JP2015010049A - Method for producing montelukast alkyl ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing a high purity 1-(((1(R)-(3-(2-(7-chloro-2-quinonyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid alkyl ester having a reduced content of a specific impurity.SOLUTION: A specific amount of a weakly basic nitrogen-containing organic compound is made to exist in a reaction system in a reaction between 2(2-(3(S)-(3-(2-(7-chloro-2-quinonyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol and 1-mercaptomethylcyclopropane acetic acid alkyl ester in the presence of a strong base.

Description

  The present invention relates to montelukast sodium (chemical name: 1-(((1 (R)-(3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2 1-((((1 (R)-(3- (2- (7-chloro-acetate))) which is a synthetic intermediate of-(1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid sodium) The present invention relates to a novel process for the preparation of 2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid alkyl ester.

  Chemical formula (1)

Is known as a therapeutic agent that binds to CysLT1 receptor on target cells such as bronchial smooth muscle as an antagonist, prevents cysteinyl leukotriene from binding to the receptor, and improves the symptoms of bronchial asthma It has been. Since montelukast sodium useful as such a therapeutic agent is desired to have a very high purity, it is extremely important to suppress the generation of impurities during the production process.

  As a manufacturing method of a montelukast sodium, Chemical formula (2) obtained by the well-known method

2- (2- (3 (S)-(3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl) -2-propanol (hereinafter, Also called mesylate form) and chemical formula (3)

(In the formula, R is a hydrogen atom or an alkyl group.)
1- (mercaptomethyl) cyclopropaneacetic acid represented by the formula (1) or a thioether by reaction with an alkyl ester thereof.

(In the formula, R is a hydrogen atom or an alkyl group.)
1-((((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) ) Phenyl) propyl) thio) methyl) cyclopropaneacetic acid (hereinafter also referred to as montelukast free acid) or its alkyl ester (hereinafter also referred to as montelukast alkyl ester), and then hydrolyzed as necessary. A method for obtaining montelukast sodium by sodium chloride is known.

  And about the said thioetherification reaction, for example, in patent document 1, chemical formula (5) is made by making a mesylate body and 1- (mercaptomethyl) cyclopropane acetic acid methyl ester react in acetonitrile solvent in the presence of cesium carbonate. )

1-((((1 (R)-(3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl)) A method for producing propyl) thio) methyl) cyclopropaneacetic acid methyl ester (hereinafter also referred to as montelukast methyl ester) is described.

  Furthermore, Patent Document 2 includes chemical formula (6).

1-(((1 (S)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) ) Phenyl) -1-propanol (hereinafter also referred to as diol) and methanesulfonic acid chloride are present in N, N-diisopropylethylamine (no description of the amount used) in a tetrahydrofuran (hereinafter also referred to as THF) solvent. Under the mesylation reaction to form a mesylate body, the reaction solution is filtered by post-treatment to remove the organic amine salt and the like, and then 1- (mercaptomethyl) cyclopropaneacetic acid methyl ester N, N-dimethylacetamide ( Hereinafter, it is also referred to as DMA.) By adding a solution and then adding an aqueous sodium hydroxide solution, thioetherification and hydrolysis are carried out in the same reaction system. A method for producing telukast free acid is described, and Patent Document 3 mesilated a diol compound in the presence of N, N-diisopropylethylamine (1.5 mol used per 1 mol of diol compound). Thereafter, without any post-treatment, 1- (mercaptomethyl) cyclopropaneacetic acid and N, N-dimethyl are present in the presence of an excess of N, N-diisopropylethylamine (approximately 0.5 mol per 1 mol of the diol). A method for producing montelukast free acid by adding formamide (hereinafter also referred to as DMF) followed by sodium methoxide is described.

JP-A-5-105665 Special table 2008-510840 gazette International Publication No. 2008/023044

  However, the present inventor examined the thioetherification reaction based on the conditions described in the above-mentioned patent documents. When montelukast free acid was reacted with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester, the chemical formula (7 )

(In the formula, R is an alkyl group.)
1-(((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-propenyl) phenyl) propyl) It was found that a large amount of thio) methyl) cyclopropaneacetic acid alkyl ester (hereinafter also referred to as methylstyrene) was by-produced. And the said chemical formula (8) which the said impurity hydrolyzes and produces | generates.

1-(((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-propenyl) phenyl) propyl) Once the thio) methyl) cyclopropaneacetic acid is produced, it is difficult to remove by purification or the like, and in order to obtain high-purity montelukast sodium, the production of the methylstyrene body is suppressed in the thioetherification step. The development of a method was desired.

  Accordingly, an object of the present invention is to provide a method for producing a high-purity montelukast alkyl ester that suppresses the formation of methylstyrene in the thioetherification step.

