KR20090085220A - An improved process for the preparation of irbesartan - Google Patents

Abstract

A method for producing an irbesartan is provided to produce the irbesartan using a zinc halide, alkali-metal azide, polar aprotic solvent with high yield in a short time. A method for producing a irbesartan comprises a step of producing the irbesartan of the chemical formula 1 at the reaction temperature of 130-170‹C using zinc halide, alkali metal azide, polar aprotic solvent. The polar aprotic solvent is selected among DMF, N-methylpyrolidone, and 1,3-dimethylimidazolidinone. The alkali metal azide is selected among lithium azide, sodium azide, potassium azide, and cerium azide.

Description

An improved process for the preparation of irbesartan

The present invention relates to a method for producing irbesartan. Irbesartan is an antagonist for angiotensin II receptors and is a useful drug for the treatment of related diseases caused by angiotensin.

Irbesartan represented by the following Chemical Formula 1 is a powerful angiotensin II receptor antagonist, which is useful in the treatment of cardiovascular diseases such as hypertension and heart failure, and has a long-acting advantage, and is described in US Pat. No. 5,270,317.

The method for preparing Irbesartan represented by Formula 1 directly from the compound of Formula 2 disclosed in the prior art can be largely represented by the following two schemes.

Scheme 1 is described in US Pat. No. 5,270,317, which has a number of disadvantages.

1) It is very cumbersome because it consists of 3 steps of manufacturing process, and the reaction time of the first stage is only 66 hours, so the reaction time is very long.

2) The overall yield is very low at 48.4%, making it uneconomical.

3) Trialkyltin azide is used during the manufacturing process, which is very toxic and can destroy mucous membranes, upper respiratory tract, eyes and skin tissues, and may cause vomiting, wheezing, laryngitis, and chemical pneumonia. Therefore, there is a great risk of harm to the health of the manufacturer, and also environmentally problematic, there is a difficulty in industrial production.

Scheme 2 is described in Example 3 of Korean Patent Laid-Open Publication No. 2007-0045275. The manufacturing method is easier than the manufacturing method of the reaction method of Scheme 1, but it was confirmed that the following disadvantages when actually carried out according to Example 3.

1) After completion of the reaction, a solution of sodium hydroxide and water is added, followed by stirring for 0.5 hour to separate the target object from the aqueous layer to the organic layer, which is not easy to separate.

2) Impurities produced during the reaction are not removed during post-reaction and recrystallization processes.

3) Although the yield of the target product is 87%, the present inventors actually reproduced, and the yield was about 65-70%.

On the other hand, European Patent Publication No. 0838458 discloses a method for producing a tetrazole derivative using zinc chloride. It is reported that tetrazole derivatives can be prepared using sodium azide, zinc chloride and a solvent selected from the solvents listed. In this example, methyl ethyl ketone (reaction temperature 60-70 ° C.), acetonitrile (reflux; about 70 Only examples using solvents such as ˜80 ° C.), DMF (reaction temperature 100 to 120 ° C.), and n-butanol (reaction temperature 105 to 115 ° C.) are shown.

In particular, in Example 6 4) (Scheme 3) and 7 (Scheme 4) shown in Example 6, in which an example of a compound having a biphenyl structure such as Irbesartan is shown, n-butanol was used as a solvent. Attempted to prepare irbesartan represented by the formula (1) according to the present invention, but the reaction did not proceed.

Moreover, THF (reaction temperature 50-60 degreeC), methyl ethyl ketone (reaction temperature 60-70 degreeC), acetonitrile (reaction temperature 70-80 degreeC), 1, 4- dioxane (reaction temperature 90-100 degreeC), etc. Attempted to produce irbesartan using each of the solvents, but most of the irbesartan were not prepared, and even though the reaction proceeded, very little irbesartan was produced and the reaction did not proceed anymore for a long time. It was not suitable as a method for preparing besartan.

Korean Patent No. 0662110 also describes a method of preparing a tetrazole derivative having a biphenyl structure (Chemical Formula 3) using zinc chloride and a pyridine solvent (Scheme 5).

