WO2012069025A1

WO2012069025A1 - (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl)-4-(1-hydroxy-1-methyl-propyl)-2-propyl-1-[2'- (1h-tetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate as an impurity of olmesartan medoxomil and a method of its preparation

Info

Publication number: WO2012069025A1
Application number: PCT/CZ2011/000112
Authority: WO
Inventors: Jan Stach; Lukas Placek; Radim Krulis; Stanislav Radl; Josef Cerny
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2010-11-24
Filing date: 2011-11-23
Publication date: 2012-05-31
Anticipated expiration: 2013-05-24
Also published as: CZ305129B6; CZ2010863A3

Abstract

The compound of formula VI and a method of its preparation, and intermediates of its preparation. Use of these intermediates as standards in analysis of the angiotensin II antagonist olmesartan medoxomil of formula I and of intermediates of its production.

Description

(5-methyI-2-oxo-l,3-dioxol-4-ylmethyl)-4-(l-hydroxy-l-methyl-propyl)-2-propyl-l-[2'- (lH-tetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate as an impurity of olmesartan medoxomil and a method of its preparation Technical Field

The invention relates to the compound of formula VI

and also to a method of its preparation, intermediates of its preparation, use intermediate products as standards in analysis of olmesartan medoxomil of formula I

and intermediates of its production.

Olmesartan medoxomil belongs to the drug group called angiotensin II antagonists, which helps to control high blood pressure. Background Art

Angiotensin II antagonists are used as drugs for the cardiovascular system, especially to control high blood pressure. This group comprises important drugs such as losartan (Cozaar^®), irbesartan (Avapro^®), or valsartan (Diovan^®). However, unlike these compounds, olmesartan medoxomil of formula I is a prodrug that releases the actual effective compound, olmesartan of formula II, in the organism. Due to better bio availability of the prodrug higher levels of olmesartan are achieved than in the case of its direct administration.

In accordance with the basic patent, US 5 616 599, olmesartan medoxomil of formula I produced in the following way:

Scheme 1 : synthesis of olmesartan medoxomil according to US patent 5 616 599

However, this method also produces some problematic, structurally similar impurities that are difficult to remove from the final product. In the current opinion of regulatory authorities, following the recommendations of the International Conference for Harmonization (ICH), every impurity in the final product with a relative content (measured e.g. by means of high performance liquid chromatography (HPLC)) higher than 0.10% must be identified.

In patent application No. WO 2006/073519, chemists of the Teva company have identified the following three impurities, which are produced by the method of the basic patent:

Disclosure of Invention The present invention provides (5-methyl-2-oxo- 1 ,3-dioxol-4-ylmethyl)-4-(l -hydroxy- 1 - methyl-propyl)-2-propyl-l-[2^'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5- carboxylate of formula VI (hereinafter also referred to as Me-OM)

and a method of its preparation.

The invention also provides the intermediates of formulae VII, 5 and 6 for the preparation of the compound of formula VI, a method for the determination of the compound of formula VI in olmesartan medoxomil, and, further, use of the intermediates of synthesis of the compound of formula VI as standards of impurities in the analysis of intermediates of olmesartan medoxomil production. Detailed description of the invention

The invention provides (5-methyl-2-oxo-l ,3-dioxol-4-ylmethyl)-4-(l-hydroxy-l-methylpro- pyl)-2-propyl-l-[2 ^'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate of formula VI (Me-OM), which the authors have managed to identify, by a combination of HPLC and mass spectroscopy, as an admixture to olmesartan medoxomil of formula I prepared in accordance with US 5 616 599, and then to prepare in the pure form allowing practical application.

It has been found that the precursor of formula VII of the compound VI has been produced by the Grignard reaction, in accordance with Scheme 2, with methyl magnesium bromide, containing ethyl magnesium bromide as an admixture:

Scheme 2: Formation of the compound of formula VII during the preparation of olmesartan in accordance with US 5 616 599

With regard to a considerable structural similarity the impurity of formula VII is quite difficult to remove by crystallization of the intermediate 1 and in the further synthetic stages the homologous impurities 5 and 6, which are formed from the precursor of formula VII, are similarly difficult to remove from the corresponding olmesartan medoxomil synthesis intermediates of formulae 2 and 3.