  The present inventor has intensively studied to solve the above problems. Specifically, as described above, a methylstyrene body is generated in the thioetherification reaction because methanesulfonic acid by-produced in the thioetherification reaction causes intramolecular dehydration of the tertiary alcohol site, A method for suppressing side reactions was investigated. Therefore, when an excessive amount of a strong base such as n-butyllithium or sodium hydroxide used for the thioetherification reaction is used to capture the methanesulfonic acid, the elimination reaction of the mesylate occurs, and the chemical formula (9)

2- (2- (3 (S)-(3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) allyl) phenyl) -2-propanol and the like represented by High-purity montelukast sodium was not obtained. Therefore, when the method for capturing the methanesulfonic acid was further studied, it was surprising that the desorption as described above was surprisingly caused by the presence of a specific amount or more of a weakly basic organic compound in the reaction system in the thioetherification reaction. The present inventors have found that a high-purity montelukast sodium in which the side reaction is suppressed without causing a separation reaction and the content of methylstyrene is finally reduced can be obtained, and the present invention has been completed.

  That is, in the present invention, the montelukast alkyl ester is obtained by reacting the mesylate body with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester in the presence of a base having a pKb of −40 or more and 0 or less. In the production method, a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less is present in the reaction system in the reaction in an amount of 1.0 mol or more relative to 1 mol of the mesylate body.

  Moreover, in this invention, the said mesylate body obtained by carrying out the mesylation of the said diol body in presence of the nitrogen-containing organic compound whose pKb is 1-6, and nitrogen-containing organic whose pKb is 1-6 The reaction liquid containing the compound can be used for the thioetherification reaction as it is. That is, another aspect of the present invention is to mix the diol form, methanesulfonic acid chloride, and a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less, and the mesylate body and the nitrogen containing pKb of 1 or more and 6 or less. A mesylation step for obtaining a solution containing an organic compound, a thioether for obtaining a solution containing the montelukast alkyl ester by mixing the solution, 1- (mercaptomethyl) cyclopropaneacetic acid ester, and a base having a pKb of −40 to 0. In the method for producing the montelukast alkyl ester comprising a crystallization step, a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less is present in the reaction system of the thioetherification step in an amount of 1.0 mol or more relative to 1 mol of the mesylate body. It is the method characterized by this. Thus, even if it continuously performs thioetherification reaction using the reaction liquid obtained by the mesylation reaction, the effect of this invention is acquired, and it is efficient and preferable.

  According to the present invention, in a method for producing a montelukast alkyl ester by reacting a mesylate form with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester in the presence of a specific strong base, a specific weak basicity is contained in the reaction system. By allowing the organic compound to exist in an amount of 1.0 mol or more with respect to 1 mol of the mesylate body, it is possible to obtain a highly pure montelukast alkyl ester in which the amount of impurities, particularly a methylstyrene body, is reduced.

  The present invention provides a method for producing a montelukast alkyl ester by reacting a mesylate body with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester in the presence of a specific strong base, wherein pKb is 1 to 6 in the reaction system. This is a method characterized in that a specific amount of a nitrogen-containing organic compound (hereinafter also referred to as a weakly basic organic compound) is present.

  The mesylate body used in the present invention is not particularly limited, and those produced by a known method can be used. Moreover, in this invention, it is preferable to use the solution containing the mesylate body obtained by making a diol body and methanesulfonic acid chloride react as the said mesylate body as it is. That is, in the present invention, following the mesylation step of obtaining a solution containing a mesylate body and a weakly basic organic compound by mixing a diol body, methanesulfonic acid chloride, and a weakly basic organic compound, the solution and 1- ( It is a preferred embodiment to perform a thioetherification step of mixing a mercaptomethyl) cyclopropaneacetic acid alkyl ester and a strong base to obtain a solution containing the montelukast alkyl ester. Therefore, the mesylation step and the thioetherification step will be described in order below.

((Mesylation process))
In the present invention, the mesylation step is a step of obtaining a mesylate body by subjecting a diol body and methanesulfonic acid chloride to a mesylation reaction in the presence of a weakly basic organic compound.

(Diol form)
As the diol body used in the mesylation step, those produced by a known method are used without particular limitation. The form of the diol body is not particularly limited, and may be a crystal, amorphous, or a mixed form thereof, a powder, a lump, or a mixed form thereof, and may be a solvate. May be. In the mesylation step, the water content of the compound to be used is preferably controlled in consideration of the reactivity of the mesylation reaction. Specifically, the water content is preferably 1% or less, More preferably, it is 0.5% or less. In addition, it is applicable also to the following methanesulfonic acid chloride, a weak basic organic compound, and a reaction solvent that it is suitable to control a moisture content to the said range.

