KR20100135130A - A novel process for preparing montelukast or its sodium salt and a thiolactone and an amine salt intermediate for the process - Google Patents

Abstract

PURPOSE: A novel method for preparing montelukast acid or sodium salt using an intermediate is provided to minimize side reaction and to enhance purification effect. CONSTITUTION: A compound of chemical formula 1a is prepared by reacting compound of chemical formulas 2 and 3 and nucleophile. The nucleophile is sodium hydroxide or potassium hydroxide. The compound of chemical formula 1a is also prepared by reacting compounds of chemical formulas 2 and 3 with alkali metal (C1-C4)alkoxide as a nucleophile to obtain a compound of chemical formula 1c and hydrolyzing the compound of chemical formula 1c.

Description

Novel process for preparing montelukast acid or its sodium salt and intermediates for iolactone and amine salts

The present invention relates to a novel process for the preparation of montelukast acid or its sodium salt, and to thiacolactone intermediates and montelukast amine salt intermediates, and more particularly, to 5-thiaspiro [2,4] heptan-6-one intermediates. By using an amine salt intermediate of montelukast acid, it is possible to minimize side reactions and significantly reduce the generation of lead substances. Accordingly, a novel production method capable of mass-producing montelukast acid or its sodium salt with high purity quality and high yield and Thiolactone intermediates and montelukast amine salt intermediates.

Montelukast acid is a compound of formula 1a, and montelukast sodium is a compound of formula 1b. Montelukast sodium is approved for the treatment of asthma as antagonists of leukotriene receptors, are being released by the trade name SINGULAIR ^® (Singulair ^®). Montelukast sodium is hygroscopic, exhibits optical activity, and is a white or off-white powder.

Methods of synthesizing the compounds of Formulas 1a and 1b are disclosed in European Patent 480717. In this patent, as shown in Scheme 1 below, the methyl- (mercaptomethyl) cyclopropane acetate and the alcohol group of compound [II] prepared from compound [III] are protected with tetrahydropyranyl (THP). Coupling compound [I], which is a ponyl intermediate, to obtain compound [IV] in methyl ester form, and then directly converting to sodium salt form while hydrolyzing with acid to obtain montelukast sodium [V] and freeze drying. Introducing. However, this method is not suitable for mass production because it has to go through several reaction steps, including a protective reaction and a deprotection reaction, and requires purification using chromatography, and is inefficient because of the low yield of the product.

US Patent 5614632 discloses the dilithium salt of compound [VIII] by reacting compound [VII] of 1- (mercaptomethyl) cyclopropaneacetic acid with n-butyllithium, as shown in Scheme 2 below. After coupling reaction with [VI] to produce compound [VIIII], compound [VIIII] was purified using dicyclohexylamine to obtain compound [X], and then reacted with sodium hydroxide to finally give a montelukast sodium salt [ V]. However, this method has a disadvantage in that it is industrially explosive, and therefore has to use n-butyllithium, which is dangerous to use and expensive, and is used as the intermediate of 1- (mercaptomethyl) cyclopropaneacetic acid. Because lithium salts are very unstable in water or air, there are many problems in process efficiency, such as the need to process all processes quickly and react at low temperatures.

US Patent 2005/0234241 discloses compound [XII] by reacting compound [XI] with n-butyllithium and then coupling compound with compound [VI] as shown in Scheme 3 below, compound [XII] The nitrile group was hydrolyzed using a strong base at a high temperature of 100 ° C. or higher to obtain montelukastic acid [VIIII], and then purified using t-butylamine to obtain compound [XIII], which was then reacted with sodium hydroxide to give a final reaction. It is described to obtain montelukast sodium salt [V]. However, this method also uses n-butyllithium, which is dangerous to use industrially and is expensive, and the yield is low because many reactions are carried out at a high temperature during the preparation of compound [VIIII], and many unwanted side reactions occur. There is a problem that a lot of by-products are generated.

WO2006 / 008751 discloses a dicyclohexylamine salt of compound [XV] by sequentially reacting compound [XIIII] with compound [VII] and dicyclohexylamine in the presence of sodium hydride, as shown in Scheme 4 below. A process for producing a montelukast amine salt of compound [XVI] and a montelukast sodium salt of compound [V] is shown. This International Patent discloses that one of the objectives of the invention is to provide a montelukast organic amine salt for use in the preparation of montelukast alkali salts, the solid state of dipropyl, alpha-methylbenzyl, dibenzyl and diisopropyl amine salts. The properties are described. However, these salts have the problem that they are obtained in relatively low yields in the range of 40-65%, and have the disadvantage that they have to react with Greenit yard with butyllithium, which is dangerous for mass production and difficult to handle. There is a disadvantage in that it is not economical to carry out in, which is a factor of the formation of lead substances due to side reactions.

