JP2015007000A - Method for producing montelukast free acid crystals - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing high-purity 1-(((1(R)-(3-(2(E)-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid (montelukast free acid) efficiently in high yield.SOLUTION: The method for producing high-purity montelukast free acid, in which acid salt of organic amine salt does not remain, efficiently in high yield comprises a step of continuously performing such a reaction that montelukast organic amine salt is led to the montelukast free acid by using an acid in a mixture of a water-soluble organic solvent with water and continuously crystallizing the montelukast free acid from the obtained reaction solution.

Description

  The present invention relates to montelukast sodium (chemical name: 1-(((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3) useful as an antiallergic agent. -(2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid sodium) 1-((((1 (R)-(3- (2- ( It relates to a novel process for the preparation of 7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid.

  Following formula (1)

Montelukast sodium (chemical name: 1-(((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1- Hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetate sodium) binds as an antagonist to CysLT1 receptor on target cells such as bronchial smooth muscle and cysteinyl leukotriene binds to the receptor It is known as a therapeutic agent that prevents this and improves the symptoms of bronchial asthma.

  It is desired that montelukast sodium useful as such a therapeutic agent has very high purity. As a method for producing high-purity montelukast sodium, the following formula (2) obtained by a known production method:

1-((((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) A crude product of) phenyl) propyl) thio) methyl) cyclopropaneacetic acid (hereinafter also referred to as montelukast free acid) is reacted with various organic amines to produce the following formula (3):

(In the formula, B represents an organic amine.)
1-((((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) ) Phenyl) propyl) thio) methyl) cyclopropaneacetic acid organic amine salt (hereinafter also referred to as montelukast organic amine salt), purified by recrystallization, etc. A method for obtaining montelukast sodium by chlorination is known. Among these, as a method for converting a montelukast organic amine salt into a montelukast free acid, a method of obtaining a montelukast free acid by acting an acid such as acetic acid is common.

  For example, Patent Document 1 discloses the following formula (4) obtained by using dicyclohexylamine as the organic amine.

The dicyclohexylamine salt represented by is reacted with acetic acid in toluene and water to convert it to the free acid, followed by post-treatment to obtain a toluene solution of montelukast free acid. How to do is shown. Patent Document 2 discloses a method for crystallizing montelukast free acid crystals by crystallization from a toluene solution of montelukast free acid obtained by the same method as in Patent Document 1. Furthermore, Patent Document 3 discloses that the dicyclohexylamine salt is reacted with acetic acid in methylene chloride and water, and the solvent is distilled off from the methylene chloride solution of montelukast free acid obtained by performing separation and extraction operations in post-treatment. However, a method for obtaining montelukast free acid as a residue is shown.

  In addition, as an example in which the above-described post-treatment is not performed, Patent Document 4 discloses a chemical formula (5) obtained using homoveratrylamine as the organic amine.

Is reacted with acetic acid in toluene, and the solid precipitated from the reaction solution is collected by filtration to obtain montelukast free acid crystals. Patent Document 5 discloses the above organic Chemical formula (6) obtained using ammonia as amine

A method of reacting the ammonium salt represented by formula (2) with acetic acid in water and collecting a solid precipitated from the reaction solution by filtration to obtain crystals of montelukast free acid is shown.

Japanese Patent No. 3640962 International Publication No. 2004/108679 International Publication No. 2003/065598 International Publication No. 2010/064257 International Publication No. 2009/027990 Special table 2007-532686 gazette Special table 2008-510840 gazette

  However, when the present inventor examined the above method, in the method of performing separation and extraction operations as a post-treatment, the montelukast free acid crystallizes in the organic layer during the operation, and the operation becomes extremely difficult, resulting in a recovery rate. It has been found that this is industrially implemented because the operation of complicated post-processing becomes more complicated. Furthermore, in the method of directly crystallizing from the reaction solution obtained by performing the reaction in a toluene solvent, the salt of the resulting montelukast free acid is obtained because the organic amine acid salt produced as a by-product is hardly soluble in the organic solvent. It was found that the organic amine acid salt remained therein and further purification was required to remove the organic amine acid salt. Further, in the method of directly crystallizing from the reaction solution obtained by carrying out the reaction in an aqueous solvent, since the montelukast organic amine salt is hardly soluble in water, the reaction does not proceed completely, and the obtained montelukast is obtained. It was found that the starting material montelukast organic amine salt remained in the free acid crystals, and further purification was required to remove the organic amine salt.

  Accordingly, an object of the present invention is to provide a method for efficiently producing high purity montelukast free acid crystals in high yield.