(Methanesulfonic acid chloride)
The methanesulfonic acid chloride used in the mesylation step is not particularly limited as a commercially available reagent or industrial product is used. The amount of the methanesulfonic acid chloride used is preferably 1.0 mol or more and 1.6 mol or less, more preferably 1.1 mol or more and 1.4 mol or less with respect to 1 mol of the diol. preferable.

(Nitrogen-containing organic compound having a pKb of 1 to 6 (weakly basic organic compound))
In the mesylation step, a nitrogen-containing organic compound (weakly basic organic compound) having a pKb of 1 or more and 6 or less is required to react the diol form with methanesulfonic acid chloride. In the mesylation step, by using an excessive weak basic organic compound, there is a weak basic organic compound that has not been consumed in the mesylation reaction in the reaction solution containing the mesylate body obtained. With the surplus weakly basic organic compound, the effect of the present invention can be obtained in the next thioetherification step.

  In the mesylation step, the weakly basic organic compound may be a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less. The reactivity in the mesylation step and methanesulfone by-produced in the next thioetherification step In view of the acid capturing ability, the ease of removal in the purification operation, and the like, the pKb is preferably 3 or more and 6 or less. Specifically, tertiary organic amines and pyridine derivatives are used, and considering reactivity and the like, trialkylamines (pKb3-6) such as triethylamine and N, N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine It is preferable to use a pyridine derivative (pKb3-6) such as N, N-diisopropylethylamine. These may be used singly or in combination of a plurality of types, and a tertiary organic amine and a pyridine derivative may be used in combination. In addition, the amount of the weakly basic organic compound used in the mesylation step may be 1 mol or more and 15 mol or less with respect to 1 mol of the mesylate, but in the next thioetherification step, the weak base is used in the reaction system. In consideration of the presence of the organic compound, the amount is preferably 2 mol or more. In the mesylation step, an excessive amount of weak basic organic compound is not used, and in the next thioetherification step, the amount of weak basic organic compound present in the reaction system is 1. It can also be added so that it becomes 0 mol or more.

(Reaction solvent)
In the mesylation step, it is preferable to use a reaction solvent. The reaction solvent is not particularly limited as long as it dissolves the diol, and specifically, acetonitrile, THF, DMF, DMA, toluene, N-methylpyrrolidone can be used, and the next thioetherification step Is considered, THF, DMF, DMA, and N-methylpyrrolidone are preferable, and THF is particularly preferably used. These may be used alone or in combination of two or more. In consideration of operability and reactivity, the reaction solvent may be used in an amount of 0.5 mL or more and 200 mL or less, preferably 1 mL or more and 100 mL or less, and preferably 2 mL or more and 50 mL or less with respect to 1 g of the diol. More preferably.

(Reaction conditions for the mesylation process)
In the mesylation step, the method of reacting the diol and methanesulfonic acid chloride in the presence of a weakly basic organic compound is not particularly limited, and the diol, methanesulfonic acid chloride, weakly basic organic compound, and The reaction solvent may be mixed if necessary, and the method and order in that case are not particularly limited. Specifically, a method of adding methanesulfonic acid chloride after dissolving a diol body and a weakly basic organic compound in a reaction solvent is preferable. In the mesylation step, the reaction temperature may be −50 ° C. or higher and 20 ° C. or lower, preferably −40 ° C. or higher and 10 ° C. or lower, and more preferably −30 ° C. or higher and 0 ° C. or lower. preferable. By setting it as the said temperature range, the byproduct of an impurity is suppressed and it can react efficiently. The reaction time is usually 2 hours or more and 24 hours or less.

  In the present invention, the reaction solution containing the mesylate and the weakly basic organic compound obtained in the mesylation step can be used as it is for the next thioetherification reaction. In the mesylation step, an acid salt by-produced by the mesylation reaction and an amine salt or a pyridine salt by-produced by the weakly basic organic compound are precipitated in the reaction solution. You may use for a process and may remove. The salt can be removed by a general method such as decantation or filtration.

((Thioetherification step))
The thioetherification step is the present invention, wherein a specific amount of a weakly basic organic compound is present in the reaction system, and the mesylate body and 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester are converted into a specific strong base. A method of producing a montelukast alkyl ester by reacting in the presence is performed, and the solution containing the mesylate obtained in the mesylation step can be used as it is.

(Mesylate body)
The mesylate body used in the present invention is not particularly limited as described above, and those produced by a known method can be used. The form of the mesylate body is not particularly limited, and may be isolated as a solid, in a solution or slurry with any solvent, and the mesylate body obtained in the mesylation step. It is preferable to use the solution containing In the case of a solid, it may be a crystal, amorphous, or a mixed form thereof, a powder, a lump, a mixed form thereof, or a solvate. Moreover, the wet body containing the solvent used for the said thioetherification reaction may be sufficient, and the other solvent may be included in the range which does not affect reaction.