As described above, conventionally known methods for preparing montelukast acid or its sodium salt are low in economic feasibility, complicated synthesis process, and are not suitable for industrial mass production, and it is difficult to remove the soft substances generated during the reaction. It is difficult to prepare montelukast acid or its sodium salt.

The present invention is to solve the problems of the prior art as described above, the object of the present invention is to minimize the side reactions generated during the process to minimize the production of related flexible materials, including styrene-based flexible materials, high purity quality and high yield It is to provide a novel production method capable of mass-producing montelukast acid or its sodium salt, and a thioractone intermediate and montelukast acid amine salt intermediate for the same.

To solve the above technical problem, the present invention provides a compound of Formula 1a, ie, montelukast acid, comprising the step of reacting a compound of Formula 2, a compound of Formula 3, and a nucleophilic agent: :

[Formula 1a]

R ² in Formula 2 is C ₁ -C ₄ alkyl (eg, methyl, ethyl, etc.), phenyl or phenyl substituted with C ₁ -C ₄ alkyl (eg, para-toluene group, etc.).

According to another aspect of the invention, reacting a compound of formula 1a prepared by the method as described above with a compound of formula 4 to produce a compound of formula 5, and the compound of formula 5 with a sodium ion source There is provided a process for the preparation of a compound of formula 1b, i.e. montelukast sodium salt, comprising the step of reacting:

NH ₂ R ³

[Chemical Formula 1b]

In Formulas 4 and 5, R ³ is amyl, isoamyl, t-amyl or 1,2-dimethylpropyl.

According to another aspect of the present invention, there is provided a compound of formula 3 useful as an intermediate of the process for preparing montelukast acid or its sodium salt as described above.

According to another aspect of the present invention, there is provided a process for preparing the compound of formula 3, wherein 1- (mercaptomethyl) cyclopropane acetic acid is cyclized in the presence of an acid.

According to another aspect of the present invention, there is provided a compound of formula 5, useful as an intermediate of the method for preparing montelukast sodium salt as described above.

According to the present invention, it is possible to mass-produce montelukast acid or its sodium salt with high purity quality and high yield in a simple process without using butyllithium which is dangerous for industrial use and expensive.

Hereinafter, the present invention will be described in more detail.

The compound of Chemical Formula 2 may be prepared by, for example, modifying a conventional manufacturing method as it is or as appropriate, as described in US Pat. No. 56,146,32 or WO 2005/105751.

The thiolactone compound of Formula 3 may be prepared by cyclization of 1- (mercaptomethyl) cyclopropane acetic acid in the presence of an acid catalyst under reflux in a suitable solvent such as benzene, toluene, xylene, and the like. As the acid catalyst, sulfuric acid, methanesulfonic acid, para-toluenesulfonic acid monohydrate, and the like can be used. The coupling reaction between the compound of formula (2) and the thiolactone ring of the compound of formula (3) is understood that the resulting thiol group anion reacts with the compound of formula (2) while the compound of formula (3) is ring-opened by a nucleophilic agent.

Nucleophiles that react with compounds of Formula 2 and compounds of Formula 3 include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or sodium methoxide, sodium ethoxide, lithium methoxide, sodium t-butoxide, potassium t-butoxide Alkali metal (C ₁ -C ₄ ) alkoxides such as the like are preferably used. More preferably sodium methoxide is used.

In the case of using an alkali metal hydroxide as a nucleophile, the compound of formula 1a, which is a desired product, is directly obtained, and in the case of using an alkali metal (C ₁ -C ₄ ) alkoxide as a nucleophile, an ester compound is used as an intermediate product. Compound 1a is obtained via compound 1c.

R ¹ in Formula 1c is C ₁ -C ₄ alkyl which was present in the alkali metal (C ₁ -C ₄ ) alkoxide used as nucleophile.

In the case of using an alkali metal (C ₁ -C ₄ ) alkoxide as a nucleophilic agent, a compound of formula 1c, which is an ester compound, is first obtained as an intermediate product, and then hydrolyzed to a compound of formula 1c, preferably in the presence of a base. Acidification after hydrolysis affords the compound of formula 1a as the desired product. As such, a series of processes for obtaining the compound of Formula 1a through the compound of Formula 1c may be continuously performed in one reactor, and as a result, the crude montelukast acid of Formula 1a may be prepared in high yield.

