KR20090051855A - Novel polymorphs of montelukast cyclohexylamine salt and the preparing method thereof - Google Patents

Abstract

The present invention provides montelukast novel cyclohexylamine crystalline forms A, B, methods of preparation thereof and uses thereof.

Montelukast, Cyclohexylamine, Crystalline, Sodium Salt

Description

Novel Polymorphs of Montelukast Cyclohexylamine Salt And The Preparing Method Thereof}

The present invention relates to montelukast amine salts and a process for their preparation.

Montelukast is an antagonist of Leukotriene receptors used to treat asthma and to relieve symptoms of seasonal allergies. Montelukast is administered orally and binds to the cysteinyl leukotriene receptor CysLT ₁ in the lungs and bronchus and inhibits the action of leukotriene D4. In this way, bronchial contraction caused by leukotriene is suppressed and inflammation is alleviated.

Montelukast has the following structural formula and was first developed by Merck and marketed under the trade name Singulair in the form of montelukast sodium salt. The original patent for this is US Patent No. 5,565,473.

The method for preparing the montelukast sodium salt described in the above patent is a method of preparing montelukast acid and immediately converting it to sodium salt without separating the acid. However, this process requires complex column chromatography purification in the preparation or final stage of the montelukast acid methyl ester intermediate and is not suitable for large scale production because of the low yield of the product.

Korean Registered Patent No. 319336 discloses a montelukast dicyclohexylamine salt and its crystalline form, and a process for crystallizing the sodium salt of montelukast by treating the salt with an acid and treating the obtained product with an ion source with sodium salt. Doing. This preparation method utilizes crystalline dicyclohexylamine salts as intermediates to separate and purify the montelukast compound more simply and effectively, providing a high yield of the final product.

US Patent Publication No. 2005/0107612 discloses a process for preparing montelukast sodium salt via montelukast t-butylamine salt or phenylethyl amine salt.

WO 2006/008751 discloses dipropylamine, α-methylbenzylamine, dibenzylamine, diisopropyl amine salt as examples of montelukast amine salts, and WO 2007/004237 discloses α-methylbenzylamine, A method for synthesizing montelukast sodium salt using cyclohexylethylamine, dipropylamine salt is disclosed.

Korean Patent Application No. 2007-7005247 (WO 2007/005965) also discloses a process for preparing montelukast sodium salt using montelukast dipropylamine and isopropylamine salts.

In addition, WO 2007/096875 discloses novel polymorphs for various montelukast amine salts, in particular crystalline Form II and Form V of cyclohexylamine salts.

It is an object of the present invention to provide new amine salts of montelukast and methods for their synthesis.

The present invention is represented by the following structural formula (I), and the chemical name is (R)-(E) -1-(((1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl)- There is provided a montelukast cyclohexylamine salt which is 3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid cyclohexylamine salt.

In the present invention, (R)-(E)-having a strong diffraction peak value (I / I ₀ ) where 2θ is 7.5, 16.6, 17.9, 18.6, 19.8, 21.7, 22.5, 24.6 in the X-ray powder diffraction pattern. 1-(((1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) Crystalline form A of thio) methyl) cyclopropaneacetic acid cyclohexylamine salt (crystalline form A of montelukast cyclohexylamine salt) is provided. More specifically, the crystalline form A of the montelukast cyclohexylamine salt of the present invention has the following X-ray powder diffraction pattern.

Diffraction angle (2θ) Strength (I / I ₀ ) Diffraction angle (2θ) Strength (I / I ₀ ) 7.5 123.0 19.8 67.3 8.3 27.9 21.7 80.6 9.1 23.5 22.5 79.0 11.3 8.1 24.6 67.3 12.6 12.7 25.9 31.0 14.4 36.4 26.7 25.5 16.6 71.7 28.3 12.1 17.9 124.0 29.2 10.0 18.6 104.0 31.6 8.6

The peak of the X-ray powder diffraction pattern may vary by ± 0.2 ° of the diffraction angle 2θ according to a change in a measuring apparatus or the like.

In addition, Form A of the montelukast cyclohexylamine salt of the present invention has a wave number (cm ⁻¹ ) of the following FT-IR spectrum; 781, 840, 862, 932, 965, 984, 1015, 1047, 1069, 1107, 1141, 1164, 1223, 1240, 1276, 1311, 1334, 1407, 1439, 1497, 1524, 1606, 1632, 2226, 2632, 2930, 2941, 3068.