(1- (Mercaptomethyl) cyclopropaneacetic acid alkyl ester)
The 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester used in the present invention is used for obtaining a montelukast alkyl ester by thioetherifying a mesylate body, and is not particularly limited. In view of the reactivity and the reactivity in the step of producing montelukast sodium from the obtained montelukast alkyl ester, the alkyl group of the alkyl ester preferably has 1 to 5 carbon atoms, and is linear. It is preferable that it is a methyl group or an ethyl group. In addition, the form of the 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester is not particularly limited, and may be a wet body containing a solvent used for the thioetherification reaction in the same manner as the mesylate body, affecting the reaction. Other solvents may be included as long as they do not reach. In the present invention, the amount of 1- (mercaptomethyl) cyclopropaneacetic acid ester used may be 1.0 mol or more and 1.5 mol or less, and 1.1 mol or more and 1.3 mol or less with respect to 1 mol of the mesylate body. It is preferably less than or equal to a mole.

(Base having a pKb of −40 or more and 0 or less (strong base))
A base having a pKb of -40 or more and 0 or less (hereinafter also referred to as a strong base) used in the present invention is necessary for a thioetherification reaction between a mesylate body and 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester. It is said. In the present invention, the value of pKb is at 25 ° C. The strong base is not particularly limited as long as the pKb value is −40 or more and 0 or less, and the thioetherification reaction proceeds sufficiently. Specifically, lithium hydroxide, sodium hydroxide are not particularly limited. Alkali metal hydroxides such as potassium hydroxide (pKb-2 to 0), metal alkoxides such as sodium methoxide, lithium methoxide, t-butoxy sodium and t-butoxy potassium (pKb-3 to -1.5) Alkyllithium such as methyllithium and butyllithium (pKb-39 to -34), metal hydride such as sodium hydride and potassium hydride (pKb-21), metal such as lithium diisopropylamide and lithium tetramethylpiperidide Amides (pKb-23 to -22) and the like, among others, t-butoxy sodium, t-butoxykaliu Are preferred, t- butoxy potassium are preferable. In the present invention, the amount of the strong base used may be 1.0 mol or more with respect to 1 mol of the mesylate body. It is preferable that it is at least 1.3 mol. In the present invention, when the solution containing the mesylate obtained in the mesylation step is used as the mesylate, the amine salt and / or pyridine salt produced as a by-product in the mesylation reaction is not removed. Since the reactivity of the thioetherification reaction is lowered by the amine salt, the amount of the strong base used is preferably 2.1 to 2.4 mol with respect to 1 mol of the mesylate.

(Nitrogen-containing organic compound having a pKb of 1 to 6 (weakly basic organic compound))
In the present invention, in the reaction system in the thioetherification step, in addition to the strong base, a nitrogen-containing organic compound (weakly basic organic compound) having a pKb of 1 or more and 6 or less is used in an amount of 1. It is characterized by being present at 0 mol or more. By making the amount of the weakly basic organic compound present, it is possible to obtain a montelukast alkyl ester in which the production of the methylstyrene body is particularly suppressed and the amount of impurities is reduced.

  In the present invention, the weakly basic organic compound may be a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less, as in the mesylation step. In view of ease of removal, etc., pKb is preferably 3 or more and 6 or less. Specifically, the compounds exemplified in the mesylation step are similarly used. By using the weakly basic organic compound, the by-produced methanesulfonic acid is captured without inhibiting the thioetherification reaction, and the content of methylstyrene as an impurity can be reduced. In the case of using a solution containing the mesylate body obtained in the mesylation step as the mesylate body and not using an excessive amount of weakly basic organic compound in the mesylation step, in the thioetherification step, It must be added so that the amount of the weakly basic organic compound present in the reaction system is 1.0 mol or more per mol of mesylate. When adding a weakly basic organic compound in the thioetherification step, the same compound as that used in the mesylation step may be used, or different compounds may be used, and a plurality of types may be used in combination. You can also.

(Reaction solvent)
In the present invention, a reaction solvent is preferably used when the mesylate body is reacted with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester. The reaction solvent is not particularly limited as long as it can dissolve the mesylate body. Specific examples include THF, DMF, DMA, N-methylpyrrolidone, and dimethyl carbonate. Among them, it is preferable to use THF. These may be used alone or in combination of two or more. Further, the amount of solvent used in the thioetherification step may be 1 mL or more and 200 mL or less with respect to 1 g of the mesylate body in consideration of operability and reactivity, and 3 mL in consideration of the reactivity and efficiency of the reaction. It is preferable to set it as 100 mL or less, and it is more preferable to set it as 5 mL or more and 50 mL or less. In the present invention, when a solution containing a mesylate obtained in the mesylation step is used as the mesylate, the type and amount of the reaction solvent are determined in consideration of the type and amount of the solvent contained in the solution. It is necessary to adjust accordingly.

