KR101469015B1 - Method for the preparation of Montelukast and intermediates used therein - Google Patents

Abstract

The present invention relates to a method for producing montelukast, which is a leukotriene inhibitor that effectively controls asthmatic inflammation, and to intermediates used therein. According to the preparation method of the present invention, it is possible to prepare the intermediate compounds which are safer and easier to purify by replacing dangerous butyllithium or unstable mesylate intermediates, which have been used conventionally, so that the preparation process is much safer. As a result, Of montelukast or its pharmaceutically acceptable salt can be mass-produced with high efficiency.

Montelukast, leukotriene, cysteinyl leukotriene, montelukast sodium

Description

TECHNICAL FIELD The present invention relates to a method for producing montelukast and a method for preparing the same,

The present invention relates to a process for the preparation of Montelukast and intermediates used in the preparation thereof.

Montelukast is a leukotrienes modulator that effectively controls asthma inflammation.

Asthma is an inflammation of the airways in the lungs that narrows the airways. When dust, smoke, or pollen comes in contact with the airways, it causes inflammation in the airways and excessive mucus secretion from inflammation makes breathing difficult.

Monterocast blocks the action of a group of leukotrienes called cysteinyl leukotrienes (CysLTs) that mediate airway inflammation and bronchoconstriction, cause leaking of fluid from the airway vessels (edema), and stimulate mucus secretion. Astrocytes and allergic rhinitis And is useful as a therapeutic agent for treating the same respiratory disease.

Recently, montelukast and sodium acceptable salts significant counter drugs are approved as antagonists of leukotriene receptors SINGULAIR ^® (SINGULAIR ^®) trade name as Merck (Merck) has been released from, the moisture absorption of the white or mibaeksaek with optically active named Powder, freely soluble in methanol, ethanol or water and insoluble in acetonitrile.

EP 480,717 discloses the synthesis of montelukast free acids in Examples 146 and 161, as shown in Scheme 1 below.

According to Scheme 1 below, the mesylate compound (II) produced by converting the hydroxyl group of the compound of formula (I) into a methanesulfonyl group is reacted with methyl 2- (1-mercaptomethyl) cyclopropyl acetate III). After hydrolysis, the obtained final compound is purified by column chromatography to obtain montelukast free acid (IV). After treatment with sodium hydroxide, freeze-drying is carried out to obtain the final product, amorphous solid Montelukast sodium (V) can be synthesized.

In addition, this method is not suitable for mass production because it is difficult to remove impurities and the yield is low when the intermediates are separated by using column chromatography and the montelukast free acid is converted into a sodium salt without purification. In order to prepare the compound of formula (I), the secondary alcohol is first protected, the tertiary alcohol is sequentially protected, and then the secondary alcohol is deprotected. After a long period of time (at least 4 days) It has disadvantages such that the yield is low due to extensive preparation time and purification through column chromatography.

U.S. Patent No. 5,614,632 discloses that compound (VIII) is synthesized by using butyllithium in an improved process of Reaction Scheme 1, then reacted with compound (VII) in a base condition, compound (IX) is reacted with dicyclohexylamine, A method for synthesizing montelukast sodium is proposed.

However, the nucleophilic substitution reaction using a lithium-based base in the production method according to the above-mentioned Reaction Scheme 2 is difficult to preserve the chirality of the product, and it has a disadvantage that it is very difficult to be applied to a practical industry due to the risk of butyllithium. In addition, since the mesylate compound (VII) used in the above method is very unstable at air and room temperature, it is not easy to store, and by-products which are lethal to the preparation process are produced. Therefore, And should be kept at a low temperature of about -15 ° C or below because the stability is very low. In addition, it is very unstable in water and air, and the stability in a solution is lowered, so that it is difficult to mass-produce the reaction quickly.

The drawback that the overall yield is reduced due to the fatal by-products generated in the manufacturing process can be confirmed in various documents ( J. Org . Chem . 1996, 61, 3398-3405, Tetrahedron : Asymmetry 1997, 8, 161-168. , Anal . Chem. 1995, 67, 2292-2295.)

As described above, the conventional method is to synthesize montelukast sodium after replacing with a leaving group such as a methanesulfonyl group. However, the separation must be performed through column chromatography, and the intermediate is not stable and the overall yield And the use of high-risk and high-priced lithium materials is not suitable for actual production.

The present inventors have conducted extensive studies to develop a process for producing montelukast which can overcome the problems of the prior art. As a result, they have succeeded in a process of using a new intermediate instead of a dangerous butyllithium or an unstable mesylate intermediate, Montelukast or a pharmaceutically acceptable salt thereof can be prepared in high yield.

Accordingly, an object of the present invention is to provide a method for producing a high-purity montelukast at a high yield.

Another object of the present invention is to provide a novel compound as an intermediate which is excellent in stability used in the production of the above-mentioned montelukast.

In order to achieve the above object, in the present invention,

A process for preparing a montelukast or a pharmaceutically acceptable salt thereof, which comprises using a compound of the formula (3) as an intermediate to prepare a montelukast of the formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (3) to provide:

1) preparing a compound of the following formula (5) by subjecting a compound of the following formula (6) to an alcohol protecting reaction;

2) optionally deprotecting the protecting group of the secondary alcohol in the compound of formula (5) to prepare a compound of formula (4); And

3) introducing a leaving group to the prepared secondary alcohol of the compound of Formula 4 to prepare a compound of Formula 3;

Formula 1

(3)

Formula 4

Formula 5

6

In this formula,

R ₁ and R ₂ are simultaneously -COOR ₄ alcohol protecting groups, wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S,

L is halogen; C ₁ -C ₄ alkyl; Nitro; Methoxy; Arylsulfonyl substituted with carboxyl; Or an alkylsulfonyl substituted by C ₁ -C ₄ alkyl or trifluoro.

