JP2016020320A - Method for manufacturing montelukast sodium - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently manufacturing high purity montelukast sodium without producing montelukast free acid.SOLUTION: There is provided a method of manufacturing high purity montelukast sodium by making a strong basic aqueous solution of sodium act on a montelukast amine salt represented by the following formula I, where Rand Rrepresent each independently hydrogen, an alkyl group or a cycloalkyl group, and Rrepresents an alkyl group or a cycloalkyl group.SELECTED DRAWING: None

Description

  The present invention relates to an improved process for producing montelukast sodium.

で表される化学名：（１−｛１−（Ｒ）−（Ｅ）−｛３−［２−（７−クロロ−キノリン−２−イル）−ビニル］−フェニル｝−３−［２−（１−ヒドロキシ−１−メチル−エチル）−フェニル］−プロピルスルファニルメチル｝−シクロプロピル）−酢酸ナトリウム（以下、「モンテルカストナトリウム」という。）であり、気管支喘息治療薬およびアレルギー性鼻炎治療薬の有効成分として有用である。 Montelukast sodium is the following formula:

Chemical name represented by: (1- {1- (R)-(E)-{3- [2- (7-chloro-quinolin-2-yl) -vinyl] -phenyl} -3- [2- (1-hydroxy-1-methyl-ethyl) -phenyl] -propylsulfanylmethyl} -cyclopropyl) -sodium acetate (hereinafter referred to as “Montelukast sodium”), a therapeutic agent for bronchial asthma and a therapeutic agent for allergic rhinitis Useful as an active ingredient.

  As a method for producing montelukast sodium, a water-soluble organic acid such as acetic acid is allowed to act on montelukast amine salt to produce montelukast free acid, and then treated with a sodium ion source such as sodium hydroxide to obtain montelukast sodium. Known (Patent Document 1). In the case of this method, since a free acid with low solubility is generated, the amount of the solvent to be used increases, so there are problems in terms of the environment and cost.

  On the other hand, a solid sodium tert-butoxide (patent document 2) or a solid sodium methoxide (non-patent document 1) as a sodium ion source is directly acted on a montelukast amine salt, and montelukast sodium is produced without generating a free acid. A method of manufacturing is also known. However, in this case, a sulfoxide compound, which is a related substance of montelukast sodium, and a by-product to which a methoxy group is added are generated, which is not a sufficient method for obtaining high-purity montelukast sodium.

Japanese Patent No. 3640962 JP 2008-510840 A

Organic Process Research & Development Vol. 14, No. 2, 2010

  An object of this invention is to provide the method of manufacturing a montelukast sodium of high purity efficiently, without producing | generating a montelukast free acid.

  As a result of intensive studies to solve the above problems, the present inventors have found that the object of the present invention can be achieved by using a strong base aqueous solution of sodium as a sodium ion source of montelukast sodium. It came to be completed.

（式中、Ｒ¹およびＲ²は各々独立して、水素、アルキル基またはシクロアルキル基であり、Ｒ³がアルキル基またはシクロアルキル基である。）
で表されるモンテルカストアミン塩に、ナトリウムの強塩基水溶液を作用させることを特徴とする、高純度モンテルカストナトリウムの製造方法。
２．ナトリウムの強塩基水溶液が、ＮａＯＨ、Ｎａ₂ＣＯ₃、Ｎａ₃ＰＯ₄の水溶液である、１．に記載の製造方法。 That is, the present invention has the following configuration.
1. In a water-insoluble solvent, Formula I:

(In the formula, R ¹ and R ² are each independently hydrogen, an alkyl group or a cycloalkyl group, and R ³ is an alkyl group or a cycloalkyl group.)
A method for producing high-purity montelukast sodium, wherein a strong base aqueous solution of sodium is allowed to act on a montelukastamine salt represented by the formula:
2. 1. A strong base aqueous solution of sodium is an aqueous solution of NaOH, Na ₂ CO ₃ , Na ₃ PO ₄ . The manufacturing method as described in.

