WO2012055380A1

WO2012055380A1 - A method of obtaining olmesartan medoxomil

Info

Publication number: WO2012055380A1
Application number: PCT/CZ2011/000104
Authority: WO
Inventors: Jan Stach; Kamal Jarrah; Radim Krulis; Stanislav Radl; Josef Cerny
Original assignee: Zentiva, K. S.
Priority date: 2010-10-29
Filing date: 2011-10-21
Publication date: 2012-05-03
Also published as: CZ2010785A3; CZ303188B6

Abstract

A method of obtaining olmesartan medoxomil of formula I, comprising the following steps: a) detritylation of trityl olmesartan medoxomil in the presence of an organic acid and water, to give olmesartan medoxomil and trityl alcohol; b) addition of water and separation of the resulting trityl alcohol; c) addition of a water-miscible aprotic solvent; d) addition of water, to give crystalline olmesartan medoxomil; e) isolation of crystalline olmesartan medoxomil of formula I. A pharmaceutical composition comprising olmesartan medoxomil of formula I obtained by the above described method.

Description

A method of obtaining olmesartan medoxomil

Technical Field

The invention relates to an improved method of obtaining olmesartan medoxomil of formula I.

Said drug belongs to the therapeutic group called angiotensin II antagonists, which helps to control high blood pressure.

Background Art

Olmesartan medoxomil of formula I belongs to the group of angiotensin II antagonists, which are therapeutically used as medicaments for the cardiovascular system, mainly for high blood pressure control. This group contains significant drugs such as losartan (Cozaar^R), irbesartan (Avapro^R), or valsartan (Diovan^R). However, unlike the above-mentioned substances olmesartan medoxomil of formula I is a prodrug that releases the proper active compound, olmesartan of formula II, in the organism. With regard to a better biological availability of the prodrug higher levels of olmesartan are achieved than in the case of its direct administration.

For the production of olmesartan medoxomil a number of methods have been described, which consist in detritylation of trityl olmesartan medoxomil of formula III,

which is obtained, according to US patent 5 616 599, in the following manner:

Example 61(b) of the above mentioned patent describes the last step which consists in detritylation of trityl olmesartan medoxomil of formula III in a mixture of acetic acid and water. After filtration of trityl alcohol crude olmesartan medoxomil is obtained by evaporation of the solution and crystallization from ethyl acetate. However, the product obtained this way contains a considerable amount of an impurity - olmesartan of formula II, which cannot easily be eliminated by means of subsequent crystallization. In accordance with a patent application of the Teva company (EP 1 706 401 ) the procedure of US 5 616 599 provides a product containing 2.2% of olmesartan. The above mentioned application of the Teva company describes an improved method of preparing olmesartan medoxomil, which results in the content of this impurity below 1%; according to Example 1 crude olmesartan medoxomil can be obtained with the content of the impurity - olmesartan of formula II - at the level of 0.9%.

The above mentioned facts indicate that no method has been described yet that would provide crude olmesartan medoxomil of formula I with a low content of olmesartan of formula II. Disclosure of Invention The invention provides a method of obtaining olmesartan medoxomil of formula I

which consists in detritylation of trityl olmesartan medoxomil of formula III with water and an acid, addition of water and subsequent separation of trityl alcohol, dilution of the obtained solution of crude olmesartan medoxomil with a water-miscible aprotic solvent, and crystallization of crude olmesartan medoxomil having a low content of olmesartan of formula II from the mixture obtained by further addition of water.

More specifically, the method of the present invention comprises the following steps:

a) detritylation of trityl olmesartan medoxomil of formula III

in the presence of an organic acid and water, to give olmesartan medoxomil of formula I and trityl alcohol of formula IV

b) addition of water and separation of the resulting trityl alcohol of formula IV

c) addition of a water-miscible aprotic solvent

d) addition of water, to give crystalline olmesartan medoxomil of formula I

e) isolation of crystalline olmesartan medoxomil of formula I.