The impurity of formula VI has been prepared in accordance with Scheme 3 and characterized by means of high resolution mass spectroscopy (HR-MS) and nuclear magnetic resonance (NMR).

Scheme 3: Synthesis of the impurity to olmesartan medoxomil of formula VI in accordance with the invention

A HPLC method for determination of the content of the impurity of formula VI (Me-OM) in olmesartan medoxomil of formula I has been developed and its identity with the impurity observed in samples of olmesartan medoxomil of formula I has been finally confirmed by using the prepared compound of formula VI as a standard.

Using the prepared compounds of formulae VII, 5 and 6, the corresponding precursors of the impurity of formula VI have also been identified in the intermediates of olmesartan medoxomil synthesis of formulae 1, 2 and 3. The compounds of formulae VI, VII, 5 and 6 are industrially applicable as standards or reference substances for the development and set-up of analytic methods suitable for analysis of olmesartan medoxomil destined for pharmaceutical purposes, or for analysis of intermediates of its production, especially for the purposes of quality control during production of olmesartan medoxomil destined for pharmaceutical use, or quality assurance of olmesartan medoxomil as the input raw material for the production of pharmaceutical preparations. Preparations of the above mentioned compounds with the weight content of at least 10%, preferably with the content of at least 50%, most preferably with the content of at least 90%, related to the total weight of the sample, can be used as reference materials.

On the basis of the acquired findings the conclusion can be drawn that an efficient solution of the technical problem of how to keep the content of the impurity of formula VI in olmesartan medoxomil, produced using the intermediate of formula I, below the ICH limit for an identifiable impurity of 0.15% by weight can be most easily achieved in a simple way: by controlling the content of any of the precursors of formulae 6, 5 or VII of the impurity of formula VI in the corresponding intermediates of formulae 3, 2 or 1, combined with releasing to the subsequent production of such an intermediate only that does not contain more than 0.15% by weight of the corresponding precursor of impurity VI. The most preferable method of ensuring compliance with the limit of 0.15% by weight for the content of impurity VI in olmesartan medoxomil then consists in using a Grignard reagent (which can generally be any methyl magnesium halide MeMgX, wherein X stands for CI, Br or I, similarly as in synthesis of compound VI), containing at most 0.15% by weight of the corresponding ethyl homologue.

The invention is elucidated in more detail in the examples below. These examples only have an illustrative character and do not limit the scope of the invention in any respect.

Example 1

HPLC measurement of the contents of impurities of olmesartan medoxomil of formula I:

Column: Symmetry C8, 250 x 4.6 mm, 5mm (Waters)

Temperature: 45 °C

Mobile phase: A: 0.015 M KH₂P0₄ pH 3.0

B: Acetonitrile

Gradient:

Injected volume: 10 μΐ

Auto-sampler temperature: 10 °C

Analysis duration (min): 50

Equilibration time (min): 5

Detection: 230 nm

15 mg of the olmesartan medoxomil substance is weighed into a 25ml volumetric flask and dissolved in acetonitrile.

Relative retention times of the substances:

Example 2

HPLC measurement of the content of impurity of formula (VII) in the 4-( 1 -hydroxy- 1 - methylethyl)-2-propyl-lH-imidazole carboxylic acid ethyl ester:

Column: XTerra RP18, 150 x 3.9 mm, 5mm (Waters)

Temperature: 40 °C

Mobile phase: A: 10 mM ΚΗ2Ρ04 pH 7.5

B: Acetonitrile

Injected volume:

Auto-sampler temperature

Analysis time (min):

Equilibration time (min):

Detection:

Sample preparation

10 mg of the substance is weighed into a 10ml volumetric flask and dissolved in a 50% aqueous solution of acetonitrile (vol/vol).