  In order to solve the above problems, the present inventor has conducted earnest research. Specifically, after reacting montelukast organic amine salt to montelukast free acid, it is a raw material in a method of crystallizing montelukast free acid directly from the reaction liquid without post-treatment such as separation or extraction. We investigated methods that do not leave impurities such as montelukast organic amine salt and by-product organic amine acid salt. As a result, the reaction between the montelukast organic amine salt and the acid is carried out in a mixture of a water-soluble organic solvent and water, so that the reaction proceeds at a high conversion rate. It is possible to crystallize montelukast free acid directly without almost crystallizing the acid salt of amine, and the content of montelukast organic amine salt which is a raw material which is an impurity and organic acid acid salt of by-product is low and high. It has been found that crystals of pure montelukast free acid can be obtained in good yield, and the present invention has been completed.

  That is, the present invention is a reaction step of reacting a montelukast organic amine salt and an acid to obtain a reaction solution containing montelukast free acid and an acid salt of organic amine, and montelukast free acid is crystallized from the reaction solution obtained in the reaction step. In the method for producing a montelukast free acid crystal including a crystallization step, a water-soluble organic solvent and water are used as a solvent in the reaction step and the crystallization step.

  In the present invention, the water-soluble organic solvent is one selected from the group consisting of methanol, ethanol, and isopropanol, and the volume ratio of the water-soluble organic solvent and water in the solvent at 25 ° C. is water-soluble organic. It is preferable that it is 1 mL or more and 10000 mL or less of water with respect to 100 mL of solvent. Furthermore, it is preferable that the temperature for performing the reaction step is 20 to 50 ° C., and the temperature for performing the crystallization step is −5 to 10 ° C. Montelukast sodium can be obtained by sodium salifying the montelukast free acid thus obtained.

  According to the present invention, in a mixture of a water-soluble organic solvent and water, an acid is used to convert the montelukast organic amine salt to the montelukast free acid, and the montelukast free acid is crystallized from the obtained reaction liquid. By carrying out continuously, it is possible to efficiently obtain a high-purity montelukast free acid crystal in which an organic amine acid salt does not remain in a high yield.

  The present invention relates to a reaction step comprising reacting a montelukast organic amine salt with an acid using a water-soluble organic solvent and water as a solvent to contain the montelukast free acid and an acid salt of the organic amine, and from the reaction solution obtained in the reaction step, montelukast It is a manufacturing method of the crystal | crystallization of a montelukast free acid including the crystallization process which crystallizes a free acid. Details of each step will be described below.

((Reaction process))
The reaction step of the present invention is a step of obtaining a reaction liquid containing montelukast free acid and an organic amine salt by mixing a montelukast organic amine salt, an acid, and a water-soluble organic solvent as a solvent and water.

(Montelukast organic amine salt)
The montelukast organic amine salt used in the present invention is an organic amine salt of montelukast free acid. In the present invention, the organic amine is a compound in which one or more hydrogen atoms of ammonia are substituted with a hydrocarbon group, a primary amine substituted with one hydrocarbon group, or a second amine substituted with two hydrocarbon groups. Including a tertiary amine and a tertiary amine substituted with three, the hydrocarbon group may have a substituent. The organic amine is not particularly limited as long as montelukast free acid can be obtained by an acid when an organic amine salt of montelukast is obtained. Specifically, the organic amine is propylamine, isopropylamine, n -Butylamine, isobutylamine, sec-butylamine, t-butylamine, t-octylamine, 2-phenylethylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, cyclododecylamine, 4-aminocyclohexanol, amantadine, etc. A primary amine substituted with 3 to 12 hydrocarbons of the following: Montelukast organic amine which is a secondary amine substituted with 3 to 7 hydrocarbons such as dipropylamine, dicyclohexylamine, dibenzylamine, etc. salt It is mentioned as known compounds. Among these, in the present invention, considering the purification efficiency of the montelukast organic amine salt and the reactivity and solubility in the reaction of the present invention, propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, t-butylamine A montelukast organic amine salt of a primary amine or a secondary amine substituted with a hydrocarbon having 3 to 6 carbon atoms such as dipropylamine or dicyclohexylamine is used as a suitable compound.

  The method for producing the montelukast organic amine salt is not particularly limited, but in general, it can be produced by reacting a crude montelukast free acid with an organic amine. And the rough body of the said montelukast free acid is the method of patent document 1, ie, chemical formula (7), for example.

