KR20090051854A - Novel salt of montelukast and the preparing method thereof - Google Patents

Abstract

The present invention provides a novel montelukast benzylamine salt, its preparation method and its use.

Montelukast, Benzylamine Salt, Crystalline Form, Sodium Salt

Description

Novel salt of Montelukast and the preparing method

The present invention relates to montelukast benzylamine salts and a process for preparing the same.

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 and 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.

It is an object of the present invention to provide a new amine salt of montelukast and its 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 benzylamine salt which is 3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid benzylamine salt.

[Formula I]

The montelukast benzylamine salt of the present invention may have a polymorph. For example, montelukast benzylamine salt is a benzylamine salt crystalline form showing a strong diffraction peak value (I / I ₀ ) where 2θ is 8.2, 16.5, 17.3, 17.7, 20.1, 20.4, 23.3 in the X-ray powder diffraction pattern. Has (I) More specifically, the montelukast benzylamine salt crystalline form (I) 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 ) 5.4 60.2 21.1 40.5 8.2 102.0 21.8 37.2 9.0 68.1 22.4 41.8 10.3 37.4 23.3 117.0 11.7 30.4 24.3 41.3 13.9 11.3 24.7 44.7 14.6 11.2 25.7 55.2 16.5 143.0 26.5 50.5 17.3 141.0 28.2 16.8 17.7 155.0 29.2 21.7 18.7 55.4 30.0 7.2 20.1 197.0 30.7 13.0 20.4 148.0 32.9 30.4

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

The montelukast benzylamine salt of the present invention has a wave number of FT-IR spectrum of 966, 980, 1066, 1133, 1144, 1162, 1237, 1263, 1279, 1312, 1406, 1495, 1592, 1607, 1633, 1697, 2153, 2895 , 2929, 2977, 3059 cm ^-1 .

The montelukast benzylamine 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 preparing the montelukast benzylamine salt of claim 1 comprising the following steps.

a) adding benzylamine 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 benzylamine salt;

  c) adding an organic solvent, water, and an acid to the crude montelukast benzylamine 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; And

e) dissolving the concentrate obtained in step d) in an organic solvent, adding benzylamine and stirring at room temperature overnight, followed by filtration to give the product.

In the above production method, the organic solvent in step a) or e) is preferably at least one selected from the group consisting of ethyl acetate, toluene, acetonitrile, isopropyl alcohol, diisopropyl ether and methanol. More preferably, the organic solvent in step e) is ethyl acetate.

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. In addition, the acid usable in step c) means an acid known in the art to react with benzylamine salt, and examples thereof include acetic acid, hydrochloric acid, tartaric acid, and the like.

The present invention also provides a method for preparing montelukast sodium salt comprising dissolving montelukast benzylamine salt of the present invention in an organic solvent, removing benzylamine using an acid, and then 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 novel montelukast benzylamine salt, thereby providing an 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.

Example  group 1 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  2 : Montelukast  Preparation of Benzylamine Salts

Crude montelukast benzylamine salt (7 g), dichloromethane (70 ml), purified water (70 ml) and acetic acid (0.87 ml) obtained in Example 1 were added and stirred at room temperature for about 30 minutes. Thereafter, the dichloromethane layer was extracted, washed with purified water (42 ml), dried over anhydrous sodium sulfate, filtered and concentrated. This concentrate was dissolved using ethyl acetate (70 ml) and benzylamine (1.1 g) was added at room temperature and then stirred overnight. Thereafter, the resulting solid was filtered, washed with ethyl acetate (25 ml), and dried under reduced pressure of 40 ° C. The yield of the final product was 5.46 g (yield: 78%) and the purity was 99.6% as determined by HPLC.

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 ) 5.4 60.2 21.1 40.5 8.2 102.0 21.8 37.2 9.0 68.1 22.4 41.8 10.3 37.4 23.3 117.0 11.7 30.4 24.3 41.3 13.9 11.3 24.7 44.7 14.6 11.2 25.7 55.2 16.5 143.0 26.5 50.5 17.3 141.0 28.2 16.8 17.7 155.0 29.2 21.7 18.7 55.4 30.0 7.2 20.1 197.0 30.7 13.0 20.4 148.0 32.9 30.4

(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.

966, 980, 1066, 1133, 1144, 1162, 1237, 1263, 1279, 1312, 1406, 1495, 1592, 1607, 1633, 1697, 2153, 2895, 2929, 2977, 3059 (The FT-IR spectrum is It was measured according to the general method recorded in the document.)

DSC diagram of the product as the title compound is as shown in Figure 3, the value was 128.6 ℃. 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 Benzylamine salt  Used Montelukast  Preparation of Sodium Salt

Montelukast benzylamine salt (6 g), dichloromethane (60 ml), purified water (60 ml) and acetic acid (1.0 ml) obtained in Example 2 were added thereto, followed by stirring 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 (0.83 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 produced montelukast sodium salt was 4.84 g, the yield was 92%, the purity was 99.7% (HPLC area).

Figure 1 shows the X-ray powder diffraction diagram of the montelukast benzylamine salt prepared in Example 2 of the present invention.

Figure 2 shows the FT-IR spectrum of the montelukast benzylamine salt prepared in Example 2 of the present invention.

Figure 3 shows the DSC diagram of the montelukast benzylamine salt prepared in Example 2 of the present invention.

Claims (7)

(R)-(E) -1-(((1- (3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3- (2- (1-hydroxy-1 -Methylethyl) phenyl) propyl) thio) methyl) cyclopropaneacetic acid benzylamine salt (montelukast benzylamine salt). The montelukast benzylamine salt of claim 1, having a strong diffraction peak value (I / I ₀ ) where 2θ in the X-ray powder diffraction pattern is 8.2, 16.5, 17.3, 17.7, 20.1, 20.4, 23.3. The method of claim 2, wherein 2θ in the X-ray powder diffraction pattern is 5.4, 8.2, 9.0, 10.3, 11.7, 13.9, 14.6, 16.5, 17.3, 17.7, 18.7, 20.1, 20.4, 21.1, 21.8, 22.4, 23.3, 24.3 Montelukast benzylamine salt which is 24.7, 25.7, 26.5, 28.2, 29.2, 30.0, 30.7, 32.9. The montelukast benzylamine salt according to claim 1, 2 or 3, having a wave number (cm ⁻¹ ) of the following FT-IR spectrum; 966, 980, 1066, 1133, 1144, 1162, 1237, 1263, 1279, 1312, 1406, 1495, 1592, 1607, 1633, 1697, 2153, 2895, 2929, 2977, 3059. A process for preparing the montelukast benzylamine salt of claim 1, 2, 3 or 4 comprising the following steps; a) adding benzylamine 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 benzylamine salt;   c) adding an organic solvent, water, and an acid to the crude montelukast benzylamine 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; And e) dissolving the concentrate obtained in step d) in an organic solvent, adding benzylamine and stirring at room temperature overnight, followed by filtration to give the product. The method for preparing montelukast benzylamine salt according to claim 5, wherein the organic solvent in step e) is at least one selected from the group consisting of ethyl acetate, toluene, acetonitrile, isopropyl alcohol, diisopropyl ether and methanol. The method for preparing montelukast sodium salt comprising dissolving the montelukast benzylamine salt of any one of claims 1 to 4 in an organic solvent, followed by removing the benzylamine using an acid and adding sodium.

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