The present invention also provides a process for preparing a montelukast of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of converting a montelukast of formula (I) into a salt with an amine to convert to a compound of formula (8)

8

In this formula,

The amine may be selected from N-methylmorpholine, morpholine, piperazine, pyridine, pyrrolidine, 2,6-dimethylpyridine, ammonia, trimethylamine, triethylamine, tributylamine, triethanolamine, But are not limited to, diethylamine, dipropylamine, diisopropylamine, diphenylamine, dibenzylamine, dicyclopentylamine, dicyclohexylamine, dicycloheptylamine, pentylamine, hexylamine, Amine, t-butylamine, benzylamine, aniline, N-ethyl aniline, 1-adamantylamine, 　 Amino-2-methyl-1-propanol, l-lysine, ornithine, venetamine, benzathine, threonine, arginine, metformin, imidazole, diphenylmethanamine, Phenylethanamine, 1,2-ethanediamine, 2-methyl-2-propanamine, phenethylamine or 2- (3,4-dimethoxyphenyl) ethanamine.

The method for producing montelukast according to the present invention is an improvement of the conventional dangerous and difficult manufacturing method and uses novel intermediate compounds having high stability and simple purification so as to obtain a final compound having high efficiency and low impurity. Accordingly, the present invention provides a preparation method which is highly suitable for mass production of montelukast or a pharmaceutically acceptable salt thereof.

The present invention relates to a process for preparing montelukast or a pharmaceutically acceptable salt thereof using a novel intermediate which can more efficiently replace the intermediate substance used in the production of montelukast in the prior art. The present invention also provides a process for the preparation of a montelukast or a pharmaceutically acceptable salt thereof, comprising the step of purifying a montelukast by reaction with an amine salt.

Hereinafter, the present invention will be described more specifically.

The compound of formula (3), which is an intermediate used to use the montelukast of formula (1) or a pharmaceutically acceptable salt thereof of the present invention, can be prepared according to the process disclosed in the following reaction formula (3). Specifically, 1) a compound of formula (VI), which is a diol compound, is prepared by simultaneously and simultaneously using an alcohol protecting group in the presence of a reaction solvent and a base in a secondary alcohol, and 2) The compound of formula (5) is selectively deprotected in the presence of a reaction solvent and a base to produce a compound of formula (4), and the resulting compound of formula (4) is introduced into a secondary alcohol in the presence of a reaction solvent and a base To give a compound of formula (3).

In this formula,

R ₁ And R ₂ is a -COR ₄ at the same time the alcohol protecting group, wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S,

L is halogen; C ₁ -C ₄ alkyl; Nitro; Methoxy; Arylsulfonyl substituted with carboxyl; Or an alkylsulfonyl substituted by C ₁ -C ₄ alkyl or trifluoro.

As shown in Scheme 3, in Step 1), the compound of Formula 5 was simultaneously introduced into a secondary alcohol using a compound of Formula 6 and an alcohol protecting group that is easy to purchase and manipulate. In general, it is known that the introduction of a protecting group of a tertiary alcohol is more difficult than a secondary alcohol and requires a long reaction time. Also in this document, a secondary alcohol is firstly protected to introduce a protecting group into a tertiary alcohol, And a long manufacturing process for carrying out a protective reaction. However, in the present invention, a protecting group is introduced at the same time into a secondary alcohol using a good alcohol protecting group which is inexpensive and reacts under mild conditions, and methylstyrene (methylstyrene) And found an easy way to remove such by-products.

The protecting group introduced is an alcohol protecting group, -COR ₄ , wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S, preferably aldehyde (-COH), acetyl (-COMe) or trifluoroacetyl (-COCF ₃ )to be.

The solvent used in the reaction may be selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, diethylether, diisopropylether, methylene chloride, chloroform, toluene, benzene, N -Methylpyrrolidone (NMP), diisopropylacetate and ethyl acetate, and preferably methylene chloride or ethyl acetate is used.

The reaction temperature according to the present invention is -20 to 100 ° C, preferably 0 to 90 ° C, and most preferably 20 to 80 ° C.

And is further characterized by promoting the reactivity by further using 4-dimethylaminopyridine or 4-pyrrolidinopyridine as a catalyst during the reaction. Preferably 4-dimethylaminopyridine.

The amount of the catalyst used is 0.1 to 2 molar equivalents, preferably 0.2 to 1 molar equivalents.

Examples of the base used in the reaction include amine base conditions such as triethylamine, tributylamine, diisopropylethylamine, methylpiperidine, N-methylpyrrolidone (NMP) or pyridine, or basic conditions such as lithium hydroxide, sodium hydroxide, Is carried out under inorganic base conditions such as calcium hydroxide, sodium hydride, potassium hydride or sodium acetate, preferably diisopropylethylamine, pyridine or triethylamine, most preferably diisopropylethylamine. The molar equivalents of the amines used in the reaction are in the range of 1.0 molar equivalents to as large as the solvent, preferably 1.2 to 3 molar equivalents.

In the above step 2), the compound of the formula (5) simultaneously protected with the secondary alcohol may be selectively deprotected only in the reaction solvent and the base to prepare the compound of the formula (4). The selective deprotection reaction can be easily performed using the difference in reactivity between the secondary alcohol and the tertiary alcohol.