1-(((1 (S)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) ) Phenyl) -1-propanol is reacted with methanesulfonic acid chloride, followed by chemical formula (8)

A method for obtaining a crude product of montelukast free acid by acting 1- (mercaptomethyl) cyclopropaneacetic acid represented by the formula, or a method described in Patent Document 6, that is, chemical formula (9)

1-(((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) Propyl) thio) methyl) cyclopropaneacetic acid methyl ester can be produced by hydrolysis of montelukast free acid crude product.

  The reaction of the crude montelukast free acid thus obtained and the organic amine is not particularly limited, but in general, the montelukast free acid crude is dissolved in an organic solvent, and the organic amine is dissolved. This is done by adding. For example, Patent Document 1 describes a method for obtaining the montelukast dicyclohexylamine salt by dissolving a crude montelukast free acid in ethyl acetate and adding dicyclohexylamine. Patent Document 7 discloses chemical formula (10).

1-((((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) ) Phenyl) propyl) thio) methyl) cyclopropaneacetic acid dipropylamine salt (hereinafter also referred to as montelukast dipropylamine salt) is prepared by dissolving the crude montelukast free acid in toluene and adding dipropylamine. The method of obtaining by doing is described.

  In the present invention, the form of the montelukast organic amine salt is not particularly limited, and may be a crystal, amorphous, or a mixed form thereof, a powder, a lump, or a mixed form thereof, An anhydride, hydrate, solvate, or a mixed form thereof may be used, and the number of water or solvent molecules in the hydrate or solvate is not particularly limited. In addition, since a water-soluble organic solvent and water are used as a solvent in the reaction step, a wet body containing a water-soluble organic solvent and / or water may be used, and the reaction step and the crystallization step are not affected. Specifically, other solvent may remain in an amount of 50% by weight or less of the montelukast organic amine salt, but most preferably no other solvent is contained. In addition, the purity of the montelukast organic amine salt is not limited, and the one obtained by the above method can be used as it is, but in order to increase the purity of the final montelukast sodium, What was refine | purified once or more as needed by methods, such as recrystallization and reslurry, may be utilized as the said montelukast organic amine salt.

(acid)
The acid used in the present invention is not particularly limited as long as the acid has a pKa of 6.4 or less, and an acid having a pKa of 2.0 or more and 6.4 or less is preferably used. Because the pKa of montelukast sodium is 6.5, it is not possible to obtain montelukast free acid when using an acid with a pKa greater than 6.4. In addition, the use of an acid having a pKa of less than 2.0 is not preferable because a compound reacted with the quinolinyl group of the montelukast organic amine salt may be purified as an impurity. Preferably, organic acids such as acetic acid (pKa 4.8), citric acid (pKa 3.1, 4.7, 5.4), and tartaric acid (pKa 3.2, 4.8) can be used. In the present invention, the amount of the acid used is not particularly limited and may be adjusted depending on the type of acid used. However, in consideration of operability and yield, the acid is used with respect to 1 mol of the montelukast organic amine salt. May be from 1 mol to 10 mol, preferably from 1 mol to 5 mol, and preferably from 1 mol to 2 mol.

(solvent)
In the reaction step of the present invention, a mixture of a water-soluble organic solvent and water is used as a solvent. By using a mixture of a water-soluble organic solvent and water as the solvent for the reaction step, the reaction proceeds at a high conversion rate, and the following crystallization step can be continuously performed.

  The water-soluble organic solvent is an organic solvent that is freely miscible with water, and is not particularly limited as long as it does not affect the reaction and crystallization of the present invention. Examples of the solvent include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropanol, and t-butyl alcohol, tetrahydrofuran, acetone, and z-cetonitrile, and methanol, ethanol, and isopropanol are particularly preferable. These solvents may be used alone or in combination as appropriate. Further, the ratio of the water-soluble organic solvent and water in the solvent is not particularly limited, but considering the operability and the recovery rate, the volume ratio of the water-soluble organic solvent and water at 25 ° C. is It may be 1 mL or more and 10000 mL or less of water with respect to 100 mL of the basic organic solvent, preferably 10 mL or more and 1000 mL or less of water, and more preferably 20 mL or more and 500 mL or less of water.

  In the present invention, the amount of the solvent to be used is not particularly limited, but in consideration of operability and yield, the solvent may be 0.1 mL or more and 200 mL or less with respect to 1 g of the montelukast organic amine salt. , 0.5 mL to 100 mL is preferable, and 1.0 mL to 50 mL is particularly preferable.

