KR20060128581A - A process for preparing pranlukast or its hydrate and a synthetic intermediate thereof - Google Patents

Abstract

A method for preparing pranlukast or a hydrate thereof is provided to remove formation of impurities, reduce cumbersome purification steps, and be applied to real production filed due to not requiring toxic solvent or reagent. And a synthetic intermediate is provided to be useful for preparing the pranlukast or the hydrate thereof. The method for preparing pranlukast or a hydrate thereof comprises a step of reacting a compound represented by the formula(2) with 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof in the presence of base such as a tertiary organic amine in an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidinone, pyridine and a mixture thereof. In the formula(2), n is an integer from 0 to 4, each R^1 and R^2 is independently H, C1-5 alkyl, halogen or nitro in case of n being 0, and A is an aromatic or aliphatic hydrocarbon ring, --- is a bond or a non-bond, each R^1 and R^2 is independently CH or CH2, and each R^3 and R^4 is independently H, C1-5 alkyl, halogen or nitro.

Description

Process for preparing pranlukast or its hydrate and a synthetic intermediate thereof

The present invention relates to a process for the preparation of Franlukast or its hydrates and to synthetic intermediates useful for the production of Franlukast or its hydrates.

Franlukast or its hydrate is a compound having leukotriene antagonism and has an excellent effect in the treatment of asthma, allergic lung disease, rhinitis and the like. The chemical name of franlukast is N- [4-oxo-2- (1H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -4- (4-phenylbutoxy) benzamide ( N- [4-oxo-2- (1H-tetrazol-5-yl) -4H-1-benzopyran-8-yl] -4- (4-phenylbutoxy) benzamide), and has the structure of Formula 1 below.

A conventional method for producing franlukast is disclosed in WO 94/12492, which is summarized in Scheme 1 below.

As shown in Scheme 1, WO 94/12492 discloses a tetrabenzo group by reacting a compound of Formula 5 with a tetrazole compound of Formula 6, and then forming a benzopyran ring to prepare franlukast. A method is disclosed. However, in the preparation method according to Scheme 1, after preparing franlukast, it is necessary to transform the franlukast into the sodium salt form to remove the impurities, and then acidify it again to obtain a target compound. Accompanied by refining processes, they are not suitable for industrial scale mass production.

On the other hand, European Patent No. 711,762 discloses a manufacturing method in which, unlike International Patent Publication No. WO94 / 12492, a benzopyran ring is first formed and a tetrazole group is introduced later. That is, as shown in Scheme 2 below, the nitrile compound of Formula 8 is reacted with hydrazine to prepare amidrazon compound of Formula 9a, 9b, and then tetrazylation reaction is carried out using nitrous acid, tranlukast. To prepare.

The manufacturing method of Scheme 2 by using a large amount of hydrazine toxic to the human body and nitrous acid causing the generation of nitrogen oxides that adversely affect the environment, the process is very dangerous, due to the large amount of harmful acid waste liquid discharged to the human body, Not suitable for industrial scale mass production.

In addition, Japanese Patent Application Laid-Open No. 61-050977 and Korean Patent Publication No. 1987-2129 disclose a method for preparing various derivatives including tranlukast by reacting a benzoic acid derivative of Formula 10 with an oxalyl chloride and an amino tetrazole derivative of Formula 11 It has been disclosed, and the reaction scheme is the same as in Scheme 3.

In Scheme 3, R ¹ is an alkyl or allyl group and n is an integer from 1 to 10.

The preparation method according to Scheme 3 is not only harmful and hygroscopic and decomposable, but also requires a large amount of very expensive oxalyl chloride, and the reaction must be carried out under anhydrous and inert gas, which makes it difficult to apply to industrial mass production. Furthermore, very toxic benzene should be used as the recrystallization solvent in the purification process after synthesis of the target compound.

Accordingly, the present inventors have conducted a study to develop a new manufacturing method that can overcome the problems of the prior art, when producing lancastast or its hydrate via a new intermediate, the production of impurities and the resulting cumbersome The present invention has been completed by discovering that the purification process can be reduced, and there is no need to use toxic solvents or reagents that are difficult to handle, and thus can be advantageously applied in actual production sites.