The solvent used in the reaction is at least one selected from the group consisting of tetrahydrofuran, dioxane, methanol, ethanol and water, preferably methanol or tetrahydrofuran. As the base used in the reaction, at least one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate and cesium carbonate is preferable, and lithium hydroxide, It is sodium.

The reaction is completed at -10 to 60 ° C for 10 minutes to 9 hours, and the compound of formula (4) in which the deprotection reaction of the secondary alcohol is selectively performed can be obtained.

Preferably, the reaction temperature is from 0 to 10 DEG C and the reaction time is from 30 minutes to 6 hours.

In the above step 3), the compound of formula (IV) prepared by the above method can be easily introduced into the secondary alcohol using a well-known production method. The compound of formula (3) can be prepared by introducing a leaving group which is inexpensive and easy to handle, and the resulting compound of formula (3) is superior to the methanesulfonyl compound used in the conventional preparation method (US Patent No. 5,614,632) It has stability. Specifically, in order to prepare the methanesulfonyl compound, the reaction should be carried out at about -30 ° C. After the separation, the intermediate compound should be stored at about -15 ° C. However, the intermediate compound of the present invention can be reacted at room temperature, It does not decompose even when dried and can be stored at room temperature. It is also a good method to inhibit the fatal by-products generated during the reaction of the conventional production method. The present invention is a more efficient method than the production method in which a leaving group is introduced in the aforementioned production method, and is a highly reproducible method. The present invention is also more stable and easier to handle at room temperature than conventional labile mesylate compounds and can be obtained in good yield.

In the compound of formula (III) of the present invention, L means a leaving group of all commonly used sulfonyl groups which convert an alcohol into a leaving group.

Arylsulfonyl usually refers to all commonly used benzenesulfonyl groups that convert an alcohol to a leaving group. For example, halogen, C ₁ -C ₄ alkyl, benzenesulfonyl substituted with nitro. Representative are benzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, nitrobenzenesulfonyl, nitromethylbenzenesulfonyl, nitrochlorobenzenesulfonyl, carboxylbenzenesulfonyl, methoxybenzenesulfonyl, toluene Sulfonyl. Alkylsulfonyl includes alkylsulfonyl substituted by C ₁ -C ₄ alkylsulfonyl or trifluoro, such as methanesulfonyl. Typically, it is methanesulfonyl, trifluoromethanesulfonyl.

In the compound of formula 3, the leaving group introduced is an arylsulfonyl substituted by halogen, C ₁ -C ₄ alkyl, nitro, methoxy, carboxyl; Or alkylsulfonyl substituted by C ₁ -C ₄ alkyl or trifluoro, and is preferably a methane sulfonyl compound which is the least expensive and simpler to handle.

The alcohol leaving group used in the reaction may be prepared using 1 to 2.0 molar equivalents, and the reaction temperature is -20 to 50 ° C, preferably -10 ° C to room temperature. When the reaction time is 10 minutes to 2 hours, the reaction is completed, whereby the compound of formula (3) can be prepared as a solid.

The amine base used in the reaction may be selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and tertiary amines such as methylpiperidine, preferably diisopropylethylamine, triethyl Amine or pyridine, most preferably diisopropylamine.

The equivalent of the amine used is 1 to 3 molar equivalents, preferably 1.5 to 2.5 molar equivalents.

The reaction solvent is selected from the group consisting of toluene, benzene, methylene chloride, chloroform, acetonitrile, tetrahydrofuran, isopropyl acetate, ethyl acetate, dimethylformamide, dimethylsulfoxide, dimethylacetamide and N- And preferably methylene chloride, toluene or ethyl acetate.

In the present invention, as shown in the following Reaction Scheme 4, the compound of Chemical Formula 3 and the compound of Chemical Formula 7 are subjected to a substitution reaction in the presence of a base and a reaction solvent to prepare a compound of Chemical Formula 2, and the compound of Chemical Formula 2 is reacted in the presence of a reaction solvent and a base Hydrolyzing or deprotecting the montelukast of Formula 1 to prepare a montelukast of Formula 1 or a pharmaceutically acceptable salt thereof.

In this formula,

R ₂ is an alcohol protecting group, -COR ₄ , wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S,

R ₃ is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclohexyl, phenyl or benzyl,

L is halogen; C ₁ -C ₄ alkyl; Nitro; Methoxy; Arylsulfonyl substituted with carboxyl; Or an alkylsulfonyl substituted by C ₁ -C ₄ alkyl or trifluoro.

In step 1) of Scheme 4, the compound of formula (2) can be prepared by coupling the compound of formula (3) and the compound of formula (7) under a reaction solvent and base. As the reaction solvent to be used therefor, an aprotic solvent Is advantageous in preserving the chirality of the product.

In the reaction, the protonic solvent solvates the nucleophile to lower the nucleophile's ground state energy and the ΔG increases, while the reaction rate decreases. The polar aprotic solvent surrounds the cation rather than the nucleophilic anion, To decrease ΔG and increase the reaction rate ( Tetrahedron Lett ., 1987, 28, 3683).

Examples of aprotic solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone (NMP), acetone, acetonitrile, dioxane, tetrahydrofuran, dimethoxyethane, 1,2-dichloroethylene, dichloromethane, methylene chloride, chloroform, toluene, benzene or ethyl acetate. Particularly, it is preferable to use dimethylformamide or tetrahydrofuran, or a mixed solvent thereof.

