A method for preparing high-purity montelukast sodium and its intermediates

Abstract

The present invention provides a high-purity montelukast sodium intermediate and a preparation method of montelukast sodium, wherein the preparation method of montelukast sodium comprises the following steps: preparation of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid disodium salt, preparation of montelukast free acid, preparation of montelukast dicyclohexylamine salt, and preparation of montelukast sodium. The preparation method can effectively improve the purity and quality of montelukast sodium products, reduce manufacturing costs, reduce synthesis steps, remove high-risk operations in the synthesis process, and reduce environmental pollution.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and medicinal chemistry, and specifically relates to a method for preparing high-purity montelukast sodium and an intermediate thereof. Background Art

[0002] Montelukast sodium is a prescription drug for the treatment of asthma developed and produced by Merck & Co., Inc. (also known as Merck) in the United States. It can be used to treat respiratory diseases such as asthma and allergic rhinitis. In pathology, montelukast sodium is an oral leukotriene receptor antagonist that can specifically inhibit cysteinyl leukotriene (CysLT1) receptors in the airways, thereby improving airway inflammation and effectively controlling asthma symptoms.

[0003] The chemical structure of montelukast sodium is as follows:

[0004]

[0005] There are several ways to synthesize montelukast sodium in the prior art: one is to obtain montelukast free acid by hydrochloric acidizing dicyclohexylamine used to prepare montelukast, and then prepare montelukast sodium salt by the free acid. For example, Merck (patent number CN1139429B) of the United States reacts 1-(mercaptomethyl)cyclopropylacetic acid dianion dilithium with 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate, and after the reaction solution is treated, it reacts with dicyclohexylamine to form dicyclohexylamine salt for purification, thereby synthesizing montelukast sodium. Another method is to convert montelukast free acid into montelukast organic group protected salt, and then convert it into montelukast sodium salt. For example, Zhejiang Chetou Pharmaceutical Co., Ltd. (publication number CN103570618A) adopts a synthesis method of converting montelukast free acid into montelukast dicyclohexylamine salt; converting montelukast dicyclohexylamine salt into montelukast di-n-propylamine salt; and converting montelukast di-n-propylamine salt into montelukast sodium salt. And Shandong New Era Pharmaceutical Co., Ltd. (publication numbers CN105585524A, CN105924392A) adopts the synthesis of montelukast acid p-aminoacetanilide salt or montelukast acid 2-amino-1-butanol salt from montelukast free acid, acidifies the above transition group protected salt, and adds a base to prepare montelukast sodium.

[0006] However, the above-mentioned synthesis method 1 has defects in controlling several impurities of montelukast sodium, among which sulfoxide impurities (USP impurity a), disulfide impurities (USP impurities c and d), and styrene impurities (USP impurity f) cannot be removed well, and n-butyl lithium, which is extremely active and dangerous, is used in the synthesis process. It can no longer meet current requirements in terms of product quality and production safety. The above-mentioned synthesis method 2 involving the conversion of montelukast free acid into montelukast organic group protected salt has the problem that the selection of organic protecting groups is not easy, and a large amount of by-products are introduced, the purity of the prepared montelukast sodium is low, and the production cost is too high. Therefore, a synthesis method of montelukast sodium with high purity, good safety, and less pollution is urgently needed.

[0007] In addition, WO 2008023044A1 discloses the use of sodium methoxide instead of n-butyl lithium to form a disodium salt reaction. However, the reaction temperature of the obtained disodium salt after adding mesylate is relatively high (10-15° C.), and there are many side reactions. The conventional ethyl acetate extraction method is used for subsequent treatment to directly obtain montelukast free acid. After purification, the product quality is relatively low, with a purity of only 98.5%-99%, which is far from the current domestic and international quality standards for montelukast sodium. Summary of the invention

[0008] In order to improve the quality of montelukast sodium products, improve industry and degree, reduce costs; reduce the synthesis steps, remove high-risk operations in the synthesis process, reduce safety risks, and reduce environmental pollution; the present invention proposes a method for preparing high-purity montelukast sodium and its intermediates. The specific scheme is as follows:

[0009] A method for preparing a montelukast sodium intermediate, characterized in that the preparation method comprises the following steps:

[0010] Step A, preparing the disodium salt of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid;

[0011] Step B, reacting (2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate) with the disodium salt described in step A to prepare montelukast sodium crude salt, extracting and removing impurities from the crude salt, and then reacting with a weak acid to prepare montelukast free acid;

[0012] Step C, reacting the montelukast free acid described in step B with dicyclohexylamine to prepare montelukast dicyclohexylamine salt.

[0013] Preferably, the step A is specifically carried out as follows: dissolving 2-[1-(mercaptomethyl)cyclopropyl]acetic acid (compound I) in reagent a, cooling to low temperature, adding alkaline solution, and reacting under low temperature conditions for several hours to prepare the disodium salt of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid (compound II).

[0014]

[0015] Preferably, the reagent a is one or more of tetrahydrofuran, toluene, and a C3-C5 ketone solvent.

[0016] Preferably, the alkaline solution is sodium hydroxide ethanol solution or sodium methoxide solution.

[0017] Preferably, the low temperature is -40 to 0°C, and the reaction time is 0.5 to 10 hours.

[0018] Preferably, the step B is specifically carried out according to the following method: (2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate) (Compound III) is added to a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid, and the reaction is carried out at low temperature for several hours. After the reaction is completed, water and dichloromethane are added, stirred and extracted, most of the impurities are extracted with dichloromethane, the dichloromethane phase is removed, reagent b is added to the aqueous phase, and the montelukast free acid is obtained after treatment with tartaric acid, and nitrogen protection is used for standby.

[0019]

[0020] Step C: reacting the montelukast free acid described in step B with dicyclohexylamine, and subjecting the obtained product to crystallization, centrifugation and drying to obtain montelukast dicyclohexylamine salt, thereby preparing a high-purity montelukast sodium intermediate.

[0021] Preferably, the reagent b is ethyl acetate or dichloromethane, the low temperature is -40 to 0° C., and the reaction time is 1 to 20 hours.

[0022] Preferably, the step C is specifically carried out according to the following method: adding dicyclohexylamine to the montelukast free acid, adjusting the reaction temperature and time to react to obtain montelukast free acid dicyclohexylamine crude salt, then adding montelukast dicyclohexylamine salt seed crystals, crystallizing, centrifuging, and drying to obtain the montelukast dicyclohexylamine salt.

[0023] Preferably, the reaction temperature is 0-40° C., and the reaction time is 10 minutes to 6 hours.

[0024] The present invention also provides a method for preparing high-purity montelukast sodium, comprising selecting a high-purity montelukast sodium intermediate obtained by the above-mentioned preparation method, performing an acid reversion treatment, and reacting with sodium hydroxide to form a crude salt, and performing concentrated crystallization and centrifugal drying treatment on the crude salt, thereby preparing high-purity montelukast sodium.

[0025] Preferably, the acid regurgitation treatment is to dissolve the montelukast dicyclohexylamine salt with reagent c, acidify, wash with water, and separate the liquids to obtain an intermediate solution; the concentration and crystallization method is to add sodium hydroxide to the intermediate solution to form a sodium salt, and then add it to reagent d for crystallization after concentration.

[0026] Preferably, the reagent c is selected from one or more of toluene, ethyl acetate, and dichloromethane; the reagent d is selected from one or more of petroleum ether, n-hexane, and n-heptane.

