KR101090325B1 - Industrial process of high purity olmesartan medoxomil - Google Patents

Abstract

The present invention relates to a method for producing high purity olmesartan medoxomil, and specifically, trityl olmesartan medoxomil is used as a starting material to deprotect the triphenylmethyl group as a protecting group under mild conditions using trimethylsilyl halide in an organic solvent. The present invention relates to a method for producing a high purity olmesartan medoxomill by inhibiting the generation of decomposition products to synthesize high purity olmesartan medoxomill.

High Purity Olmesartan Medoxomil, Trimethyl Silyl Halide, Manufacturing Method

Description

Manufacturing process of high purity olmesartan medoxomil {Industrial process of high purity olmesartan medoxomil}

The present invention relates to a method for producing high purity olmesartan medoxomil, and in particular tritrimethylmethyl (trityl) group, which is a protecting group using trityl olmesartan medoxomil (MTT) as a starting material, using trimethyl silyl halide in an organic solvent The present invention relates to a method for producing high purity olmesartan medoxomil by deprotection under mild conditions to suppress the generation of decomposition products to synthesize high purity olmesartan medoxomill.

The chemical name of olmesartan medoxomil is 4- (1-hydroxy-1-methylethyl) -2-propyl-1-[[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl ] -4-yl] methyl] -1H-imidazol-5-carboxylic acid (5-methyl-2-oxo-1,3-diosol-4-yl) methyl ester; (Merck Index 13th Edition).

The chemical structure of Olmesartan Medoxomil is as follows:

Olmesartan Medocsome Mill. (OLM-Mod)

The empirical formula is C29H30N6O6. The molecular weight is 558.58.

Olmesartan Medoxomil is a product that is hydrolyzed upon absorption and is a selective AT1 subtype angiotensin II receptor antagonist. A process for preparing olmesartan medoxyl wheat is disclosed in US Pat. No. 5,616,599 to Yanagisawa et al. It is marketed as a treatment for hypertension. Synthesis of olmesartan medoxomil (OLM-Mod) is exemplified as follows (see Annu. Rep. Sankyo Res. Lab 2003, 55, 1-91):

Looking at the synthetic methods of the prior art, the focus is on the coupling between substituted imidazole and substituted biphenyl methyl bromide. Further synthetic methods of these olmesartan medoxomil intermediates are disclosed in JP 11302260, JP 11292851, JP 07053489, JP 06298683, US 5621134, EP 838458, DE 19757995, US 6111114 and US 6214999. .

Looking at the reaction of step (h) (deprotection step) in the synthesis process described in US Pat. No. 5,616,599, in Example 61 (b) 4- (1-hydroxy-1-methylethyl) -2-propyl-1 -[[2 '-(1H-trityltetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -1H-imidazole-5-carboxylic acid (5-methyl- Crude olmesartan medoxomill is prepared from a mixture of 2-oxo-1,3-dioxol-4-yl) methyl ester (hereinafter abbreviated as "trityl olmesartan medoxomill (MTT),") and an aqueous solution of acetic acid The method is disclosed (176 columns, 24-37 lines). The resulting triphenyl carbinol (TPC) is removed and the olmesartan medoxomill is concentrated to separate. In this process, acidic conditions and the presence of water have the disadvantage of hydrolyzing ester bonds to form a large amount of impurity OLM-acid. The chemical structure of OLM-acid is as follows:

[ OLM-산의 화학구조 ].

[Chemical structure of OLM-acid].

The empirical formula for OLM-acid is C24H26N6O3, with a molecular weight of 446.50.

In another prior patent, WO2006 / 029056, in the reaction of deprotection step (h) of trityl olmesartan medoxomil (MTT), when acetone and water are used as a solvent and sulfuric acid is added to carry out deprotection reaction, It contains less OLM acid (approximately 1%) than the acetic acid use method of the '599 patent. However, this method also has a disadvantage in that the formation of a large amount of OLM-acid during the reaction process because it contains water in the reaction system.

In addition, the contents of a patent filed as WO 2006/098705 show that de-protection is carried out using methanol-acetone as a solvent and hydroxyammonium chloride as the deprotection reagent in the deprotection step of trityl olmesartan medoxomil (MTT). It is reported that methoxytriphenylmethane is produced instead of triphenyl carbinol (TPC) when the reaction is carried out, and it is claimed that methoxytriphenylmethane is easier to remove in the reaction system than the former due to the difference in polarity. have. Furthermore, it is argued that due to the low water content in the reaction system, the reaction proceeds in milder conditions as compared to the deprotection using acetic acid or sulfuric acid, resulting in high purity products in high yield. The researchers here invented a new synthetic method while investigating innovative and more efficient manufacturing methods, reviewing the results.

