KR101266224B1

KR101266224B1 - An improved process for the preparation of trityl olmesartan medoxomil

Info

Publication number: KR101266224B1
Application number: KR1020100086001A
Authority: KR
Inventors: 이기용; 권재욱; 서명원; 강재훈
Original assignee: 일동제약주식회사
Priority date: 2010-09-02
Filing date: 2010-09-02
Publication date: 2013-05-21
Also published as: KR20120022418A

Abstract

The present invention relates to (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl as the main intermediate of olmesartan medoxomil. -1-((2 '(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate (hereafter trityl olmesartan medoc It relates to a method for producing roughness).
The present invention relates to the preparation of medosomyl chloride represented by the following formula (3) in toluene, xylene or acetone solvent in the presence of an alkali metal iodide, an 18-crown-6 catalyst, and an inorganic basic compound represented by the following formula (2) Roxypropan-2-yl) -2-propyl-1 ((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5- Provided is a method for producing trityl olmesartan medoxomil represented by Chemical Formula 1 by one-pot reaction with carboxylic acid (hereinafter trityl olmesartan).

&Lt; Formula 1 >< EMI ID =

(3)

Description

An improved process for the preparation of trityl olmesartan medoxomil}

The present invention relates to a process for preparing trityl olmesartan medoxomill, which is the main intermediate of olmesartan medoxomill. Olmesartan Medoxomil is an antagonist for angiotensin II receptors and is a useful drug for the treatment of cardiovascular diseases.

Olmesartan Medoxomil, represented by Formula 4, is a potent angiotensin II receptor antagonist for the treatment of essential hypertension in which blood pressure is not sufficiently controlled by monotherapy and in the treatment of cardiovascular diseases such as the circulatory system, heart, and hypertension. Useful, long-acting drugs are described in US Pat. No. 5,515,599. In addition, trityl olmesartan medoxomil represented by the following formula (1) can be prepared from trityl olmesartan represented by the formula (2) as a main intermediate of olmesartan medoxomil represented by the formula (4).

&Lt; Formula 4 >

The process for preparing trityl olmesartan medoxomil disclosed in the prior art can generally be represented by the following schemes.

Scheme 1 is described in Example 78 of Korean Patent 1992-002676, which is a patent of the original developer, and has the following disadvantages.

1) Trityl olmesartan lithium monohydrate was dissolved in K ₂ CO ₃ and 4-chloro methyl-5-methyl-2-oxo-1,3-dioxolene (hereinafter referred to as medoxomil chloride) in a dimethyl acetamide (hereinafter DMA) solvent. It is used to produce trityl olmesartan medoxomil by reacting at 45 ~ 50 ℃ for 3 hours using). DMA, a solvent used in the reaction, is difficult to remove and is toxic to human body. Difficult to do

2) Since the starting material trityl olmesartan lithium salt is purified by column and then used in the reaction, it is not economical and is not suitable for industrial mass production.

3) Since the produced trityl olmesartan medoxomill is not separated into crystals and used directly in the next step, the purity is low, and thus the purity and yield of the finally prepared olmesartan medoxomill is low.

On the other hand, successive two to four step one-pot reactions including a method of synthesizing trityl olmesartan medoxomil using medoxomil chloride as in Scheme 2 are described in EP1816131 Example 2, International Publication No. WO2007148344 Examples 1 to 3, International Publication No. WO2007048361 Examples 2 to 3, International Publication No. WO2008043996 Examples 1 to 5, International Publication No. WO2007047838 Example 5, International Publication No. EP1916246 3 to 4 and International Patent Publication No. WO2009019304 Examples 1 to 3 are described.

Problems of the method for preparing trityl olmesartan medoxomile in the above patents are difficult to remove with a reaction solvent, using DMA or DMSO, which is a toxic solvent to the human body, or using a toxic solvent such as methyl ethyl ketone in an amount of 15 times or more. It should be.

In addition, the patents use an excess (1.4-2.6 equivalents) of medoxomil chloride which is difficult to remove. In this case, there is a problem in that medoxomil chloride remains, resulting in the impurity of trityl olmesartan medoxomil as the target product and olmesartan medoxomil as the final target.

Meanwhile, the inventors of the present invention actually synthesized trityl olmesartan medoxomil in accordance with the method of Example 1 of European Patent No. EP1816131, and confirmed the final target olmesartan medoxomill without separation and purification. Is described as 75% but in practice a low yield of only 42.7% yielded impure brown crystals.