It is therefore an object of the present invention to provide a method for producing franlukast or its hydrate.

It is also an object of the present invention to provide synthetic intermediates useful for the preparation of franlukast or its hydrates.

According to one aspect of the invention, comprising reacting a compound of Formula 2 with 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof in the presence of a base, Provided are methods of making franlukast or its hydrates:

Wherein n is an integer of 0 to 4; when n is 0, R ¹ and R ² are independently hydrogen, C ₁ -C ₅ alkyl, halogen, or nitro; when n is an integer from 1 to 4, A represents an aromatic or aliphatic hydrocarbon ring, --- (dotted line) represents a bond or a non-bond, R ¹ and R ² are independently CH or CH ₂ , R ³ and R ⁴ is independently hydrogen, C ₁ -C ₅ alkyl, halogen, or nitro.

는 인접한 R¹ 및 R² 와 함께 벤젠 (방향족 환)을 형성할 수 있으며, 이때

는 =CH-CH=, R¹ 및 R² 는 각각 CH 를 나타낸다. In the compound of Formula 2, when n is an integer of 1 to 4, A together with adjacent R ¹ and R ² forms an aromatic or aliphatic hydrocarbon ring. For example, if n is 2,

May form benzene (aromatic ring) with adjacent R ¹ and R ² , wherein

= CH-CH =, R ¹ and R ² each represent CH.

8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof can be prepared as disclosed in Japanese Patent Laid-Open No. 61-050977. In the preparation method of the present invention, the salt of the compound may be a conventional acid addition salt, and may be, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid phosphoric acid, or a salt with an organic acid such as acetic acid, citric acid or oxalic acid. Of these, 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran hydrochloride form, which forms a stable salt, can be preferably used.

As the base, a base commonly used in the field of organic chemistry may be used, and preferably a tertiary organic amine may be used. The tertiary organic amines include pyridine, 4- (dimethylamino) pyridine, 1-methylimidazole, imidazole, tertiary C ₁ -C ₅ alkylamines and the like. In the production method of the present invention, the amount of the base used is not particularly limited, but may be used in the range of 1 to 10 equivalents, preferably in the range of 1 to 2 equivalents. In addition, in the case of using an excess of liquid base such as pyridine, it can also function as a solvent, so that the use of a separate solvent can be avoided, and thus it can be used more preferably.

The reaction of the compound of Formula 2 with 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof may be preferably performed in an aprotic polar organic solvent. Organic solvents include tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidinone, pyridine, or mixtures thereof. Among them, amide organic solvents such as dimethylformamide, dimethylacetamide, or methylpyrrolidinone are more preferable in view of the reaction rate and the degree of generation of impurities due to the difference in solubility of the reactants.

The reaction ratio of the compound of Formula 2 to 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof may be 1 to 3 equivalents based on 1 equivalent of the compound of Formula 2 It is possible to react preferably at a reaction ratio of 1 to 1.5 equivalents.

In the reaction of the compound of Formula 2 with 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof, the reaction temperature depends on the type of organic solvent or base used. Depending on the temperature, it may range from about 20 ° C. to 100 ° C. That is, the reaction may be carried out at room temperature or may be carried out by heating. The reaction time also varies depending on the type of organic solvent or base used, but may range from about 2 to 7 hours. Of course, the reaction temperature and reaction time is not limited to the above range, it can be used to change depending on the conditions.

In the preparation method of the present invention, after the reaction is carried out as described above, the obtained product is composed of C _{1 ~} C ₄ alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, dioxane, toluene, xylene, and mixtures thereof By addition of a solvent selected from the group, it can be separated in the form of precipitates. Therefore, the preparation method of the present invention can obtain a high purity target compound (ie, franlukast) by simply separating the precipitate by addition of the solvent, and simply filtering and washing. Among the solvents used for forming the precipitate, isopropyl alcohol, acetone, toluene or a mixed solvent thereof can be more preferably used.