  According to the method of the present invention, montelukast free acid is not generated, and highly pure montelukast sodium free of impurities can be produced efficiently. Moreover, according to the method of the present invention, it is advantageous in that it is possible to suppress the mixing of the raw material montelukastamine salt remaining unreacted.

（式中、Ｒ¹およびＲ²は各々独立して、水素、アルキル基またはシクロアルキル基であり、Ｒ³がアルキル基またはシクロアルキル基である。）
で表される。ここで、式中のアルキル基またはシクロアルキル基は、特に限定されるものではないが、好ましくは、炭素数１〜１０の直鎖又は分岐アルキル基、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、sec−ブチル基、ｔ−ブチル基、ペンチル基等、または炭素数３〜１０のシクロアルキル基、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等である。
本発明で使用される式Ｉで表されるモンテルカストアミン塩は、モンテルカストジプロピルアミン塩、モンテルカストジシクロヘキシルアミン塩、モンテルカストイソプロピルアミン塩等が好ましく、モンテルカストジプロピルアミン塩が特に好ましい。 The present invention will be specifically described below.
In the present invention, the starting material montelukastamine salt is represented by the following formula I:

(In the formula, R ¹ and R ² are each independently hydrogen, an alkyl group or a cycloalkyl group, and R ³ is an alkyl group or a cycloalkyl group.)
It is represented by Here, the alkyl group or cycloalkyl group in the formula is not particularly limited, but is preferably a linear or branched alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, Isopropyl group, butyl group, sec-butyl group, t-butyl group, pentyl group, etc., or a cycloalkyl group having 3 to 10 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc. It is.
The montelukast amine salt represented by the formula I used in the present invention is preferably montelukast dipropylamine salt, montelukast dicyclohexylamine salt, montelukast isopropylamine salt, etc., and montelukast dipropylamine salt is particularly preferred.

  The montelukastamine salt represented by the formula I used in the present invention is commercially available or can be produced by methods well known to those skilled in the art. For example, a montelukast dipropylamine salt can be obtained by adding dipropylamine to montelukast in toluene and allowing it to crystallize.

  The present invention is characterized in that a strong base aqueous solution of sodium is allowed to act on the montelukastamine salt represented by the formula I in a water-insoluble solvent.

The water-insoluble solvent used in the present invention is not particularly limited as long as it dissolves the montelukastamine salt. For example, aromatic compounds such as benzene, toluene, xylene and mesitylene, diethyl ether, methyl -Ether compounds such as -t-butyl ether and diisopropyl ether, and halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. These water-insoluble organic solvents may be used alone or in combination of two or more. Among these, aromatic compounds such as toluene and xylene are preferable, and toluene is particularly preferable.
The concentration of the montelukast amine salt in the water-insoluble solvent used in the present invention is usually 0.01 to 5 mmol / mL, preferably 0.1 to 5 mmol / mL.

The strong base aqueous solution of sodium used in the present invention is not particularly limited as long as it is a strong base aqueous solution that becomes a sodium ion source of montelukast sodium. For example, NaOH, Na ₂ CO ₃ , Na ₃ PO ₄ An aqueous solution can be mentioned, and an aqueous solution of NaOH and Na ₂ CO ₃ is preferable, and an aqueous solution of NaOH is particularly preferable.
The amount of sodium strong base used in the present invention is usually 1 to 5 equivalents, preferably 1 to 2 equivalents relative to the montelukastamine salt, and the concentration of the sodium strong base aqueous solution is usually 10 to 50%. And preferably 10 to 25%.

  The reaction temperature is usually 20 to 100 ° C, preferably 20 to 80 ° C, particularly preferably 30 to 50 ° C. The reaction time varies depending on the reaction temperature and the type and amount of the compound used, but is usually 1 to 12 hours.

Sodium chloride may be added after the reaction to promote dehydration of the organic layer by salting out. Sodium chloride may be added in a solid state or in an aqueous solution state, preferably in a solid state. The usage-amount of sodium chloride is 1-5 equivalent with respect to a montelukast amine salt, Preferably it is 1-2 equivalent.
The temperature after adding sodium chloride is usually 20 to 100 ° C, preferably 20 to 80 ° C, particularly preferably 20 to 40 ° C.