Relative retention times of the substances:

Example 3

4-(l-Hydroxy-l-methylpropyl)-2-propyl-lH-imidazol-5-carboxylic acid ethyl ester of formula VII

A mixture of 15 ml of 3M methyl magnesium chloride and 20 ml of 2M ethyl magnesium chloride in tetrahydrofuran (THF) was added to 5 g of the diester of formula 4 dissolved in 20 ml of tetrahydrofuran under cooling during 20 minutes (the temperature of the reaction mixture was maintained at 25 °C). After 2 hours ethyl acetate (200 ml) was added and the mixture was washed with diluted acetic acid (4%, 3 x 20 ml). Chromatography was performed on a Merck Pharmprep silica gel column with the particle size of 40 - 63 /xm in an ethyl acetate/hexane system (1 : 1), controlling the contents of the substance of formula VII in the collected fractions by thin-layer chromatography in a petroleum ether/acetone system (volume ratio (v/v) 7/3) on Merck silica gel (FP KG F 254). The fractions containing the desired product without a visible admixture of the substance of formula 1 (Rf(vii) = 0.55; R ) = 0.50) were combined and evaporated, producing 2 g of a colourless oil.

Ή NMR spectrum (CDC1₃): 0.85 t, 3 H, J = 7.4; 0.95 t, 3 H, J = 7.3; 1.35 t, 3 H, J = 7.1; 1,60 s, 3 H; 1.70-1.80 m, 2 H; 1.80-1.90 m, 1 H; 1.90-2.00 m, 1 H; 2.70 t, 2 H, J= 6.5; 4.35 q, 2 H, J = 7.1 ; 5.30-5.90 brs, 1 H; 9.00-9.60 brs, 1 H. ¹³C NMR spectrum (CDC1₃): 8.51, 13.82, 13.87, 14.51 , 21.94, 30.58, 35.31, 61.48, 66.98, 125.48, 142.38, 148.65, 173.12.

HR-MS: for Ci3H₂₃N₂0₃ [M+H]⁺, calculated mass-to-charge ratio (hereinafter referred to as m/z) 255.1703 m/z, found 255.1702 m/z.

Example 4

Ethyl 4-(l-hydroxy-l-methylethyl)-2-propyl-l-((2'-(l-trityl-lH-tetrazol-5-yl)biphenyl-4-yl)- methyl)-lH-imidazole-5-carboxylate of formula 5

10 ml of acetone were added to 2 g of the 4-(l-hydroxy-l-methylpropyl)-2-propyl-lH- imidazole-5-carboxylic acid ethyl ester of formula VII, 4,2 g of 5-(4'-bromomethyl-l,l ^'- biphenyl-2-yl-)-l -triphenylmethyl-lH-tetrazole (BBTT), 2 g of potash and 0.2 g of polyethylene glycol 400. The resulting mixture was heated up to boiling for 11 h. It was cooled to 25 °C, the solid fraction was aspirated, the filtrate was mixed with 20 ml of demineralised water and the solid fraction which separated after stirring for 1 hour was aspirated and freely dried; yield 3.1 g.

Ή NMR spectrum (CDC1₃): 0.80-0.90 m, 6 H; 1.30 t, 3 H, J= 7.2; 1,60 s, 3 H; 1.65-1.70 m, 2 H; 1.80-1.90 m, 1 H; 2.00-2.10 m, 1 H; 2.50 t, 2 H, J = 7.7; 4.10 q, 2 H, J = 7.1 ; 5.35 s, 2 H; 5.70 s, 1 H; 6.70 d, 2 H, J = 7.8; 6.90-7.00 m, 6 H; 7.10 d, 2 H, J = 7.9; 7.25-7.30 m, 6 H; 7.30-7.40 m, 4 H; 7.40-7.50 m, 2 H; 7.85 d, 2 H, J = 7.6. ¹³C NMR spectrum (CDC1₃): 8.73, 13.91, 14.00, 21.37, 27.05, 29.33, 34.91 , 48.89, 61.28, 73.20, 83.01, 1 17.44, 124.95, 126.49, 127.74, 127.80, 128.42, 129.83, 130.09, 130.36, 130.52, 130.85, 135.85, 140.50, 141.44, 141.69, 151.39, 157.79, 161.65, 164.25.