In addition, if necessary, a precipitate selected from the group consisting of C ₁ -C ₄ alcohol, acetonitrile, acetone, tetrahydrofuran, dioxane, and mixtures thereof, or a mixed solvent of water and It can be purified more purely by adding and refluxing.

Franlukast itself has the property of absorbing moisture in the air to take the form of a hemihydrate ((1/2 hydrate), so that the prepared franlukast is about 1-10 hours at room temperature, preferably about It can be converted to franlukast hemihydrate (1/2 hydrate) form by standing for 3-5 hours.

The compound of Formula 2 used as a starting material of the present invention may be prepared by reacting 4- (4-phenylbutoxy) benzoic acid and the compound of Formula 3 in the presence of a phosphine compound of Formula 4:

Wherein n, A, --- (dotted line), R ¹ , R ² , R ³ , and R ⁴ are the same as defined above,

Y ¹ , Y ² , and Y ³ are independently C ₁ -C ₅ alkyl, phenyl, benzyl, toluyl, or allyl.

4- (4-phenylbutoxy) benzoic acid can be prepared as disclosed in Japanese Patent Laid-Open No. 61-050977. The compound of formula 3 may be prepared by oxidizing 2-mercaptobenzothiazole (US Pat. No. 3,463,783), and the phosphine compound of formula 4 may be prepared according to a known method from phosphorus trichloride. (Ber. 37, 4621, (1904)).

The phosphine compound of Formula 4 may be used in the range of 1 to 3 equivalents based on 1 equivalent of 4- (4-phenylbutoxy) benzoic acid, and considering the yield and purification efficiency, 4- (4-phenylbutoxy) 1-1.5 equivalents can be used preferably with respect to 1 equivalent of benzoic acid.

The reaction with 4- (4-phenylbutoxy) benzoic acid and the compound of formula 3 can preferably be carried out in the presence of a base, for example tertiary organic amine, commonly used in the field of organic chemistry. The tertiary organic amines include pyridine, imidazole, tertiary C ₁ -C ₅ alkylamine, 4- (dimethylamino) pyridine, 1-methylimidazole and the like, and are preferably inexpensive pyridine and imidazole. , Tertiary C ₁ -C ₅ alkylamine, more preferably triethylamine. The base may be used in the range of 1 to 3 equivalents based on 1 equivalent of 4- (4-phenylbutoxy) benzoic acid, and in view of the yield and the purification efficiency, based on 1 equivalent of 4- (4-phenylbutoxy) benzoic acid 1-1.5 equivalents can be used preferably.

In addition, the reaction with 4- (4-phenylbutoxy) benzoic acid and the compound of formula 3 is carried out with ethyl acetate, acetonitrile, dibutylether, tetrahydrofuran, dioxane, dichloromethane, toluene, xylene, and mixtures thereof. It may be carried out in a solvent selected from the group consisting of, and in view of purification efficiency, toluene or xylene may be more preferably used.

The reaction ratio of 4- (4-phenylbutoxy) benzoic acid and the compound of Formula 3 may be 1 to 3 equivalents based on 1 equivalent of 4- (4-phenylbutoxy) benzoic acid, preferably 1 to 1.5 The reaction can be carried out at an equivalent reaction ratio.

In the reaction with 4- (4-phenylbutoxy) benzoic acid and the compound of the formula (3), the reaction temperature and reaction time vary depending on the type of organic solvent or base used, but at about 0 ° C to 50 ° C. It can be carried out for 2 to 5 hours. Of course, the reaction temperature and reaction time is not limited to the above range, it can be used to change depending on the conditions.

After completion of the reaction with 4- (4-phenylbutoxy) benzoic acid and the compound of formula 3, the compound of formula 2 can be purified and obtained in a white solid state by simple filtration and washing. It is stable against moisture and warm, and is a stable compound that does not decrease in purity even when stored for a long time, and thus can be used as an intermediate useful for industrial mass production.

Accordingly, the present invention includes compounds of formula 2, useful as intermediates for the preparation of franlukast or its hydrates:

<Formula 2>

In the formula, n, A, --- (dashed line), R ¹ , R ² , R ³ , and R ⁴ are the same as defined above.