The invention also provides (R)-(E) -1 having a strong diffraction peak value (I / I ₀ ) where 2θ is 8.5, 15.3, 16.7, 17.9, 19.9, 20.5, 21.1 in the X-ray powder diffraction pattern. -(((1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio Crystalline B (crystalline form B of montelukast cyclohexylamine salt) is provided as a) methyl) cyclopropaneacetic acid cyclohexylamine salt. More specifically, the crystalline form B of the montelukast cyclohexylamine salt of the present invention has a peak of the X-ray powder diffraction pattern described in the following table.

Diffraction angle (2θ) Strength (I / I ₀ ) Diffraction angle (2θ) Strength (I / I ₀ ) 6.7 7.7 21.1 49.6 8.5 45.4 22.7 24.9 9.1 35.6 24.3 32.2 14.3 39.1 25.7 15.8 15.3 40.4 26.9 9.6 16.7 80.2 28.3 10.4 17.9 133.0 31.5 8.8 19.9 86.3 34.8 5.1 20.5 50.6

In addition, Form B of the montelukast cyclohexylamine salt of the present invention has a wave number (cm ⁻¹ ) of the following FT-IR spectrum; 837, 926, 966, 1015, 1067, 1164, 1223, 1242, 1275, 1335, 1390, 1406, 1440, 1496, 1526, 1557, 1606, 1633, 2212, 2856, 2934, 3050.

The montelukast cyclohexylamine salt of the present invention may be prepared according to a known method for preparing montelukast amine salt, and may also be prepared by the following method.

Accordingly, the present invention provides a process for the preparation of Form A of montelukast cyclohexylamine salt comprising the following steps;

a) adding amine to montelukast acid dissolved in an organic solvent and stirring to generate a solid;

b) filtering the solid produced in step a) and drying under reduced pressure to obtain a crude montelukast amine salt;

  c) adding an organic solvent, water, and an acid to the crude montelukast amine salt obtained in step b), stirring, and then extracting with an organic solvent;

d) washing the organic layer extracted in step c) with water and concentrating;

e) dissolving the concentrate obtained in step d) in toluene, adding cyclohexylamine and stirring overnight at room temperature to produce a solid; And

f) adding acetonitrile to the solution in which the solid was formed in step e), followed by further stirring, followed by filtration and drying under reduced pressure to obtain a product.

The present invention also provides a process for preparing Form B of montelukast cyclohexylamine salt comprising the following steps;

a) adding amine to montelukast acid dissolved in an organic solvent and stirring to produce a solid;

b) filtering the solid produced in step a) and drying under reduced pressure to obtain a crude montelukast amine salt;

  c) adding an organic solvent, water, and an acid to the crude montelukast amine salt obtained in step b), stirring, and then extracting with an organic solvent;

d) washing the organic layer extracted in step c) with water and concentrating;

e) dissolving the concentrate obtained in step d) in ethyl acetate and adding cyclohexylamine and stirring at room temperature overnight to produce a solid; And

f) adding diisopropyl ether to the solution in which the solid was formed in step e), followed by further stirring, followed by filtration and drying under reduced pressure to obtain a product.

In the method for preparing crystalline forms A and B of the montelukast cyclohexylamine salt, the amine of step a) means an amine used to prepare the montelukast amine salt, for example, benzylamine, α-methylbenzylamine, t- Butylamine, phenylethylamine, dibenzylamine, diisopropylamine, cyclopentylamine, cyclohexylethylamine, dipropylamine and the like. In addition, the organic solvent in step a) is preferably at least one selected from the group consisting of ethyl acetate, toluene, acetonitrile, isopropyl alcohol, diisopropyl ether and methanol.

In the above production method, the organic solvent of step c) means an organic solvent commonly used in the art, for example, dichloromethane, ethyl acetate, ether and the like. Acids usable in step c) mean acids known in the art to react with amine salts, such as acetic acid, hydrochloric acid, tartaric acid and the like.

The present invention also provides a method for preparing montelukast sodium salt comprising dissolving montelukast cyclohexylamine salt of the present invention in an organic solvent, removing cyclohexylamine using an acid, and adding sodium. The organic solvents and acids used here are the same as mentioned above. In addition, in the preparation of montelukast sodium salt, the available sodium donor compound means a sodium donor compound used to form sodium salts known in the art, for example, sodium t-butoxide, sodium methoxide, sodium Toxoxide, sodium hydroxide and the like.

