base: catalyst: SM2: SM1 is (1.05-2.0): (0.05-0.3): (1.1-1.8):

1.

4. The preparation method according to claim 1, characterized in that: In the step 1), the temperature of the insulation reaction is 50-80° C., and the reaction time is 2-10 hours; preferably, the temperature of the insulation reaction is 65° C., and the reaction time is 5 hours.

5. The preparation method according to claim 1, characterized in that: In the step 1), the post-treatment method is that after the reaction liquid is kept warm, the reaction liquid is cooled and added to water, extracted with ethyl acetate, and the ethyl acetate phase is dried and concentrated to dryness to obtain Int1.

6. The preparation method according to claim 1, characterized in that: In the step 2), the alkaline reagent is selected from one or more of tetramethylguanidine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

7. The preparation method according to claim 1, characterized in that: In the step 2), the molar ratio of the alkaline reagent: SM3: Int1 is (3-5): (1.05-2): 1; preferably, the molar ratio of the alkaline reagent: SM3: Int1 is (3.5-4.5): (1.05-1.5):

1.

8. The preparation method according to claim 1, characterized in that: In the step 2), the insulation temperature is 60-100°C, and the reaction time is 4-10h; preferably, the insulation temperature is 80°C, and the reaction time is 7h; the post-treatment method is to add the reaction solution to water for quenching, extract with ethyl acetate, add water to the ethyl acetate phase, adjust the solution pH to 1-3, separate the liquids, adjust the pH of the aqueous phase to 10-13, extract and separate the liquids with ethyl acetate, and dry the organic phase and concentrate to dryness.

9. The preparation method according to claim 1, characterized in that: In the step 3), the mixed solvent is ethanol and N,N-dimethylformamide; the temperature is 55-75°C; the volume ratio of ethanol and N,N-dimethylformamide in the mixed solvent is 16:1, and the mass volume ratio of fumaric acid to the mixed solvent is 1:10; the mass volume ratio of Int2 to ethanol in the Int2 ethanol solution is 1:3; the molar ratio of fumaric acid to Int2 is 2:

1.

10. A method for preparing emedastine fumarate, characterized in that: The chemical reaction equation of the method is as follows: The method comprises the following steps: Step 1): SM1 is added to N,N-dimethylformamide to dissolve, and then an organic base is added for activation to obtain an activated solution; SM2 is added to N,N-dimethylformamide, and then a catalyst is added and stirred, and then the activated solution is added dropwise and kept warm for reaction, and Int1 is obtained after post-treatment; The organic base is selected from one or more of 2,6-lutidine, diethylamine, 1-methylimidazole, 4-methylpyridine, and quinoline; the catalyst is selected from one or more of sodium molybdate, sodium tungstate, sodium vanadate, and sodium chromate; The molar ratio of the organic base: catalyst: SM2: SM1 is (1.05-2.0): (0.05-0.3): (1.1-1.8): 1; The temperature of the insulation reaction is 65°C and the reaction time is 5h; The post-treatment method is as follows: after the reaction liquid is heated to a high temperature, the reaction liquid is cooled and added dropwise to water, extracted with ethyl acetate, and the ethyl acetate phase is dried and concentrated to dryness to obtain Int1; Step 2): Int1 is added to an alkaline reagent and stirred at a temperature of 60-100°C, and then SM3 is added and kept warm for reaction, and Int2 is obtained after post-treatment; The alkaline reagent is selected from one or more of tetramethylguanidine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); The molar ratio of the alkaline reagent: SM3: Int1 is (3.5-4.5): (1.05-1.5): 1; The insulation temperature is 80°C and the reaction time is 7h; The post-treatment method is to add the reaction solution to water for quenching, extract with ethyl acetate, add water to the ethyl acetate phase, adjust the solution pH to 1-3 with hydrochloric acid solution, separate the liquids, adjust the pH of the aqueous phase to 10-13 with sodium hydroxide solution, extract and separate the liquids with ethyl acetate, and dry the organic phase with anhydrous magnesium sulfate and concentrate to dryness; Step 3): Add fumaric acid to a mixed solvent and heat to dissolve, add Int2 ethanol solution dropwise to keep warm for reaction, cool to crystallize, filter and dry to obtain emedastine fumarate; The mixed solvent is ethanol and N,N-dimethylformamide; the reaction temperature is 55-75°C; The volume ratio of ethanol to N,N-dimethylformamide in the mixed solvent is 16:1, and the mass volume ratio (m / V, mass / volume) of fumaric acid to the mixed solvent is 1:10; The mass volume ratio (m / V, mass / volume) of Int2 to ethanol in the Int2 ethanol solution is 1:3; The molar ratio of fumaric acid to Int2 is 2:1.

Images