There is no particular limitation on the amount of the nucleophile used in the reaction with the compound of the formula (2) and the compound of the formula (3). It may be used in the range of 1.5 to 2 moles, but is not necessarily limited thereto. There are no particular limitations on the reaction solvent during the coupling reaction of the compounds of Formula 2 and Formula 3, but preferably tetrahydrofuran, acetonitrile, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, enmethylpyrrolidone, and the like. A single solvent or a mixed solvent thereof may be used, more preferably a tetrahydrofuran solvent is used. The coupling reaction of the compound of formula (2) and compound of formula (3) is preferably carried out at -10 ° C to 30 ° C, more preferably at 0 ° C to 10 ° C.

According to a preferred embodiment of the present invention, it is preferable to add the nucleophile at the end of the reaction at a relatively low temperature during the reaction with the formulas (2) and (3) to improve the progress of the reaction, to increase the yield and minimize side reactions. For example, first, the compound of formula 3 is added to a reactor with a suitable solvent, such as tetrahydrofuran, cooled to 0 to 5 ° C., and then the compound of formula 2 is mixed with the compound of formula 3, and then Reacting with the nucleophile in the mixture showed better yields and reduced side reactions than different orderings of the components under the same temperature conditions.

The compound of Formula 1a prepared as described above is reacted with the organic amine compound of Formula 4 to form an amine salt compound of Formula 5, and the amine salt compound is sodium hydroxide, sodium methoxide, sodium t-butoxide, or the like. Reaction with the same source of sodium ions yields the montelukast sodium salt of Formula 1b.

Thus, the montelukast acid organic amine salt of formula (5), which is an intermediate product, is prepared using the organic amine of formula (4), and then purified and reacted with a source of sodium ions to remove most of the flexible substances generated during the production of montelukast sodium salt. It is possible to lower the content of the final product of the difficult styrene-based flexible material to 0.1% or less and the content of the sulfoxide flexible material to 0.1% or less, and as a result, it is possible to prepare a very high montelukast sodium salt. The organic amine of the general formula (4) used at this time is amylamine, isoamylamine, t-amylamine, 1,2-dimethylpropylamine, preferably amylamine or t-amylamine is used. There is no particular limitation on the amount of the formula 4 amine used in the preparation of the amine salt of formula 5, preferably in the range of 1 to 2 moles per 1 mole of jomontelukastic acid of formula 1a, more preferably in the range of 1.2 to 1.6 moles. Can be used as As a reaction solvent used in the preparation of the amine salt of Formula 5, ethyl acetate, esters such as propyl acetate, hydrocarbons such as toluene, n-hexane, n-heptane, and cyclohexane may be used alone or in combination. The solvent is not limited thereto, and an ethyl acetate single solvent may be used, or a mixed solvent thereof with hydrocarbon may be used. According to one embodiment of the present invention, ethyl acetate, propyl acetate, or toluene may be used as a sole solvent, or n-hexane, n-heptane or cyclohexane may be used together as an auxiliary solvent.

The present invention will be described in more detail with reference to the following Examples. However, these examples are not intended to limit the scope of the present invention.

Example

[Production Example 1]

2- (2- (3 (S)-(3- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-methanesulfonyloxy propyl) phenyl) -2-propanol (Formula 2 compound) Manufacture

2- (2- (3 (S)-(3- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-hydroxypropyl) phenyl) -2-80 ml of tetrahydrofuran under nitrogen atmosphere. 20 g (43.67 mmol) of propanol was added thereto, cooled to -10 ° C. to -5 ° C., and then 10.8 ml of diisopropylethylamine was added while maintaining the same temperature, and 6 g (52.403 mmol) of methanesulfonyl chloride was slowly added for 30 minutes. Added dropwise. Stir for 2 hours at -10 ° C to -5 ° C, filter the resulting solid under nitrogen atmosphere and wash with 20 ml of cooled tetrahydrofuran to give 2- (2- (3 (S)-(3- (7 -Chloro-2-quinolinyl) ethenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl) -2-propanol was prepared. The obtained filtrate was used directly in the subsequent reaction step.

[Production Example 2]

Preparation of 5-thiaspiro [2,4] heptan-6-one (Formula 3)

50 g (341.97 mmol) of 1- (mercaptomethyl) cyclopropane acetic acid and 0.8 g (4.27 mmol) of para-toluene sulfonic acid monohydrate were sequentially added to 500 ml of toluene, followed by stirring for 3 hours under reflux. After cooling to room temperature, the solution was washed sequentially with 5% aqueous sodium bicarbonate solution and purified water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 43 g of 5-thiaspiro [2,4] heptan-6-one (yield: 98%).