Examples of the base to be used include lithium hydroxide, sodium hydroxide, sodium hydride, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, t-butoxy potassium, t-butoxy sodium, cesium carbonate, n- Sodium and ethoxy sodium. Preferably, sodium hydroxide or an aqueous solution thereof is inexpensive and easy to handle. The equivalent used is 1 to 4 molar equivalents, preferably 1.5 to 4 molar equivalents, 2.0 molar equivalents.

The reaction temperature is -20 to 40 ° C, preferably 0 ° C to room temperature, and the reaction time is 10 minutes to 18 hours, preferably 30 minutes to 3 hours. The compound of formula (7) may be used in an amount of 1 to 3 molar equivalents, preferably 1.2 to 2 molar equivalents.

Step 2) of Scheme 4 can be carried out by any method known to those skilled in the art as a hydrolysis step, and a pharmacologically possible salt formation reaction is possible according to the inorganic salt used. In addition, the hydrolysis reaction and the deprotection reaction of the tertiary alcohol occur simultaneously in the base condition.

The solvent which can be used in the above reaction is at least one selected from the group consisting of methanol, ethanol, tetrahydrofuran and water, preferably tetrahydrofuran or a mixed solvent of methanol and water.

The base used in the reaction may be sodium hydroxide, sodium carbonate, potassium carbonate or potassium hydroxide, whereby a sodium or potassium salt can be formed after the reaction. Preferably, sodium hydroxide is used in an amount of 1 to 10 molar equivalents, the reaction temperature is from room temperature to 60 DEG C, and the reaction time is from 1 to 5 hours.

In the second reaction, which is capable of forming a salt after the reaction at a base condition, the montelukast of the formula (1) can be obtained by extraction using an acid. The acid used is selected from hydrochloric acid, sulfuric acid, acetic acid or tartaric acid.

In addition, 1- (mercaptomethyl) cyclopropaneacetic acid (R < ₃ > = H), the equivalent is 2 to 3 molar equivalents, the base is 3 to 4 molar equivalents, and the reaction time is 2 to 12 hours relative to the compound of formula (3). The tertiary alcohol can then be deprotected to form a salt, which can be treated with an acid to give the montelukast of formula (1).

In the present invention, a montelukast of the formula (1) or a pharmaceutically acceptable salt thereof is prepared by preparing an amine salt of the formula (8) using the amine and then purifying the montelukast of the formula (1) This process comprises reacting montelukast free acid montelukast of Formula 1 extracted under acidic conditions with various amines using an amine salt to prepare an amine salt of Formula 8 to remove impurities, , Montelukast free acid is extracted from the purified compound under an acid condition selected from the purified compound, and montelukast of formula (1), which is a target compound of high purity, can be obtained through salt formation reaction. The method using amine as a method for purifying montelukast of formula (1) can be carried out by a method known in the art (WO 95/17107), and all impurities produced in the reaction through the purification method using amine are reduced to 0.2 % To 0.1% or less. In addition, a pharmaceutically acceptable salt compound of the montelukast of formula (1) can be prepared through a salt formation reaction step using the purified product.

As the amine salt usable for purifying the montelukast of Formula 1 in the above Reaction Scheme 5, pharmaceutically acceptable salts include organic salts and inorganic salts, and organic salts such as N-methylmorpholine, morpholine, piperazine, pyridine, Amines such as triethylamine, triethylamine, triethanolamine, triethanolamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, diphenylamine, Dicyclopentylamine, dicycloheptylamine, pentylamine, hexylamine, heptylamine, octylamine, isopropylamine, t-butylamine, benzylamine, aniline, N-ethyl aniline, 1-adamantylamine, 　 Amino-2-methyl-1-propanol, 1-phenyl-2-methyl-1-propanol, lysine, ornithine, venetamine, benzathine, threonine, arginine, metformin, imidazole, diphenylmethanamine, Ethanamine, 1,2-ethanediamine, 2-methyl-2-propanamine, phenethylamine or 2- (3,4-dimethoxyphenyl) ethanamine, 4-dimethoxyphenyl) ethane amine, and inorganic salts such as alkali metals such as lithium, sodium, potassium and cesium, alkaline earth metals such as magnesium, calcium and strontium, aluminum, bismuth, zinc or iron . Preferably, sodium is used to obtain the currently available montelukast sodium. The sodium salt formation reaction is carried out by using montelukast of formula (1) with 1 molar equivalent of sodium hydroxide.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1-1

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) - Preparation of acetate

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) -Ol were dissolved in 500 mL of methylene chloride and the mixture was stirred at 50-55 < 0 > C. To this solution, 45.5 mL of triethylamine, 41.5 mL of acetic anhydride, and 2.65 g of 4-dimethylaminopyridine were added in this order, followed by stirring for 13 hours. After the completion of the reaction, the reaction mixture was washed with 300 mL of a saturated aqueous sodium bicarbonate solution, and then with 300 mL of a saturated aqueous sodium chloride solution, and then the organic layer was dried over anhydrous magnesium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain 57.95 g (yield 97.9%, purity> 96%) of the desired compound as a yellow solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.39 (d, 1H, J = 8.6 Hz), 8.00 ~ 7.97 (m, 2H), 7.92 ~ 7.86 (m, 2H), 7.77 (s, 1H), 7.69 (d, 1H, J = 7.6 Hz), 7.59 ~ 7.37 (m, 4H), 7.27 ~ 7.09 (m, 4H), 5.87 (t, 1H, J = 6.2 Hz), 2.95 ~ 2.66 (m, 2H) , 2.14 ~ 2.07 (m, 5H), 1.90 (s, 3H), 1.68 (s, 3H), 1.63 (s, 3H); MS (ESI, C ₃₃ H ₃₂ ClNO ₄ ) m / z = 542.0 (M + 1).