[0027] The present invention achieves the following beneficial effects:

[0028] The invention replaces n-butyl lithium with sodium methoxide which has low activity and small risk factor, and adopts the method of slowly adding active substances into reactants, which can effectively control the temperature and reduce side reactions. At the same time, the method of directly using ethyl acetate to extract the product into an organic solvent after the disodium salt or disolithium salt and mesylate are reacted to form montelukast crude sodium salt in all the currently disclosed synthesis methods is abandoned. The characteristics of montelukast crude sodium salt that is soluble in water and will not be carried away by dichloromethane are utilized. After the reaction is completed, impurities are extracted with dichloromethane, and the product remains in the aqueous phase. The aqueous phase is then used to extract the product with ethyl acetate to directly obtain a montelukast free acid solution with a purity greater than or equal to 99%, which can effectively improve the purity and quality of the montelukast sodium product. The purity of the montelukast sodium free acid solution is more than 99%, and the yield is more than 85%. The purity of the montelukast dicyclohexylamine salt is more than 99.9%, and the yield is more than 90%. The purity of montelukast sodium is more than 99.9%, and the yield is more than 95%, which reduces the manufacturing cost, reduces the synthesis steps, removes high-risk operations in the synthesis process, and reduces environmental pollution. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The nuclear magnetic resonance spectrum of montelukast sodium synthesized in this application.

[0030] Figure 2 Infrared spectrum of montelukast sodium synthesized in this application.

[0031] Figure 3 High-resolution mass spectrum of the acid radical portion of montelukast sodium synthesized in the present application. DETAILED DESCRIPTION

[0032] The present invention is further described below by way of examples. It should be understood that the preparation methods of the examples of the present invention are merely for illustrative purposes and are not intended to limit the present invention, and that improvements to the preparation methods of the present invention within the scope of the present invention are all within the scope of the present invention.

[0033] Example 1

[0034] Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of tetrahydrofuran into a 500 ml three-necked flask, stir to dissolve and then cool to -10°C, add 30 g of sodium methoxide solution (containing 15.1 g, 0.28 mol of sodium methoxide), and keep the mixture at -10 to 0°C for 1 hour. Preferably, the temperature of the reaction is kept at -10 to -5°C to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for later use.

[0035] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (37.8g pure amount, 0.071mol) of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate was added, and the reaction was carried out at -10 to 0°C for 2 hours. 200ml of dichloromethane and 400ml of water were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, 40g of tartaric acid was added to the aqueous phase, stirred for 30 minutes, 500ml of ethyl acetate was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 446g of montelukast free acid with a purity of 99.02% (content 8%, yield 85.7%) for standby use.

[0036] Add 250g of the prepared montelukast sodium free acid solution to a 1000ml three-necked flask. Add 12g of dicyclohexylamine, react at 10-30°C for 1 hour, add 0.2g of montelukast dicyclohexylamine salt seed, keep at 10-30°C for 10 hours, filter, and dry at 60°C for 12 hours to obtain 24g of montelukast dicyclohexylamine salt with a purity of 99.926% and a yield of 91.7%.

[0037] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide / ethanol solution (prepared by adding 0.5g of sodium hydroxide to 15g of ethanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-heptane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.5g of montelukast sodium with a purity of 99.913% and a yield of 95%.

[0038] Example 2

[0039] Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of toluene into a 500 ml three-necked flask, stir to dissolve and then cool to -10°C, add 30 g of an ethanol solution of sodium hydroxide (containing 11.2 g, 0.28 mol of sodium hydroxide), and keep the mixture at -10 to 0°C for 1 hour. Preferably, the temperature of the reaction is kept at -10 to -5°C to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for later use.

[0040] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (37.8g of pure amount, 0.071mol) of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate was added, and the reaction was carried out at -10 to 0°C for 2 hours. 200ml of dichloromethane and 400ml of water were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, 40g of tartaric acid was added to the aqueous phase, stirred for 30 minutes, 500ml of dichloromethane was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 450g of montelukast free acid solution with a purity of 99.08% (content 7.9%, yield 85.4%) for standby use.

[0041] Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask. Add 12 g of dicyclohexylamine, react at 10-30° C. for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10-30° C. for 10 hours, filter, and dry at 60° C. for 12 hours to obtain 23.6 g of montelukast dicyclohexylamine salt with a purity of 99.93% and a yield of 91.3%.

