CN111170939A - Preparation method of high-purity montelukast sodium and intermediate thereof - Google Patents
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Abstract
The invention provides a high-purity montelukast sodium intermediate and a preparation method of montelukast sodium, wherein the preparation method of the montelukast sodium comprises the following steps: the preparation method comprises the steps of preparing the disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid, preparing montelukast free acid, preparing the dicyclohexylamine salt of montelukast, and preparing montelukast sodium. The preparation method can effectively improve the purity and quality of the montelukast sodium product, reduce the manufacturing cost, reduce the synthesis steps, remove high-risk operation in the synthesis process and reduce the environmental pollution.
Description
Technical Field
The invention belongs to the field of organic chemistry and pharmaceutical chemistry, and particularly relates to a preparation method of high-purity montelukast sodium and an intermediate thereof.
Background
Montelukast sodium is a prescription drug developed and produced by the american company moendong (also called merck corporation) for treating asthma, and can be used for treating respiratory diseases such as asthma, allergic rhinitis and the like. Pathologically, montelukast sodium is an oral leukotriene receptor antagonist, and can specifically inhibit cysteinyl leukotriene (CysLT1) receptors in airways, so that airway inflammation is improved, and asthma symptoms are effectively controlled.
The chemical structural formula of montelukast sodium is as follows:
the prior art methods for synthesizing montelukast sodium have several approaches: one is the preparation of montelukast sodium salt from the free acid by hydrochlorination of dicyclohexylamine to prepare montelukast to obtain the montelukast free acid. For example, montelukast sodium is synthesized by reacting dilithium dianion of 1- (mercaptomethyl) cyclopropylacetic acid with methanesulfonate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolinyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol, treating the reaction solution, reacting with dicyclohexylamine to obtain dicyclohexylamine salt, and purifying. One is by conversion of the montelukast free acid to the montelukast organic group protecting salt, which is then converted to the montelukast sodium salt. For example, Zhejiang Takeda pharmaceuticals, Inc. (publication No. CN103570618A) has adopted the conversion of montelukast free acid to montelukast dicyclohexylamine salt; converting the montelukast dicyclohexylamine salt to the montelukast di-n-propylamine salt; a synthetic process for converting montelukast di-n-propylamine salt to montelukast sodium salt. And Shandong New times pharmaceutical Co., Ltd (publication Nos. CN105585524A, CN105924392A) used to synthesize a montelukast acid p-aminoacetanilide salt by using montelukast free acid or a montelukast acid 2-amino-1-butanolate salt, acidify the salt protected by the transition group, and add a base to prepare montelukast sodium.
However, the first synthesis method has disadvantages in controlling several impurities of montelukast sodium, in which sulfoxide impurities (usp impurities a), disulfide impurities (usp impurities c and d), and styrene impurities (usp impurity f) are not well removed, and n-butyllithium having a very high activity and a very high risk is used in the synthesis process. The product quality and the production safety can not meet the current requirements. The second synthesis method for converting the montelukast free acid into the montelukast organic group protective salt has the problems that the organic protective group is not easy to select, a large amount of byproducts are introduced, the purity of the prepared montelukast sodium is low, and the production cost is overhigh. Therefore, a synthesis method of montelukast sodium with high purity, good safety and less pollution needs to be solved urgently.
Disclosure of Invention
In order to improve the quality of montelukast sodium products, improve the industry and degree and reduce the cost; the synthesis steps are reduced, high-risk operation in the synthesis process is removed, the safety risk is reduced, and the environmental pollution is reduced; the invention provides a preparation method of high-purity montelukast sodium and an intermediate thereof. The specific scheme is as follows:
a preparation method of a montelukast sodium intermediate, which is characterized by comprising the following steps:
step A, preparing disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid;
step B, reacting (2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol mesylate) with the disodium salt in the step A to prepare a crude montelukast sodium salt, and reacting the crude salt with a weak acid after extraction and impurity removal to prepare montelukast free acid;
and C, reacting the montelukast free acid in the step B with dicyclohexylamine to prepare the montelukast dicyclohexylamine salt.
Preferably, the step a is specifically performed according to the following method: dissolving 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid (compound I) in a reagent a, cooling to low temperature, adding an alkaline solution, and reacting for several hours at low temperature to obtain the disodium salt (compound II) of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid.
Preferably, the reagent a is one or more of tetrahydrofuran, toluene, and ketone solvent of C3-C5.
Preferably, the alkaline solution is an ethanol solution of sodium hydroxide or a solution of sodium methoxide.
Preferably, the low temperature is-40 to 0 ℃, and the reaction time is 0.5 to 10 hours.