In this patent, the solvents listed in EP 0838458 were used to prepare the compound represented by Chemical Formula 3, but the reaction was hardly produced or a large amount of impurities could not be produced. It is described that preparation is possible only with pyridine solvents not listed in EP 0838458.

Therefore, the present inventors attempted to prepare Irbesartan represented by Chemical Formula 1 using zinc chloride in a pyridine solvent as described in the above patent, but this reaction did not proceed at all, and moreover, pyridine was used as a solvent. There were problems such as the inherent adverse smell, difficulty in removing residual solvents, and poor economical efficiency by using excessive amount of sodium azide and zinc chloride.

In another comparative example, the present inventors prepared intermediates (Formula 4) required for the preparation of candesartan, an antagonist to angiotensin II receptors such as irbesartan (Formula 4) from sodium azide and zinc chloride, and the European Experiments were also made using the solvents listed in EP 0838458, but none of the reactions proceeded.

In preparing a tetrazole derivative from the compounds having a biphenyl structure as described above, a method using zinc chloride, which is generally known, has not been commonly applied in all cases. In other words, the desired object could not be prepared or the object was produced in very small amounts.

Therefore, in order to prepare tetrazole derivatives from compounds having a biphenyl structure, the appropriate amount of sodium azide and zinc chloride, the solvent and the amount of the solvent used, It is a field that needs to search for the optimal reaction conditions uniquely in each case, such as newly configuring the reaction conditions such as the reaction temperature or finding a new method instead of using zinc chloride.

An object of the present invention is to provide a method for industrially mass production of irbesartan represented by the following formula (1), and to be environmentally friendly.

In addition, an object of the present invention is to provide a method capable of producing irbesartan represented by the formula (1) with a high yield in a short time characteristically.

The present inventors have overcome the problems of conventional tetrazole derivative preparation techniques such as the use of a very long reaction time of 36 to 66 hours, a low yield, and a highly toxic substance such as trialkyltin azide. In order to find an industrially easy method for producing irbesartan represented by the formula (1), studies using alkali metal azide and zinc halide have been repeated.

As a result, in the case of Irbesartan, it was found that the reaction hardly proceeds at low reaction temperature conditions as in the prior arts, and surprisingly, the reaction can proceed smoothly and be completely terminated only when the reaction temperature is 130 ° C or higher. The invention was constructed. Suitable solvents that may be employed are those having a high boiling aprotic solvents.

More surprisingly, in the prior art, the preparation of tetrazole derivatives having a biphenyl structure is generally carried out using very large amounts of alkali metal azide (3.93 to 7.89 molar equivalents) and zinc halide (1.93 to 3.9 molar equivalents). The reaction had to be carried out for a long time such that time to 66 hours, even the exact time is not mentioned, in the present invention is characterized by a much smaller amount of alkali metal azide than the prior art in the reaction temperature conditions of 140 ℃ ~ 170 ℃ ( 2.5 molar equivalents) and zinc halide (2.0 molar equivalents), while significantly shortening the reaction time to 12 to 22 hours, yielding Irbesartan with high yield.

On the other hand, the reaction temperature conditions can be higher than 170 ℃, but from an industrial and economic point of view, 140 ℃ ~ 170 ℃ will be suitable because the operation at a higher temperature than necessary is not economical.

Following this study, the present inventors further found that irbesartan can be produced uniquely using zinc bromide or zinc fluoride, which has not been used in the prior art.

On the other hand, as a comparative study, instead of zinc halide, a person of ordinary skill in the art tried to confirm the production possibility of Irbesartan using the same Lewis acid aluminum halide which can be easily inferred. .

As a result of the above research, the present invention is a characteristic and original invention in preparing Irbesartan, a tetrazole derivative.

It is an object of the present invention to provide an improved process for producing irbesartan. In another aspect, the present invention provides a method for producing industrially, 1) easy to produce, 2) environmentally friendly and economical, and 3) high yield of irbesartan in a short time.

A method for preparing irbesartan is illustrated in Scheme 6 below.

In the irbesartan synthesis reaction, the reaction temperature may be selected from 130 to 190 ° C, and preferably 140 to 170 ° C.

