SI22092A - Procedure for preparation of olmertsan medoximil - Google Patents

Abstract

The present invention relates to an improved process for the manufacture of olmertsan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.

Description

The present invention relates to an improved process for the preparation of olmesartan and its pharmaceutically acceptable chests and esters as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions.

A technical problem

Olmesartan medoxomyl of formula (I) is chemically described as (5-methyl-2-oxo-1,2oxyxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (tetrazol-5yl) phenyl] phenyl} methylimidazole-5-carboxylate. Because of its ability to inhibit the angiotensin-converting enzyme, it is widely used to treat hypertension and related diseases and conditions. Olmesartan medoxomil as an angiotensin II receptor antagonist avoids the side effects of calcium antagonists but has high stability and obvious curative effects.

(I)

As outlined below, it would be very useful to provide a shorter and more economical technological process for the production of olmesartan medoxomil.

BACKGROUND OF THE INVENTION

EP O 503 785 BI describes examples 61, 70, 78 and 18 of the preparation of olmesartan medoxomil. In Example 61, olmesartan medoxomil was prepared by reaction of (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole5-carboxylate and 4- [2 -trityltetrazol-5-yl) phenyl] benzyl bromide in N, N-dimethylacetamide and in the presence of potassium carbonate and, in the case of 18, ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate and 4- [2- Trityltetrazol-5-yl) phenyl] benzyl bromide is digested in N, N-dimethylformamide and in the presence of sodium hydride as a base. Example 70 describes the alkylation of ethyl 4- [1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate with 4'bromomethylbiphenyl-2-carbonitrile in N / N-dimethylacetamide and in the presence of potassium / butoxide. The disadvantage of these processes is that column chromatography must be used to obtain a satisfactory purity of the alkylated product. In Example 78, the resulting product was further hydrolyzed with alkali hydroxide, the salt isolated and further esterified to give the medoxomil ester. In the last step, the trityl protecting group is removed by the reaction of the trityl medoxomil ester in acetic acid. The disadvantage of this process is that they carry out two more isolations and that column chromatography must be used to achieve the desired purity. Furthermore, if acetic acid is used as a solvent in the last reaction step, further crystallization is required as this may otherwise lead to the formation of persistent impurities during the drying process and may also be difficult to remove from a pharmaceutically active compound when present as a residual solvent.

In J. Med. Chem., 1996, 39, 323-338 carry out the alkylation step between 4- [2-triethyltetrazol-5-yl) phenyl] benzyl bromide or its analogs and the imidazole intermediate also in N, N-dimethyl acetamide and in the presence of potassium / butoxide. The disadvantage of the process described again is that EtOAc and water should be added to the reaction mixture and that the product should be extracted into EtOAc. Purification of the product was achieved using flash column chromatography (EtOAc / hexane, 1: 2) and optionally by additional crystallization from IPE, hexane, EtOAc or mixtures thereof.

EP O 796 852 BI describes a safer and easier preparation of 5-substituted tetrazoles without the use of Bu ₃ SnN ₃ . The process involves reacting a nitrile with an inorganic azide salt in an aromatic hydrocarbon solvent in the presence of an amine salt.

WO 2004/085428 describes a new process for the preparation of olmesartan medoxomil. The process results in the ring breaking of 4,4-dimethyl-2-propyl-1- {4- [2- (triphenyl methyl tert.azol-5-yl) phenyl] phenyl} methyl-4,6-dihydrofuran [3,4d ] imidazol-6-one, obtained 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (triphenyl-methyl tert-azol-5yl) phenyl] phenyl} methylimidazole-5-carboxylic acid then condensed with 4-bromo (or chloro) methyl-5-methyl-2-oxy-1,3-dioxyheterocyclopentene by the alkali effect, and after deprotection of the triphenylmethyl protecting group, olmesartan medoxomil is obtained.

WO 2004/083213 relates to the compounds represented by the following formula (II) and to their pharmaceutically acceptable salts and to a process for their preparation. They are used as intermediates for the preparation of an angiotensin II receptor antagonist, e.g. olmesartan medoxomil.