Further, a saturated aqueous solution of an inorganic salt may be added to promote dehydration of the organic layer. The inorganic salt is not particularly limited as long as the water contained in the organic layer can be removed by the saturated aqueous solution, and examples thereof include NaOH, NaCl, KOH, and KCl, and preferably NaOH.
The temperature after adding the saturated aqueous solution of the inorganic salt is usually 20 to 100 ° C, preferably 20 to 80 ° C, particularly preferably 20 to 40 ° C.

Concentration is vacuum concentration or normal pressure concentration, preferably vacuum concentration. The temperature at the time of concentration is usually 40 to 110 ° C, preferably 40 to 60 ° C. In order to promote dehydration of the concentrated solution by azeotropic distillation, an arbitrary amount of the non-aqueous solvent used in the reaction may be added, and the concentration may be repeated any number of times.
The concentration of montelukast sodium in the non-aqueous solvent after the concentration is usually 0.01 to 5 mmol / mL, preferably 0.1 to 5 mmol / mL.

  The method for obtaining solid montelukast sodium can be carried out by methods well known to those skilled in the art. For example, solid montelukast sodium can be obtained by dropping montelukast sodium in a water-insoluble solvent by dropping it into a nonpolar solvent after filtering the insoluble matter.

The nonpolar solvent is not particularly limited as long as the solubility of montelukast sodium is low, and examples thereof include saturated hydrocarbon compounds such as pentane, hexane, and heptane, and heptane is particularly preferable. The amount of the nonpolar solvent used is 2 to 10 times, preferably 2 to 4 times the amount of the water-insoluble solvent used during the reaction. The temperature during and after the dropping is usually 20 to 80 ° C, preferably 20 to 40 ° C.
EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to these.

Example 1
Under a nitrogen gas atmosphere, montelukast dipropylamine salt (5.0 g) was added to toluene (25.0 mL) at room temperature and stirred. Thereto was added a 10% aqueous sodium hydroxide solution (3.06 g, 1.05 eq), heated to 40 ° C., and stirred for 2 hours.
Sodium chloride (0.69 g) was added to the solution after the reaction and stirred, then cooled to 25 ° C., and stirring was stopped at 25 ° C. Two layers were formed, the aqueous layer was removed, 48% aqueous sodium hydroxide solution (5.0 g) was added to the obtained organic layer, and the mixture was stirred at 25 ° C. After stopping stirring at 25 ° C., two layers were formed and the aqueous layer was removed.
About the obtained organic layer, it concentrated under reduced pressure at 50 degreeC until the quantity of the concentrate became about 20 mL. Toluene (10 mL) was added to the obtained concentrated solution, and the solution was concentrated again under reduced pressure at 50 ° C. until the amount of the concentrated solution reached about 20 mL. While the obtained concentrated liquid was filtered, the container was washed with toluene (2.5 mL), and the washing liquid was also filtered to obtain a toluene solution of montelukast sodium. In a nitrogen gas atmosphere, the above toluene solution of montelukast sodium was added dropwise to heptane (75 mL). The container was washed with toluene (2.5 mL), and the washing solution was also added dropwise. After dropping, the mixture was stirred at room temperature for 5 hours, filtered, and cake washed with heptane (15 mL) to obtain a solid montelukast sodium (6.05 g) containing moisture.