The polar aprotic solvent used in the Irbesartan synthesis reaction is preferably selected from DMF, N-methylpyrrolidone and 1,3-dimethylimidazolidinone.

The alkali metal azide used in the irbesartan synthesis reaction is not particularly limited, but is preferably selected from lithium azide, sodium azide, potassium azide and cerium azide.

The zinc halide used in the irbesartan synthesis reaction can be selected from zinc chloride, zinc bromide, and zinc fluoride.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example

Irbesartan  Produce

Reference Example  1 (European Publication No. 0838458) Example  6, 4) and Example  7).

One)

16 ml n-butanol, 3.4 g zinc chloride and 4.2 g sodium azide were stirred for 30 minutes, and 5 g of compound 2 was added thereto. And after stirring for 24 hours at 105 ~ 115 ℃ confirmed the reaction progress, but the reaction did not proceed.

2)

16 ml n-butanol, 3.4 g zinc chloride and 3.3 g sodium azide were stirred for 30 minutes, and 5 g of compound 2 was added thereto. And after stirring for 24 hours at 105 ~ 115 ℃ confirmed the reaction progress, but the reaction did not proceed.

Reference Example  2 (Korea Patent Registration No. 0662110 Example  One).

5 g of compound 2 was added to 5 ml pyridine and 3.9 g zinc chloride and 7.9 g sodium azide were added. The reaction proceeded after refluxing for 24 hours, but the reaction did not proceed.

Reference Example  3 (Korea Patent Publication No. 2007-0045275 Example  3).

2 g of compound 2 and 1.6 g of triethylamine hydrochloride, 0.75 g of sodium azide and 4.13 g of N-methyl pyrrolidinone were stirred at about 122 ° C. for 24 hours, then cooled to room temperature and the reaction was terminated. . The reaction was cooled to about 45 ° C., an aqueous sodium hydroxide solution (35%, 12 g) and 6 g of water were added, followed by stirring at about 20-40 ° C. for about 0.5 hours. The aqueous layer was discarded and the organic layer was treated with 3.9 g toluene and 10 g water and stirred at about 20-30 ° C. for about 0.5 hour. The organic layer was then discarded, the aqueous layer was washed with 3.6 g of ethyl acetate and treated with concentrated hydrochloric acid until the pH was adjusted to about 4.8-5.2. Precipitation occurred and the resulting suspension was stirred at about 20-25 ° C. for about 1 hour. The precipitate was collected and washed three times with water. The crude wet product was recrystallized using a mixture of 0.79 g of isopropanol and 9 g of water to yield 1.5 g of irbesartan. (Yield 67.5%)

Example  1.N- Methylpyrrolidone  In solvent Zinc chloride  Used Irbesartan  Produce

10 g of compound 2, 7.1 g of zinc chloride, 4.2 g of sodium azide and 30 ml N-methylpyrrolidone were stirred at 145 to 155 ° C for 12 hours. After confirming the completion of the reaction, the reaction mixture was cooled to 50 ° C, 40 ml of toluene was added, and 100 ml of constant was slowly added while stirring. After cooling to 35 ° C. and filtration, the filtrate was stirred with 120 ml of 3N aqueous sodium hydroxide solution and 300 ml of isopropanol-methylene chloride mixed solution to completely dissolve and the organic layer was separated. The separated organic layer was extracted with a constant of 2L and adjusted to pH 4.5-5.5 with 1N aqueous hydrochloric acid solution. After further stirring for 1 hour while crystals were formed, the mixture was filtered, washed with a constant, and dried in vacuo at 50 ° C to obtain 10.1 g of Irbesartan. (Yield 91%)

Example  2. 1,3- Dimethylimidazolidinone  In solvent Zinc chloride  Used Irbesartan  Produce

10 g of compound 2, 7.1 g of zinc chloride, 4.2 g of sodium azide and 30 ml 1,3-dimethylimidazolidinone were stirred at 140 to 150 ° C for 19 hours. After confirming the completion of the reaction, 9.8 g of Irbesartan was obtained through the same method as in Example 1. (Yield 88%)