(Reaction conditions)
In the reaction step, the method of reacting the montelukast organic amine salt and the acid is not particularly limited, and the montelukast amine salt, the acid, and the solvent may be mixed, and the mixing method and order are not particularly limited. The solvent may be a premixed water-soluble organic solvent and water, or the water-soluble organic solvent and water may be added sequentially in the process, and the mixing order is particularly limited. Is not to be done. For example, the acid may be added after mixing the montelukast organic amine salt, the water-soluble organic solvent and water, or the water-soluble organic solvent, water and acid may be mixed in advance and then the montelukast organic amine salt may be added. Considering the reactivity of the reaction, it is preferable to mix and dissolve the montelukast organic amine salt and the water-soluble organic solvent in advance, and then add acid and water to lead to montelukast free acid.

  Further, the temperature in the reaction step is not particularly limited, but considering the solubility and operability of the montelukast organic amine salt and the purity of the obtained montelukast free acid, the temperature of the reaction solution is 0 ° C. or higher and 80 ° C. or lower. It is preferably 10 ° C. or higher and 60 ° C. or lower, more preferably 20 ° C. or higher and 50 ° C. or lower. By setting the temperature range, high-purity montelukast can be efficiently produced without degradation of reactivity due to decomposition of montelukast organic amine salt or decrease in solubility of montelukast organic amine salt, or decomposition of montelukast organic amine salt. Free acid can be obtained. Moreover, although the time which reaction requires depends on temperature, it is 1 to 60 minutes normally.

((Crystallization process))
The crystallization step of the present invention is a step of crystallizing montelukast free acid from the reaction solution obtained in the reaction step. Continuing from the reaction step, the crystallization step is carried out in a water-soluble organic solvent and water, so that the organic amine acid salt produced as a by-product is hardly crystallized, and the high-purity montelukast free acid crystals are collected. It can be obtained efficiently.

  The said crystallization process is performed by hold | maintaining the reaction liquid obtained at the said reaction process for a fixed time, and you may stir and mix at this time. The temperature in the crystallization step may be determined by the concentration of montelukast free acid in the reaction solution, the ratio of the water-soluble organic solvent and water, etc., and cannot be uniquely limited. The reaction may be performed at the same temperature as the reaction step or at a lower temperature, and the temperature may be changed over time. Specifically, considering the operability, the recovery rate, and the physical properties of the crystals obtained, the temperature of the reaction solution obtained in the reaction step is preferably −20 ° C. or higher and 50 ° C. or lower, and −15 ° C. or higher and 30 ° C. or lower. It is more preferable to set it as ℃ or less, and it is especially preferable to set it as -5 to 10 degreeC. In addition, the retention time in the crystallization step may be 1 hour or more and 72 hours or less in consideration of the recovery rate. Particularly preferred is an embodiment in which the temperature of the reaction solution obtained in the reaction step is set to −5 ° C. or more and 10 ° C. or less, and aging is performed for 1 hour or more in the temperature range. Can be obtained.

  Moreover, in the said crystallization process, the seed crystal of a montelukast free acid can also be added to the solution obtained at the said reaction process. When using a seed crystal, it is preferable to mix the said seed crystal in the obtained solution at 50 degrees C or less after the said reaction process. The seed crystal is not particularly limited, and a seed crystal obtained by a known method can be used. The amount of the seed crystal used is not particularly limited, but may be 0.0001 g or more and 0.1 g or less, and 0.001 g or more and 0.05 g based on 1 g of the montelukast free acid crude product. The following is preferable.

  The crystals of montelukast free acid thus precipitated can be solid-liquid separated by a known method such as filtration or centrifugation, and can be used in the next step as a wet body, or can be naturally dried, blown dry, or vacuum dried. It can be easily isolated by drying it.

((Monelukast free acid sodium chloride))
Montelukast sodium is obtained by sodium chloride the montelukast free acid obtained by the reaction step and the crystallization step. Since the montelukast free acid obtained by the present invention has a very high purity, by using the montelukast free acid, it is possible to produce high-purity montelukast sodium that can be efficiently used for pharmaceuticals without excessive purification operations. can do.

  The sodium chloride is not particularly limited, and is performed by a known method, for example, by reacting montelukast free acid with a base such as sodium hydroxide or sodium methoxide. The usage-amount of the said base should just be 1 mol with respect to 1 mol of montelukast free acids. Moreover, it is preferable to perform the said sodium chloride in a solvent, Although the kind and usage-amount of the said solvent are not specifically limited, It is preferable to use 10 mL of methanol etc. with respect to 1 g of montelukast free acids. Further, the temperature and time of the reaction are not particularly limited, and may be 20 ° C. for 1 hour.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited by these Examples.

