KR20230081455A - Process for preparing purified losartan potassium - Google Patents

Abstract

One aspect includes adding a potassium hydroxide solution to a solution comprising losartan free base to form a losartan potassium product; adding triphenylphosphine to the losartan potassium product to aminate the azido group of the azido impurity to produce an amine compound; and then adding a crystallization solvent to crystallize and filter the losartan potassium to remove the amine compound. It relates to a pharmaceutical composition for antihypertensive comprising.

Description

Method for preparing purified losartan potassium {Process for preparing purified losartan potassium}

The present invention relates to a method for producing purified losartan potassium, and more particularly, to a high purity purified losartan by removing azido impurities, which are genotoxic substances, generated during the production of losartan potassium with a simple process and low cost. It relates to a method for producing purified losartan potassium, which can provide potassium.

Losartan, a compound represented by the following formula (1), is an angiotensin II receptor antagonist and is well known as an antihypertensive drug.

[Formula 1]

Losartan is commercially available (Cozaar ^® ) in the form of a salt of Losartan potassium, and since it was first marketed in the United States in 1995, it has been widely used worldwide as an antihypertensive drug.

However, recently, there has been an issue of azido impurities being generated in losartan raw materials and finished drugs, and thus, the production of high-purity losartan from which impurities generated during the production of losartan are removed has become an important task. The azido impurity is a by-product produced due to the use of sodium azide (NaN ₃ ) added to form a tetrazole ring during the production of losartan.

According to a recent study, 5-[4'-[(5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-[1, It was confirmed that 1'-biphenyl] 2-yl] -1H-tetrazole (CAS 727718-93-6 (LAZ-A)) was detected, and the azido impurity was positive in the bacterial mutagenicity (Ames) test. It has been shown to be received and is known to be genotoxic.

Among the impurities produced during the production of losartan potassium, it is known that impurities having an azido structure listed in Table 1, including the above-mentioned LAZ-A, can be formed, and they are named "Losartan azido impurities" there is.

structure Substance name One

Azido-Tz-BBC

Azido-Tz-BBC 5-(4′-(azidomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole 2

LAZ-A 5-(4′-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-yl) -1H-tetrazole 3

LAZ-B 4′-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile 4

LAZ-C 5-(4′-((4-(azidomethyl)-2-butyl-5-chloro-1H-imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-yl) -1H-tetrazole 5

LAZ-D 5-(azidomethyl)-2-butyl-4-chloro-1H-imidazole

It is known that nitrosoamine, a genotoxic substance, is also produced in addition to the azido impurity during the production of losartan. In the synthesis of losartan, sodium azide (NaN ₃ ) is used to form a tetrazole ring as shown in the reference reaction equation below, and NaNO ₂ is used to remove unreacted residues of added sodium azide (NaN ₃ ). do.

[Reference Reaction Formula]

It is known that nitrosamine, a carcinogen, is produced in the process. A method for preparing losartan free of nitrosamine impurities is disclosed in PCT Publication No. WO 2021036193A1 (Patent Document 1).

According to the disclosure in Patent Document 1, for the purpose of avoiding the production of nitrosamines, losartan free base is prepared, and then, in order to remove unreacted NaN ₃ , triphenylphosphine (TPP) is used instead of NaNO ₂ Use Specifically, after preparing the losartan free base, the intermediate layer is separated, then TPP and carbon are added to the intermediate layer, and after stirring, various processes such as filtration (removal of carbon), solvent removal by distillation under reduced pressure, and crystallization are performed. In addition, the method uses a large amount of TPP (2 to 10% by weight of losartan free base). Moreover, the method does not disclose any removal of impurities.

Therefore, there is a demand for a method for producing purified rosatran potassium, which is simple in process, economically and efficiently capable of removing azido impurities.

WO 2021036193A1

One aspect is to provide a method for producing purified rosatran potassium, which can remove azido impurities in a simple, economical and efficient process.

Another aspect is to provide purified losartan potassium prepared according to the above production method.

Another aspect is to provide an antihypertensive pharmaceutical composition comprising the purified losartan potassium prepared according to the above preparation method as an active ingredient.

aspect of work,

adding a potassium hydroxide solution to a solution comprising losartan free base to form a losartan potassium product;

adding triphenylphosphine to the losartan potassium product to aminate the azido group of the azido impurity contained in the losartan potassium product to produce an amine compound; and

Then, a method for producing purified losartan potassium is provided, comprising adding a crystallization solvent to crystallize and filtering the losartan potassium to remove the amine compound.

Another aspect provides purified losartan potassium prepared according to the above production method.

Another aspect provides a pharmaceutical composition for antihypertensives, comprising the purified losartan potassium prepared according to the above preparation method as an active ingredient.