Detailed Description of Invention:

The method of preparing olmesartan medoxomil according to the invention comprises detritylation of trityl olmesartan medoxomil of formula III with the use of water and an organic acid. As the organic acid any organic acid of the general formula RCOOH can be used, wherein R is hydrogen, a saturated or unsaturated linear or branched alkyl, which may also contain other substituents. The organic acid is preferably used in a proportion of from 0.1 to 6 v/w relative to the starting compound (the symbol v/w symbol represents a proportion of the volume expressed in litres to the weight of the starting compound expressed in kilograms) and the proportion of water to the starting compound is preferably from 0.1 to 3 v/w. The temperature at which detritylation is usually carried out is between 10°C and 60°C, a temperature of about 50°C, preferably from 48°C to 52°C, being especially suitable. The duration of this reaction is preferably in the range of from 1 to 15 hrs, more preferably in the range of from 1.5 to 4 hours. After the detritylation is complete, water is added, preferably in a proportion of from 0.1 to 1 volume/weight of the starting compound, and subsequently trityl alcohol is removed, preferably by filtration. After the separation of trityl alcohol a water- miscible aprotic solvent is added, preferably in a proportion of from 0.5 to 5 v/w. Suitable organic acids include especially organic acids well soluble in water, e.g. formic, acetic, propionic, butyric or isobutyric acids; unsaturated acids such as acrylic or methacrylic acid; or substituted acids such as glycolic, lactic, chloroacetic, dichloroacetic, trichloroacetic or trifluoroacetic acids. Acetic acid is an especially preferred acid. A water-miscible solvent denotes either a solvent which has unlimited miscibility with water or at least miscibility to such an extent that dilution of the filtrate after separation of trityl alcohol can produce a homogeneous solution that would not be divided into two liquid phases even after subsequent addition of water. A water-miscible solvent in this sense can be either one substance or a mixture of more substances. A water-miscible aprotic solvent can thus include, e.g., acetone, tetrahydrofuran, acetonitrile, dioxane, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone or a mixture of several these substances. A preferred mixture is that of two substances only. Acetone is an especially preferred solvent. After addition of the water-miscible aprotic solvent water is being added, preferably for a period of from 1 to 15 hrs and in an amount of from 1 to 5 v/w, resulting in crystallization of crude olmesartan medoxomil. The latter is then isolated using a common method such as filtration on a Nutsche filter or centrifugation. As compared to the method described in US 5 616 599, which produces a gel-like product after concentration and to the method of EP 1 706 401 , wherein crude olmesartan is obtained by addition of a base, the method of the invention is advantageous in obtaining the crude product by direct crystallization without use of unsuitable evaporation or addition of further inorganic compounds, which increase the risk of partial decomposition of the product or contamination of the final product with inorganic ballast. Unlike the above mentioned methods that provide the crude product containing about 2% (US 5 616 599), or about 0.9% (EP 1 706 401) of the impurity of formula II, the method of the present invention provides the crude product having a content of impurity of formula II of about 0.3%.

The method of the invention has the advantage that to re-purify the crude olemsartan medoxomil, obtained according to the invention to a final quality required for obtaining pharmaceutical formulations, a single re-crystallization by any of the well-known methods, such as described in patent application EP 1 816 131, is sufficient, such that the method of this invention leads to lower losses during the final purification and hence to simplification of the entire process and improvement of its economy and environment friendliness as compared to prior art methods. The robustness of the process of the invention represents an advantage in terms of ensuring quality of the produced active substance.

The use of the final olmesartan medoxomil product of formula I obtained by the method of the invention for the preparation of a pharmaceutical composition allows to reliably achieve high quality of therapeuticals containing olmesartan medoxomil as the active compound at low costs.

Accordingly, the invention further relates to a pharmaceutical composition, comprising, as the active ingredient, olmesartan medoxomil obtained by the above-described process. In addition to the active ingredient, the composition may comprise usual pharmaceutically acceptable adjuvants and/or additives.