In this example, the purity of montelukast organic amine salt and montelukast free acid was measured as follows.
<Measurement method of purity>
Apparatus: High-performance liquid chromatograph (manufactured by Waters Corporation)
Detector: UV absorption detector (manufactured by Waters Corporation)
Measurement wavelength: 238 nm
Column: ZORBAX SB-PHENYL, inner diameter 4.6 mm, length 50 mm (manufactured by Agilent Technologies, Inc.)
Column temperature: 30 ° C. Constant temperature Sample temperature: 25 ° C. Constant temperature mobile phase A: distilled water / trifluoroacetic acid = 1000 / 1.5 (v / v)
Mobile phase B: acetonitrile / trifluoroacetic acid = 1000 / 1.5 (v / v)
Transfer of mobile phase: Concentration control is performed by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.
Flow rate: 1.2 ml / min Measurement time: 45 minutes Under the above conditions, peaks of montelukast organic amine salt and montelukast free acid are observed at about 7.7 min. In the following Examples and Comparative Examples, the purity of montelukast organic amine salt and montelukast free acid is the ratio of the peak area value of each compound to the sum of the area values of all peaks measured under the above conditions.

In this example, the amount of the organic amine acid salt in the montelukast organic acid was measured as follows.
<Measurement method of acid amount of organic amine>
Apparatus: Solution 500 MHz FT-NMR (manufactured by JEOL Ltd.)
Measuring solvent: CDCl ₃
The amount of the organic amine salt in the montelukast organic acid is calculated by calculating the weight composition ratio from the intensity ratio of the spectrum inherent to each of the montelukast free acid and the organic amine acid salt measured under the above conditions, and expressed as weight%. Yes.

Production Example 1
Under a nitrogen atmosphere, a solution in which 0.86 g of dipropylamine was dissolved in 5 ml of butyl acetate in 45 ml of butyl acetate added to 5.0 g of a crude montelukast free acid (purity 92.7%) and stirred. It was dripped. After confirming that all the solids were dissolved, 5.0 mg of seed crystals of montelukast dipropylamine salt were added, stirred at room temperature for 3 hours, cooled to 4 ° C., stirred at the same temperature for 16 hours, and brought to −10 ° C. The mixture was cooled and stirred at the same temperature for 2 hours. The precipitated crystals were collected by pressure filtration, washed with 5 ml of butyl acetate and 10 ml of heptane, and dried under reduced pressure to obtain 3.0 g (purity 99.7%) of montelukast dipropylamine salt crystals (yield) 71%).

Production Example 2
Under a nitrogen atmosphere, a solution of 0.31 g of dicyclohexylamine dissolved in 2 ml of ethyl acetate was added dropwise to a solution obtained by adding 8 ml of ethyl acetate to 1.0 g of crude montelukast free acid (purity 91.5%) and stirring and mixing them. did. The solution was stirred at room temperature for 16 hours, 20 ml of hexane was added, and the mixture was further stirred at room temperature for 6 hours. The precipitated crystals were collected by pressure filtration, washed with 2 ml of ethyl acetate and 4 ml of heptane, and dried under reduced pressure to obtain 1.1 g (purity 95.1%) of montelukast dicyclohexylamine salt (yield 81). %).

Example 1
Under a nitrogen atmosphere, 60 ml of isopropanol was added to 10.0 g of montelukast dipropylamine salt (purity 99.7%) and stirred and mixed. This mixed solution was heated to 40 ° C. and dissolved. After adding 0.96 g of acetic acid and 30 ml of water to this solution, it was cooled to 4 ° C. and stirred at the same temperature for 17 hours. The precipitated crystals were collected by pressure filtration, washed with a mixed solution of 20 ml of isopropanol and 10 ml of water, dried under reduced pressure, and 8.4 g of montelukast free acid crystals (purity 99.9%, containing dipropylamine acetate) 0%) was obtained (yield 98%).

Example 2
Under a nitrogen atmosphere, 20 ml of isopropanol was added to 5.0 g of montelukast dipropylamine salt (purity 99.7%) and mixed with stirring. This mixed solution was heated to 40 ° C. and dissolved. To this solution, 0.48 g of acetic acid and 15 ml of water were added, stirred at room temperature for 2 hours, cooled to 0 ° C., and stirred at the same temperature for 16 hours. The precipitated crystals were collected by pressure filtration, washed with 10 ml of isopropanol, and dried under reduced pressure to obtain 4.1 g of montelukast free acid crystals (purity 99.9%, dipropylamine acetate content 0%). (Yield 97%).