HR-MS: for C₄₆H₄₇N₆0₃ [M+H]⁺, calculated 731.3704 mlz, found 731.3704 mlz.

Example 5

(5 -Methyl-2-oxo- 1 ,3 -dioxol-4-yl)m ethyl 4-( 1 -hydroxy- 1 -methylpropyl)-2-propyl- 1 -((2'-( 1 - trityl- lH-tetrazol-5-yl)biphenyl-4-yl)methyl)- lH-imidazole-5-carboxylate of formula 6

10 ml of tetrahydrofuran and a solution of 0.45 g of potassium hydroxide in 8 ml of water were added to 3 g of ethyl 4-(l-hydroxy-l-methylethyl)-2-propyl-l-((2'-(l-trityl-lH-tetrazol- 5-yl)biphenyl-4-yl)-methyl)-lH-imidazole-5-carboxylate of formula 5 and the mixture was stirred at 25 °C for 48 h. After addition of 50 ml of ethyl acetate the mixture was washed with brine (2 x 10 ml), concentrated and ethyl methyl ketone (10 ml), medoxomil chloride (0.9 g), potash (0.5 g) and potassium iodide (0.02 g) were added. The mixture obtained this way was stirred at 40 °C for 24 h, concentrated and the resulting product was crystallized from ethanol. 2.2 g of a white crystalline substance were obtained.

Ή NMR spectrum (CDC1₃): 0.85 t, 3 Η, J = 7.5; 0.90 t, 3 Η, J = 7.3; 1.25 t, 3 Η, J = 7.0; 1,60 s, 3 Η; 1.65-1.75 m, 2 Η; 1.80-1.90 m, 1 Η; 2.00 s, 3 Η; 2.00-2.10 m, 1 Η; 2.55 t, 2 Η, J= 7.6; 4.70 s, 2 Η; 5.30 s, 2 Η; 5.55 brs, 1 Η; 6.65 d, 2 Η, J= 7.8; 6.95-7.00 m, 6 Η; 7.10 d, 2 Η, J = 7.7; 7.25-7.30 m, 6 Η; 7.30-7.40 m, 3 Η; 7.40 d, 1 Η, J= 7.6; 7.45 d, 1 Η, J= 7.5; 7.50 d, 1 Η, J = 7.5; 7.85 d, 2 Η, J = 7.7. ¹³C NMR spectrum (CDC1₃): 8.68, 9.37, 13.89, 21.38, 26.93, 29.36, 34.78, 46.70, 49.30, 53.87, 73.33, 83.02, 1 16.46, 124.56, 126.47, 127.83, 129.89, 130.21, 130.32, 130.54, 130.70, 139.52, 140.52, 140.58, 141.44, 141.49, 151.96, 152.15, 152.25, 159.61 , 160.78, 164.34.

HR-MS: for C₄9H₄₇N₆0₆ [M+H]⁺, calculated 815.3552 mlz, found 815.3551 mlz. Example 6

(5-Methyl-2-oxo- 1 ,3-dioxol-4-ylmethyl) 4-( 1 -hydroxy- 1 -methylpropyl)-2-propyl- 1 -[2 '-( 1H- tetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate of formula VI (5-Methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 4-( 1 -hydroxy- 1 -methylpropyl)-2-propyl- 1 -((2'-( 1 - trityl-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-imidazole-5-carboxylate of formula 6; 2,1 g were dissolved in acetic acid (10 ml) and after addition of water (5 ml) the mixture was heated to 50 °C for 4 h. After aspiration of trityl alcohol, evaporation and concentration crystallization from ethyl acetate was performed. 1.14 g of the product were obtained in the form of a white, crystalline substance with the content of 94.4% by weight as determined using the HPLC method in accordance with Example 1.