Examples 1-2 to 1-4

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) -2- (2-acetoxypropan-2-yl) phenyl) propane-2-acetate was prepared and the results are shown in Table 1 below:

Example base Yield% Purity% 1-2 Dyessofyl ethyl amine 98.2 > 97 1-3 Pyridine 95.7 > 94 1-4 Diaisofϊf ethylamine + NMP 96.1 > 92

Examples 1-5

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) - Preparation of acetate

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) -Ol were dissolved in 500 mL of ethyl acetate and the mixture was stirred at 75-80 < 0 > C. To this solution, 152.2 mL of triethylamine, 103.2 mL of acetic anhydride and 2.67 g of 4-dimethylaminopyridine were added in this order, followed by stirring for 9 hours. After completion of the reaction, the reaction mixture was washed with 300 mL of a saturated aqueous sodium bicarbonate solution and with 300 mL of a saturated aqueous sodium chloride solution, and then the organic layer was dried over anhydrous magnesium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain 58.19 g (yield 98.4%, purity> 96%) of the desired compound as a yellow solid.

Examples 1-6 and 1-7

(S, E) -1- (3- (2- (7-chloroquinolin-2- (2-acetoxypropan-2-yl) phenyl) propane-2-acetate was prepared and the results are shown in Table 2 below:

Example base Yield% Purity% 1-6 Dyessofyl ethyl amine 95.6 > 96 1-7 Pyridine 95.7 > 94

Examples 1-8

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) Manufacture of pivalate

The target compound was obtained in 93.8% yield (purity > 93%) as yellow solid in the same manner as in Example 1-1, using 2.4 molar equivalents of pivaloyl chloride.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.39 (d, 1H, J = 8.6 Hz), 8.00 ~ 7.95 (m, 2H), 7.92 ~ 7.86 (m, 2H), 7.77 (s, 1H), 7.68 (d, 1H, J = 7.6 Hz), 7.59 ~ 7.37 (m, 4H), 7.27 ~ 7.09 (m, 4H), 5.84 (t, 1H, J = 6.2 Hz), 2.94 ~ 2.65 (m, 2H) , 2.14-2.07 (m, 2H), 1.68 (s, 3H), 1.63 (s, 3H), 1.45 (s, 9H), 1.34 (s, 9H); MS (ESI, C ₃₉ H ₄₄ ClNO ₄ ) m / z = 626.1 (M + 1).

Examples 1-9

(S, E) -1- (3- (2- (7-chloroquinolin-2-yl) vinyl) Manufacturing

The target compound was obtained in 91.9% yield (purity > 92%) in the same manner as in Example 1-1, using 2.6 molar equivalent of benzoyl chloride as a yellow solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.40 (d, 1H, J = 8.6 Hz), 8.00 ~ 7.81 (m, 14H), 7.75 (s, 1H), 7.64 (d, 1H, J = 7.6 Hz), 7.55 ~ 7.36 (m , 4H), 7.26 ~ 7.07 (m, 4H), 5.82 (t, 1H, J = 6.2 Hz), 2.97 ~ 2.65 (m, 2H), 2.11 ~ 2.05 (m, 2H) , 1.69 (s, 3 H), 1.59 (s, 3 H); MS (ESI, C ₄₃ H ₃₆ ClNO ₄ ) m / z = 666.0 (M + 1).

Example 2-1

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin- Produce

((S, E) -1- (3- (2- (7-chloroquinolin-2-yl) Phenyl) propane-2-acetate (57.9 g, 0.107 mol) was dissolved in methanol (500 mL), potassium carbonate (29.5 g) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 60 mL of acetic acid is added, and the suspension is made to be transparent while stirring for 30 minutes. Distribute the methanol under reduced pressure, add 600 mL of ethyl acetate, wash with 300 mL of saturated sodium bicarbonate solution, and wash with 300 mL of saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 52.27 g (yield 97.8%, purity> 93%) of the desired compound as a yellow solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.38 (d, 1H, J = 8.7 Hz), 8.00 ~ 7.97 (m, 2H), 7.3 ~ 7.86 (m, 2H), 7.75 (s, 1H), 7.61 ~ 7.56 (m, 2H) 7.47 (d, 1H, J = 16.4 Hz), 7.42 ~ 7.36 (m, 2H), 7.26 ~ 7.07 (m, 4H), 5.40 (d, 1H, J = 4.2 Hz), 4.74 (m, 1H), 2.99-2.70 (m, 2H), 1.91-1.86 (m, 5H), 1.68 (s, 3H), 1.64 (s, 3H); MS (ESI, C ₃₁ H ₃₀ ClNO ₃ ) m / z = 500.0 (M + 1).

Examples 2-2 to 2-7

The reaction was carried out in the same manner as in the above Example 2-1 except that the base shown in the following Table 3 was used as a base to prepare (S, E) -2- (2- (3- (3- (2- Yl) vinyl) phenyl) -3-hydroxypropyl) phenyl) propan-2-ylacetate, the results of which are shown in Table 3 below:

Example base Yield% Purity% 2-2 Sodium hydroxide 95.2 > 94 2-3 Potassium hydroxide 94.5 > 93 2-4 Lithium hydroxide 97.9 > 96 2-5 Sodium carbonate 97.2 > 94 2-6 Sodium bicarbonate 94.7 > 89 2-7 Cesium carbonate 96.4 > 94

Examples 2-8

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin- Produce

The target compound was obtained in 93.9% yield (purity > 91%) as yellow solid in the same manner as in Example 2-1 using tetrahydrofuran as a solvent.