(Example 2)
Under a nitrogen gas atmosphere, montelukast dipropylamine salt (5.0 g) was added to toluene (25.0 mL) at room temperature and stirred. Thereto, 25% aqueous sodium hydroxide solution (1.16 g, 1.0 eq) was added, heated to 40 ° C. and stirred for 2 hours.
Then, it concentrated under reduced pressure at 50 degreeC until the quantity of the concentrate became about 20 mL. Toluene (10 mL) was added to the obtained concentrated solution, and the solution was concentrated again under reduced pressure at 50 ° C. until the amount of the concentrated solution reached about 20 mL. The obtained concentrated liquid was filtered to obtain a toluene solution of montelukast sodium. The montelukast sodium toluene solution was added dropwise to heptane (75 mL) under a nitrogen gas atmosphere. The container was washed with toluene (5 mL), the washing liquid was filtered, and the washing liquid was also added dropwise. After dropping, the mixture was stirred at room temperature for 11 hours, filtered, and cake washed with heptane (15 mL) to obtain a solid montelukast sodium (3.23 g) containing moisture.

(Example 3)
Under a nitrogen gas atmosphere, montelukast dipropylamine salt (5.0 g) was added to toluene (25.0 mL) at room temperature and stirred. Thereto, 25% aqueous sodium hydroxide solution (1.16 g, 1.0 eq) was added, heated to 70 ° C. and stirred for 2 hours.
Thereafter, a solid montelukast sodium (4.09 g) containing moisture was obtained in the same manner as in Example 2.

Example 4
Under a nitrogen gas atmosphere, montelukast dipropylamine salt (5.0 g) was added to toluene (25.0 mL) at room temperature and stirred. Thereto, 10% aqueous sodium hydroxide solution (5.82 g, 2.0 eq) was added, heated to 40 ° C., and stirred for 2 hours.
Thereafter, a solid montelukast sodium (4.61 g) containing moisture was obtained in the same manner as in Example 2.

(Comparative Example 1)
Under a nitrogen gas atmosphere, solid (pellet) sodium hydroxide (1.72 kg, 1.1 eq) and montelukast dipropylamine salt (26.55 kg) were added to toluene (69.1 kg) at room temperature and heated to 70 ° C. And stirred for 6.5 hours. The deposition of a white solid was confirmed, and a part of the reaction solution was sampled and analyzed. As a result, about 30 mol% of montelukast dipropylamine salt remained.
Sodium hydroxide (1.32 kg, 0.8 eq) was added, and the mixture was stirred at 70 ° C. for 3 hr. Sodium sulfate (1.64 kg, 0.062% w / w) was added at 25 ° C., and the mixture was stirred for 1 hour. To another reactor, heptane (271.7 kg) was added under a nitrogen gas atmosphere, and the mixture was stirred at 25 ° C. The toluene solution of said montelukast sodium was dripped through the filter. The line was washed with toluene (22.8 kg), and the washing solution was also added dropwise. The mixture was stirred at 25 ° C. for 1 hour, filtered, washed with heptane (54.6 kg), and dried at 60 ° C. for 9 hours to obtain solid montelukast sodium (19.92 kg).
As a result of NMR analysis, the obtained sodium montelukast contained 12.3 mol% of montelukast dipropylamine salt.

  When using an aqueous sodium hydroxide solution (Examples 1 to 4) or solid sodium hydroxide (Comparative Example 1) as a sodium ion source, the obtained montelukast dipropylamine salt (MTK-D) in montelukast sodium was obtained. The remaining amounts are shown in the table below.

(Comparative Example 2)
Under a nitrogen gas atmosphere, solid (powder) sodium methoxide (0.12 g, 1.5 eq) and montelukast dipropylamine salt (1.0 g) were added to toluene (5.0 mL) at room temperature and heated to 70 ° C. Stir for 1 hour.
When a part of the reaction solution was sampled and analyzed, impurities added with a methoxy group increased. (0.007% before addition of sodium methoxide → 0.128% after 1 hour of reaction)

Claims (2)

In a water-insoluble solvent, Formula I:

(In the formula, R ¹ and R ² are each independently hydrogen, an alkyl group or a cycloalkyl group, and R ³ is an alkyl group or a cycloalkyl group.)
A method for producing high-purity montelukast sodium, wherein a strong base aqueous solution of sodium is allowed to act on a montelukastamine salt represented by the formula: A strong base aqueous solution of sodium, NaOH, an aqueous solution of _{Na 2 CO 3, Na 3 PO} 4, The method according to claim 1.