According to the preparation method of the present invention, a process for preparing franlukast or its hydrate using 4- (4-phenylbutoxy) benzoic acid as a starting material is shown in Scheme 4 below.

In Scheme 4, n, A, --- (dotted line), R ¹ , R ² , R ³ , R ⁴ , Y ¹ , Y ² , and Y ³ are as defined above.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these examples.

는 =CH-CH=, R¹= -CH-, R²= -CH-, R³=수소, R⁴=수소)의 제조Example 1 S- (1,3-benzothiazol-2-yl) -4- (4-phenylbutoxy) benzenecarbothioate (Compound of Formula 2: n = 2, A is an aromatic hydrocarbon ring,

= CH-CH =, R ¹ = -CH-, R ² = -CH-, R ³ = hydrogen, R ⁴ = hydrogen)

3.2 L of toluene was added to 4- (4-phenylbutoxy) benzoic acid (100 g, 0.37 mol) and 2,2'-dibenzothiazolyl disulfide (185 g, 0.56 mol), followed by stirring at room temperature for 10 minutes. Triphenylphosphine (146 g, 0.56 mol) was added. To the reaction mixture was added dropwise a solution of triethylamine (56.2 g, 0.56 mol) in 200 mL of toluene, followed by further stirring for 2 hours. The resulting solid was filtered, washed with 2.3 L of 90% isopropanol aqueous solution and dried to give 149 g (yield: 96%) of the title compound.

Melting point 124 ° C .;

¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.8 (m, 4H), 2.7 (m, 2H), 4.0 (t, 2H), 6.9 (s, 2H), 7.2-7.3 (m, 3H)), 7.5 (t, 2H), 7.9-8.0 (m, 4H)

Example 2: Preparation of Franlukast 1/2 Carb

8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran hydrochloride (8.7 g, 32.8 mmol) and S- (1,3-benzothiazole- prepared in Example 1 above 87 ml of dimethylformamide was added to 2-yl) -4- (4-phenylbutoxy) benzenecarbothioate (13.7 g, 32.8 mmol), and 4- (dimethylamino) pyridine (12.0 g, 98.4 mmol) was added. After the addition, the mixture was warmed and stirred at 40 to 50 ° C. for 5 hours. 217 ml of toluene was added to the reaction mixture, followed by further stirring at the same temperature for 1 hour. The reaction mixture was cooled and stirred at room temperature for 2 hours. The resulting solid was filtered, and 111 ml of 50% acetone aqueous solution was added to the obtained solid, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, filtered and dried, and left in air for 5 hours at room temperature to prepare 13.5 g (yield: 83%) of the title compound.

Melting point 231 to 233 ° C (decomposition);

¹ H-NMR (DMSO-d ₆ , 300 MHz) δ 1.9 (m, 4H), 2.7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, 1H), 7.2 -7.3 (m, 5H), 7.6 (t, 1H), 7.9 (t, 1H), 8.0 (m, 2H), 8.3 (t, 1H), 10.0 (s, 1H)

Example 3: Preparation of Franlukast 1/2 Carb

8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran hydrochloride (8.7 g, 32.8 mmol) and S- (1,3-benzothiazole- prepared in Example 1 above 43.5 ml of dimethylformamide was added to 2-yl) -4- (4-phenylbutoxy) benzenecarbothioate (13.7 g, 32.8 mmol), 43.50 ml of pyridine was added, and warmed to 5 at 70 to 75 ° C. Stir for hours. 130.5 ml of toluene was added to the reaction mixture, which was further stirred for 1 hour at the same temperature. The reaction mixture was cooled and stirred at room temperature for 2 hours. The resulting solid was filtered, and 111 ml of 50% acetone aqueous solution was added to the obtained solid, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, filtered and dried and left for 5 hours at room temperature to give 14.9 g (yield: 91%) of the title compound.

