KR20150004495A - Method of producing related substance of olmesartan medoxomil - Google Patents

Abstract

The present invention relates to a manufacturing method of related substances of olmesartan medoxomil which are RNH6373 and RNH6363 denoted by chemical formula 3 and 4. In a process of evaluating the quality of olmesartan medoxomil products, the manufacturing method is allowed to efficiently synthesize essential substances, thereby accurately measuring the amount of impurity generated in a manufacturing process and manufacturing the related substances of olmesartan medoxomil at an affordable price and in an easy manner.

Description

[0001] METHOD OF PRODUCING RELATED SUBSTANCE OF OLMESARTAN MEDOXOMIL [0002]

The present invention relates to a process for preparing a flexible material of olmesartan medoxomil.

The chemical name of Olmesatan methoxylate is 4- (1-hydroxy-1-methylethyl) -2-propyl-1 - [[2- (lH-tetrazol-5-yl) Methyl] -2-oxo-1,3-dioxol-4-yl) methyl ester represented by the following general formula (1).

Olmesatan Medoxomil is an angiotensin II receptor antagonist, a prodrug that is hydrolyzed by olmesartan in the absorption process from the gastrointestinal tract. It is not only excellent in blood pressure lowering effect but also has excellent protective effect against target organ damage, It is an imidazole-based drug widely used for treatment.

Olmesan Medoxomil was first developed by a Japanese pharmaceutical company, Daiichi-Sankyo, and was first disclosed in the patent literature in U.S. Patent No. 5,616,599 (Patent Document 1) Quot ;, all of which are incorporated herein by reference in their entirety)

Thereafter, the method of producing olmesatan medoxomil was improved and improved in the direction of identifying impurities other than the main component and decreasing it.

An improved production method of Olmesatin Medoxomil can be exemplified by Korean Patent Application No. 10-2012-0070352 (Patent Document 2) filed by the present applicant on the Korean Intellectual Property Office (hereinafter, referred to as Patent Document 2) Quot; is incorporated herein by reference in its entirety as the content of the prior art in the specification of the present invention). Patent Document 2 discloses a method for producing olmesartan medoxomil, in which the amount of a soft substance is small, the yield is high, and the particle size is fine, so that a separate grinding step is unnecessary.

Conventional techniques for the production of olmesartan medoxomil other than the above can further exemplify Patent Documents 3 to 14 and Non-Patent Document 3, and the contents of the documents exemplified thereby can be found in the prior art All are quoted as content.

The presence of so-called suppositories, which are impurities in medicines, can significantly affect the efficacy and stability of the medicines. Therefore, it is necessary to set a content standard for the active pharmaceutical ingredient (API) Studies and tests for toxicity confirmation are indispensable. To achieve this, it is very important to have raw materials for the active drug substance as well as its flexible substances, and the olmesartan medoxomil is also different.

However, the problem is that it is known that the synthesis route of the flexible substance is complicated and the separation and refinement of only the flexible substance is very difficult in the case of Olmeta satin medoxomil, and it is necessary to develop a more effective synthesis method for the flexible substance The non-patent documents 1 to 2 and the patent document 15 can be understood in more detail and the non-patent documents 1 to 2 and the patent document 15 are all contents of the prior art in the description of the present invention Quot;).

US 5,616,599 A KR 10-2012-0070352 A US 5,763,619 A US 7,345,072 B2 US 20060148870 A1 US 7,528,258 B2 US 7,563,814 B2 WO 2012055994 A1 CN 102079747 A WO 2007/148344 A2 WO 2011/036674 A1 EP 1916246 A2 US 2008076932 A1 CN 1381453 A WO 2010/126013 A1

 Karrothu srihari Babu, etc., "Synthesis of related substances of olmesartan medoxomil, anti-hypertensive drug #", ARKIVOC 2010, (ii), pp. 292-302.  Hiroaki Yanagisawa, et al., "Nonpeptide Angiotensin II Receptor Antagonists: Synthesis, Biological Activities, and Structure Relationships of Imidazole-5-carboxylic Acids Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds" Med. Chem. 1996, 39 (1), pp. 323-338.  Synthetic Communications, 2009, 39 (2), pp. 291-298.