Ή NMR spectrum (CDC1₃): 0.85 t, 3 H, J= 7.5; 0.90 t, 3 H, J= 7.4; 1,55 s, 3 H; 1.65-1.70 m, 2 H; 1.80-1.90 m, 1 H; 1.95-2.05 m, 1 H; 2.20 s, 3 H; 2.55 t, 2 H, J = 7.5; 4.95 s, 2 H; 5.35 d, 1 H, J = 17.1 ; 5.45 d, 1 H, J = 17.1 ; 6.80 d, 2 H, J = 8.2; 7.10 d, 2 H, J= 8.2; 7.45 t, 1 H, J = 6.9; 7.50-7.55 m, 1 H; 7.55-7.60 m, 1 H; 7.80 d, 1 H, J = 7.7 ¹³C NMR spectrum (CDC1₃) 5.53, 9.41, 13.75, 21.17, 26.31, 29.10, 34.55, 49.10, 50.16, 53.84, 62.66, 73.41, 116.57, 122.79, 125.24, 128.24, 129.51, 130.71, 131.01, 131.37, 133.22, 135.25, 136.48, 138.72, 140.56, 140.91, 152.49, 152.88, 154.99, 160.26, 160.74.

HR-MS: pro C₃₀H₃₃N₆O₆ [M+H]⁺, calculated 573.2456 m/z, found 573.2456 m/z.

Claims

C L A I M S

1. (5-Methyl-2-oxo- 1 ,3-dioxol-4-ylmethyl) 4-( 1 -hydroxy- 1 -methylpropyl)-2-propyl- 1 -[2 '- (lH-tetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate of formula VI

having the purity of at least 90 percent by weig

2. A method for the preparation of the compound of formula VI according to claim 1, characterized in that it comprises the following steps:

(a) reacting the compound of formula 4 with a mixture of an ethyl magnesium halide EtMgX and methyl magnesium halide MeMgX (wherein X = CI, Br or I), to give the compound of formula VII;

H

(b) separating the compound of formula VII from the mixture of products of step (a).

3. The method according to claim 2, characterized in that it further comprises the following steps:

(c) reacting the compound of formula VII with 5-(4'-bromomethyl-l,l '-biphenyl-2-yl)- 1-triphenylmethyl-lH-tetrazole to give the compound of formula 5;

(d) subjecting the compound of formula 5 to alkaline hydrolysis to convert the ester group to a carboxylic group, followed by reacting with a medoxomil halide of formula 7 to give the compound of formula 6; and

(e) reacting the compound of formula 6 with a mixture of water and acetic acid to give the com ound of formula VI

(wherein X = CI, Br or I)

4. 4-(l -Hydroxy- l -methylpropyl)-2-propyl-lH-imidazole-5-carboxylic acid ethyl ester of formula VII

having the content of at least 10% of the total weight of the sample.

5. Ethyl 4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 -((2'-( 1 -trityl- 1 H-tetrazol-5 -yl)biphenyl-4-yl)- methyl)-lH-imidazole-5-carboxylate of formula 5

having the content of at least 10 % of the total weight of the sample.

6. (5-Methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 4-( 1 -hydroxy- 1 -methylpropyl)-2-propyl- 1 -((2'-( 1 - trityl- 1 H-tetrazol-5 -yl)biphenyl-4-yl)methyl)-lH-imidazole-5-carboxylate of formula 6

having the content of at least 10 % of the total weight of the sample.

7. Use of a substance selected from the group including the compounds of formulae VI, VII, 5 and 6 according to claims 1, 4, 5 and 6 as a reference material or a standard in analysis of olmesartan medoxomil destined for pharmaceutical purposes.

8. Use of a substance selected from the group including the compounds of formulae VI, VII, 5 and 6 according to claims 1, 4, 5 and 6 in quality control of production of olmesartan medoxomil for pharmaceutical purposes.