⁰ (H)

The above objective is solved by the present invention.

Summary of the Invention

The present invention provides an improved synthesis for the preparation of olmesartan and its pharmaceutically acceptable salts and esters as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions comprising an alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5- of carboxylate (III) with 4- [2- (triethyltetrazol-54 yl) phenyl] benzyl bromide (IVa) or 4'-bromomethylbiphenyl-2-carbonitrile (IVb) in an organic solvent and in the presence of a base where the same solvent is used as a reaction solvent and as crystallizations solvent.

The first embodiment of the present invention relates to an improved synthesis for the preparation of olmesartan medoxomil comprising:

alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4- [2- (triethyltetrazol-5-yl) phenyl] -benzyl bromide (IVa) in an organic solvent and in the presence bases where the same solvent is used as the reaction solvent and as the crystallization solvent, and the one-pot process comprising the hydrolysis of ethyl ester V, esterification with 4-substituted methyl-5-methyl-2-oxo-1,3-dioxolene derivative (VI) and subsequent deprotection of the trityl protecting group without any isolation during the process.

Another embodiment of the present invention relates to an improved synthesis for the preparation of olmesartan medoxomil comprising:

the alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4'-bromomethylbiphenyl-2-carbonitrile (IVb) in an organic solvent and in the presence of a base, where the same solvent is used as a reaction solvent and as a crystallization solvent, and a process comprising the hydrolysis of ethyl ester, esterification with 4-substituted methyl-5methyl-2-oxo-1,3-dioxolene derivative (VI) and the subsequent cycloaddition reaction of cyano to a tetrazole group.

It has been unexpectedly found that in the preparation of olmesartan medoxomil, the alkylation step leads to much higher yields and lower impurity levels when carried out in acetonitrile and in the presence of potassium carbonate as a base instead of using N / V-dimethylformamide as a solvent, as is known in the art . In this way, extraction with another water-immiscible solvent can be reduced as well as purification of the product by column chromatography, since it has surprisingly proved that acetonitrile can be very well used as a reaction and crystallization solvent. In particular, the latter feature represents an important advantage for industrial processes because purification by column chromatography is rarely used on an industrial scale.

Scheme 1:

When the alkylation step is carried out with 4'-bromomethylbiphenyl-2-carbonitrile (IVb), deprotection of the trityl protecting group is replaced by a cycloaddition reaction and can also be carried out before hydrolysis of the ethyl ester and esterification with 4-substituted methyl 5-methyl-2-oxo-1. 3-dioxolene derivative (VI). The cycloaddition reaction to the tetrazole moiety can be performed by any procedure known in the art, e.g. using Bu ₃ SnN ₃ , NaN ₃ / ZnCl2, or as described in EP 0 796 852 BI. Optionally, a trityl protecting group may be used or any other suitable protecting group known to one skilled in the art can be used to achieve the purification.

Scheme 2:

(Villa) (D

Ί

A further aspect of the present invention is an improved process for the preparation of a pharmaceutical formulation containing very pure olmesartan medoxomil.

A further aspect of the present invention is olmesartan medoxomil, which is substantially free of dehydro and N-alkyl impurities of structural formulas

The following are preferred embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved synthesis for the preparation of olmesartan medoxomil comprising the alkylation of 4- [2- (triethyltetrazol-5-yl) ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (III) ) phenyl] benzyl bromide (IVa) or 4'-bromomethylbiphenyl-2carbonitrile (IVb) in an organic solvent and in the presence of a base, where the same solvent is used as a reaction solvent and, as a crystallization solvent, preferably acetonitrile is used.

Another aspect of the present invention describes a one-pot process following an alkylation step comprising hydrolysis of ethyl ester (Va), esterification with a 4-substituted methyl-5-methyl-2-oxo-1,3-dioxolene derivative and subsequent deprotection trityl protecting groups without any isolation during the process. If the alkylation reaction is carried out with 4'-bromomethylbiphenyl-2-carbonitrile (IVb), the second aspect of the present invention includes a process comprising the hydrolysis of ethyl ester, esterification with 4-substituted methyl-5-methyl-2-oxo-1,3-dioxolene derivative ( VI) and the subsequent cycloaddition reaction cyano acts in the tetrazole group.