The present invention provides a polymorph of the novel montelukast cyclohexylamine salt, and provides the effect of making the montelukast sodium salt manufacturing process simpler and more efficient.

The invention is further illustrated by the following examples. The following non-limiting examples merely illustrate the preparation of the invention and do not limit the scope of the invention. The production method according to the invention is characterized in that it can be easily applied to general industrial production. Crystal forms A and B of the montelukast cyclohexylamine salt formed by the following examples are characterized by X-ray diffraction patterns by X-ray diffraction and peaks seen in the FT-IR spectrum.

Starting material Production Example Joe Montelukast Of benzylamine salt  Produce

2- (2- (3 (S)-(3- (2- (7-chloro-2-quinolinyl) -ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-propanol (30 g) Was added to tetrahydrofuran (THF, 120 ml) followed by diisopropylethylamine (DIPEA, 11.5 g). The solution was then cooled to -15 [deg.] C. and kept below -10 [deg.] C. to this solution was added methanesulfonylchloride (8.7 g). After that, the solution was stirred for about 1 hour at -10 ° C ~ 0 ° C, and then filtered.

Sodium hydroxide (13.1 g) was dissolved in purified water (15 ml), and dimethyl sulfoxide (DMSO, 120 ml) and 1- (mercaptomethyl) cyclopropaneacetic acid (19.2 g) were added to the solution, followed by cooling. To this solution was added the filtrate prepared above. Thereafter, the mixture was stirred for 2 hours at room temperature, and ethyl acetate (540 ml) and 10% NaCl aqueous solution (540 ml) were added to the solution to terminate the reaction. The organic layer was extracted using a separatory funnel, and the water layer was extracted once more with ethyl acetate (180 ml). The organic layer was washed with 0.5 M aqueous tartaric acid solution (330 ml) and 10% aqueous NaCl solution (260 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The oily compound was dissolved in ethyl acetate (300 ml) and benzylamine (7.0 g) was added at room temperature and then stirred overnight. The resulting solid was filtered, washed with ethyl acetate (100 ml) and dried under reduced pressure at 40 ° C. Yield of the product was 29.99 g (yield: 66%) and purity was 98.6% (HPLC area).

Example  One : Montelukast Of cyclohexylamine salt  Form A Preparation

Crude montelukast benzylamine salt (7 g), dichloromethane (70 ml), purified water (70 ml) and acetic acid (0.87 ml) obtained in the starting material preparation were added and stirred at room temperature for about 30 minutes. Thereafter, the dichloromethane layer was extracted and washed with purified water (42 ml), dried over anhydrous sodium sulfate, filtered and concentrated. Toluene (91 ml) was added to this concentrated solution, and cyclohexylamine (1.0 g) was added at room temperature, followed by stirring overnight. Acetonitrile (7 ml) was added and stirred well, then the solid was filtered, washed with toluene (25 ml) and dried under reduced pressure at 40 ° C. The yield of the final product was 6.30 g (yield: 90%) and the purity was 99.5% (HPLC area). X-ray powder diffraction data of the product is shown in the following table, the graph is shown in FIG.

Diffraction angle (2θ) Strength (I / I ₀ ) Diffraction angle (2θ) Strength (I / I ₀ ) 7.5 123.0 19.8 67.3 8.3 27.9 21.7 80.6 9.1 23.5 22.5 79.0 11.3 8.1 24.6 67.3 12.6 12.7 25.9 31.0 14.4 36.4 26.7 25.5 16.6 71.7 28.3 12.1 17.9 124.0 29.2 10.0 18.6 104.0 31.6 8.6

(The X-ray powder diffraction data was analyzed using a powder X-ray diffractometer model D8 FOCUS (2.2KW) of BRUKER AXS equipped with a rotational meter and a solid state detector, and the analysis range was 5 ° to 40 ° and 3 ° per minute). Obtained by methods known in the art under rate conditions.)

The wave number (cm ⁻¹ ) of the FT-IR spectrum of the product is as follows, and the graph is as shown in FIG. 2.