(Reaction conditions for the thioetherification step)
In the present invention, the method of reacting the mesylate form with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester in the presence of a specific strong base is not particularly limited, and the mesylate form, 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester. , Strong base, weak basic organic compound, and reaction solvent may be mixed if necessary, and the method and order in that case are not particularly limited, but weak basic organic compound exists in the reaction system at the start of the reaction It is preferable. Specifically, for example, a solution containing the mesylate obtained in the mesylation step is mixed with 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester, and a weakly basic organic compound is added as necessary. From the above, a method of adding a strong base, 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester, a strong base, and a reaction solvent are mixed in advance, and a weakly basic organic compound is added as necessary. The method of adding etc. is mentioned. Moreover, in this invention, the temperature of reaction should just be -30-20 degreeC, when the reactivity and efficiency of the said reaction are considered, it is preferable to set it as -20-15 degreeC, and it shall be -10-10 degreeC. It is more preferable. The reaction time is usually 4 to 48 hours.

  The solution containing the montelukast alkyl ester obtained in the present invention can be obtained as a crude product or a crystal by appropriately performing post-treatment, but the montelukast alkyl ester has poor crystallinity. It is preferable to use for the next process in the state of a solution. That is, the montelukast alkyl ester can be converted to montelukast sodium by a known method, for example, hydrolysis to form montelukast free acid and then sodium chloride. Since the montelukast alkyl ester obtained in the present invention has a high purity with a reduced content of methylstyrene as an impurity, a very high purity montelukast sodium is obtained by using the montelukast alkyl ester. be able to.

((Hydrolysis step))
The said hydrolysis process is a process of hydrolyzing the montelukast alkylester obtained by this invention, and obtaining a montelukast free acid. The method for hydrolysis of the montelukast alkyl ester is not particularly limited. Specifically, the method described in Patent Document 1, that is, a method of mixing the montelukast alkyl ester and an aqueous sodium hydroxide solution in a mixed solvent of THF and methanol. Is mentioned. Further, the montelukast alkyl ester can be used as a solution obtained in the thioetherification step, or as a crude product or a crystal, and it is preferable to use the solution obtained in the thioetherification step as it is.

  The thus obtained montelukast free acid can be converted into sodium chloride as it is, but it is preferable that the montelukast free acid is once purified after being purified as an amine salt and then neutralized again. Since the amine salt of montelukast free acid is easier to purify than montelukast free acid and montelukast sodium, the final montelukast sodium can be highly purified.

  The method for amine-converting montelukast free acid is not particularly limited, but generally, the amine salt of montelukast free acid is obtained by reacting montelukast free acid with the corresponding amine. The kind of amine used in the amine chlorination is not particularly limited, and known ones are used, and the amount used is preferably 1.0 equivalent or more and 2.0 equivalent or less. Moreover, acetate and toluene such as ethyl acetate and butyl acetate can be used as the reaction solvent, but it is preferable to use acetate in consideration of the purification effect. The amount of the solvent used is not particularly limited as long as a solution of an amine salt of montelukast free acid may be obtained. In consideration of operability and recovery rate, the reaction solvent is 1 mL or more and 100 mL or less with respect to 1 g of montelukast free acid. It is preferable to make it. Furthermore, the reaction temperature for amine chlorination is not particularly limited, but is preferably 0 ° C. or higher and 80 ° C. or lower. After the reaction, the amine salt of montelukast free acid can be obtained as a solid by solid-liquid separation by a known method such as evaporation of the solvent. Specifically, by cooling the temperature of the reaction solution to 10 ° C. or less, the crystal of the amine salt of montelukast free acid is precipitated, and solid-liquid separation is performed by a method such as filtration or centrifugation, thereby It is preferred to obtain the amine salt as crystals. The montelukast free acid amine salt solid thus obtained is purified once or more by a known method, for example, recrystallization or reslurry, so that the final obtained montelukast sodium has a higher purity. Therefore, it is preferable.