The prior art method of the '599 patent yields crude olmesartan medoxomill containing 2.2% OLM-acid per% HPLC area. It also discloses that the compound can be further purified by conventional means, including recrystallization (64 columns, lines 43-45). BENICAR® contains 0.3% OLM-acid per% HPLC area.

The present invention provides a method for minimizing the hydrolysis of ester bonds in the olmesartan medoxomill production process for synthesizing the purer memestan medoxomill as to improve the above problems. In addition, the present invention provides a novel innovative process for pure olmesartan medoxomill with low OLM-acid concentrations, which preferably omits the chromatography and recrystallization purification steps in mass production.

The present invention provides 4- (1-hydroxy-1-methylethyl) -2-propyl-1-[[2 '-(1H-trityltetrazol-5-yl) [1,1'-biphenyl]- 4-yl] methyl] -1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester [trityl olmesartan medoxomil (MTT)] To react with trimethyl silyl halide in an organic solvent to deprotect the triphenylmethyl group to produce high purity olmesartan medoxomil having a content of olmesartan medoxomylic acid (OLM-acid) of 0.05% or less. It is about.

The present invention is a method for minimizing hydrolysis of ester bonds in olmesartan medoxomill production process for synthesizing pure olmesartan medoxomill, and according to the method of the present invention, high purity olmesartan with low content of OLM-acid in high yield Medoxomime is effective in obtaining.

In the present invention, triphenylmethyl (trityl) group, which is a protecting group using trityl olmesartan medoxomil (MTT) as a starting material, is deprotected under mild conditions using trimethyl silyl halide in an organic solvent to suppress the occurrence of decomposition products. Provides an innovative new process for the synthesis of high purity olmesartan medoxomil.

The present invention has a short reaction time by reacting trimethyl silyl chloride and trityl olmesaltan medoxomil in a water-miscible organic solvent, preferably methanol or a mixed solvent of methanol and acetone, and easily deprotects triphenylmethyl group under mild conditions. Obtaining a solution of olmesartan medoxomil; Lowering the temperature of the solution and contacting with a base to obtain a precipitate of methoxytriphenylmethane; Filtering and separating the precipitate of methoxytriphenylmethane precipitated in the solution; Concentrating the filtrate under reduced pressure and obtaining a precipitate of olmesartan medoxomil by adding an organic solvent and purified water to the residue; The precipitate of olmesartan medoxomil is recovered by filtration and recrystallization in an organic solvent for purification.

In more detail, the present invention provides a solution of olmesartan medoxomil in a C1-4 alcohol single solvent or a mixed solvent of C1-4 alcohol and C3-6 ketone; Deprotection by adding trimethyl silyl halide to the solution; And recovering the purified olmesartan medoxomill. Preferably, the C1-4 alcohol is methanol, ethanol, isopropyl alcohol, n-propyl alcohol or t-butanol and the like, most preferably methanol. C3-6 ketones are acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone or t-butyl methyl ketone and the like, most preferably acetone.

In order to provide a solution of a single solvent of olmesartan medoxomil in C1-4 alcohols, the preferred amount of alcohol is at least about 3 vol, more preferably at least about 5 vol alcohol relative to about 1 g of solid trityl olmesartan medoxomil. In addition, in order to prepare a mixed solvent solution of olmesartan medoxomil, the preferred amount of C1-C4 alcohol to be used is preferably about 3 vol or more of alcohol with respect to about 1 g of solid trityl olmesartan, and the preferred amount of C3-6 ketone is solid A mixed solvent is prepared using at least about 0.5 volume, more preferably at least about 1 volume of ketone, with respect to about 1 g of trityl olmesartan medoxomil.

The method may further comprise heating a solution of olmesartan medoxomil in a mixed solvent of C1-4 alcohol single solvent and C1-4 alcohol and C3-6 ketone. In this embodiment, the solution of olmesartan medoxomil in the alcohol single solvent or the mixed solvent of alcohol and ketone may preferably be heated to about 10 ° C. to about reflux temperature, more preferably about 20 ° C. to 40 ° C. . As used herein, the term "room temperature" means a temperature of about 20 ° C to 30 ° C, preferably about 20 ° C to 25 ° C.