¹ H-NMR (CDCl ₃ , ppm): 3.25 (s, 2H), 2.49 (s, 2H), 0.75 (m, 4H)

¹³ C-NMR (CDCl ₃ , ppm): 208, 49.50, 41.96, 21.13, 12.48, 12.42

Example 1

Preparation of Montelukast Acid (Compound 1a Compound) Via Ester Intermediates

In a nitrogen atmosphere, 8.4 g (65.60 mmol) of 5-thiaspiro [2,4] heptan-6-one was added to 40 ml of tetrahydrofuran and cooled to 0-5 ° C. 2- (2- (3 (S)-(3- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl obtained in Preparation Example 1 at the same temperature) 2-propanol and 7 g (129.58 mmol) of sodium methoxide were added sequentially, followed by stirring for 3 hours. 35 ml of methanol and 35 ml of 10% aqueous sodium hydroxide solution were sequentially added to the reaction solution, and the temperature was raised to 25˜30 ° C. and stirred at the same temperature for 20 hours. After confirming that the reaction was completed, 190 ml of ethyl acetate and 190 ml of 10% aqueous sodium chloride solution were added to the reaction solution, washed, separated, and the organic layer was taken. 190 ml of purified water was added to the organic layer, which was then stirred. Then, an aqueous 10% tartaric acid solution was added to adjust the pH to 4-5, and 190 ml of ethyl acetate was added to the organic layer. After drying the obtained organic layer with anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure. 70 ml of isopropyl alcohol was added to the concentrate, and the mixture was heated and dissolved. The mixture was cooled to room temperature, filtered, and dried in vacuo at 50 ° C. to obtain 18.7 g of crude montelukast acid (72.9%, purity: 98.9%). .

Melting Point: 152.5 ~ 154.5 ℃

¹ H-NMR (CDCl ₃ , ppm): 8.11-7.09 (m, 15H), 4.01 (t, 1H), 3.18 (m, 1H), 2.93 (m, 1H), 2.65 (dd, 2H), 2.35 ( dd, 2H), 2.20 (m, 2H), 1.62 (s, 3H), 1.61 (s, 3H), 0.56-0.46 (m, 4H)

[Example 2]

Preparation of montelukast acid (compound 1a compound) without via ester intermediate

0.84 g (6.55 mmol) of 5-thiaspiro [2,4] heptan-6-one was added to 4 ml of dimethylformamide at room temperature under a nitrogen atmosphere, and 2- (2- (3 (S)-) prepared in Preparation Example 1 was prepared. (3- (7-chloro-2-quinolinyl) ethenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl) -2-propanol, 0.52 g (13.09 mmol) of sodium hydroxide, and 0.12 ml of purified water It was. Stirred at room temperature for 1 hour, cooled to 0 ~ 5 ℃ and then stirred for a further 5 hours. After confirming that the reaction was completed, 19 ml of ethyl acetate and 19 ml of 10% aqueous sodium chloride solution were added to the reaction solution, and the mixture was washed and separated to obtain an organic layer. 19 ml of purified water was added to the organic layer, followed by stirring. 10% aqueous tartaric acid solution was added to adjust the pH to 4-5, 19 ml of ethyl acetate was added thereto, followed by stirring. The organic layer was dried, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. . 7 ml of isopropyl alcohol was added to the concentrate, and the mixture was heated and dissolved. The mixture was cooled to room temperature, filtered, and dried under vacuum at 50 ° C. to obtain 1.28 g of crude montelukast acid (total yield: 50.1%, purity: 98.2%) from Preparation Example 1.

Melting Point: 152.5 ~ 154.5 ℃

¹ H-NMR (CDCl ₃ , ppm): 8.11-7.09 (m, 15H), 4.01 (t, 1H), 3.18 (m, 1H), 2.93 (m, 1H), 2.65 (dd, 2H), 2.35 ( dd, 2H), 2.20 (m, 2H), 1.62 (s, 3H), 1.61 (s, 3H), 0.56-0.46 (m, 4H)

EXAMPLES 3-6

Preparation of Montelukast Organic Amine Salt (Compound 5)

10 g (17.06 mmol) of jomontelukastic acid and 1.8 g (20.65 mmol) of amyl amine were added to 60 ml of ethyl acetate under a nitrogen atmosphere, and the mixture was stirred at 25 to 30 ° C. for 30 minutes. The reaction solution was seeded with montelukast amylamine salt and stirred for 15 hours, then 40 ml of ethyl acetate and 50 ml of n-heptane were added, followed by further stirring for 4 hours. The product was filtered and dried in vacuo at 50 ° C. to obtain 10.9 g of montelukast amylamine salt (yield: 95%, purity: 99.5%).