781, 840, 862, 932, 965, 984, 1015, 1047, 1069, 1107, 1141, 1164, 1223, 1240, 1276, 1311, 1334, 1407, 1439, 1497, 1524, 1606, 1632, 2226, 2632, 2930, 2941, 3068 (The FT-IR spectra were measured according to the general method recorded in the Korean Pharmacopoeia.)

DSC diagram of the product as the title compound is as shown in Figure 3, the value was 102.9 ℃. DSC is a value measured by reaction temperature of 10 degree-C / min and temperature range of 25-200 degreeC using Seiko Exstar 6000 (DSC6100) (manufacturer: SEICO INST. (JAPAN)).

Example  2: Montelukast Of cyclohexylamine salt  Form B Production

Crude montelukast benzylamine salt (7 g), dichloromethane (70 ml), purified water (70 ml) and acetic acid (0.87 ml) obtained in the starting material preparation were added and stirred at room temperature for about 30 minutes. Thereafter, the dichloromethane layer was extracted and washed with purified water (42 ml). The dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated. Ethyl acetate (49 ml) was added to the concentrated solution, and cyclohexylamine (1.0 g) was added at room temperature, followed by stirring overnight. Diisopropyl ether (98 ml) was added, the mixture was sufficiently stirred and the solid was filtered. It dried under reduced pressure. The yield of the final product was 6.44 g (yield: 92%) and the purity was 98.9% (HPLC area). The X-ray powder diffraction data of the product is shown in the following table, and the graph is shown in FIG. 4 (the measurement method of X-ray powder diffraction is the same as in Example 1).

Diffraction angle (2θ) Strength (I / I ₀ ) Diffraction angle (2θ) Strength (I / I ₀ ) 6.7 7.7 21.1 49.6 8.5 45.4 22.7 24.9 9.1 35.6 24.3 32.2 14.3 39.1 25.7 15.8 15.3 40.4 26.9 9.6 16.7 80.2 28.3 10.4 17.9 133.0 31.5 8.8 19.9 86.3 34.8 5.1 20.5 50.6

The wave number of the FT-IR spectrum of the product (cm ⁻¹ ) is as follows, and the graph is as shown in FIG. 5.

837, 926, 966, 1015, 1067, 1164, 1223, 1242, 1275, 1335, 1390, 1406, 1440, 1496, 1526, 1557, 1606, 1633, 2212, 2856, 2934, 3050

(The FT-IR spectrum was measured according to the general method recorded in the Korean Pharmacopoeia.)

DSC diagram of the product as the title compound is as shown in Figure 6, the value was 120.2 ℃. DSC is a value measured by reaction temperature of 10 degree-C / min and temperature range of 25-200 degreeC using Seiko Exstar 6000 (DSC6100) (manufacturer: SEICO INST. (JAPAN)).

Example 3 : Montelukast Cyclohexylamine salt  Used Montelukast  Preparation of Sodium Salt

Montelukast cyclohexylamine salt (6 g), dichloromethane (60 ml), purified water (60 ml) and acetic acid (1.0 ml) obtained in Example 1 were added thereto, and the mixture was stirred at room temperature for about 30 minutes. Then, dichloromethane layer was extracted, which was washed with purified water (36ml). The dichloromethane layer was dried over anhydrous sodium sulfate and filtered, then sodium t-butoxide (0.84 g) was added, stirred and concentrated. This concentrate was dissolved in toluene (30 ml) and added to the flask containing heptane (90 ml) in portions to form a precipitate, stirred for 1 hour and the solid was filtered off. The filtered solid was washed with a mixed solvent of toluene: heptane 1: 3 (v / v) and dried under reduced pressure at 40 ° C. The yield of the resulting montelukast sodium salt was 4.79 g, the yield was 90%, the purity was 99.5% (HPLC area).

FIG. 1 shows an X-ray powder diffraction diagram of crystalline Form A of montelukast cyclohexylamine salt prepared in Example 1 of the present invention.

Figure 2 shows the FT-IR spectrum of Form A of the montelukast cyclohexylamine salt prepared in Example 1 of the present invention.

       Figure 3 shows the DSC diagram of the crystalline Form A of the montelukast cyclohexylamine salt prepared in Example 1 of the present invention.

Figure 4 shows the X-ray powder diffraction diagram of crystalline Form B of montelukast cyclohexylamine salt prepared in Example 2 of the present invention.