  Furthermore, the method for neutralizing the amine salt to make it again a montelukast free acid is not particularly limited, but in general, it can be made montelukast free acid by reacting the amine salt with an acid. The kind and amount of the acid used in the neutralization are not particularly limited, and an organic acid such as acetic acid or oxalic acid, or an inorganic acid such as hydrogen chloride or sulfuric acid can be used, but it is preferable to use an organic acid. As the reaction solvent, alcohols such as methanol and ethanol, acetate esters such as ethyl acetate and butyl acetate, halogen solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene can be used. There is no particular limitation on the amount used, and the amine salt of the montelukast free acid may be dissolved. However, in consideration of operability and recovery rate, the solvent is 1 mL or more and 100 mL or less with respect to 1 g of the montelukast free acid amine salt. It is preferable to use it. Furthermore, the reaction temperature for neutralization is not particularly limited, but is preferably 0 ° C. or higher and 60 ° C. or lower. After the reaction, the temperature of the reaction solution is cooled to 30 ° C. or lower to precipitate montelukast free acid crystals, and solid-liquid separation is performed by a method such as filtration or centrifugation to obtain montelukast free acid as crystals. be able to.

((Sodium chloride process))
The sodium chloride step is a step of sodium montelukast free acid to obtain montelukast sodium. The method for sodium montelukast free acid 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. After the reaction, a crystal or amorphous of montelukast sodium can be obtained by solid-liquid separation.

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

Moreover, in the present Example, the purity and impurity amount of montelukast methyl ester, montelukast dipropylamine salt, montelukast sodium and methylstyrene were measured as follows.
<Measurement method of purity and impurity amount>
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
Mobile phase B: acetonitrile / trifluoroacetic acid = 1000 / 1.5
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, montelukast methyl ester is about 12.9 minutes, montelukast free acid, montelukast dipropylamine salt and montelukast sodium are about 7.7 minutes, methylstyrene body Shows a peak at about 19.9 minutes. In the following Examples and Comparative Examples, the purity or content of the above compound is the ratio of the area value of each compound peak to the total area value of all peaks measured under the above conditions.

Example 1
(Mesylation process)
In a nitrogen atmosphere, 15 ml of toluene, 40 ml of acetonitrile and 2.1 g of N, N-diisopropylethylamine were added to 5.0 g of diol (purity 99.6%), and the resulting mixture was stirred and mixed. After that, a solution in which 1.4 g of methanesulfonic acid chloride and 5 ml of acetonitrile were mixed was dropped over 30 minutes, and the reaction solution was stirred at the same temperature for 5 hours. The precipitated crystals were collected by pressure filtration and washed with 5 ml of acetonitrile and 10 ml of hexane to obtain 5.1 g (yield: 85.9%) of mesylate crystals.
(Thioetherification step)
Under a nitrogen atmosphere, 1.5 g of 1- (mercaptomethyl) cyclopropaneacetic acid methyl ester, 1.0 g of triethylamine and 50 ml of DMF were added to 5.0 g of mesylate crystals, and the resulting solution was dissolved. After cooling to 10 ° C., 1.3 g of t-butoxypotassium was added over 30 minutes, and the reaction solution was heated to 4 ° C. and stirred at the same temperature for 16 hours. The obtained reaction solution was heated to 20 ° C., 50 ml of ethyl acetate and 100 ml of water were added, the organic layer was separated, the solvent was distilled off, and 6.39 g of montelukast methyl ester oil (montelukast methyl ester purity 80 0.6%, methylstyrene content 1.03%).

Example 2
In the thioetherification step of Example 1, the same operation was performed except that 1.0 g of triethylamine was changed to 1.1 g of N, N-diisopropylethylamine, and 6.39 g of montelukast methyl ester oil (Montelukast methyl ester purity 80.6) %, Methylstyrene body content 0.92%).

Example 3
(Mesylation process)
Under a nitrogen atmosphere, 15 ml of THF and 2.1 g of N, N-diisopropylethylamine were added to 5.0 g (purity 99.5%) of a diol, and the mixture was stirred and mixed. After cooling the resulting liquid to −10 ° C., methane A solution prepared by mixing 1.4 g of sulfonic acid chloride and 5 ml of THF was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The obtained reaction solution was filtered to remove the solid, and a THF solution of mesylate was obtained.
(Thioetherification step)
Under a nitrogen atmosphere, 1.8 g of 1- (mercaptomethyl) cyclopropaneacetic acid methyl ester, 2.1 g of N, N-diisopropylethylamine and 30 ml of THF were added to a THF solution of the mesylate form, and the resulting mixture was stirred and dissolved. After cooling the solution to −10 ° C., 1.4 g of potassium t-butoxy was added over 30 minutes, and the reaction solution was heated to 4 ° C. and stirred at the same temperature for 16 hours. The resulting reaction solution was heated to 20 ° C. and 10 ml of 5% saline was added to stop the reaction. The aqueous layer was separated, and the organic layer was washed with 10 ml of 5% saline to obtain a THF solution of montelukast methyl ester (Montelukast methyl ester purity 83.9%, methylstyrene content 0.77%). .