The first aspect of the present invention relates to an improved synthesis for the preparation of olmesartan medoxomil comprising:

i. alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4- [2- (triethyltetrazol-5-yl) phenyl] -benzyl bromide (IVa) in an organic solvent and in the presence bases using the same solvent as the reaction solvent and as the crystallization solvent; and ii. one-pot process comprising the hydrolysis of ethyl ester, esterification with 4-substituted methyl-5-methyl-2-oxo-1,3-dioxolene derivative (VI) and subsequent deprotection of the trityl protecting group without any isolation during the process.

Another embodiment of the present invention relates to an improved synthesis for the preparation of olmesartan medoxomil comprising:

alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4'-bromomethylbiphenyl-2-carbonitrile (IVb) in an organic solvent and in the presence of a base using the same solvent as the reaction solvent and as a crystallization solvent and a process comprising the hydrolysis of ethyl ester, esterification with 4-substituted methyl-5methyl-2-oxo-1,3-dioxolene derivative (VI) and the subsequent cycloaddition reaction of cyano to a tetrazole group.

When the alkylation step is carried out with 4'-bromomethylbiphenyl-2-carbonitrile (IVb), deprotection of the trityl protecting group is replaced by a cycloaddition reaction and can also be carried out before hydrolysis of the ethyl ester and esterification with 4-substituted methyl 5-methyl-2-oxo-1. 3-dioxolene derivative (VI).

Optionally, after the alkylation step is ethyl 4- (1-hydroxy-1-methylethyl) -2propylimidazole-5-carboxylate (III) with 4- [2- (triethyltetrazol-5-yl) phenyl] -benzyl bromide (IVa ) or 4'-bromomethylbiphenyl-2-carbonitrile (IVD) complete, the organic solvent was partially evaporated to facilitate crystallization of the product. If necessary, the alkylated product (Vac) can also be suspended in water and recrystallized from the same solvent as used in the alkylation reaction.

In a preferred embodiment, the present invention relates to an improved synthesis for the preparation of olmesartam medoxomil comprising:

i. alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4- [2- (triethyltetrazol-5-yl) phenyl] -benzyl bromide (IVa) in acetonitrile and in the presence of potassium carbonate as a base to give compound Va, where acetonitrile is used as the reaction solvent and as the crystallization solvent, and ii. one-pot process comprising the hydrolysis of ethyl ester, esterification with 4-substituted methyl-5-methyl-2-oxo-1,3-dioxolene derivative (VI), preferably 4-chloromethyl-5-methyl-2-oxo-1,3 -dioxolene, and subsequent deprotection of the trityl protecting group without any isolation during a process where deprotection of the trityl protecting group is carried out in EtOAc and in the presence of HCl and co-solvents.

If desired, after the alkylation reaction is complete, the acetonitrile is partially evaporated to facilitate crystallization of the product (Va). If necessary, the product can also be suspended in water and recrystallized from acetonitrile.

Surprisingly, the use of the same organic solvent as the reaction and crystallization solvent during the alkylation reaction between 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4- [2- (triethyltetrazol-5-yl) phenyl] benzyl bromide (IVa) led to much higher yields (88%) and lower impurity levels despite the fact that the extraction step was lowered with another water-immiscible solvent as well as the purification of the product by column chromatography. Preferably acetonitrile is used as the reaction and crystallization solvent during the alkylation step. The product, ethyl 4- (1-hydroxy-methylethyl) -2-propyl-1- {4- [2- (triethyltetrazol-5-yl) phenyl] phenyl} -methyl imidazole-5-carboxylate (Va) and ethyl 4- (1-Hydroxy-1-methylethyl) -2-propyl-1- {4- [2-cyanobiphenyl} methyl imidazole-5carboxylate (Vb) was isolated by crystallization. If desired, the reaction mixture is concentrated to about 1/3 of the original volume and cooled to a temperature below 25 ° C. After the precipitated product is filtered off, it is suspended in water to remove excess inorganic base. The product can be recrystallized from an organic solvent, e.g. from acetonitrile.