It has been known that, in the production of the oligosaccharide medoxomil suppository, separation and purification of only the suppository is very difficult when the suppositories generated during the manufacturing process of olmesatan medoxomil are separated, This is a low problem.

Therefore, although it is preferable to prepare a flexible material of olmesartan medoxomil through separate synthesis, the conventional method of synthesizing olmesartan medoxomil is very complicated.

Accordingly, it is an object of the present invention to provide a novel method for producing a flexible material of olmesatan medoxomil to solve the problems of the prior art.

According to the present invention, there is provided a process for preparing a soft substance of olmesatan medoxomil,

(2'- (1 H -tetrazole-1-yl) methyl) -1,2,3,4-tetrahydronaphthalene- 5-yl) biphenyl-4-yl) methyl) -4- (2-chloropropan-2-yl) -2-propyl-1 H -imidazole-5-carboxylate compound; And

And then synthesizing a compound represented by the following general formula (3) by removing the synthesized compound of the general formula (2).

(2)

(3)

The present invention also provides a process for preparing RNH6373, a olmesatan medoxomil soft substance, characterized in that the halogenation reaction is a chlorination reaction.

In the present invention, the chlorination reaction is carried out with at least one selected from SOCl ₂ , PCl ₅ , and POCl _3. The present invention provides a process for preparing RNH 6373, a olmesatan medoxomil compact.

In the present invention, the halogenation reaction is carried out in a dichloromethane solvent in the presence of triethylamine. The process for preparing RNH6373, an oligosaminone medoxomil soft substance, is also provided.

Also, the present invention provides a process for preparing RNH6373, a olmesatan medoxomil soft substance, characterized in that the elimination reaction is carried out with pyridine.

Also, the present invention provides a process for preparing RNH6373, a olmesatan medoxomil soft substance, characterized in that the elimination reaction is carried out in a dichloromethane solvent.

The present invention also provides a process for preparing RNH6363, a olmesartan medoxomal precursor, which comprises hydrolyzing a compound represented by the formula (3) to synthesize a compound represented by the formula (4).

[Chemical Formula 4]

Also, the present invention provides a process for preparing RNH6363, a olmesatan medoxomil soft substance, characterized in that the hydrolysis reaction occurs in the presence of a base.

In the present invention, there is also provided a process for preparing RNH6363 of olmesartan medoxomil, which is characterized in that the base is lithium hydroxide.

In the present invention, there is also provided a process for the preparation of olmesatan medoxomil soft substance RNH6363, which is carried out in a solvent which is selected from 1,4-dioxane and water, or a mixture thereof.

INDUSTRIAL APPLICABILITY The present invention effectively assists in the quantitative determination of the amount of impurities generated in the manufacturing process and the like by effectively synthesizing a substance essential to the process of evaluating the quality of olmesartan medox product, And it is easy to manufacture.

Fig. 1 shows HPLC results of the supernatant RNH6373 obtained in Example 1 of the present invention. Fig.
Fig. 2 shows the HPLC results for the supernatant RNH6363 obtained in Example 2 of the present invention.

First, the terms in this specification are defined.

A "related substance" refers to a substance that is likely to be included in the raw material synthesis process or on the finished product, and is a kind of impurity for the main active ingredient that can be used for the quality evaluation of the finished product.

The "halogenation reaction" is a reaction in which a part of the compound is substituted with a halogen element, and includes a chlorination reaction, a fluorination reaction, a bromination reaction, and the like.

The "elimination reaction" includes a dehydrohalogenation reaction, a dehalogenation reaction, a dehydration reaction and the like as a reaction in which a part of the molecules of the saturated organic compound are separated and produce olefins.

The term "hydrolysis" refers to a reaction in which water is reacted with water to break it into several ions, molecules, or compounds. In the reaction, a part of the compound is desorbed by water in the presence of a catalyst or an enzyme such as a base, .

Hereinafter, the present invention will be described in detail.

The present invention relates to a process for preparing a flexible material of olmesartan medoxomal represented by the following chemical formulas 3 and 4, wherein RNH6373 is represented by the following chemical formula 3 and RNH6363 is represented by the chemical formula 4 below: I use these aliases in my life world.