Example 4
(Mesylation process)
Under a nitrogen atmosphere, 15 ml of THF and 2.1 g of N, N-diisopropylethylamine were added to 5.0 g (purity 99.5%) of a diol, and the mixture was stirred and mixed. After cooling the resulting liquid to −10 ° C., methane A solution prepared by mixing 1.4 g of sulfonic acid chloride and 5 ml of THF was added dropwise over 30 minutes and stirred at the same temperature for 2 hours to obtain a THF solution of mesylate.
(Thioetherification step)
Under a nitrogen atmosphere, 1.8 g of 1- (mercaptomethyl) cyclopropaneacetic acid methyl ester, 2.1 g of N, N-diisopropylethylamine and 30 ml of THF were added to a THF solution of the mesylate form, and the resulting mixture was stirred and dissolved. After cooling the solution to −10 ° C., 2.8 g of potassium t-butoxy was added over 30 minutes, and the reaction solution was heated to 4 ° C. and stirred at the same temperature for 16 hours. The resulting reaction solution was heated to 20 ° C. and 10 ml of 5% saline was added to stop the reaction. The aqueous layer was separated, and the organic layer was washed with 10 ml of 5% saline to obtain a THF solution of montelukast methyl ester (Montelukast methyl ester purity 83.9%, methylstyrene content 0.77%). .

Example 5
In the thioetherification step of Example 4, the same operation was performed except that the amount of N, N-diisopropylethylamine used was changed from 2.1 g to 0.7 g, and a solution of montelukast methyl ester in THF (Montelukast methyl ester purity 80. 1% and methylstyrene content 0.90%).

Example 6
In the mesylation step of Example 4, the amount of N, N-diisopropylethylamine used was changed from 2.1 g to 4.2 g, and the same operation was performed except that N, N-diisopropylethylamine was not used in the thioetherification step. As a result, a solution of montelukast methyl ester in THF (montelukast methyl ester purity 82.6%, methylstyrene content 0.58%) was obtained.

Example 7
In the mesylation step of Example 6, the same operation was performed except that 4.2 g of N, N-diisopropylethylamine was changed to 4.0 g of triethylamine, and a solution of montelukast methyl ester in THF (montelukast methyl ester purity 80.1%, A methylstyrene body content of 0.91%) was obtained.

Example 8
In the mesylation step of Example 6, the same operation was performed except that 4.2 g of N, N-diisopropylethylamine was changed to 2.6 g of pyridine, and a solution of montelukast methyl ester in THF (montelukast methyl ester purity 81.1%, Methylstyrene body content 0.84%) was obtained.

Example 9
In the thioetherification step of Example 6, the same procedure was performed except that 1.5 g of 1- (mercaptomethyl) cyclopropaneacetic acid methyl ester was changed to 1.6 g of 1- (mercaptomethyl) cyclopropaneacetic acid ethyl ester, and montelukast A THF solution of ethyl ester (Montelukast ethyl ester purity 81.3%, methylstyrene content 0.73%) was obtained.

Example 10
In the thioetherification step of Example 6, the same operation was performed except that 2.8 g of potassium t-butoxy was changed to 2.6 g of sodium t-butoxy, and a solution of montelukast methyl ester in THF (montelukast methyl ester purity 81.0% , Methylstyrene body content 0.74%).

Example 11
In the thioetherification step of Example 6, the same operation was performed except that 2.8 g of t-butoxypotassium was changed to 1.4 g of sodium methoxide, and a solution of montelukast methyl ester in THF (montelukast methyl ester purity 80.0%, A methylstyrene body content of 0.69%) was obtained.