Preferably, the step B is specifically performed according to the following method: the mesylate of (2- (2- (3S) - (3- (2- (7-chloro-2-quinolinyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol) (compound iii) was added to a solution of the disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid, reacted at low temperature for several hours, after the reaction was completed, water and dichloromethane were added, stirred and extracted, after which reagent b was added to the aqueous phase and treated with tartaric acid to give the montelukast free acid, protected with nitrogen for further use.
And C: and C, reacting the montelukast free acid obtained in the step B with dicyclohexylamine, and crystallizing, centrifuging and drying the obtained product to obtain the montelukast dicyclohexylamine salt so as to prepare the high-purity montelukast sodium intermediate.
Preferably, the reagent b is ethyl acetate or dichloromethane, the low temperature is-40 to 0 ℃, and the reaction time is 1 to 20 hours.
Preferably, the step C is specifically performed according to the following method: adding dicyclohexylamine into the montelukast free acid, adjusting the reaction temperature and time to react to obtain crude dicyclohexylamine salt of the montelukast free acid, then adding a montelukast dicyclohexylamine salt seed crystal, crystallizing, centrifuging, and drying to obtain the montelukast dicyclohexylamine salt.
Preferably, the reaction temperature is 0 to 40 ℃, and the time is 10 minutes to 6 hours.
The invention also provides a preparation method of the high-purity montelukast sodium, wherein the high-purity montelukast sodium intermediate obtained by the preparation method is selected to be subjected to reverse acid treatment and reacts with sodium hydroxide to form crude salt, and the crude salt is subjected to concentration crystallization and centrifugal drying treatment, so that the high-purity montelukast sodium is prepared.
Preferably, the inverse acid treatment is to dissolve the montelukast dicyclohexylamine salt by using a reagent c, acidify, wash and separate the solution to obtain an intermediate solution; the concentration crystallization method is to add sodium hydroxide into the intermediate solution to form sodium salt, and add the sodium salt into a reagent d for crystallization after concentration.
Preferably, the reagent c is one or more of toluene, ethyl acetate and dichloromethane; the reagent d is one or more of petroleum ether, n-hexane and n-heptane.
The invention obtains the following beneficial effects:
the preparation method can effectively improve the purity and quality of the montelukast sodium product, the yield of the montelukast dicyclohexylamine salt is more than 94%, the yield of the montelukast sodium is more than 95%, the manufacturing cost is reduced, meanwhile, the synthesis steps are reduced, high-risk operation in the synthesis process is eliminated, and the environmental pollution is reduced.
Drawings
Figure 1 nuclear magnetic resonance spectrum of montelukast sodium synthesized in the present application.
Figure 2 infrared spectrum of montelukast sodium synthesized herein.
Figure 3 high resolution mass spectrum of the acid moiety of montelukast sodium synthesized in the present application.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the preparation methods of the examples are illustrative only and not limiting, and that modifications to the preparation methods of the invention that are within the spirit of the invention are within the scope of the claimed invention.
Example 1
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of tetrahydrofuran into a 500ml three-necked bottle, stirring to dissolve, cooling to-10 ℃, adding 30g of sodium methoxide solution, keeping the temperature at-10-0 ℃ for reaction for 3 hours to obtain a disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
Adding the prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid into a 2000ml three-necked bottle, adding 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol, reacting at 10-0 ℃ for 10 hours, adding 200ml of dichloromethane and 400ml of water, stirring for 30 minutes, standing for 30 minutes for liquid separation, adding 40g of tartaric acid into an aqueous phase, stirring for 30 minutes, adding 500ml of ethyl acetate, stirring for 30 minutes, and standing for liquid separation to obtain montelukast free acid with the purity of more than 99% for later use.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 10-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 10-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding a sodium hydroxide/ethanol solution (prepared by adding 15g of ethanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from the filtrate at 50 ℃, adding into 100ml of n-heptane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with single impurity less than 0.03%, purity more than 99.9%, and yield of 95%.
Example 2
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of toluene into a 500ml three-necked bottle, stirring for dissolving, cooling to-20 ℃, adding 30g of ethanol solution of sodium hydroxide, and reacting at the temperature of-10-0 ℃ for 5 hours to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
Adding the prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid into a 2000ml three-necked bottle, adding 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol, reacting at 10-0 ℃ for 10 hours, adding 200ml of dichloromethane and 400ml of water, stirring for 30 minutes, standing for 30 minutes for liquid separation, adding 40g of tartaric acid into an aqueous phase, stirring for 30 minutes, adding 500ml of dichloromethane, stirring for 30 minutes, and standing for liquid separation to obtain montelukast free acid with the purity of more than 99% for later use.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 10-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 10-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of ethyl acetate are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding a sodium hydroxide/ethanol solution (prepared by adding 15g of ethanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from the filtrate at 50 ℃, adding into 100ml of n-hexane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with the single impurity of less than 0.03 percent and the purity of more than 99.9 percent, wherein the yield is 95 percent.