Another aspect of the invention describes a one-pot process following an alkylation step comprising the hydrolysis of ethyl ester, esterification with 4-substituted methyl-5-methyl-2-oxo-1, 3dioxolene derivative and subsequent deprotection of the trityl protecting group without any isolation during the process. A 4-substituted 5-methyl-2-oxo-1,3-dioxolene derivative (VI) is a compound where R represents a good leaving group, e.g. halogen such as Cl, Br and J, p-toluenesulfonyloxy (tosylate), p-bromobenzenesulfonyloxy (brosylate), pnitrobenzenesulfonyloxy (nosylate) or methylsulfonyloxy (mesylate) group. In a preferred embodiment, 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene is used.

Ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (triethyltetrazol-5-yl) phenyl] phenyl} -methyl imidazole-5-carboxylate (Va) is dissolved in a suitable solvent , the first base is added and the reaction mixture is stirred for 24 hours, preferably 4 to 12 hours, at a temperature between 15 ° C and 30 ° C, preferably at room temperature.

After the hydrolysis of the ethyl moiety is complete, a surprisingly 4-substituted methyl 5-methyl-2-oxo-1,3-dioxolene derivative, preferably 4-chloro methyl-5-methyl-2-oxo-1, 3dioxolene can be easily added to the reaction mixture together with the second base without first isolating the resulting salt. The mixture was cooled below 5 ° C before addition and both reagents were added at this temperature. The reaction mixture is heated for up to 5 hours, preferably for 2 hours, at a temperature between room temperature and 100 ° C, preferably at a temperature of 30 ° C and 40 ° C.

As solvents for the hydrolysis and esterification step, Ν, imet dimethylacetamide, other amide solvents, nitriles or any other water immiscible polar solvent can be used. In a preferred embodiment, the solvent is DMA.

Alkali hydroxides, metal alkoxides or carbonates in the amount of 1 to 1.5 equivalents are used as the first bases. In a preferred embodiment, sodium hydroxide is used as the first base.

Alkali or alkaline earth alkali hydroxides, metal alkoxides or carbonates in the amount of 0.5 to 1.5 equivalents are used as the other bases. In a preferred embodiment, potassium carbonate is used as the second base.

In a preferred embodiment, olmesartan medoxomil is substantially free of dehydro and N-alkylated impurities in the present invention. The present invention also provides a process for synthesizing olmesartan medoxomil comprising an amount of dehydro and alkylated impurities of not more than 0.2%, preferably not more than 0.10%, comprising:

analyzing and selecting commercial baths of a 4-substituted methyl-5 ~ methyl-2oxo-1,3-dioxolene derivative or purifying a 4-substituted methyl-5-methyl2-oxo-1,3-dioxolene derivative and analyzing the purified product using dioxolene batch batches having a content greater than 90%, preferably greater than 95%.

After the esterification step is complete, the reaction mixture is cooled below 15 ° C, a second water-immiscible solvent is added to the reaction mixture, together with some brine and extracted. The organic fractions were collected, washed with brine and dried over desiccant, e.g. anhydrous sodium or magnesium sulfate (VI). The extractions are carried out at a temperature below 25 ° C.

Low-solubility solvents for olmesartan medomoxil, such as esters, ethers, halogenated hydrocarbons, can be selected as water-miscible solvents for extraction. Preferably, the water-immiscible solvent is ethyl acetate.

In the deprotection step, the second water-immiscible solvent added after the esterification step can be partially evaporated and acid selected from organic acid, inorganic acid, their derivatives and mixtures thereof, and co-solvent added. The co-solvent can be selected from alcohols, ketones, nitriles or water. The co-solvent concentration is up to 30% (v / v), preferably up to 20% (v / v). Preferably, the co-solvent is MeOH or EtOH. The solvents used for the deprotection step of the trityl moiety are the same solvents as for the extraction step mentioned above. Preferably the solvent for the deprotection step of the trityl moiety is ethyl acetate.