Purified olmesartan medoxomil can be recovered by any method known in the art, such as filtration or centrifugation. The method may further comprise a step of drying the precipitated purified olmesartan medoxomil. Drying can be performed by heating to the temperature of about 30 degreeC-60 degreeC, for example. For example, the drying process may be accelerated by reducing the pressure to 1 atmosphere or less, more preferably about 100 mm Hg or less.

Trimethyl silyl halide deprotects the triphenylmethyl group to form olmesartan medoxomil. Trimethyl silyl chloride, bromide, iodide and the like may be used as the trimethyl silyl halide used in this step, but trimethyl silyl chloride is most preferred. The amount of trimethyl silyl chloride is preferably about 0.5 to 2 equivalents, more preferably about 0.8 to 1.5 equivalents.

When trityl olmesartane medoxomil and trimethyl silyl chloride are reacted, the temperature is preferably about 15 ° C to 60 ° C, more preferably about 20 ° C to 30 ° C. In a preferred embodiment, it is preferable to maintain the trityl olmesartan medoxomil and the alcohol alone or a mixture of the alcohol and the ketone mixed solvent and the trimethyl silyl chloride for about 1 to 4 hours, more preferably about 1.5 to 3 hours. It is good.

In the step of neutralizing by adding a base to the olmesartan medoxomil reaction solution, suitable bases include, but are not limited to, alkali and alkaline earth metal hydroxides, carbonates and bicarbonate salts. Specific illustrative bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate and the organic amines include trimethylamine, diethylamine, triethylamine, tripropylamine, n -Propyl amine, n-butylamine, and the like. Preferred inorganic bases are potassium carbonate and especially sodium bicarbonate, and triethylamine is preferred as organic amine. The amount of base used is preferably about 0.8-1.5 equivalents relative to the amount of acid used. The base raises the pH of the solution, but the pH of the solution does not have to reach the basic pH. After contacting the solution with the base, it is preferably maintained at approximately 10 ° C. or less. The solution is kept at low temperature until methoxytriphenylmethane precipitates.

In a preferred embodiment, prior to filtration and separation of methoxytriphenylmethane, the byproducts of the reaction are precipitated to the greatest extent of precipitation. Preferably, the mixture is cooled to 0-5 DEG C and stirred for about 0.5-2 hours. The precipitated methoxytriphenyl crystals can be separated and removed from the solution by filtration or any known means. The crystals formed by concentrating the filtrate to remove the solvent and adding the appropriate amount of organic solvent and purified water to the residue, i.e. crude olmesartan medoxomil, can be recovered by any means known in the art such as filtration or centrifugation. The recovered crude olmesartan medoxomill is recrystallized in a suitable organic solvent to obtain pure olmesartan medoxomill. According to the process of the present invention, high purity olmesartan medoxomill is obtained with low OLM-acid content in high yield.

The percentage of impurities disclosed herein are provided as HPLC area% at 220 nm and 250 nm. Crude olmesartan medoxomill prepared according to US 5,616,599 is said to contain 2.2% OLM-acid. In contrast, the crude olmesartan medoxomil prepared according to the invention contains up to about 0.5% OLM-acid or up to about 0.3% OLM-acid.

Based on the purified product, Olmesartan Medoxomil Formulation BENICAR® contains 0.3% OLM-acid. The prior art method therefore reduces the OLM-acid in crude Olmesartan Medoxomil from 2.2% to less than 0.3%. However, when such crude olmesartan medoxomill is prepared and purified according to the method of the present invention, the amount of OLM-acid is reduced to less than 0.15%, more preferably less than about 0.1%, most preferably less than about 0.05%. It provides high purity olmesartan medoxomil containing OLM-acid.

The present invention is disclosed in a preferred embodiment. Those skilled in the art can understand appropriate variations of the invention as illustrated without departing from the spirit and scope of the invention as disclosed herein. This embodiment is disclosed to aid the understanding of the present invention, and is not intended to limit the scope of the present invention in any way and should not be so interpreted.

Example 1 Preparation of Olmesartan Medoxomil.