Melting Point: 76.6 ~ 78 ℃

¹ H-NMR (CDCl ₃ , ppm): 8.09-7.07 (m, 15H), 3.98 (t, 1H), 3.20 (m, 1H), 2.86 (m, 1H), 2.75 (t, 2H), 2.54 ( m, 2H), 2.35 (m, 2H), 2.29-2.12 (m, 2H), 1.61 (s, 3H), 1.59 (s, 3H), 1.52 (m, 2H), 1.26 (m, 4H), 0.87 (m, 3H), 0.53-0.32 (m, 4H)

In the same manner, the preparation of the amine salt of jomontelukastic acid was carried out using an organic amine other than amylamine. The results are summarized in the table below.

Example 7

Preparation of montelukast sodium salt (compound 1b compound)

After dissolving 2 g (2.97 mmol) of montelukast t-amylamine salt in 20 ml of methylene chloride under nitrogen atmosphere, adding 10 ml of 10% acetic acid aqueous solution and stirring for 30 minutes, the organic layer was washed twice with 10 ml of purified water and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 12 ml of toluene was added to the concentrate to dissolve it, and then 0.12 g of sodium hydroxide dissolved in 10 ml of methanol was added thereto, followed by stirring for 30 minutes. After concentrating under reduced pressure at 40 ° C. or lower, the concentrate was dissolved in 10 ml of toluene, and then concentrated again after treatment with activated carbon. 3 ml of toluene was added to the concentrate and dissolved, and the dissolved solution was slowly added to 20 ml of n-heptane and stirred for 1 hour. The product was filtered under nitrogen atmosphere, washed with n-heptane and dried in vacuo at 50 ° C. to obtain 1.53 g of montelukast sodium (yield: 85%, purity: 99.7%).

¹ H-NMR (CDCl ₃ , ppm): 7.97-6.95 (m, 15H), 3.92 (t, 1H), 3.24 (m, 1H), 2.69 (m, 1H), 2.42 (dd, 2H), 2.18 ( m, 3H), 2.03 (m, 1H), 1.54 (s, 3H), 1.49 (s, 3H), 0.39-0.11 (m, 4H)

Claims (10)

A method for preparing a compound of Formula 1a comprising reacting a compound of Formula 2, a compound of Formula 3 and a nucleophilic agent: [Formula 2]

(3)

[Formula 1a]

R ² in Formula 2 is phenyl substituted with C ₁ -C ₄ alkyl, phenyl or C ₁ -C ₄ alkyl. The method of claim 1, wherein sodium or potassium hydroxide as a nucleophile is reacted with a compound of Formula 2 and a compound of Formula 3 to prepare a compound of Formula 1a. The method of claim 1, wherein an alkali metal (C ₁ -C ₄ ) alkoxide as a nucleophile is reacted with a compound of Formula 2 and a compound of Formula 3 to obtain a compound of Formula 1c, and then hydrolyzed to a compound of Formula 1c Method for producing a compound of: [Formula 1c]

R ¹ in Formula 1c is C ₁ -C ₄ alkyl. The method according to claim 1, wherein the compound of Formula 2 and the compound of Formula 3 are mixed at 0 to 5 ° C, and then reacted by adding a nucleophilic agent to the mixture. Reacting the compound of formula 1a prepared by the method according to any one of claims 1 to 4 with a compound of formula 4 to produce a compound of formula 5, and the compound of formula 5 with a sodium ion source A process for preparing a compound of formula 1b, comprising the step of reacting: [Formula 4] NH ₂ R ³ [Chemical Formula 5]

[Chemical Formula 1b]

In Formulas 4 and 5, R ³ is amyl, isoamyl, t-amyl or 1,2-dimethylpropyl. The method of claim 5 wherein the sodium ion source is sodium hydroxide, sodium methoxide, or sodium t-butoxide. Compound of Formula 3: (3)

A process for preparing a compound of formula (3) characterized by cyclization of 1- (mercaptomethyl) cyclopropaneacetic acid in the presence of an acid: (3)

The method of claim 8 wherein the acid is para-toluenesulfonic acid monohydrate, methanesulfonic acid or sulfuric acid. Compound of formula 5: [Chemical Formula 5]

In Formula 5, R ³ is amyl, isoamyl, t-amyl or 1,2-dimethylpropyl.