The reaction mixture is heated at a temperature between 15 and 30 ° C, preferably at room temperature for up to 5 hours, preferably 3 hours.

The acid can be selected from HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ or other suitable inorganic acids. Preferably, HCI is added as a solution in water or in an organic solvent or in gaseous form.

After deprotection is complete, the reaction mixture is cooled, preferably to room temperature, and neutralized with an inorganic base solution to a pH of up to 6, preferably to a pH of between 3 and 5. The phases are separated and the aqueous phase can be extracted with an organic solvent. The collected organic phases are dried, filtered and concentrated. The mixture was cooled and the product precipitated.

The final product (I) was filtered and collected with fresh organic solvent and the reaction by-product (trityl alcohol) was completely dissolved in the filtrate.

Suitable inorganic bases used for neutralization are NaOH, KOH, LiOH, Ca (OH) ₂ , Na ₂ CO ₃ , NaHCO ₃ , K ₂ CO ₃ , KHCO ₃ inorganic phosphates. Preferably an aqueous NaOH solution is used.

The crude product can be recrystallized from organic solvents such as acetates, ketones, alcohols, nitriles and mixtures thereof. The crystalline forms of the products crystallized from the above solvents were the same as described in the Annual Report of Sankyo Research Laboratories Vol. 55 (2003). If the solution of olmesartan medoxomil slowly crystallizes from isobutanol or THF, a new form of olmesartan medoxomil is obtained, which has a melting point of 182-184 ° C. By slow crystallization, crystallization is meant where the olmesartan medoxomil solution is allowed to crystallize for more than 8 hours.

Olmesartan medoxomil solvates may form during the crystallization process and during filtration.

The amorphous form of olmesartan medoxomil is prepared when a solution of olmesartan medoxomil in an organic solvent such as ethers, halogenated hydrocarbons and alcohols is evaporated, spray dried or lyophilized, and is characterized by a glass transition temperature of about 120-140 ° C.

When olmesartan medoxomil is crystallized from organic solvents at pH less than 2, the olmesartan metoxomil salt is isolated. This pH can be achieved by the addition of inorganic acids such as HCl, H ₂ SO ₄ , H ₃ PO ₄ , HBr, or strong organic acids such as CF ₃ COOH, HCOOH, CH ₃ COOH, acetanhydride, etc.

It is important to control the particle size of olmesartan medoxomil during its preparation. The average particle size used in our work is 10 to 80 µm, preferably below 30 µm, usually obtained by crystallization of olmesartan medoxomil from organic solvents or mixtures thereof with water with stirring. If not stirred, crystallization from organic solvents or mixtures thereof with water may also give rise to larger particles, e.g. with an average diameter of more than 100 µm, to be ground or processed in any other way that reduces the size of the particles, before being used in pharmaceutical formulations. However, it is not enough to control only the average particle size, but also the particle size distribution. We define the following parameters to control the particle size distribution:

% particles less than 20 pm, preferably less than 15 pm;

% particles greater than 20 pm, preferably greater than 40 pm;

% particles greater than 10 pm, preferably greater than 20 pm.

Average particle size and particle size distribution are important to ensure that the process process is industrially appropriate, i.e. not to cause segregation of the constituents of the tabletting compound, unless tableted / compressed immediately after preparation of the tabletting compound.

Olmesartan medoxomil formulations can be prepared by known technological methods, such as direct compression or wet granulation (with water or organic solvents, e.g. MeOH, or mixtures thereof), dry granulation or lyophilization. Preferably, the direct compression process is used. The direct compression process can be carried out in such a way that (a) the excipient mixture is added to the active ingredient and compressed or (b) the active ingredient is mixed together with the excipients and compressed.

A solid dosage form (eg tablet cores) can be optionally coated.