Example 12
Under a nitrogen atmosphere, 30 ml of methanol and 10.3 g of 10% aqueous sodium hydroxide solution were added to the THF solution of montelukast methyl ester obtained in Example 3, and the mixture was stirred and mixed at 25 ° C. for 6 hours. 30 ml of toluene was added to the obtained reaction solution to separate the organic layer, 10.3 g of 0.5M tartaric acid was added to the separated organic layer to adjust the pH to 4, the solvent was distilled off, and the amount of the organic layer was reduced. Was stirred at 5 ° C. for 12 hours. The precipitated solid was collected by filtration, washed twice with 5 ml of toluene, and dried under reduced pressure to give 5.1 g of a crude montelukast free acid (montelukast free acid purity 95.3%, methylstyrene content 0.92%) )
Under a nitrogen atmosphere, 45 ml of butyl acetate was added to 5.0 g of the crude montelukast free acid and mixed with stirring. To the resulting liquid, a solution of 0.86 g of dipropylamine dissolved in 5 ml of butyl acetate was added dropwise. After confirming that all the solid was dissolved, 1-(((1 (R)-(3- (2 (E)-(7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- ( After adding 5.0 mg of seed crystals of 1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid dipropylamine salt (hereinafter also referred to as montelukast dipropylamine salt) and stirring for 3 hours. The mixture was cooled to 4 ° C., stirred at the same temperature for 16 hours, cooled to −10 ° C., 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, dried under reduced pressure, and 4.7 g of crystals of montelukast dipropylamine salt (montelukast dipropylamine salt purity 99.7%, methyl Styrene content 0.03%) was obtained (yield 79.8%).
It is obtained by adding 30 ml of toluene and 15 ml of water to 3.0 g of crystals of montelukast dipropylamine salt, stirring and mixing, adding 0.30 g of acetic acid to the resulting liquid, stirring for 30 minutes, and then removing the aqueous layer. The organic layer was cooled to 4 ° C., and the precipitated crystals were collected by pressure filtration and dried under reduced pressure to obtain montelukast free acid crystals. To the liquid obtained by adding 30 ml of methanol to the obtained montelukast free acid crystals and stirring and mixing, 0.15 g of sodium hydroxide was added and stirred for 1 hour, then the solvent was distilled off, and the precipitated crystals were filtered by pressure filtration. Taking and drying under reduced pressure, 2.9 g of Montelukast sodium (Montelukast sodium purity 99.9%, methylstyrene content 0.02%) was obtained (yield 93.2%).

Comparative Example 1
In the thioetherification step of Example 1, the same operation was performed except that triethylamine was not used, and 6.28 g of montelukast methyl ester oil (montelukast methyl ester purity 77.0%, methylstyrene content 3.12%) was obtained. Obtained.

Comparative Example 2
In the thioetherification step of Example 3, the same operation was performed except that N, N-diisopropylethylamine was not used, and a solution of montelukast methyl ester in THF (montelukast methyl ester purity 78.6%, methylstyrene content 2.31). %).

Comparative Example 3
About the THF solution of the montelukast methyl ester obtained by the comparative example 2, operation similar to Example 12 was performed and the montelukast sodium (Montelukast sodium purity 99.5%, methylstyrene body content rate 0.33%) was obtained.

  In Examples 1 to 11, in the thioetherification step, the reaction was carried out in such a manner that 1.0 mol or more of a weakly basic organic compound was present per 1 mol of the mesylate in the reaction system. The production of styrene was suppressed, and a highly pure montelukast methyl ester having a purity of 80% or more and a methylstyrene content of 1% or less was obtained. On the other hand, in Comparative Examples 1 and 2, in the thioetherification step, when the reaction was carried out with the weakly basic organic compound present in the reaction system being less than 1.0 mole relative to 1 mole of mesylate body, a large amount of methylstyrene body was produced. However, high purity montelukast methyl ester could not be obtained. Furthermore, when montelukast sodium was produced using the THF solution of montelukast methyl ester obtained in the present invention, montelukast sodium having a high purity and a low content of montelukast methylstyrene was obtained.

Claims (3)

Following formula (1)

Is reacted with a 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester in the presence of a base having a pKb of −40 or more and 0 or less to give the following formula (2):

(In the formula, R is an alkyl group.)
In a method for producing a montelukast alkyl ester represented by:
A method comprising causing a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less to exist in the reaction system in the reaction in an amount of 1.0 mol or more with respect to 1 mol of the mesylate body. Following formula (3)

And a nitrogen-containing organic compound having a pKb of 1 to 6 in the following formula (1):

And a mesylation step for obtaining a solution containing a mesylate body represented by formula (1) and a nitrogen-containing organic compound having a pKb of 1 to 6, and the solution, 1- (mercaptomethyl) cyclopropaneacetic acid alkyl ester and pKb of −40 to 0 The following formula (2) by mixing with a certain base

(In the formula, R is an alkyl group.)
In the method for producing the montelukast alkyl ester, comprising a thioetherification step of obtaining a solution containing the montelukast alkyl ester represented by:
A method wherein a nitrogen-containing organic compound having a pKb of 1 or more and 6 or less is present in the reaction system in the thioetherification step in an amount of 1.0 mol or more relative to 1 mol of the mesylate body. The method according to claim 1 or 2, wherein the following formula (2)

(In the formula, R is an alkyl group.)
A process for producing a montelukast alkyl ester represented by the following formula (4):

A method for producing montelukast sodium, comprising: a hydrolysis step for obtaining montelukast free acid, and a sodium salification step for obtaining montelukast sodium by sodium chlorinating the montelukast free acid.