Example 3-1

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- methanesulfonyloxypropyl) Preparation of acetate

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- hydroxypropyl) phenyl) propane 2-yl acetate (10 g, 0.02 mol) is dissolved in 30 mL of methylene chloride, and then 5.5 mL of diisopropylethylamine is slowly added dropwise under a nitrogen atmosphere. 1.8 mL of diluted methane sulfonyl chloride in 10 mL of methylene chloride is slowly added dropwise at room temperature for 5 minutes. After stirring for 1 hour, 300 mL of methylene chloride is added and washed with a saturated aqueous sodium chloride solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 11.5 g (yield: 99.5%, purity:> 96%) of the desired compound as a yellow solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.41 (d, 1H, J = 8.6 Hz), 8.01 ~ 7.99 (m, 2H), 7.93 ~ 7.88 (m, 3H), 7.75 (s, 1H), 1H, J = 6.2 Hz), 3.10 (s, 3H), 3.05-2.68 (m, 2H), 2.29-2.14 (m, m, 2H), 1.89 (s, 3H), 1.68 (s, 3H), 1.63 (s, 3H); MS (ESI, C ₃₂ H ₃₂ ClNO ₅ S) m / z = 578.0 (M + 1).

Example 3-2

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- methanesulfonyloxypropyl) Preparation of acetate

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- hydroxypropyl) phenyl) propane -2-ylacetate (10 g, 0.02 mol) is dissolved in 30 mL of ethyl acetate, and then 6.2 mL of diisopropylethylamine is slowly added dropwise under a nitrogen atmosphere. 2.5 mL of diluted methanesulfonyl chloride in 10 mL of ethyl acetate is slowly added dropwise at room temperature for 10 minutes. After stirring for 1 hour, add 300 mL of ethyl acetate and wash with saturated aqueous sodium chloride solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 11.1 g (yield: 96.0%, purity:> 95%) of the desired compound as a yellow solid.

Example 3-3

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- methanesulfonyloxypropyl) Preparation of acetate

In the same manner as in Example 3-1, dimethylformamide was used as a solvent to obtain the target compound in a yield of 94.5% (purity > 92%) as a yellow solid.

Examples 3-4 to 3-8

The reaction was carried out in the same manner as in Example 3-3, except that the compounds shown in the following Table 4 were used as solvents to prepare (S, E) -2- (2- (3- (3- (2- Yl) vinyl) phenyl) -3-methanesulfonyloxypropyl) phenyl) propan-2-ylacetate, the results of which are shown in Table 4 below:

Example menstruum Yield% Purity% 3-4 toluene 96.6 > 92 3-5 Tetrahydrofuran 94.0 > 93 3-6 Toluene / acetonitrile 95.8 > 89 3-7 Dimethylformamide / tetrahydrofuran < RTI ID = 0.0 > 91.6 > 93 3-8 Dichloroethane 92.3 > 92

Examples 3-9

(S, E) -2- (2- (3- (3- (2- (7-chloroquinolin- Preparation of diacetate

1.1 molar equivalent of para-toluenesulfonyl chloride was used in the same manner as in Example 3-1 to obtain the desired compound in a yield of 97.9% (purity > 92%) as a yellowish-white solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.41 (d, 1H, J = 8.6 Hz), 8.01 ~ 7.99 (m, 2H), 7.93 ~ 7.47 (m, 12H), 7.27 ~ 7.06 (m, 4H 2H), 1.90 (s, 3H), 1.68 (s, 3H), 5.81 (t, 1H, J = 6.1 Hz), 3.02-2.64 3H), 1.62 (s, 3H); MS (ESI, C ₃₈ H ₃₆ ClNO ₅ S) m / z = 654.1 (M + 1).

Example 4-1

(R, E) -methyl-2- (1- (3- (2- (2-acetoxypropan- Yl) vinyl) phenyl) propylthio) methyl) cyclopropyl) acetate

1) To a reactor charged with nitrogen was added 6.37 g of methyl-2- (1- (mercaptomethyl) cyclopropyl) acetate (R3 = Me) in 1.59 g of sodium hydroxide and 10 mL of dimethylformamide, Lt; / RTI >

2) Synthesis of 2- (2- (3 (S) - (3- (7-chloro-2-quinolinyl) -ethenyl) -3-methanesulfonyloxypropyl) phenyl- -Propanol (11.5 g, 0.0199 mol) is dissolved in 40 mL of dimethylformamide.

3) Under a nitrogen atmosphere, the prepared 1) step solution is added dropwise to the 2) step solution at room temperature and stirred for 1 hour. After completion of the reaction, 500 mL of ethyl acetate was added, and the mixture was washed twice with 300 mL of a saturated aqueous sodium chloride solution to separate the organic layer. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 12.4 g (yield 97.1%, HPLC purity> 94%) of the desired compound as a yellow liquid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.35 (d, 1H, J = 8.6 Hz), 8.00 ~ 7.82 (m, 4H), 7.77 (s, 1H), 7.62 (d, 1H, J = 7.0 2H), 7.43-7.37 (m, 2H), 7.26-7.08 (m, 4H), 4.01 (t, 1H, J = 7.1 Hz), 3.53 2H), 1.86 (s, 3H), 1.58 (s, 3H), 0.57-0.31 (m, 2H) (m, 4H); MS (ESI, C ₃₈ H ₄₀ ClNO ₄ S) m / z = 642.0 (M + 1).