The direct compression process is performed because of the low percentage of the active ingredient in the total weight of the tablet. Percentage refers to the weight% of the active substance in the total weight of the tablet. A low percentage of the active ingredient means less than 20% by weight of the active ingredient in the total weight of the tablet.

The excipients can be optionally processed by wet granulation using either water or an organic solvent or a mixture thereof as a granulation fluid. By the treatment of wet granulation excipients, the homogenization of the excipients and the addition of granulation fluid to their mixture are intended. The granulation fluid may optionally contain a binder or binders, either individually or mixtures thereof.

If desired, surfactants may be included in the solid pharmaceutical formulation. Surfactants can be selected from the group of non-ionic or ionic surfactants or mixtures thereof.

Suitable non-ionic surfactants selected from the group alkilglukozidi, alkilmaltozidi, alkiltioglukozidi, AIN makrogolgliceridi, polyoxyethylene alkylphenols, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polioksietilenpolioksipropilen block copolymers, polyglyceryl fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, sterols and mixtures thereof. Preferred non-ionic surfactants are polyoxyethylene sorbitan fatty acid esters sold under the trade names Polysorbate or Tween.

Suitable ionic surfactants are selected from the group of fatty acid salts, bile salts, phospholipids, phosphoic acid esters, carboxylates, sulfates, sulfonates and mixtures thereof. A preferred ionic surfactant is sodium sulfate.

The pharmaceutical composition of the invention comprises 0.1 to 10% by weight, preferably 0.1 to 5% by weight of surfactant.

A suitable mixing device for direct compression or, if desired, wet granulation as described above, is the conventional equipment used for mixing the active ingredients, excipients or combination of the active ingredient (s) and excipients. Typical equipment are passive mixers, fluidized cushions, diffusion skis, two-cone diffusion, two-cone, turbulence, cubic, planetary, Υ-, V-shaped or high shear mixer, drum, etc. In the case of wet granulation as described above, the equipment is selected from standard drying equipment, i.e. fluidized bed dryer, trays, etc.

The solid dosage form may be e.g. immediate release dosage form, rapid melting dosage form, controlled release dosage form, lyophilized dosage form, sustained release dosage form, sustained release dosage form, pulse release dosage form, immediate release or controlled release dosage form combination.

The solid dosage form is preferably a tablet formulation that can be optionally coated. The solid dosage form is preferably an immediate release dosage form that offers advantages over the bioavailability of the active compound.

If an immediate release dosage form is selected, it will be appreciated by one skilled in the art that the amount of release agent or agents, either individual or mixtures thereof, to be used in the formation of the outer portion will be determined on the basis of various parameters such as the desired emissivity properties, including the amount of active substance or substance to be dispensed, the desired rate of release of the active substance or substance, and the size of the micrometrix particles.

The pharmaceutical composition consists of:

up to 99% by weight, preferably 5-50% by weight, more preferably 5-15% by weight of olmesartan medoxomil, up to 99% by weight, preferably 20-99% by weight more preferably 50-99% by weight of diluent, up to 90% by weight, preferably 1-50% by weight of binder, up to 50% by weight, preferably 2-40% by weight of disintegrant or super-disintegrant, 0.1 to 10% lubricants,

0.1-10% by weight, preferably 0.1-5% by weight of surfactant, and optionally 0.1 to 10% of the film coating layer.

The excipients present in the composition of the invention may be diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextrates, other sugars, such as mannitol, siliconized microcrystalline cellulose, phosphate, calcium carbonate, calcium lactate or combination diluents. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.

The composition of the invention may also comprise binders such as povidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (comprising from 5 to 16% by weight hydroxypropyl groups), hydroxypropylmethyl cellulose, or other cellulose ether, cellulose ether or polymethacrylate or a mixture of binders. Preferably, the excipients include at least one binder selected from microcrystalline cellulose and low substituted hydroxypropyl cellulose.