4- (1-hydroxy-1-methylethyl) -2-propyl-1-[[2 '-(1H-trityltetrazol-5-yl) [1,1'-biphenyl] -4-yl ] Methyl] -1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester [trityl olmesartan medoxomil (MTT)] 10 g ( 12.48 mmol) was added to 50 mL of methanol and 10 mL of acetone. Then, 1.90 mL (14.97 mmol) of trimethylsilyl chloride was added slowly with stirring at 10 ° C., and then the reaction temperature was adjusted to 20 ° C. for 2 hours, and the reaction temperature was adjusted to 0˜5 ° C. After cooling, 0.21 mL of triethylamine is added, the pH of the reaction solution is adjusted to 4.0-4.5, and stirred to precipitate crystals of methoxytriphenylmethane. The precipitated crystals were stirred for 1 hour, filtered, and the filtrate was concentrated under reduced pressure. 30 mL of isopropyl acetate and 80 mL of purified water were added to the residue, followed by stirring to precipitate crystals. The precipitated crystals were filtered after stirring for 1 hour at room temperature, and 50 mL of isopropyl acetate was added to the filtered crystals, and the mixture was stirred at 40 ° C for 1 hour, cooled to 10 ° C, and filtered after stirring for 1 hour, and then 6.27 g of olmesartan medoxomill ( Yield = 90%).

Example 2: Preparation of Olmesartan Medoxomil.

10 g (12.48 mmol) of trityl olmesartan medoxomil (MTT) were added to 50 mL of methanol and 10 mL of acetone, and then slowly added 2.37 mL (18.72 mmol) of trimethylsilyl chloride while stirring at 10 ° C., followed by reaction for 1 hour. After cooling the reaction temperature to 0∼5 ℃, add 0.26 mL of triethylamine, adjust the pH of the reaction solution to 4.0∼4.5 and stir to precipitate crystals of methoxytriphenylmethane. The crystals were stirred for 30 minutes, filtered and the filtrate was concentrated under reduced pressure. 30 mL of isopropyl acetate and 80 mL of purified water were added to the residue, followed by stirring. The precipitated crystals were stirred at room temperature for 1 hour, filtered, and 50 mL of isopropyl acetate was added to the filtered crystals, and the mixture was stirred at 40 ° C for 1 hour, cooled to 10 ° C, and filtered after stirring for 1 hour, and 6.41 g of olmesartan medoxomill ( Yield = 92%).

Example 3: Preparation of Olmesartan Medoxomil.

10 g (12.48 mmol) of trityl olmesartan medoxomil (MTT) was added to 100 mL of methanol, and 1.9 mL (14.97 mmol) of trimethylsilyl chloride was added slowly with stirring at 10 ° C, and then reacted for 2.5 hours after adjusting at 20 ° C. After cooling to 0∼5 ℃, 0.21 mL of triethylamine is added, the pH of the reaction solution is adjusted to 4.0∼4.5 and stirred to precipitate methoxytriphenylmethane crystals. The crystals were stirred for 30 minutes, filtered and 10 mL of isopropyl acetate and 100 mL of water were added to the filtrate, followed by stirring. The precipitated crystals were stirred at room temperature for 1 hour, filtered, and 50 mL of isopropyl acetate was added to the filtered crystals. The mixture was stirred at 40 ° C for 1 hour, cooled to 10 ° C, and filtered after stirring for 1 hour, and then 6.34 g of olmesartan medoxomill (yield = 91%) is obtained.

Claims (7)

In the method for producing high purity olmesartan medoxomil, the preparation method is 4- (1-hydroxy-1-methylethyl) -2-propyl-1-[[2 '-(1H-trityltetrazol-5- Yl) [1,1'-biphenyl] -4-yl] methyl] -1H-imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl High-purity olmesartan medoc with the content of olmesartan medoxomilic acid (OLM-acid) of 0.05% or less by reacting ester [trityl olmesartan medoxomil (MTT)] with trimethyl silyl halide in an organic solvent to deprotect the triphenylmethyl group A method for producing high purity olmesartan medoxo mill, characterized in that it is produced from low-density wheat. The method of claim 1, wherein the trimethyl silyl halide is any one selected from trimethyl silyl chloride, bromide and iodide.        The method of claim 2, wherein the trimethyl silyl halide is trimethyl silyl chloride. The method of claim 1, wherein the organic solvent is a C1-C4 alcohol single solvent; And C1-C4 alcohol and a mixed solvent of C3-C6 ketone. The method of claim 4, wherein the C1-C4 alcohol is any one selected from methanol, ethanol, isopropyl alcohol, n-propyl alcohol and tert-butanol, C3-C6 ketone is acetone, methyl ethyl ketone, diethyl ketone, Method for producing olmesartan medoxomil, characterized in that any one selected from methyl isobutyl ketone and tert- butyl methyl ketone. The method of claim 1, wherein the reaction is 20-30 ° C. 6. The method of claim 1, wherein the reaction is characterized by using any one of a neutralizing agent selected from potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diethylamine, tripropylamine, n-propylamine and n-butylamine. The manufacturing method of olmesartan medoxo mill which is used.