When the synthesis of trityl olmesartan medoxomill was performed according to the method of Example 3 of WO2007148344, the reaction was not completed, and when the final object olmesartan medoxomill was synthesized without separation and purification, Satan medoxomil did not separate into pure crystals.

In addition, even when the synthesis of trityl olmesartan medoxomil was carried out according to the method of Example 3 of WO2007048361, the reaction was not completed, and no trityl olmesartan medoxomil crystals were produced.

As a result of the present inventors performing the prior arts as described above, in the manufacturing process of trityl olmesartan medoxomill, the reaction was generally not completed and the starting material remained and did not separate into pure crystals. Further, when olmesartan medoxomill was prepared directly from such trityl olmesartan medoxomill without separation and purification, olmesartan medoxomill could not be obtained as a crystal or only in a very impure state.

Thus, the present inventors confirmed that when the final target olmesartan medoxomill is obtained without obtaining trityl olmesartan medoxomill as pure crystals, the yield is low and impure, so it is unsuitable for industrial mass production. It was.

It is an object of the present invention to overcome many problems as discussed above, and to provide a manufacturing method which can easily obtain pure trityl olmesartan medoxomil as crystals even in industrial mass production.

The present inventors overcome the problems of the prior art that use solvents that are harmful to the human body and are difficult to remove, or that the reaction is not completed and cannot be purified purely, while being economical and simple in process, it is easy to mass produce industrially. In addition, various studies have been conducted to find a method for producing trityl olmesartan medoxomill with high yield and high purity.

In the meantime, it was found that medosomyl chloride was unstable and gradually decomposed when the reaction temperature was above 40 ° C., resulting in a low conversion of the reaction and formation of a flexible substance. When the inventors have carried out according to the prior art, it was found that the reason that the reaction conversion rate was actually low was because of such a cause.

As a result, when the inventors reacted trityl olmesartan and medoxyl chloride by using alkali metal iodide and 18-crown-6 in toluene, xylene, acetone or a mixed solvent thereof, which is inexpensive and easy to remove, It has been surprisingly found that trityl olmesartan medoxomil can be produced in purely high yields even at low temperatures.

In addition, in the present invention, despite the use of a smaller amount of medoxomil chloride (1.1-1.2 equivalents) than the prior art, it is possible to obtain trityl olmesartan medoxomil, which is a reaction target, as pure white crystals with high reaction conversion rate.

Another advantage of the present invention is that the overall process is simple and convenient.

In order to increase the reactivity, medosomyl chloride is mixed with alkali metal iodide and 18-crown-6 to form medoxomil iodide, together with trityl olmesartan, starting material from the beginning, in a reactor. By reacting, a one-pot reaction in which two reactions proceed simultaneously is possible. In addition, in the case of using toluene or xylene as a solvent, it is possible to wash with water immediately after the reaction is terminated, so the treatment process after the reaction is very convenient.

In the present invention, the reaction solvent is characterized by using a solvent selected from toluene, xylene, acetone or a mixed solvent thereof, and also using an alkali metal iodide and an 18-crown-6 catalyst at a low temperature. Is short, has a high conversion rate, but generates little lead.

On the other hand, the present inventors found that olmesartan medoxomill was prepared using benzene, an aromatic solvent such as toluene and xylene under the same reaction conditions, and found that the reaction time was particularly long, which was not suitable for industrial mass production. It was. In addition, when using acetonitrile and ethyl acetate, which are similar in polarity to acetone and are generally used, the reactants are not particularly dissolved well, and surprisingly, the viscosity is very high so that the stirring is not performed, resulting in a very low reaction conversion rate.

Therefore, the present invention can be easily prepared in a short time even under mild temperature conditions using alkali metal iodide and 18-crown-6 under toluene, xylene, acetone or a mixed solvent thereof, and can be separated into pure crystals. The present invention provides a method for preparing trityl olmesartan medoxomil, which is easy for industrial mass production.

As a result of the above, in the production of trityl olmesartan medoxomill, the present invention can be said to be a distinctive and original invention.

The present invention is environmentally friendly, economical because it uses 1) less solvent which is inexpensive and easy to remove, and 2) trityl olmesartan medoxomill can be produced in a short time under mild temperature conditions under characteristic reaction conditions. 3) It can be separated into pure crystals in high yield, and 4) it provides a manufacturing method that is easy to mass production industrially because the overall reaction process is simple.

Trityl olmesartan medoxomil is prepared as in Scheme 3 below.