In addition, disintegrants and / or super-disintegrants, such as starches (eg corn starch, potato starch), modified starches (sodium starch glycolate), modified cellulose (croscarmellose, i.e. cross-linked sodium carboxymethylcellulose), microcrystalline peroxidase, crosslinked peroxidase, crocodyl peroxidine, crosslinked peroxidase, peroxidase, peroxidase, peroxidase , sodium carboxymethylcellulose, Amberlite®, alginic acid, sodium alginate, guar gum, gellan gum, Xanthan SM®. When used as a disintegrant, microcrystalline cellulose is preferably used in an amount of 0.5 to 15% by weight. Preferably, the excipients include at least one disintegrant or super-disintegrant selected from croscarmellose, crospovidone and microcrystalline cellulose.

Further, lubricants such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, macrogols may also be present as excipients.

Preferably, the excipients include at least one lubricant selected from magnesium stearate, talc and macrogols.

Excipients may have multiple functions, i.e. one excipient may be a diluent and an additional binder, binder and disintegrant, etc.

Optionally, the tablet cores can be coated with conventional materials used for film coating. Film-coated formulations typically contain the following components: polymer (s), plasticizer (s), colorant (s) / opacifying agent (s), solvent (solvents). Smaller amounts of aromas, surfactants and waxes can be used in the film coating suspension. The vast majority of polymers used in film coating are either cellulose derivatives, such as cellulose ethers or acrylic polymers and copolymers. High molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials are occasionally encountered.

Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose. Acrylic polymers comprise a group of synthetic polymers with different functionalities. Some of these can be further modified to increase swelling and permeability by embedding materials such as water-soluble cellulose ethers and starches to ensure complete disintegration / dissolution of the film.

Commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol, macrogols), organic esters (phyllate esters, dibutyl sebacetate, citrate esters, triacetin) and oils / glycerides (castor oil, acetylated monoglycerides, fractions.

Dyes / colorants are classified into several groups: organic dyes and varnishes, inorganic dyes, natural dyes.

The combination of different materials from each group can be combined in a defined ratio. Film-coated suspensions can be used as commercially available preparations.

The film coating dispersion can be prepared using various solvents such as water, alcohols, ketones, esters, chlorinated hydrocarbons, preferably water.

Particularly preferred is a coating suspension composition (converted to dry material) comprising:

1-99% by weight of polymer, preferably 1-95% by weight of polymer,

1-50% by weight of the plasticizer, preferably 1-40% by weight of the plasticizer,

0.1-20% coloring agent / opacifying agent, preferably 0.1-10% coloring agent / opacifying agent.

The immediate release dosage form may also include material that improves the processing of the release control agent. Such materials are generally referred to as plasticizers. Preferred softeners are acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, ethylene glycol, propylene glycol, triethyl citrate, triacetin, tripropinolate, acetate, acetyl acetate, acetyl acetate , castor oil, triethyl citrate, polyhydric alcohols, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxyethyl acetate, trioxylate, diethyl acetate -n-octyl phthalate, dioctyl phthalate, di-i-decyl phthalate, di-nundecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimethylate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2 -Ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate, glycerol distearate and glyceryl monocapryl.

The present invention is illustrated by the following examples without being limited thereto.

Melting points were recorded on a Koffler melting point apparatus and IR spectra were recorded on a Paragon 100 Perkin-Elmer FT-IR spectrometer.

Examples

Preparation of olmesartan medoxomil

Example 1

17.3 g (124.8 mmol) of K ₂ CO ₃ , 15 g (62.4 mmol) of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (III) and 38.3 g ( 68.7 mmol) 4- [2- (Trityltetrazol-5yl) phenyl] -benzyl bromide (IVa) was suspended in 750 ml of acetonitrile. The suspension was then heated under reflux until the reaction was complete (7 hours). Distillate 510 ml of acetonitrile and cool the concentrate to 23 to 25 ° C. The mixture was stirred at this temperature overnight, then the suspension was cooled to 0 ° C and stirred at this temperature for 1 hour. The crude product (Va) was filtered off and washed twice with 20 ml of chilled acetonitrile. The wet product was suspended in 450 ml of water, stirred for 1.5 hours and then filtered. The weight of the dried product (Va) is 39.5 g (89%).