According to the method for producing purified losartan potassium according to one aspect, by introducing a small amount of triphenylphosphine during the conventional losartan potassium production process, azido impurities are reduced to an amine compound, and conventional crystallization for obtaining losartan potassium And if the filtration process is used as it is, ajido impurities can be filtered and removed. Therefore, while using the conventional Losartan potassium manufacturing process as it is, by adding a very simple process of adding only a small amount of triphenylphosphine and further stirring for a certain period of time, azido impurities that cause genotoxicity can be efficiently removed. can be removed The quality of the losartan potassium obtained in this way is not abnormal, and the production yield can be maintained without loss because there is no additional extraction or separate treatment process. Therefore, according to one aspect, through the addition of a very simple process, it is possible to economically and efficiently obtain purified losartan potassium from which azido impurities are removed, and eventually, for antihypertensive drugs containing safe and economical losartan potassium A pharmaceutical composition may be provided.

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

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by one of ordinary skill in the art related to the present invention. In addition, preferred methods, samples, conditions, etc. are described in this specification, but are not limited thereto as examples, and similar or equivalent ones are also included in the scope of the present invention. In addition, numerical values described herein are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications cited herein by reference are hereby incorporated by reference in their entirety.

Definition of Terms

As used herein, unless otherwise indicated, the following terms have the meanings as defined below.

As used herein, the term "losartan free base" refers to a state in which losartan does not exist as any salt and exists as a base of losartan alone.

As used herein, the term "rosartan azido impurity" is an impurity having an azido group, which is a by-product produced by sodium azide added to form a tetrazole ring, which is produced during the production of losartan potassium, LAZ-A, LAZ-B, LAZ-C, LAZ-D, Azido-Tz-BBC, but are not limited thereto.

As used herein, the term "purified losartan potassium" refers to potassium losartan in which the losartan azido impurity is present at less than 500 ppm, specifically less than 300 ppm, more specifically less than 200 ppm, and even more specifically less than 100 ppm. It refers to losartan potassium, present in parts per million or less.

As used herein, the term “room temperature” refers to a temperature in the air and may be 1 to 35° C.

One aspect is a method for producing purified losartan potassium,

adding a potassium hydroxide solution to a solution comprising losartan free base to form a losartan potassium product;

adding triphenylphosphine to the losartan potassium product to aminate the azido group of the azido impurity contained in the losartan potassium product to produce an amine compound; and

Then, a method for producing purified losartan potassium is provided, comprising adding a crystallization solvent to crystallize and filtering the losartan potassium to remove the amine compound.

The step of adding a potassium hydroxide solution to the solution containing the losartan free base to form the losartan potassium product may be performed in the same manner as a conventional method of forming losartan potassium. In one embodiment, a solution is prepared by dissolving the losartan free base in a solvent such as isopropanol (IPA), followed by adding a potassium hydroxide solution, such as a potassium hydroxide solution in methanol (MeOH), and stirring to obtain the losartan potassium can form. The reaction may be carried out at room temperature, and a potassium hydroxide solution may be added to facilitate the reaction, followed by stirring for about 20 minutes to about 60 minutes. A process of performing stirring, removing insoluble matter by filtration, and washing with a solvent such as a mixed solvent of isopropanol and methanol may be further included.

Thus, the obtained losartan potassium product is obtained by adding triphenylphosphine (TPP) as it is to the losartan potassium product without performing a separate extraction or treatment process for additional work-up, etc. A step of generating an amine compound by amination of the azido group of the contained azido impurities may be performed. The triphenylphosphine may be added in an amount of 0.001 to 0.02 equivalents relative to the losartan free base, or 1 to 20 equivalents, more specifically 5 to 10 equivalents relative to the residual LAZ-A in the losartan free base. can In one embodiment, when adding triphenylphosphine, water may be added together, and then the reaction may be performed by stirring for about 30 minutes to 2 hours in the range of about 50 to 70 °C. The reaction of reducing an azido compound to an amine compound using triphenylphosphine uses a reaction known as "Staudinger reaction" (see mechanism below), and triphenylphosphine reacts with azido group to form imimophosphorane. After forming N ₂ , phosphazide is produced as N 2 is dropped, and hydration by water proceeds thereto to form triphenylphosphine oxide, thereby producing an amine compound. That is, the water is used for hydration in the process of reducing an azido compound to an amine compound using triphenylphosphine. The water may be added in an amount of 10 to 250 equivalents relative to residual LAZ-A in losartan free base, or 0.03 to 0.9 wt% relative to losartan free base.