Example 4: Preparation of Franlukast 1/2 hydrate

8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran hydrochloride (8.7 g, 32.8 mmol) and S- (1,3-benzothiazole- prepared in Example 1 above 87 ml of dimethylformamide was added to 2-yl) -4- (4-phenylbutoxy) benzenecarbothioate (13.7 g, 32.8 mmol), and 1-methylimidazole (5.4 g, 65.6 mmol) was added. Then, it was warmed and stirred for 7 hours at 50 ~ 60 ℃. Toluene 217 ml was added to the reaction mixture, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was cooled and stirred at room temperature for 2 hours. The resulting solid was filtered, and 111 ml of 50% acetone aqueous solution was added to the obtained solid, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, filtered and dried, and left in air for 5 hours at room temperature to give 14.1 g (yield: 86%) of the title compound.

Since the production method of the present invention prepares franlukast or its hydrate via a new intermediate, it can reduce the generation of impurities and the cumbersome purification process resulting therefrom, and does not require the use of toxic solvents or reagents that are difficult to handle. It can be advantageously applied in the field. In addition, it is easy to operate and economical, and in particular, franlukast or its hydrate can be produced in high purity only by simple filtration and washing process of the solid produced by the addition of a solvent after completion of the reaction. In addition, the compound of the formula (2) according to the present invention can be usefully used for the preparation of franlukast or its hydrate.

Claims (10)

Franlukast, or a compound thereof, comprising reacting a compound of Formula 2 with 8-amino-4-oxo-2-tetrazol-5-yl-4H-1-benzopyran or a salt thereof in the presence of a base Preparation method of hydrate: <Formula 2>

Wherein n is an integer of 0 to 4; when n is 0, R ¹ and R ² are independently hydrogen, C ₁ -C ₅ alkyl, halogen, or nitro; when n is an integer from 1 to 4, A represents an aromatic or aliphatic hydrocarbon ring, --- (dotted line) represents a bond or a non-bond, R ¹ and R ² are independently CH or CH ₂ , R ³ and R ⁴ is independently hydrogen, C ₁ -C ₅ alkyl, halogen, or nitro. A process according to claim 1 wherein the base is a tertiary organic amine. The method of claim 1, wherein the reaction is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidinone, pyridine, and mixtures thereof. Manufacturing method. The method of claim 1, wherein after completion of the reaction, C ₁ ~C ₄ precipitate was added to a solvent selected from an alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, dioxane, toluene, xylene, and mixtures thereof Manufacturing method characterized in that it further comprises the step of forming. The obtained precipitate is added with a solvent selected from the group consisting of C ₁ -C ₄ alcohols, acetonitrile, acetone, tetrahydrofuran, dioxane, and mixtures thereof, or a mixed solvent of the solvent and water, The method further comprises the step of heating to reflux. The method according to claim 1, further comprising the step of converting the obtained franlukast into franlukast hemihydrate (1/2 hydrate) form by standing at room temperature for 1-10 hours. The compound of any one of claims 1 to 6, wherein the compound of formula (2) is obtained by reacting 4- (4-phenylbutoxy) benzoic acid and the compound of formula (3) in the presence of a phosphine compound of formula (4). Manufacturing Method: <Formula 3>

<Formula 4>

Wherein n, A, --- (dotted line), R ¹ , R ² , R ³ , and R ⁴ are the same as defined in claim 1, Y ¹ , Y ² , and Y ³ are independently C ₁ -C ₅ alkyl, phenyl, benzyl, toluyl, or allyl. The process according to claim 7, wherein the reaction of 4- (4-phenylbutoxy) benzoic acid with the compound of formula 3 is carried out in the presence of a tertiary organic amine. The reaction according to claim 7, wherein the reaction of 4- (4-phenylbutoxy) benzoic acid with the compound of formula 3 is ethyl acetate, acetonitrile, dibutyl ether, tetrahydrofuran, dioxane, dichloromethane, toluene, xylene And a mixture selected from the group consisting of a mixture thereof. Compound of Formula 2: <Formula 2>

In the formula, n, A, --- (dotted line), R ¹ , R ² , R ³ , and R ⁴ are the same as defined in claim 1.