Figure 5 shows the FT-IR spectrum of Form B of the montelukast cyclohexylamine salt prepared in Example 2 of the present invention.

       FIG. 6 is a DSC diagram of crystalline Form B of montelukast cyclohexylamine salt prepared in Example 2 of the present invention.

Claims (9)

(R)-(E) -1- () with strong diffraction peak value (I / I ₀ ) where 2θ is 7.5, 16.6, 17.9, 18.6, 19.8, 21.7, 22.5, 24.6 in the X-ray powder diffraction pattern ((1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl ) Crystalline form A of cyclopropane acetic acid cyclohexylamine salt (crystalline form A of montelukast cyclohexylamine salt). The method of claim 1, wherein 2θ in the X-ray powder diffraction pattern is 7.5, 8.3, 9.1, 11.3, 12.6, 14.4, 16.6, 17.9, 18.6, 19.8, 21.7, 22.5, 24.6, 25.9, 26.7, 28.3, 29.2, 31.6 Form A of Phosphorus Montelukast Cyclohexylamine Salt. The crystalline form A of claim 1 or 2, wherein the montelukast cyclohexylamine salt has a wave number (cm ⁻¹ ) of the following FT-IR spectrum; 781, 840, 862, 932, 965, 984, 1015, 1047, 1069, 1107, 1141, 1164, 1223, 1240, 1276, 1311, 1334, 1407, 1439, 1497, 1524, 1606, 1632, 2226, 2632, 2930, 2941, 3068. A process for preparing Form A of the montelukast cyclohexylamine salt of claim 1, 2 or 3 comprising the following steps; a) adding amine to montelukast acid dissolved in an organic solvent and stirring to produce a solid; b) filtering the solid produced in step a) and drying under reduced pressure to obtain a crude montelukast amine salt;   c) adding an organic solvent, water, and an acid to the crude montelukast amine salt obtained in step b), stirring, and then extracting with an organic solvent; d) washing the organic layer extracted in step c) with water and concentrating; e) dissolving the concentrate obtained in step d) in toluene, adding cyclohexylamine and stirring overnight at room temperature to produce a solid; And f) adding acetonitrile to the solution in which the solid was formed in step e), followed by further stirring, followed by filtration and drying under reduced pressure to obtain a product. (R)-(E) -1-(((with the strong diffraction peak value (I / I ₀ ) where 2θ is 8.5, 15.3, 16.7, 17.9, 19.9, 20.5, 21.1 in the X-ray powder diffraction pattern) 1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclo Form B of propane acetic acid cyclohexylamine salt (crystalline form B of montelukast cyclohexylamine salt). The montelukast of claim 5 wherein 2θ in the X-ray powder diffraction pattern is 6.7, 8.5, 9.1, 14.3, 15.3, 16.7, 17.9, 19.9, 20.5, 21.1, 22.7, 24.3, 25.7, 26.9, 28.3, 31.5, 34.8 Form B of cyclohexylamine salt. The crystalline form B of montelukast cyclohexylamine salt according to claim 5 or 6, having a wave number (cm ⁻¹ ) of the following FT-IR spectrum; 837, 926, 966, 1015, 1067, 1164, 1223, 1242, 1275, 1335, 1390, 1406, 1440, 1496, 1526, 1557, 1606, 1633, 2212, 2856, 2934, 3050. A process for preparing Form B of montelukast cyclohexylamine salt of claim 5, 6 or 7 comprising the following steps; a) adding amine to montelukast acid dissolved in an organic solvent and stirring to produce a solid; b) filtering the solid produced in step a) and drying under reduced pressure to obtain a crude montelukast amine salt;   c) adding an organic solvent, water, and an acid to the crude montelukast amine salt obtained in step b), stirring, and then extracting with an organic solvent; d) washing the organic layer extracted in step c) with water and concentrating; e) dissolving the concentrate obtained in step d) in ethyl acetate and adding cyclohexylamine and stirring at room temperature overnight to produce a solid; And f) adding diisopropyl ether to the solution in which the solid was formed in step e), followed by further stirring, followed by filtration and drying under reduced pressure to obtain a product. After dissolving the montelukast cyclohexylamine salt of any one of claims 1 to 3 and 5 to 7 in an organic solvent, cyclohexylamine is removed using an acid and sodium is added. Method for preparing montelukast sodium salt.

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