Example 3
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of acetone into a 500ml three-necked bottle, stirring to dissolve, cooling to-30 ℃, adding 30g of sodium methoxide solution, keeping the temperature at-30 to-10 ℃ for 10 hours, and reacting to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
The prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid is added into a 2000ml three-necked bottle, 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol is added, the mixture is incubated at 30 to-10 ℃ for 20 hours, 200ml of dichloromethane and 400ml of water are added, the mixture is stirred for 30 minutes, the mixture is kept still for 30 minutes for liquid separation, 40g of tartaric acid is added into the water phase, the mixture is stirred for 30 minutes, 500ml of ethyl acetate is added, the mixture is stirred for 30 minutes and kept still for liquid separation, and montelukast free acid with the purity of more than 99 percent is obtained for standby.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 10-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 10-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of dichloromethane are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand for liquid separation. Adding a sodium hydroxide/ethanol solution (prepared by adding 15g of ethanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from the filtrate at 50 ℃, adding into 100ml of n-hexane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with the single impurity of less than 0.03 percent and the purity of more than 99.9 percent, wherein the yield is 95 percent.
Example 4
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of butanone into a 500ml three-necked bottle, stirring to dissolve, cooling to-40 ℃, adding 30g of sodium methoxide solution, keeping the temperature at-40 ℃ and reacting for 3 hours to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
The prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid is added into a 2000ml three-necked flask, 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol is added, the mixture is kept at 40 ℃ for 20 hours, 200ml of dichloromethane and 400ml of water are added, the mixture is stirred for 30 minutes, the mixture is kept still for 30 minutes for liquid separation, 40g of tartaric acid is added into the water phase, the mixture is stirred for 30 minutes, 500ml of ethyl acetate is added, the mixture is stirred for 30 minutes, and the liquid separation is kept still to obtain montelukast free acid with the purity of more than 99 percent for standby.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 0-30 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 0-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding sodium methoxide solution (prepared by adding 15g of methanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from filtrate at 50 ℃, adding into 100ml of n-heptane, crystallizing for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain the montelukast sodium with the single impurity of less than 0.03 percent, the purity of more than 99.9 percent, 7.5g and the yield of 95 percent.
Example 5
Adding 20g (0.137mol) of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and 200ml of cyclopentanone into a 500ml three-necked bottle, stirring to dissolve, cooling to 0 ℃, adding 30g of sodium methoxide solution, and keeping the temperature at 0 ℃ for reaction for 3 hours to obtain the disodium salt solution of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid for later use.
The prepared disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid was added to a 2000ml three-necked flask, 54g (0.1mol) of mesylate of 2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol was added thereto, the mixture was reacted at 0 ℃ for 2 hours, 200ml of dichloromethane and 400ml of water were added thereto, the mixture was stirred for 30 minutes, and the mixture was allowed to stand for 30 minutes for liquid separation, 40g of tartaric acid was added to the aqueous phase, and then stirred for 30 minutes, 500ml of ethyl acetate was added thereto, stirred for 30 minutes, and then allowed to stand for liquid separation to obtain montelukast free acid having a purity of more than 99% for use.
The montelukast sodium free acid prepared above was added to a 1000ml three-necked flask. Adding 11g of dicyclohexylamine, reacting for 2 hours at 0 ℃, adding 0.2g of montelukast dicyclohexylamine salt seed crystal, carrying out heat preservation and crystallization for 10 hours at 0-30 ℃, filtering, and drying for 12 hours at 60 ℃ to obtain 21g of montelukast dicyclohexylamine salt with single impurity less than 0.03%, wherein the yield is 94%.
10g of the prepared montelukast dicyclohexylamine salt and 60ml of toluene are added into a 250ml three-necked flask, and after the mixture is stirred and dissolved, 100ml of water and 2g of glacial acetic acid are added, the mixture is stirred for 30 minutes, and the mixture is kept stand and separated. Adding sodium methoxide solution (prepared by adding 15g of methanol into 0.5g of sodium hydroxide), reacting at room temperature for 30 minutes, adding 1g of activated carbon, decoloring at room temperature for 30 minutes, filtering, distilling 20g of solvent from filtrate at 50 ℃, adding into 100ml of n-hexane for crystallization for 2 hours, filtering, and drying at 60 ℃ for 24 hours to obtain 7.5g of montelukast sodium with single impurity less than 0.03%, purity more than 99.9% and yield of 95%.