Examples 4-2 to 4-7

The reaction was carried out in the same manner as in the above Example 4-1 except that the compounds shown in the following Table 5 were used as solvents in steps 1 and 2 to obtain (R, E) -methyl-2- (1 - ((3- (2-acetoxypropan-2-yl) phenyl) -1- (3- (2- (7- chloroquinolin-2- yl) vinyl) phenyl) propylthio) methyl) cyclopropyl) acetate The results are shown in Table 5 below:

Example menstruum Yield% Purity% 4-2 Dimethyl sulfoxide 89.5 > 89 4-3 Tetrahydrofuran 92.1 > 87 4-4 Toluene / acetonitrile 93.5 > 91 4-5 Dimethylformamide / tetrahydrofuran < RTI ID = 0.0 > 90.2 > 92 4-6 Acetonitrile 92.5 > 92 4-7 toluene 93.4 > 91

Examples 4-8 to 4-11

The reaction was carried out in the same manner as in the above Example 4-1 except that the compound shown in the following Table 6 was used as a solvent in Step 1 to obtain (R, E) -methyl-2- (1 - ((3- Yl) phenyl) -1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) propylthio) methyl) cyclopropyl) acetate, The results are shown in Table 6 below:

Example base Yield% Purity% 4-8 Cesium carbonate 92.5 > 88 4-9 Sodium hydride 93.8 > 85 4-10 Sodium carbonate 93.8 > 90 4-11 t-Butoxy potassium 94.6 > 92

Examples 4-12 to 4-15

The reaction was carried out in the same manner as in the above Example 4-1 except that the solvent shown in the following Table 7 was used as the solvent in Step 1 to obtain (R, E) -methyl-2- (1 - ((3- Yl) phenyl) -1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) propylthio) methyl) cyclopropyl) acetate, The results are shown in Table 7 below:

Example R3 Yield% Purity% 4-12 Hydrogen (Preparation of Chemical Formula 1) 92.5 > 91 4-13 Cyclohexyl 93.8 > 92 4-14 Phenyl 93.8 > 89 4-15 benzyl 94.6 > 93

Example 5

2- (1 - ((1- (3- (2- (7-chloroquinolin-2-yl) Yl) phenyl) propylthio) methyl) cyclopropyl) acetic acid

2- (1 - ((3- (2- (2-acetoxypropan-2-yl) phenyl) -1- (3- (2- (7- Yl) vinyl) phenyl) propylthio) methyl) cyclopropyl) (12.4 g, 0.193 mol) was dissolved in 100 mL of methanol and heated to 50 ° C. 7.72 g of sodium hydroxide are added and stirred at 50 < 0 > C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol, and 400 mL of ethyl acetate was added to dilute the reaction mixture. The solution is adjusted to pH 4.0 to 4.5 with acetic acid and stirred for 30 minutes. Purified water is added to the solution, the organic layer is separated and washed three times with 200 mL of a saturated aqueous sodium bicarbonate solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 10.9 g of the desired compound (yield 96.3%, HPLC purity> 93%, chiral purity 99.5% ee) as a yellow solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 12.04 (s, 1H), 8.39 (d, 1H, J = 8.6 Hz), 8.01 ~ 7.85 (m, 4H), 7.71 (s, 1H), 7.62 ~ 1H, J = 16.3 Hz), 7.41-7.33 (m, 3H), 7.13-7.03 (m, 3H), 4.90 (br, J = 7.1 Hz), 3.06 ~ 2.69 (m, 2H), 2.53 ~ 2.44 (m, 2H), 2.29 (s, 2H), 2.21 ~ 2.04 (m, 2H), 1.41 (s, 6H), 0.59 ~ 0.33 (m, 4H); _{MS (ESI, C 35 H 36} ClNO 3 S) m / z = 586.0 (M + 1).

Example 6

Purification of montelukast free acid using 2- (3,4-dimethoxyphenyl) ethanamine

2- (1 - ((1- (3- (2- (7-chloroquinolin-2-yl) Yl) phenyl) propylthio) methyl) cyclopropyl) acetic acid was dissolved in ethyl acetate under a nitrogen atmosphere, 3.7 g of 2- (3,4-dimethoxyphenyl) ethanamine was added Stir at room temperature for 12 hours. The resulting white precipitate is filtered off and washed with ethyl acetate. The resulting white solid is slurried with 30 ml of ethyl acetate for 18 hours, filtered and washed with 10 ml of ethyl acetate. The obtained white solid was slurried in 30 mL of ethyl acetate for 6 hours, filtered and vacuum-dried at 40 DEG C for 24 hours to obtain 13.7 g of the target compound (yield: 96%, HPLC purity> 99%, chiral purity 99.8% ee).