Then, a step of crystallizing losartan potassium by adding a crystallization solvent and filtering to remove the amine compound may be performed. Specifically, the amine compound may be removed by crystallizing and filtering the losartan potassium in the product from which the amine compound is generated, and discarding the filtrate. More specifically, a crystallization solvent is gradually added to the product in which the amine compound is generated while maintaining the temperature in the range of 50 to 70 ° C., a part of the crystallization solvent is removed by distillation, and then cooled to room temperature to obtain a losartan potassium product. Purified losartan potassium can be obtained by crystallization followed by filtration and washing. The crystallization solvent may be a non-polar solvent such as a linear alkane (eg, n-hexane or n-hexane) or a cycloalkane (eg, cyclohexane). In one embodiment, the crystallization solvent may be cyclohexane. The amine compound can be removed through the filtrate when crystallizing the losartan potassium product and then performing filtration, and through washing when washing. The added triphenylphosphine may also be removed through the crystallization, filtration, and washing processes.

eventually forming the losartan potassium product; And the step of generating an amine compound may be performed in one single pot, and one specific example of the reaction may be performed as shown in Scheme 1 below.

[Scheme 1]

Therefore, according to the method for producing purified losartan potassium according to one aspect described above, in order to remove impurities from losartan azido produced during the manufacturing process of losartan, losartan potassium is conventionally prepared during the manufacturing process of losartan potassium. Prior to the crystallization process to obtain the corresponding Losartan azi by using the conventional crystallization and filtration process of Losartan potassium, except that only a small amount of triphenylphosphine was added and stirred to reduce the azido impurity into an amine compound. Impurities can also be removed. Without an extraction or separate treatment process for additional work up, etc., it is possible to effectively remove genotoxic substances by simply adding and stirring triphenylphosphine before crystallization in the existing manufacturing method of losartan potassium. The quality of the losartan potassium prepared in this way is normal, and since there is no additional extraction or separate treatment process in the conventional manufacturing method of losartan potassium, the manufacturing yield can be maintained without loss of yield obtained in the conventional manufacturing method.

Another aspect provides purified losartan potassium prepared according to the method of the first aspect.

The purified losartan potassium may contain 100 ppm or less, specifically 50 ppm or less, more specifically 30 ppm or less, and still more specifically 10 ppm or less of the losartan azido impurity.

Therefore, the purified losartan potassium can be used as an antihypertensive drug so as not to exceed the permissible daily intake (1.5 μg/day) of losartan azido impurities stipulated by the Ministry of Food and Drug Safety.

Another aspect provides an antihypertensive pharmaceutical composition comprising the purified losartan potassium prepared according to the aspect as an active ingredient.

As described above, the antihypertensive pharmaceutical composition contains losartan potassium purified in an economical and efficient manner in high yield as an active ingredient, and thus can be provided as a safe and economical medicine without genotoxic agents.

The antihypertensive pharmaceutical composition may have a conventional formulation of a pharmaceutical composition containing losartan potassium, and may be prepared according to a conventional formulation method.

In addition, the antihypertensive pharmaceutical composition may be administered according to a conventional dosage and administration method of a pharmaceutical composition containing losartan potassium.

[Example]

Hereinafter, examples are presented to aid understanding of the present invention. The following examples are merely illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications can be made within the scope and spirit of the present invention, and it is natural that these changes and modifications fall within the scope of the appended claims.

Explanation of Abbreviations

The abbreviations used below are:

TPP: triphenylphosphine

Azido-Tz-BBC: 5-(4′-(azidomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole

LAZ-A: 5-(4′-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1′-biphenyl]- 2-day)-1H-tetrazole

LAZ-B: 4'-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbo nitrile

LAZ-C: 5-(4′-((4-(azidomethyl)-2-butyl-5-chloro-1H-imidazol-1-yl)methyl)-[1,1′-biphenyl]- 2-day)-1H-tetrazole

LAZ-D: 5-(azidomethyl)-2-butyl-4-chloro-1H-imidazole

Example 1: Preparation of Losartan Potassium (TPP: 0.0095 equivalent used)

320 g of losartan and 900 mL of isopropanol were added to the reaction vessel and stirred for 10 minutes. A solution of 50.9 g of potassium hydroxide dissolved in 260 mL of methanol was added to the reaction solution at room temperature and stirred for 30 minutes. The insoluble matter was removed by filtration and washed with a mixed solvent of 60 mL of isopropanol and 60 mL of methanol. After adding 1.88 g of triphenylphosphine (0.0095 equivalent to Losartan (0.59 wt%, 10 equivalent to the residual LAZ-A of Losartan)) and 0.3 mL of water to the filtrate, the mixture was stirred at 60° C. for 1 hour. While maintaining the temperature at 55-60 ° C., 3.84 L of cyclohexane was slowly added for 1 hour and 30 minutes. Thereafter, 1.44 L of cyclohexane was distilled off at 65° C. or less, and the temperature of the reaction solution was cooled to room temperature for 2 hours. After stirring at room temperature for 12 hours, the resulting solid was filtered, washed with a mixed solvent of isopropanol and cyclohexane, and dried with nitrogen at 40 ° C. to obtain 323.2 g of purified losartan potassium (yield: 93%) as the target compound. .