[0042] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of ethyl acetate to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide / ethanol solution (prepared by adding 0.5g of sodium hydroxide to 15g of ethanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.56g of montelukast sodium with a purity of 99.912% and a yield of 96%.

[0043] Example 3

[0044] Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of acetone to a 500 ml three-necked flask, stir to dissolve and then cool to -10 ° C, add 30 g of sodium methoxide solution (containing 15.1 g of sodium methoxide, 0.28 mol), and keep the reaction at -10 to 0 ° C for 2 hours. Preferably, the insulation reaction temperature is selected from -10 to -5 ° C to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for standby use.

[0045] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (37.8g of pure amount, 0.071mol) of wet methanesulfonate of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol was added, and the reaction was carried out at -10 to 0°C for 3 hours, and dichloromethane 200ml and water 400ml were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, tartaric acid 40g was added to the aqueous phase, stirred for 30 minutes, ethyl acetate 500ml was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 430g of montelukast free acid solution with a purity of 99.053% (content 8.3%, yield 85.8%) for standby use.

[0046] Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask. Add 12.5 g of dicyclohexylamine, react at 10-30° C. for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10-30° C. for 10 hours, filter, and dry at 60° C. for 12 hours to obtain 24.5 g of montelukast dicyclohexylamine salt with a yield of 90.2%.

[0047] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of dichloromethane to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide / ethanol solution (prepared by adding 0.5g of sodium hydroxide to 15g of ethanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.6g of montelukast sodium with a purity of 99.91% and a yield of 96%.

[0048] Example 4

[0049] Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of butanone into a 500 ml three-necked flask, stir and dissolve, then cool to -10°C, add 30 g of sodium methoxide solution (containing 15.1 g, 0.28 mol of sodium methoxide), and keep the mixture at -10°C to 0°C for 2 hours. Preferably, the temperature of the reaction is kept at -10 to -5°C to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for standby use.

[0050] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (37.8g of pure amount, 0.071mol) of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate was added, and the reaction was carried out at -10°C to 0°C for 2 hours. 200ml of dichloromethane and 400ml of water were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, 40g of tartaric acid was added to the aqueous phase, stirred for 30 minutes, 500ml of ethyl acetate was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 436g of montelukast free acid solution with a purity of 99.01% (content 8.2%, yield 85.9%) for standby use.

[0051] Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask. Add 12.3 g of dicyclohexylamine, react at 10-30° C. for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10-30° C. for 10 hours, filter, and dry at 60° C. for 12 hours to obtain 24.2 g of montelukast dicyclohexylamine salt with a yield of 90%.

[0052] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide solution (prepared by adding 0.5g of sodium hydroxide to 15g of methanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-heptane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.55g of montelukast sodium with a purity of 99.909% and a yield of 95%.

[0053] Example 5

[0054] Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of cyclopentanone into a 500 ml three-necked flask, stir to dissolve and then cool to -20°C, add 30 g of sodium methoxide solution (containing 15.1 g of sodium methoxide, 0.28 mol), and keep the mixture at -20°C to -10°C for 4 hours to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for later use.

[0055] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (pure amount 37.8g, 0.071mol) of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol mesylate was added, and the reaction was carried out at -20°C to -10°C for 5 hours, and dichloromethane 200ml and water 400ml were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, tartaric acid 40g was added to the aqueous phase, stirred for 30 minutes, ethyl acetate 500ml was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 450g (content 8.1%, yield 87.6%) of montelukast free acid solution having a purity exceeding 99.09%, which was used for standby.

[0056] Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask. Add 12.2 g of dicyclohexylamine, react at 10°C to 30°C for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10°C to 30°C for 10 hours, filter, and dry at 60°C for 12 hours to obtain 24.6 g of montelukast dicyclohexylamine salt with a yield of 92.8%.

[0057] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide solution (prepared by adding 0.5g of sodium hydroxide to 15g of methanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.52g of montelukast sodium with a purity of 99.928% and a yield of 95%.

