JP2016023158A - Method for producing high purity olmesartan medoxomil - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing high purity olmesartan medoxomil.SOLUTION: There is provided a method for producing trityl olmesartan medoxomil which comprises: (a) a step of saponifying trityl olmesartan ethyl ester with a base in a water-soluble organic solvent; and (b) a step of reacting the product in the step a) and 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolane in the presence of 0.5-fold more moles of an alkali metal iodide salt with respect to trityl olmesartan ethyl ester.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing olmesartan medoxomil, and more specifically to a method for producing high-purity olmesartan medoxomil with less impurities during the production of olmesartan medoxomil.

で表される化合物（化学名：（５−メチル−２−オキソ−１，３−ジオキソール−４−イル）メチル−４−（１−ヒドロキシ−１−メチルエチル）−２−プロピル−１−｛［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル｝イミダゾール−５−カルボキシレート）であり、アンジオテンシンII受容体拮抗剤として、高血圧症の治療や予防のための医薬の有効成分として有用な化合物である（特許文献１〜５、非特許文献１〜２）。 Olmesartan medoxomil has the following formula 4:

(Chemical name: (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- { [2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl} imidazole-5-carboxylate), and as an angiotensin II receptor antagonist, a pharmaceutical for the treatment and prevention of hypertension It is a compound useful as an active ingredient (patent documents 1 to 5, non-patent documents 1 and 2).

It is known that olmesartan medoxomil can be produced by the following reaction (Patent Documents 1 to 5, Non-Patent Document 2).

In order to use olmesartan medoxomil as a medicine, it is necessary to produce olmesartan medoxomil with high purity. However, in the known synthesis method based on the above reaction, trityl olmesartan ethyl ester (formula 1) and 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (formula 2) are obtained. In olmesartan medoxomil (formula 3), trityl olmesartan medoxomil-chloro adduct is produced as an impurity by side reaction, and in the olmesartan medoxomil produced by the subsequent acid treatment, olmesartan medoxomil-chloro adduct (formula 5) Is present as an impurity.

  This olmesartan medoxomil-chloro adduct cannot be easily separated from the produced olmesartan medoxomil, and a long time is required for the removal operation.

In order to avoid such problems and to produce high-purity olmesartan medoxomil that can be used as a medicine, in Patent Document 4, the amount of impurities such as trityl olmesartan medoxomil-chloro adduct in trityl olmesartan medoxomil is 0.1. Olmesartan medoxomil is produced by synthesizing olmesartan medoxomil from the selected trityl olmesartan medoxomil sample so that impurities such as olmesartan medoxomil-chloro adduct are less than 0.1%. ing. However, Patent Document 4 does not describe a method for reducing trityl olmesartan-chloro adduct or olmesartan medoxomil-chloro adduct or a method for removing them.
In Patent Document 5, olmesartan medoxomil is produced with high yield, but the purity of olmesartan medoxomil, which is the final target product, is not described.

Japanese Patent Publication No. 7-121918 (Patent No. 2082519) US Pat. No. 5,616,599 Special Table 2007-509992 (International Publication No. 2006/029056) Special Table 2007-526342 (International Publication No. 2006/073519) International Publication 2011/007368

J. Med. Chem., 39, 323-338 (1996). Annu. Rep. Sankyo Res. Lab. (Sankyo Kenkyosho Nenpo) 55, 1-91 (2003)

  The present invention produces high-purity olmesartan medoxomil by reducing olmesartan medoxomil-chloro adduct, which is an impurity that is difficult to separate, in the reaction step of the synthesis and performing simple purification operations such as ordinary recrystallization. The purpose is to do.

  As a result of intensive studies to solve the above problems, the present inventors have converted an alkali metal iodide salt into trityl olmesartan ethyl ester (formula 1) in the process of producing trityl olmesartan medoxomil which is a precursor of olmesartan medoxomil. On the other hand, by adding more than 0.5 moles, it was found that olmesartan medoxomil-ol adduct containing no olmesartan medoxomil can be stably produced, and the present invention has been completed.

で表されるトリチルオルメサルタンメドキソミルの製造方法において、
ａ）水溶性有機溶媒中、式１：

で表されるトリチルオルメサルタンエチルエステルを塩基でけん化する工程と、
ｂ) 前記工程ａ）の生成物と式２：

で表される４−クロロメチル−５−メチル−２−オキソ−１，３−ジオキソレンを、トリチルオルメサルタンエチルエステルに対して、０.５倍モルより多くのヨウ化アルカリ金属塩の存在下で反応させる工程
を含むトリチルオルメサルタンメドキソミルの製造方法。
２．水溶性有機溶媒がＮ,Ｎ−ジメチルアセトアミドである上記１に記載のトリチルオルメサルタンメドキソミルの製造方法。
３．ヨウ化アルカリ金属塩の添加量が式（１）に対して１倍モル以上である上記１又は２に記載のトリチルオルメサルタンメドキソミルの製造方法。
４．ヨウ化アルカリ金属塩がヨウ化ナトリウムまたはヨウ化カリウムである上記１〜３のいずれかに記載のトリチルオルメサルタンメドキソミルの製造方法
５．上記１〜４に記載の方法で製造されたトリチルオルメサルタンメドキソミルを脱トリチル化する式４：