The characterization results of montelukast sodium synthesized by the methods described in examples 1-5 are shown in fig. 1-3. Referring to fig. 1-2, characteristic peaks in the nmr spectrum and the ir spectrum of the montelukast sodium sample may correspond to characteristic peaks in the standard spectrum in a one-to-one correspondence; referring to fig. 3, [ M + H ] in the high resolution mass spectrometry data of the acid moiety of the montelukast sodium sample]+Measured value (M/z) of 586.2165, and [ M + H]+Has a molecular ion peak molecular composition of C in the acid radical part of the sample, and has a theoretical value (m/z)586.2177 very close to each other35H37NO3SCl, molecular formula C35H36NO3SCl. From the above characterization, it can be seen that montelukast sodium can be synthesized in high purity by the methods described herein.
Although the present invention has been described with reference to the above embodiments, the present invention is not limited to the above embodiments, which are only illustrative and not restrictive, and those skilled in the art can make various modifications without departing from the spirit and scope of the present invention as claimed in the claims.
Claims (10)
1. A preparation method of a montelukast sodium intermediate, which is characterized by comprising the following steps:
step A, preparing disodium salt of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid;
step B, reacting (2- (2- (3S) - (3- (2- (7-chloro-2-quinolyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol mesylate) with the disodium salt in the step A to prepare a crude montelukast sodium salt, and reacting the crude salt with a weak acid after extraction and impurity removal to prepare montelukast free acid;
and C, reacting the montelukast free acid in the step B with dicyclohexylamine to prepare the montelukast dicyclohexylamine salt.
2. The process for preparing a montelukast sodium intermediate as claimed in claim 1, wherein: the step A comprises the following steps: dissolving 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid in a reagent a, cooling to low temperature, adding an alkaline solution, and reacting for several hours at low temperature to prepare the disodium salt of the 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid.
3. The process for preparing montelukast sodium intermediate according to claim 2, characterized in that: the reagent a is one or more of tetrahydrofuran, toluene and C3-C5 ketone solvent, the alkaline solution is sodium hydroxide ethanol solution or sodium methoxide solution, the low temperature is-40-0 ℃, and the reaction time is 0.5-10 hours.
4. The process for preparing a montelukast sodium intermediate as claimed in claim 1, wherein: the step B comprises the following steps: the mesylate of (2- (2- (3S) - (3- (2- (7-chloro-2-quinolinyl) -vinyl-phenyl) -3-hydroxypropyl) phenyl) -2-propanol) was added to the disodium salt solution of 2- [1- (mercaptomethyl) cyclopropyl ] acetic acid and reacted at low temperature for several hours, after the reaction was completed, water and dichloromethane were added, stirred and extracted, after which reagent b was added to the aqueous phase and treated with tartaric acid to give the montelukast free acid, which was kept under nitrogen.
5. The process for preparing montelukast sodium intermediate according to claim 4, characterized in that: the reagent b is ethyl acetate or dichloromethane, the low temperature is-40-0 ℃, and the reaction time is 1-20 hours.
6. The process for preparing a montelukast sodium intermediate as claimed in claim 1, wherein: the step C comprises the following steps: adding dicyclohexylamine into the montelukast free acid, adjusting the reaction temperature and time to react to obtain crude dicyclohexylamine salt of the montelukast free acid, then adding a montelukast dicyclohexylamine salt seed crystal, crystallizing, centrifuging, and drying to obtain the montelukast dicyclohexylamine salt.
7. The process for preparing montelukast sodium intermediate according to claim 6, characterized in that: the reaction temperature is 0-40 ℃, and the time is 10 minutes to 6 hours.
8. A preparation method of montelukast sodium is characterized by comprising the following steps: the high-purity montelukast sodium intermediate obtained by the preparation method of any one of claims 1 to 7 is selected, subjected to reverse acid treatment and reacted with sodium hydroxide to form a crude salt, and the crude salt is subjected to concentration crystallization and centrifugal drying treatment, so that the high-purity montelukast sodium is prepared.
9. The method for preparing montelukast sodium according to claim 8, comprising the steps of: the inverse acid treatment is to dissolve the montelukast dicyclohexylamine salt by using a reagent c, acidify, wash and separate the solution to obtain an intermediate solution; and/or the concentration crystallization method is to add sodium hydroxide into the intermediate solution to form sodium salt, and add the sodium salt into the reagent d for crystallization after concentration.
10. The method for preparing montelukast sodium according to claim 9, comprising: the reagent c is one or more of toluene, ethyl acetate and dichloromethane; the reagent d is one or more of petroleum ether, n-hexane and n-heptane.
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| CN112028824A (en) * | 2020-09-30 | 2020-12-04 | 山东安信制药有限公司 | Preparation method of montelukast sodium |
| CN112409252A (en) * | 2019-12-20 | 2021-02-26 | 牡丹江恒远药业股份有限公司 | Preparation method of high-purity montelukast sodium and intermediate thereof |
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| CN112028824A (en) * | 2020-09-30 | 2020-12-04 | 山东安信制药有限公司 | Preparation method of montelukast sodium |
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