[0058] Example 6

[0059] To a 500ml three-necked flask, add 20g (0.137mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200ml of tetrahydrofuran, stir to dissolve and then cool to -30°C, add 30g of sodium methoxide solution (containing 15.1g of sodium methoxide, 0.28mol), and keep the mixture at -30°C to -20°C for 6 hours to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for later use.

[0060] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (37.8g of pure amount, 0.071mol) of wet methanesulfonate of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol was added, and the reaction was carried out at -30°C to -20°C for 8 hours, and 200ml of dichloromethane and 400ml of water were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, 40g of tartaric acid was added to the aqueous phase, stirred for 30 minutes, 500ml of ethyl acetate was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 450g of montelukast free acid solution with a purity of 99.17% (content 8.2%, yield 88.7%) for standby use.

[0061] Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask. Add 12.2 g of dicyclohexylamine, react at 10°C to 30°C for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10°C to 30°C for 10 hours, filter, and dry at 60°C for 12 hours to obtain 25.1 g of 99.975% montelukast dicyclohexylamine salt, with a yield of 93.5%.

[0062] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide solution (prepared by adding 0.5g of sodium hydroxide to 15g of methanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.54g of montelukast sodium with a purity of 99.949% and a yield of 95.2%.

[0063] Example 7

[0064] Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of toluene into a 500 ml three-necked flask, stir to dissolve and then cool to -40°C, add 30 g of sodium methoxide solution (containing 15.1 g of sodium methoxide, 0.28 mol), and keep the mixture at -40°C to -30°C for 8 hours to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for later use.

[0065] The above-prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid was added to a 2000ml three-necked flask, and then 54g (37.8g of pure amount, 0.071mol) of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol methanesulfonate was added, and the reaction was kept at -40°C to -30°C for 12 hours, and 200ml of dichloromethane and 400ml of water were added, stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for separation. The dichloromethane phase was discarded, 40g of tartaric acid was added to the aqueous phase, stirred for 30 minutes, 500ml of ethyl acetate was added, stirred for 30 minutes, and the mixture was allowed to stand for separation to obtain 456g of montelukast free acid solution with a purity of 99.17% (content 8.1%, yield 88.8%) for standby use.

[0066] Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask. Add 12.2 g of dicyclohexylamine, react at 10°C to 30°C for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10°C to 30°C for 10 hours, filter, and dry at 60°C for 12 hours to obtain 25.1 g of 99.977% montelukast dicyclohexylamine salt, with a yield of 94.7%.

[0067] Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand for separation. Add sodium hydroxide solution (prepared by adding 0.5g of sodium hydroxide to 15g of methanol), react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.52g of montelukast sodium with a purity of 99.94% and a yield of 95%.

[0068] The characterization results of montelukast sodium synthesized by the method described in Examples 1-7 are shown in the attached Figure 1-3 See also Figure 1-2 The characteristic peaks in the nuclear magnetic resonance spectrum and infrared spectrum of the montelukast sodium sample can be matched one by one with the characteristic peaks of the standard spectrum; see Figure 3 , in the high-resolution mass spectrometry data of the acid radical portion of the montelukast sodium sample [M+H]+ The measured value (m / z) is 586.2165, which is consistent with [M+H] + The theoretical value (m / z) of 586.2177 is very close. The molecular composition of the molecular ion peak of the acid radical part of this sample is C 35 H 37 NO3SCl, molecular formula is C 35 H 36 NO3SCl. From the above characterization, it can be seen that high-purity montelukast sodium can be synthesized by the method described in the present application.

[0069] Although the embodiments of the present invention are described above, the present invention is not limited to the above-mentioned specific implementation modes, which are merely illustrative and not restrictive. Under the guidance of the present invention, those skilled in the art may make various derivative forms without departing from the purpose of the present invention and the scope of protection claimed in the claims, and all of these concepts fall within the scope of protection of the present invention.