Trityl olmesartan medoxomil is prepared by reacting trityl olmesartan and medoxyl chloride using 18-crown-6 with an alkali metal iodide and a catalyst in toluene, xylene, acetone or a mixed solvent thereof.

At this time, the reaction temperature is preferably 20 to 35 ° C, more preferably 30 to 35 ° C.

As the alkali metal iodide used in the reaction, sodium iodide or potassium iodide may be used, and preferably sodium iodide is used.

In the reaction, the inorganic basic compound may be potassium carbonate, sodium carbonate or potassium hydrogen carbonate, sodium hydrogen carbonate or the like, which is an alkali metal carbonate, and preferably potassium carbonate.

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

Preparation of Trityl Olmesartan Medoxomil

Example 1.

250 ml of toluene, 24.05 g of trityl olmesartan and 7.5 g of potassium carbonate are stirred at 40 ° C. for 30 minutes. After cooling to room temperature, 1.81 g of 18-crown-6, 5.72 g of sodium iodide and 5.95 g of medoxomil chloride are added. After stirring the reaction again at 30 ~ 35 ℃ for 4 hours, it is confirmed that the reaction is completed and the suspended solids are filtered off.

250 ml of constant is added to the filtrate, the mixture is stirred, the organic layer is separated, and the aqueous layer is extracted with 125 ml of toluene. The organic layers are combined and washed with a saturated aqueous sodium thiosulfate solution. The organic layer is dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated.

Isopropyl alcohol was added to the residue and concentrated again. Then, 125 ml of ethanol was added to the residue, the mixture was stirred at room temperature, filtered, and dried at 40 DEG C to obtain 25.44 g of trityl olmesartan medoxomil crystals. (Yield 91%), (Purity by HPLC: 99.73%)

Example 2.

120 ml of xylene, 15.0 g of trityl olmesartan and 4.6 g of sodium carbonate are stirred at 40 ° C. for 30 minutes. After cooling to room temperature, 1.2 g of 18-crown-6, 3.61 g of sodium iodide and 3.65 g of medoxomil chloride are added. The reaction was stirred again for 4 hours at 30 ~ 35 ℃, it was confirmed that the reaction was completed. Thereafter, the procedure was carried out as in Example 1, to obtain 15.0 g of trityl olmesartan medoxomil crystals. (Yield 86%)

Example 3.

A mixture of 60 ml of toluene and 60 ml xylene, 15.0 g of trityl olmesartan and 4.6 g of potassium carbonate are stirred at 40 ° C. for 30 minutes. After cooling to room temperature, 1.2 g of 18-crown-6, 3.61 g of potassium iodide and 3.65 g of medoxomil chloride are added. After the reaction was stirred at 20-25 ° C. for 12 hours, it was confirmed that the reaction was completed. Thereafter, the procedure was carried out as in Example 1, to obtain 14.3 g of trityl olmesartan medoxomil crystals. (Yield 82%)

Example 4.

120 ml of acetone, 15.0 g of trityl olmesartan and 4.6 g of potassium carbonate are stirred at 40 ° C. for 30 minutes. After cooling to 20-25 ° C., add 1.2 g 18-crown-6, 3.61 g sodium iodide and 3.65 g medoxomil chloride. After stirring the reaction again at 30 ~ 35 ℃ for 4 hours, it is confirmed that the reaction is completed and the suspended solids are filtered off.

The filtrate was concentrated to remove the solvent, and 120 ml of ethyl acetate and a constant were added to the residue, followed by stirring. The organic layer was separated. The aqueous layer was once again extracted with 50 ml of ethyl acetate, the organic layers were collected and washed with saturated aqueous sodium thiosulfate solution, the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated.

Isopropyl alcohol was added to the residue, concentrated again, 60 ml of ethanol was added thereto, stirred at room temperature, filtered, and dried at 40 ° C. to obtain 15.15 g of trityl olmesartan medoxomil crystals. (Yield 87%)

Claims

A method of preparing trityl olmesartan medoxomil by reacting trityl olmesartan with medoxyl chloride using an alkali metal iodide and an alkali metal iodide in a toluene solvent and 18-crown-6 as a catalyst.

The production process according to claim 1, wherein the reaction temperature at the time of reacting trityl olmesartan and medoxyl chloride is 20 to 35 ° C.

The production method according to claim 1 or 2, wherein the alkali metal iodide is selected from sodium iodide and potassium iodide.