_{^{1 H NMR (DMSO- d 6,}} 400MHz) ppm 8.40 (d, 1H, J = 8.6 Hz), 8.02 ~ 7.99 (m, 2H), 7.95 ~ 7.86 (m, 2H), 7.72 (s, 1H), 7.63 ~ 7.57 (m, 2H), 7.50 (d, 1H, J = 16.4 Hz), 7.42 ~ 7.04 (m, 3H), 6.85 ~ 6.80 (m, 2H), 6.70 (d, 1H, J = 8.1 Hz), 5.43 (br, 1H), 4.00 (t, 1H, J = 7,2 Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.08 ~ 3.01 (m, 1H), 2.83 ~ 2.48 (m, 7H), 2.28 ~ 2.08 (m, 4H), 1.43 (s, 6H), 0.46 ~ 0.27 (m, 4H); MS (ESI, C ₄₅ H ₅₁ ClN ₂ O ₅ S) m / z = 586.0 (M + 1).

Example 7

2- (1 - ((1- (3- (2- (7-chloroquinolin-2-yl) Yl) phenyl) propylthio) methyl) cyclopropyl) acetic acid sodium salt (montelukast sodium)

1) 13.7 g of the material obtained in Example 6 are dissolved in 300 ml of ethyl acetate. 10% acetic acid is added to the present carrier liquid to adjust the pH to 4.0 to 4.5, followed by stirring for 30 minutes. The organic layer was separated and washed twice with 100 mL of a saturated aqueous sodium chloride solution. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 10.4 g of the title compound as a yellow solid. The obtained yellow solid compound was slurried with 100 mL of acetonitrile for 5 hours, filtered and used immediately in the next step.

2) Add the montelukast free acid obtained in Step 1 to methanol / purified water (50 mL, 3/2). To this suspension is added 1 molar equivalent of sodium hydroxide and stir well until the yellow solid compound is completely dissolved. The clear yellow solution is filtered, and the filtrate is concentrated under reduced pressure to remove methanol. Add 200 mL of ethyl acetate, wash with 100 mL of 10% aqueous sodium chloride solution, dry the separated organic layer with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain the target compound as an off-white solid. The solid compound is slurried with isopropyl ether for 6 hours, then the precipitate is filtered and washed with 300 mL of isopropyl ether. And dried under vacuum at 40 DEG C for 24 hours to obtain 10.2 g of the desired compound (yield 97.5%, HPLC purity> 99.5%, chiral purity 99.8% ee) as a white solid.

_{^{1 H NMR (DMSO- d 6,}} 400 MHz) ppm 8.38 (d, 1H, J = 8.6 Hz), 8.01 ~ 7.97 (m, 2H), 7.93 ~ 7.85 (m, 2H), 7.71 (s, 1H), 7.61 ~ 7.55 (m, 2H) , 7.48 (d, 1H, J = 16.4 Hz), 7.40 ~ 7.32 (m, 3H), 7.12 ~ 7.02 (m, 3H), 3.99 (t, 1H, J = 7.0 Hz) 2H), 2.19-2.04 (m, 4H), 1.41 (s, 3H), 1.40 (s, 3H) , 0.41-0.18 (m, 4H); _{MS (ESI, C 35 H 35} ClNNaO 3 S) m / z = 586.0 (M + 1).

Claims (7)

A process for preparing a montelukast or a pharmaceutically acceptable salt thereof of the formula (1) using a compound of the formula (3) as an intermediate, wherein the compound of the formula (3) is prepared by a process comprising the steps of: 1) preparing a compound of the following formula (5) by subjecting a compound of the following formula (6) to an alcohol protecting reaction; 2) optionally deprotecting the protecting group of the secondary alcohol in the compound of formula (5) to prepare a compound of formula (4); And 3) introducing a leaving group to the prepared secondary alcohol of the compound of Formula 4 to prepare a compound of Formula 3; Formula 1

(3)

Formula 4

Formula 5

6

In this formula, R ₁ and R ₂ are simultaneously -COOR ₄ alcohol protecting groups, wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S, L is halogen; C ₁ -C ₄ alkyl; Nitro; Methoxy; Arylsulfonyl substituted with carboxyl; Or an alkylsulfonyl substituted by C ₁ -C ₄ alkyl or trifluoro. The method according to claim 1, Reacting a compound of formula (3) obtained in step 3) with a compound of formula (7) to prepare a compound of formula (2) and hydrolyzing or deprotecting the compound of formula (2) Formula 1

(2)

(3)

Formula 7

In this formula, R ₂ is an alcohol protecting group, -COR ₄ , wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S, R ₃ is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclohexyl, phenyl or benzyl, L is halogen; C ₁ -C ₄ alkyl; Nitro; Methoxy; Arylsulfonyl substituted with carboxyl; Or an alkylsulfonyl substituted by C ₁ -C ₄ alkyl or trifluoro. The method according to claim 1, Characterized in that in step 1) the secondary alcohol of the compound of formula (VI) is simultaneously protected. Compounds of formula 5:

In this formula, R ₁ and R ₂ are simultaneously -COOR ₄ alcohol protecting groups, wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl comprising one or two heteroatoms selected from N, O and S. A compound of formula 2: (2)

In this formula, R ₂ is an alcohol protecting group, -COR ₄ , wherein R ₄ is hydrogen; Linear or branched C ₁ -C ₈ alkyl; -CF _3; Phenyl substituted with halogen or NO ₂ ; Or C ₄ -C ₁₀ heteroaryl containing one or two heteroatoms selected from N, O and S, R < ₃ > is cyclohexyl, phenyl or benzyl. A method for producing a montelukast of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of converting a montelukast of formula (1) into a salt with an amine to convert to a compound of formula (8) Formula 1

8

Wherein the amine is 2- (3,4-dimethoxyphenyl) ethanamine. Compounds of formula 8: 8

In this formula, The amine is 2- (3,4-dimethoxyphenyl) ethanamine.