で表されるオルメサルタンメドキソミルの製造方法。 That is, the present invention includes the following inventions.
1. Formula 3:

In the method for producing trityl olmesartan medoxomil represented by:
a) In a water-soluble organic solvent, formula 1:

A step of saponifying trityl olmesartan ethyl ester represented by the formula:
b) Product of step a) above and formula 2:

The 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene represented by the formula is reacted with trityl olmesartan ethyl ester in the presence of an alkali metal iodide salt having a molar amount greater than 0.5 times. The manufacturing method of the trityl olmesartan medoxomil including the process to make.
2. 2. The method for producing trityl olmesartan medoxomil according to 1 above, wherein the water-soluble organic solvent is N, N-dimethylacetamide.
3. 3. The method for producing trityl olmesartan medoxomil according to 1 or 2 above, wherein the addition amount of the alkali metal iodide is at least 1 mol per mol of the formula (1).
4). 4. The method for producing trityl olmesartan medoxomil according to any one of 1 to 3 above, wherein the alkali metal iodide is sodium iodide or potassium iodide. Formula 4 for detritylating trityl olmesartan medoxomil produced by the method described in 1 to 4 above:

The manufacturing method of olmesartan medoxomil represented by these.

  According to the method of the present invention, high-purity olmesartan having a reduced impurity content by suppressing the formation of olmesartan medoxomil-chloro adduct, which is an impurity that is difficult to separate later, in the process of synthesizing olmesartan medoxomil. Medoxomil can be produced.

As shown in the following reaction formula, the method of the present invention comprises trityl olmesartan ethyl ester represented by Formula 1 and 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene represented by Formula 2. The reaction is carried out in a solvent in a basic condition in the presence of 0.5 moles or more of an alkali metal iodide salt with respect to trityl olmesartan ethyl ester.

  The raw material compound used as a starting material in the present invention is not particularly limited in its obtaining method, and a commercially available one may be used or synthesized by a known method (Patent Documents 1 to 5, Non-Patent Documents). 1, 2).

  The alkali metal iodide salt used in the present invention is lithium iodide, sodium iodide or potassium iodide, preferably sodium iodide or potassium iodide, most preferably potassium iodide. In the present invention, the addition amount of the alkali metal iodide is important, and it is important that the amount is more than 0.5 times mol with respect to trityl olmesartan ethyl ester. If the addition amount of the alkali metal iodide is more than 0.5 times mol with respect to the trityl olmesartan ethyl ester, although there is no particular limitation, excessive use is not desirable from the economical viewpoint. The amount of 2 mol or less is sufficient. Usually, it is preferable to use an amount of 1.5 mol or less, particularly about an equivalent mol (1 mol).

The importance of the addition amount of the alkali metal iodide salt will be described in the case of using potassium iodide as the alkali metal iodide salt.
In the present invention, it is an essential requirement that the amount of potassium iodide is more than 0.5 moles compared to trityl olmesartan ethyl ester. When the amount of potassium iodide is 0.5 mol or less with respect to trityl olmesartan ethyl ester, the effect as a catalyst for promoting the reaction is seen, but the effect of suppressing the formation of by-products is not shown. When the amount of potassium iodide added was 0.5 mol or less with respect to trityl olmesartan ethyl ester, olmesartan medoxomil-chloro adduct was detected from the purified olmesartan medoxomil by HPLC analysis. On the other hand, when the addition amount of potassium iodide was more than 0.5 times mol with respect to trityl olmesartan ethyl ester, olmesartan medoxomil-chloro adduct was not detected by HPLC analysis from the purified olmesartan medoxomil.

  Even when sodium iodide was added at a 1.0-fold molar ratio to trityl olmesartan ethyl ester instead of potassium iodide, olmesartan medoxomil-chloro adduct was not detected by HPLC analysis from the purified olmesartan medoxomil.

  The solvent used in the present invention is not particularly limited as long as it is a water-soluble organic solvent. For example, lower alkanols such as methanol, ethanol and isopropanol, cellosolves such as methyl cellosolve, ethyl cellosolve and butyl cellosolve, acetone and the like Ketones, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, sulfones such as dimethyl sulfone and diethyl sulfone, N, N-dimethylformamide, N, N-diethylformamide, N, N-dimethylacetamide, N, N Amides such as diethylacetamide, lactams such as N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone and N-hydroxyethyl-2-pyrrolidone, 1,3-dimedyl -2-Imidazolidinone and other imi Zolidinones, glycols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, propylene glycol monobutyl ether, dipropylene glycol Examples include glycol ethers such as monomethyl ether and dipropylene glycol monoethyl ether, and cyclic ethers such as tetrahydrofuran and tetrahydropyran. These water-soluble organic solvents may be used alone or in combination of two or more. Among these, ketones such as acetone, nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, amides such as N, N-dimethylformamide and N, N-dimethylacetamide are preferable, and acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide is particularly preferred.