Claims

1. A method for preparing montelukast sodium, characterized in that: The preparation method comprises the following steps: Add 20 g of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of tetrahydrofuran to a 500 ml three-necked flask, stir to dissolve, then cool to -30°C, add 30 g of sodium methoxide solution, the sodium methoxide solution containing 15.1 g of sodium methoxide, and react at -30°C to -20°C for 6 hours to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid, which is set aside; Add the prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid into a 2000ml three-necked flask, then add 54g of wet methanesulfonate of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol and 37.8g of the wet methanesulfonate, and react at -30°C to -20°C for 8 hours, add 200ml of dichloromethane and 400ml of water, stir for 30 minutes, stand for 30 minutes for separation, discard the dichloromethane phase, add 40g of tartaric acid to the aqueous phase, stir for 30 minutes, add 500ml of ethyl acetate, stir for 30 minutes, stand for separation, and obtain 450g of montelukast free acid solution with a purity of 99.17%, the montelukast free acid content is 8.2%, and the yield is 88.7%, which is reserved for use; Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask, add 12.2 g of dicyclohexylamine, react at 10°C to 30°C for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10°C to 30°C for crystallization for 10 hours, filter, and dry at 60°C for 12 hours to obtain 25.1 g of 99.975% montelukast dicyclohexylamine salt, with a yield of 93.5%; Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, then add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand to separate the liquids; add sodium hydroxide solution, the sodium hydroxide solution is prepared by adding 0.5g of sodium hydroxide and 15g of methanol, react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of the solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.54g of montelukast sodium with a purity of 99.949% and a yield of 95.2%.

2. A method for preparing montelukast sodium, characterized in that: The preparation method comprises the following steps: Add 20 g (0.137 mol) of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid and 200 ml of toluene into a 500 ml three-necked flask, stir to dissolve and then cool to -40°C, add 30 g of sodium methoxide solution, the sodium methoxide solution contains 15.1 g of sodium methoxide, and react at -40°C to -30°C for 8 hours to obtain a disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid for standby use; Add the prepared disodium salt solution of 2-[1-(mercaptomethyl)cyclopropyl]acetic acid into a 2000ml three-necked flask, then add 54g of wet methanesulfonate of 2-(2-(3S)-(3-(2-(7-chloro-2-quinolyl)-vinyl-phenyl)-3-hydroxypropyl)phenyl)-2-propanol and 37.8g of the wet methanesulfonate, and react at -40°C to -30°C for 12 hours, add 200ml of dichloromethane and 400ml of water, stir for 30 minutes, stand for 30 minutes for separation, discard the dichloromethane phase, add 40g of tartaric acid to the aqueous phase, stir for 30 minutes, add 500ml of ethyl acetate, stir for 30 minutes, stand for separation, and obtain 456g of montelukast free acid solution with a purity of 99.17%, a montelukast free acid content of 8.1%, and a yield of 88.8%, which is ready for use; Add 250 g of the prepared montelukast sodium free acid solution to a 1000 ml three-necked flask, add 12.2 g of dicyclohexylamine, react at 10°C to 30°C for 2 hours, add 0.2 g of montelukast dicyclohexylamine salt seed, keep at 10°C to 30°C for crystallization for 10 hours, filter, and dry at 60°C for 12 hours to obtain 25.1 g of 99.977% montelukast dicyclohexylamine salt, with a yield of 94.7%; Add 10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene to a 250ml three-necked flask, stir to dissolve, then add 100ml of water and 1g of glacial acetic acid, stir for 30 minutes, and stand to separate the liquids; add sodium hydroxide solution, the sodium hydroxide solution is prepared by adding 0.5g of sodium hydroxide and 15g of methanol, react at room temperature for 30 minutes, add 1g of activated carbon, decolorize at room temperature for 30 minutes, filter, distill out 20g of the solvent from the filtrate at 50°C, add it to 100ml of n-hexane for crystallization for 2 hours, filter, and dry at 60°C for 24 hours to obtain 7.52g of montelukast sodium with a purity of 99.94% and a yield of 95%.

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