(3)

[Chemical Formula 4]

According to the production method of the present invention, it is possible to synthesize more easily the high purity olmecanic medoxomil softeners RNH6373 (Formula 3) and RNH6363 (Formula 4).

In particular, the conventional RNH6373 synthesis method is described in ARKIVOC 2010, (ii), pp. 292-302 (Non-Patent Document 1), there is a disadvantage in that it is impossible to secure a flexible substance from the finished drug substance, and thus a separate substance must be secured, since it is a method of synthesizing from the olmesartan medoxomil derivative , The yield was not good, and it was not economical. The following Reaction Scheme 1 is a method for synthesizing RNH6373 disclosed in Non-Patent Document 1.

[Reaction Scheme 1]

In the above Scheme 1, (i) PTSA / Toluene, (ii) acetic acid, 55-60 ° C.

In addition, the conventional RNH6373 synthesis method is not a method of using olmesartan methoxycin as a starting material but is a method of synthesizing from other compounds, so that an undesired isomer may be generated in the synthesis process. In this case, There is also a need for a separate process for removal.

On the other hand, the production method of the present invention is capable of securing a flexible material from a finished drug raw material and synthesizing a flexible substance using olmesartan medoxomil as a starting material, thereby achieving a high yield and highly economically managing the finished drug quality can do. Furthermore, since olmesatan medoxomil is used as a starting material, there is no problem of isomerization that may occur during the synthesis process, and there is no need for a separate process for isomer purification, so that the synthesis route is simple and very economical.

The process for synthesizing the flexible substance RNH6373 (Formula 3) of the present invention is shown in the following Reaction Scheme 2.

[Reaction Scheme 2]

That is, as shown in Reaction Scheme 2, in the present invention, chlorination reaction of the hydroxyl group of olmesartan methoxycinnamic acid is carried out using olmesartan methoxycinosilicate (formula 1) Yl) methyl) - (2'- (1 H- tetrazol-5-yl) biphenyl-4-yl) To synthesize 4- (2-chloropropan-2-yl) -2-propyl-1 H -imidazole-5-carboxylate compound. Thereafter, a process for synthesizing the oligosaccharide medoxomil soft substance RNH6373 represented by the general formula (3) is carried out through the elimination reaction which is the next reaction without separation and purification.

The synthesis process of the flexible substance RNH6363 (Formula 4) of the present invention is shown in the following Reaction Scheme 3.

[Reaction Scheme 3]

That is, as shown in Reaction Scheme 3, in the present invention, the oligomeric RNH6373 of olmesartan methoxycinnamic acid represented by the general formula (3) is subjected to a hydrolysis reaction to synthesize the oligomeric RNH6363, .

Hereinafter, the present invention will be described in more detail with reference to examples. It is to be understood that the following embodiments are for the purpose of illustration only, and are not intended to limit the scope of the invention.

Example  One

Was dissolved in 112 L (0.20 mol) of olmesartan methoxysilane represented by the general formula (1) in 1.10 L of dichloromethane. After the solution was cooled to 0 ° C, 28.0 mL (0.20 mol) of triethylamine was added, and SOCl ₂ 22.0 mL (0.30 mol) was added. The reaction solution was gradually warmed to room temperature and stirred at room temperature for 3 hours. After the completion of the reaction was confirmed by TLC, 48.0 mL (0.59 mol) of pyridine was added and the mixture was stirred at room temperature for 3 hours.

After the completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and then ethyl acetate and water were added. The separated organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The concentrate was separated and purified by column chromatography to obtain (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl1 - ((2 '- (1 H -tetrazol-5-yl ) of biphenyl-4-yl) methyl) -4- (prop-1-en-2-yl) -2-propyl-1 H -imidazole-5-carboxylate 45.5 g (42%) was obtained as a white solid.

_{^{1 H NMR (400MHz, CDCl 3}} ) 7.78-7.40 (4H, m), 7.06 (2H, d, J = 7.2 Hz), 6.77 (2H, d, J = 7.6 Hz), 5.43 (2H, s), 5.04 (2H, m), 2.07 (3H, s), 1.85 (3H, s), 1.58-1.63 (2H, m) ), 0.87 (3H, t, J = 7.2 Hz). MS (m / z) = 541.10 (M < + >).