The examples below are only illustrative and do not limit the scope of the invention in any way.

Specific Working Examples

Example 1

Olmesartan medoxomil of formula I

20 g of the starting compound of formula III were stirred up in 90 ml of acetic acid and after stirring for 10 minutes 20 ml of water were added dropwise during 5 minutes. Then, the suspension was put in a bath thermostated at 50 °C (i.e. ca. ± 2°C) and stirred for 1.5 h. Then, 16 ml of water were added dropwise in 5 minutes, the mixture was taken out of the bath and after 5 minutes it was put into a cooling bath with the temperature of 10°C. After 20 minutes the separated insoluble fraction, containing the side product trityl alcohol, was aspirated and washed with a mixture of 4 ml of acetic acid (AcOH) and 2 ml of water. 40 ml of acetone and then 50 ml of water were added to the filtrate at 30°C, the separated product was aspirated and 1 1 g (79 %) of the product were obtained.

Example 2 Olmesartan medoxomil of formula I

20 g of the starting compound of formula III were stirred up in 75 ml of acetic acid and after stirring for 10 minutes 30 ml of water were added dropwise during 5 minutes. Then, the suspension was put in a 50°C bath and stirred for 4 hours. Then 16 ml of water were added dropwise in 5 minutes, the mixture was taken out of the bath and after 5 minutes it was put in a cooling bath with the temperature of 10°C. After 20 minutes the separated insoluble fraction, containing the side product trityl alcohol, was aspirated and washed with a mixture of 4 ml of AcOH + 2 ml of water. 40 ml of acetone and then 70 ml of water were added to the filtrate at 30°C, the separated product was aspirated and 1 1.5 g (82 %) of the product were obtained.

Claims

C L A I M S

1 . A method of obtainin olmesartan medoxomil of formula I,

comprising the following steps:

a) detritylation of trityl olmesartan medoxomil of formula III

in the presence of an organic acid of the general formula RCOOH, wherein R is hydrogen, a saturated or unsaturated linear or branched alkyl having one to three carbon atoms, optionally substituted with the hydroxyl group, one to three atoms of chlorine or three atoms of fluorine at one of the carbon atoms, and water, to give olmesartan medoxomil of formula I and trityl alcohol of formula IV

b) addition of water and separation of the resulting trityl alcohol of formula IV c) addition of a water-miscible aprotic solvent

d) addition of water, to give crystalline olmesartan medoxomil of formula I

e) isolation of crystalline olmesartan medoxomil of formula I.

2. The method according to claim 1 , characterized in that the volume of water for detritylation of trityl olmesartan medoxomil is in the proportion of from 0.1 to 3 relative to the weight of the starting compound.

3. The method according to claims 1 or 2, characterized in that the volume of the organic acid for detritylation of trityl olmesartan medoxomil is in the proportion of from 0.1 to 6 relative to the weight of the starting compound.

4. The method according to any one of claims 1-3, characterized in that the organic acid used is acetic acid.

5. The method according to any one of the preceding claims, characterized in that the water- miscible aprotic solvent used is acetone.

6. The method according to any one of the preceding claims, characterized in that the volume of water in step d) is in the proportion of from 1 to 5 relative to the weight of the starting compound.

7. The method according to any one of the preceding claims, characterized in that step a) is carried out at a temperature of from 10°C to 60°C.

8. The method according to any one of the preceding claims, characterized in that step a) is carried out at a temperature of from 48°C to 52°C.

9. The method according to any one of the preceding claims, characterized in that step a) is carried out for from 1 h to 15 h.

10. The method according to any one of the preceding claims, characterized in that step a) is carried out for from 1.5 h to 4 h.

1 1. The method according to any one of the preceding claims, characterized in that the volume of water added before the separation of trityl alcohol of formula IV is in the proportion of from 0.1 to 1 relative to the weight of the starting compound.

12. A pharmaceutical composition, comprising olmesartan medoxomil prepared by a method according to any one of claims 1 -11.