  There is no restriction | limiting in particular as an alkali which makes a solvent an alkaline condition by this invention, Alkali metal carbonates, such as generally used alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate , Alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide, alkaline earth metal hydroxides such as calcium carbonate and barium carbonate, etc. are used as appropriate, but alkali such as sodium hydroxide and potassium hydroxide. Metal hydroxide is particularly preferred.

  The amount of the solvent and alkali used in the present invention, the reaction temperature, the reaction time, and the like can be appropriately set within the same ranges as known methods (Patent Documents 1 to 5, Non-Patent Documents 1 and 2). For example, with respect to the reaction temperature, all the above steps can be appropriately performed within a temperature range of 1 ° C to 80 ° C, preferably 10 ° C to 50 ° C, more preferably 15 ° C to 40 ° C, as in the known method. It can be carried out in the temperature range.

Detritylation of trityl olmesartan medoxomil is performed according to a known method (Patent Documents 1 to 5, Non-Patent Documents 1 and 2). Here, the acid used is not particularly limited. For example, organic acids such as formic acid, acetic acid, benzoic acid, oxalic acid, p-toluenesulfonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, hydrobromic acid Inorganic acids such as Of these, hydrochloric acid is preferred.
The amount of the acid used is not particularly limited as long as it is 1 equivalent or more, but preferably 1 to 5 equivalents.
Equivalent weight is particularly preferred.

[Example 1]
Trityl olmesartan ethyl ester (6.00 g, 8.37 mmol) and N, N-dimethylacetamide (9 mL) were mixed. Subsequently, 85% potassium hydroxide (939 mg, 14.23 mmol) was added, and the mixture was heated to 40 ° C. and stirred overnight. After cooling the reaction solution to 20 ° C., potassium iodide and trityl olmesartan ethyl ester were equimolar (1.39 g, 8.37 mmol), 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene ( 1.74 g, 11.7 mmol) and N, N-dimethylacetamide (1.8 mL) were added. After completion of the addition, the mixture was stirred for 43 hours, acetic acid (0.28 g, 4.69 mmol) was added, and the reaction solution was added dropwise to water (28.2 mL) to precipitate crystals. The precipitate was collected by filtration and washed with water (20 mL) to obtain wet crystals of trityl olmesartan medoxomil. The wet crystal was dried at 50 ° C. to obtain 5.90 g of a crude trityl olmesartan medoxomil.
Subsequently, a detritylation reaction was performed according to a known method, and the obtained olmesartan medoxomil crude product was recrystallized and purified to obtain a purified olmesartan medoxomil (yield 55%).

[Example 2]
Purified olmesartan medoxomil was obtained in the same manner as in Example 1 except that the amount of potassium iodide added was 1.5 times mol (2.08 g) of trityl olmesartan ethyl ester (yield 51%).

[Example 3]
1.25 g of sodium iodide was added instead of potassium iodide, and a purified olmesartan medoxomil was obtained in the same manner as in Example 1 (yield 54%).

[Comparative Example 1]
Purified olmesartan medoxomil was obtained in the same manner as in Example 1 except that the amount of potassium iodide added was 0.2 mol (277 mg) of trityl olmesartan ethyl ester (yield 54%).

[Comparative Example 2]
Purified olmesartan medoxomil was obtained in the same manner as in Example 1 with the addition amount of potassium iodide 0.5 mol (695 mg) of trityl olmesartan ethyl ester (yield 54%).

  Table 1 shows the results of HPLC measurement of the purified olmesartan medoxomil obtained in Examples 1-3 and Comparative Examples 1-2.

  The recrystallization of the crude olmesartan medoxomil is carried out, for example, as follows.

[Reference Example 1]
A mixture of crude olmesartan medoxomil (3.00 g, 5.37 mmol), acetone (23.0 mL) and water (0.96 mL) obtained by the method described in Example 1 was stirred at 70 ° C. The reaction solution was allowed to cool to room temperature, stirred for 16 hours, and then crystallized crystals were collected by filtration and washed with acetone (3.0 ml). The crystals were dried at 50 ° C. to obtain a purified product of olmesartan medoxomil (2.1 g, yield 70%).

Claims (5)

Formula 3:

In the method for producing trityl olmesartan medoxomil represented by:
a) In a water-soluble organic solvent, formula 1:

A step of saponifying trityl olmesartan ethyl ester represented by the formula:
b) Product of step a) above and formula 2:

The 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene represented by the formula is reacted with trityl olmesartan ethyl ester in the presence of an alkali metal iodide salt having a molar amount greater than 0.5 times. The manufacturing method of the trityl olmesartan medoxomil including the process to make.   The method for producing trityl olmesartan medoxomil according to claim 1, wherein the water-soluble organic solvent is N, N-dimethylacetamide.   The method for producing trityl olmesartan medoxomil according to claim 1 or 2, wherein the addition amount of the alkali metal iodide is 1 mol or more with respect to trityl olmesartan ethyl ester.   The method for producing trityl olmesartan medoxomil according to any one of claims 1 to 3, wherein the alkali metal iodide is sodium iodide or potassium iodide. Formula 4 for detritylating the trityl olmesartan medoxomil produced by the method according to any one of claims 1-4.

The manufacturing method of olmesartan medoxomil represented by these.