Example 3
In Example 1, the same operation was performed except that the amount of acetic acid was changed from 0.96 g to 0.86 g, from 10.0 g of montelukast dipropylamine salt to 10.0 g (purity 95.1%) of montelukast dicyclohexylamine salt. This gave 7.4 g of crystals of montelukast free acid (purity 99.5%, dicyclohexylamine acetate content 0%) (yield 97%).

Example 4
In Example 1, the same operation was carried out except that 60 ml of isopropanol was changed to 60 ml of methanol to obtain 8.3 g of montelukast free acid crystals (purity 99.9%, dipropylamine acetate content 0%) ( Yield 97%).

Example 5
In Example 1, the same operation was carried out except that isopropanol was changed to acetone to obtain 8.1 g of montelukast free acid crystals (purity 99.9%, dipropylamine acetate content 0%) (yield) 95%).

Example 6
In Example 1, the same operation was performed except that 0.96 g of acetic acid was changed to 2.4 g of tartaric acid, and 8.4 g of crystals of montelukast free acid (purity 99.9%, dipropylamine tartrate content 0%) (Yield 98%) was obtained.

Example 7
To 2 g of the montelukast free acid crystals obtained in Example 1, 10 ml of methanol was added and stirred and mixed, 0.14 g of sodium hydroxide was added and stirred for 1 hour, the solvent was distilled off, and the precipitated crystals were added. The product was collected by pressure filtration and dried under reduced pressure to obtain 1.9 g (purity 99.9%) of montelukast sodium (yield 92%).

Comparative Example 1
Under a nitrogen atmosphere, 544 ml of ethyl acetate and 272 ml of water were added to 54.4 g (purity 99.7%) of montelukast dipropylamine salt and mixed with stirring. Under ice cooling, 9.51 g of acetic acid was added to this solution, and then the organic layer was separated. The obtained organic layer was washed twice with 272 ml of water to remove diisopropylamine acetate, and then concentrated to obtain a residue. The obtained solid was blown and dried with nitrogen to obtain 46.4 g (purity 99.7%) of montelukast free acid solid.
186 ml of isopropanol was added to the obtained solid, stirred at room temperature for 30 minutes, cooled to 4 ° C., and stirred at the same temperature for 16 hours. The precipitated crystals were collected by pressure filtration, washed with 92 ml of isopropanol, and dried under reduced pressure to obtain 45.5 g of montelukast free acid crystals (purity 99.8%, dipropylamine acetate content 0%). (Yield 89%).

Comparative Example 2
Under a nitrogen atmosphere, 20 ml of isopropanol was added to 5.0 g of montelukast dipropylamine salt (purity 99.7%) and mixed with stirring. This mixed solution was heated to 40 ° C. and dissolved. To this solution, 0.48 g of acetic acid was added, stirred at room temperature for 50 minutes, cooled to 4 ° C., and stirred at the same temperature for 17 hours. The precipitated crystals were collected by pressure filtration, washed with 10 ml of isopropanol, and dried under reduced pressure. 3.6 g of montelukast free acid crystals (purity 99.9%, dipropylamine acetate content 0.11%) (Yield 85%).

Claims (5)

Following formula (1)

(In the formula, B represents an organic amine.)
A montelukast organic amine salt represented by the following formula (2)

A reaction step of obtaining a reaction solution containing a montelukast free acid and an organic amine acid salt represented by the following, a crystallization step of crystallizing the montelukast free acid represented by the above formula (2) from the reaction solution obtained in the reaction step In the manufacturing method of the said montelukast free acid containing, The method of using a water-soluble organic solvent and water as a solvent in the said reaction process and the said crystallization process. The method according to claim 1, wherein the water-soluble organic solvent is at least one selected from the group consisting of methanol, ethanol, and isopropanol. The method according to claim 1 or 2, wherein the volume ratio of the water-soluble organic solvent and water in the solvent at 25 ° C is 1 mL or more and 10000 mL or less of water with respect to 100 mL of the water-soluble organic solvent. The method according to any one of claims 1 to 3, wherein a temperature at which the reaction step is performed is 20 to 50 ° C, and a temperature at which the crystallization step is performed is -5 to 10 ° C. A method for producing montelukast sodium by producing the montelukast free acid represented by the above formula (2) by the method according to claim 1, followed by sodium chloride of the montelukast free acid.