Example  2

Methyl-2-oxo-1,3-dioxol-4-yl) methyl 1 - ((2 '- (1 H -tetrazol-5-yl) biphenyl- -4- (prop-1-en- 2-yl) -2-propyl-1 H -imidazole-5-carboxylate 2.5 g of 1,4-dioxane was added to 25 ml, water 25 mL in (4.62 mmol) LiOH · H ₂ O 0.97 g (23.1 mmol) were added thereto, and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction was confirmed by TLC, the reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane, and then dichloromethane and water were added. The separated organic layer was dried over anhydrous MgSO ₄ and filtered. The concentrate was separated and purified by column chromatography to obtain 1 - ((2 '- (1 H -tetrazol-5-yl) biphenyl- 2-yl) -2-propyl- 1H -imidazole-5-carboxylic acid as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6) 7.65-7.60 (2H, m), 7.55-7.48 (2H, m), 7.04 (2H, d, J = 7.2 Hz), 6.92 (2H, d, J = 7.6 Hz), 5.49 (2H, s ), 5.29 (1H, d, J = 1.6 Hz), 5.12 (1H, d, J = 1.6 Hz), 2.01 (3H, s), 1.57-1.48 (2H, m), 0.82 (3H, t, J = 7.2 Hz). MS (m / z) = 429.15 (M < + >).

Test Example

With the following analysis conditions, the fractions RNH6373 and RNH6363 obtained in the above Examples 1 and 2 were analyzed.

Detector: ultraviolet absorbance photometer (measuring wavelength 250 nm)

Column: A column packed with octadecylsilyl silica gel for liquid chromatography of 5 m in diameter in a stainless steel pipe having an inner diameter of about 4.6 mm and a length of about 15 cm

Flow rate: 1.0 mL / min

Column temperature: 40

Mobile phase A: A mixture of 800 mL of buffer and 200 mL of acetonitrile

Mobile phase B: A mixture of 200 mL of buffer and 800 mL of acetonitrile

Buffer: 2.04 g of KH ₂ PO ₄ was dissolved in distilled water, and the final volume was adjusted to 1 L, adjusted to pH 3.5 with phosphoric acid

Slope of mobile phase: time (minutes), mobile phase A%, mobile phase B%

Time (minutes) Mobile phase B (%) Mobile A (%) 0-10 75 25 10-35 75 → 0 25 → 100 35-45 0 100

As described above, according to the manufacturing method of the present invention, it is possible to easily synthesize a flexible material from Olmesan Medoxomil, and it is also possible to obtain a more economical and effective finished drug quality test and management It will be possible.

While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, but many variations and modifications may be made without departing from the spirit and scope of the invention. . Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by the appended claims and equivalents thereof.

Claims (10)

(2'- (1 H -tetrazole-1-yl) methyl) -1,2,3,4-tetrahydronaphthalene- 5-yl) biphenyl-4-yl) methyl) -4- (2-chloropropan-2-yl) -2-propyl-1 H -imidazole-5-carboxylate compound; And
And then synthesizing a compound represented by the following general formula (3) by removing the synthesized compound of the general formula (2).
(2)

(3)

The process according to claim 1, wherein the halogenation reaction is a chlorination reaction. The method according to claim 2, wherein the chlorination reaction is carried out with at least one selected from SOCl ₂ , PCl ₅ , and POCl ₃ . The process according to claim 1, wherein the halogenation reaction is carried out in a dichloromethane solvent in the presence of triethylamine. The process according to claim 1, wherein the elimination reaction is carried out with pyridine. The method according to claim 1, wherein the elimination reaction is performed in a dichloromethane solvent. Wherein the compound represented by the general formula (3) is hydrolyzed to synthesize the compound represented by the general formula (4).
[Chemical Formula 4]

[Claim 7] The method according to claim 7, wherein the hydrolysis reaction occurs in the presence of a base. [Claim 9] The method according to claim 8, wherein the base is lithium hydroxide. Process according to claim 7, characterized in that the process is carried out in a solvent which is selected from 1,4-dioxane and water, or mixtures thereof, in water.

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