Example 2: Preparation of Losartan Potassium (using 0.0071 equivalent of TPP)

Losartan potassium was prepared in the same manner as in Example 1 using 1.41 g of TPP (0.0071 equivalent to Losartan (0.44wt%, 7.5 equivalent to the residual LAZ-A of Losartan)).

Example 3: Preparation of Losartan Potassium (using 5 equivalents of TPP)

Losartan potassium was prepared in the same manner as in Example 1 using 0.94 g of TPP (0.0047 equivalent to Losartan (0.29 wt%, 5 equivalent to the residual LAZ-A of Losartan)).

Example 4: Preparation of Losartan Potassium (using 3 equivalents of TPP)

Losartan potassium was prepared in the same manner as in Example 1 using 0.56 g of TPP (0.0028 equivalents compared to Losartan (0.18 wt%, 3 equivalents compared to residual LAZ-A of Losartan)).

Example 5: Preparation of Losartan Potassium (using 2 equivalents of TPP)

Losartan potassium was prepared in the same manner as in Example 1 using 0.38 g of TPP (0.0019 equivalent to Losartan (0.12 wt%, 2 equivalent to the residual LAZ-A of Losartan)).

Comparative Example 1: Preparation of losartan potassium (preparation without using TPP)

320 g of losartan and 900 mL of isopropanol were added to the reaction vessel and stirred for 10 minutes. A solution of 50.9 g of potassium hydroxide dissolved in 260 mL of methanol was added to the reaction solution at room temperature and stirred for 30 minutes. The insoluble matter was removed by filtration and washed with a mixed solvent of 60 mL of isopropanol and 60 mL of methanol. The temperature of the filtrate was raised to 60°C. While maintaining the temperature at 55-60 ° C., 3.84 L of cyclohexane was slowly added for 1 hour and 30 minutes. Thereafter, 1.44 L of cyclohexane was distilled off at 65° C. or less, and the temperature of the reaction solution was cooled to room temperature for 2 hours. After stirring at room temperature for 12 hours, the resulting solid was filtered, washed with a mixed solvent of isopropanol and cyclohexane, and dried with nitrogen at 40° C. to obtain 323.2 g of the target compound, losartan potassium (yield: 93%).

Experimental Example 1: LAZ-A, Azido-Tz-BBC residual amount, and TPP residual amount analysis according to TPP usage

The results of analyzing the residual amounts of LAZ-A, Azido-Tz-BBC, and TPP in the losartan potassium obtained by the methods of Examples 1 to 5 and Comparative Example 1 were summarized based on the amount of TPP used. The results are shown in Table 2 below.

[Table 2]

Claims (10)

adding a potassium hydroxide solution to a solution comprising losartan free base to form a losartan potassium product;
adding triphenylphosphine to the losartan potassium product to aminate the azido group of the azido impurity contained in the losartan potassium product to produce an amine compound; and
Then, crystallizing and filtering the losartan potassium product to remove the amine compound, a method for producing purified losartan potassium. The method according to claim 1, further comprising the step of filtering and removing insoluble matters after the step of generating losartan potassium, and washing with a mixed solvent of isopropanol and methanol. The method according to claim 1, wherein the triphenylphosphine is added in an amount of 0.001 equivalent to 0.02 equivalent based on losartan free base. The method according to claim 1, wherein the triphenylphosphine is added in an amount of 1 equivalent to 20 equivalents relative to the residual LAZ-A of losartan free base. The method according to claim 1, wherein the triphenylphosphine is added in an amount of 5 to 10 equivalents relative to the residual LAZ-A of the losartan free base. The method according to claim 1, wherein water is additionally added when the triphenylphosphine is added, and stirred while maintaining in the range of 50 to 70 ° C. to produce an amine compound. The method according to claim 1, wherein the step of crystallizing and filtering the losartan potassium product to remove the amine compound is slowly adding cyclohexane while maintaining the temperature in the range of 50 to 70 ° C., distilling off a part of the cyclohexane, and then returning to room temperature. cooling to crystallize the losartan potassium product followed by filtration and washing to obtain purified losartan potassium. Purified losartan potassium prepared according to the method of any one of claims 1 to 7. The purified losartan potassium according to claim 8, which contains less than 10 ppm of azido compounds including LAZ-A. A pharmaceutical composition for antihypertensives comprising the purified losartan potassium according to claim 9 as an active ingredient.