Example  3. DMF  In solvent Zinc chloride  Used Irbesartan  Produce

10 g of compound 2, 7.1 g of zinc chloride, 8.4 g of sodium azide and 30 ml DMF were refluxed for 22 hours. After confirming the completion of the reaction, 8.8 g of Irbesartan was obtained through the same method as in Example 1. (Yield 79%)

Example 4 Preparation of Irbesartan Using Zinc Bromide in N-Methylpyrrolidone Solvent

10 g of compound 2, 11.7 g of zinc bromide, 4.2 g of sodium azide and 30 ml N-methylpyrrolidone were stirred at 145 to 155 ° C for 14 hours. After confirming the completion of the reaction, 9.7 g of Irbesartan was obtained through the same method as in Example 1. (Yield 87%)

Example 5 Preparation of Irbesartan with Zinc Fluoride in N-Methylpyrrolidone Solvent

10 g of Compound 2, 5.4 g of zinc fluoride, 4.2 g of sodium azide and 30 ml N-methylpyrrolidone were stirred at 145 to 155 ° C for 14 hours. After confirming the completion of the reaction, 9.2 g of Irbesartan was obtained through the same method as in Example 1. (Yield 83%)

Example  6. THF  In solvent Zinc chloride  Used Irbesartan  Produce

10 g of compound 2, 7.1 g of zinc chloride, 8.4 g of sodium azide and 30 ml THF were refluxed for 24 hours. And the reaction progress was confirmed, but the reaction did not proceed at all.

Example 7 Preparation of Irbesartan Using Zinc Chloride in Methylethylketone Solvent

10 g of compound 2, 7.1 g of zinc chloride, 8.4 g of sodium azide and 30 ml of methyl ethyl ketone were stirred under reflux for 24 hours. And it was confirmed whether the reaction proceeded, but only a partial reaction proceeded, and further stirred for 24 hours after reflux, but no significant change.

Example 8 Preparation of Irbesartan Using Zinc Chloride in 1,4-Dioxane Solvent

10 g of compound 2, 7.1 g of zinc chloride, 8.4 g of sodium azide and 30 ml 1,4-dioxane were refluxed for 24 hours. And it was confirmed whether the reaction proceeded, but only a partial reaction proceeded, and after stirring for an additional 24 hours reflux also did not change significantly.

Example  9. N- Methylpyrrolidone  Using Aluminum Chloride in Solvent Irbesartan  Produce

10 g of compound 2, 6.9 g of aluminum chloride, 4.2 g of sodium azide and 30 ml of N-methylpyrrolidone were stirred at 130 ° C. for 12 hours. And the reaction progress was confirmed, but only the starting material and the flexible material remained.

compare Example

Preparation of Compound 4

compare Example  1.N- Methylpyrrolidone  In solvent Zinc chloride  Preparation of Used Compound 4

2 g of compound 4, 1.24 g of zinc chloride, 1.52 g of sodium azide and 6 ml N-methylpyrrolidone were stirred at 130 ° C. for 19 hours. And the reaction progress was confirmed, but only the starting material and the flexible material remained.

compare Example  2. 1,3- Dimethylimidazolidinone  In solvent Zinc chloride  Preparation of Used Compound 4

1 g of compound 4, 0.62 g of zinc chloride, 0.76 g of sodium azide and 4 ml 1,3-dimethylimidazolidinone were stirred at 130 ° C. for 12 hours. And the reaction progress was confirmed, but only the starting material and the flexible material remained.

Claims (4)

A method of preparing Irbesartan at a reaction temperature of 130 to 170 ° C. using zinc halide, alkali metal azide, and a polar aprotic solvent from a compound represented by Chemical Formula 2 as in Scheme 6 below.

The method according to claim 1, wherein the polar aprotic solvent is selected from DMF, N-methylpyrrolidone and 1,3-dimethylimidazolidinone. The method according to claim 1, wherein the alkali metal azide is selected from lithium azide, sodium azide, potassium azide and cerium azide. The method according to claim 1, wherein the zinc halide is selected from zinc chloride, zinc bromide, and zinc fluoride.