T = 165-169 ° C

IR: 1666, 1525, 1291, 1446, 1177, 881, 756, 699, 640

Example 2

36.0 g (50.3 mmol) ethyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (triethyltetrazol-5yl) phenyl] phenyl} -methyl imidazol-5- of carboxylate (Va) and 3.0 g (75.4 mmol) of NaOH were suspended in 413 ml of dimethylacetamide. The suspensions were then stirred at room temperature for 20 hours and then 6.9 g (50.3 mmol) of K ₂ CO _{3 was added} . The mixture was cooled to 0 [deg.] C. and a solution of 15.4 g (70.4 mmol) of 4-chloromethyl-5-methyl-2-oxo-l, 3dioxolene in 39 ml of dimethylacetamide was slowly added. The mixture was slowly warmed to 50 ° C and stirred at this temperature for 2 hours. When the esterification is complete, the mixture is cooled to 10 ° C and poured into a mixture of 625 ml of ethyl acetate and 625 ml of 10% NaCl and stirred at 25 ° C for 15 minutes. The phases were separated and the organic phase was washed twice with 500 ml of 10% NaCl, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to 1/2 (about 270 g) under reduced pressure.

To the solution thus obtained is added 80 ml of ethanol and 8.3 ml (100 mmol) of conc. HCl and stirred for 3 hours at 24-26 ° C. 600 ml of water were added to the cooled mixture and the pH of the suspension was adjusted to 5 with 5 M NaOH. The phases were stirred for 15 minutes and separated. The aqueous phase was extracted with 150 ml of ethyl acetate. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Add 560 ml of ethyl acetate and evaporate the mixture again. Then 300 ml of ethyl acetate are added, the mixture is cooled to 20 ° C and stirred for 1 hour, filtered and washed with 20 ml of fresh ethyl acetate. The yield of product (I) was 21 g (75%).

Crystallization of olmesartan medoxomil:

Example 3

1.11 g of olmesartan medoxomil was dissolved in 12.5 ml of 2-butanone at reflux temperature. The solution was slowly cooled to room temperature and stirred at this temperature for 20 hours. During this process, olmesartan medoxomil crystallizes slowly. The product was filtered and dried for 18 hours at room temperature. 0.98 g of olmesartan medoxomil is obtained.

The crystalline form of the product is the same as described in the Annual Report of Sankyo Research Laboratories Vol. 55 (2003).

Example 4

Dissolve 1.2 g of olmesartan medoxomil in 8.5 ml of 2-butanone at reflux temperature. The solution was slowly cooled to room temperature and stirred at this temperature for 20 hours. During this process, olmesartan medoxomil crystallizes slowly. The suspension was then cooled to 0 ° C and stirred at this temperature for 2 hours. The product was filtered and dried under reduced pressure at 30-40 ° C for 3 hours. 0.98 g of olmesartan medoxomil is obtained.

The crystalline form of the product is the same as described in the Annual Report of Sankyo Research Laboratories Vol. 55 (2003).

Example 5

Dissolve 0.5 g of olmesartan medoxomil in 4 ml of isobutanol at reflux temperature. The solution was slowly cooled to 0 ° C and stirred at this temperature for 3 hours. During this process, olmesartan medoxomil crystallizes slowly. The product was filtered and dried for 18 hours at room temperature. The crystalline form of olmesartan medoxomil (0.45 g) was obtained.

T = 182-184 ° C.

Example 6 g of olmesartan medoxomil was dissolved in 30 ml of THF at reflux temperature. The solvent was slowly evaporated under reduced pressure to a dry residue. During this process, olmesartan medoxomil crystallizes slowly. The product was collected and dried for 18 hours at room temperature. The crystalline form of olmesartan medoxomil (1.86 g) was obtained.

T = 182-184 ° C.

Example 7

Dissolve 0,5 g of olmesartan medoxomil in 18 ml of methylene chloride at reflux temperature. The solvent was slowly evaporated under reduced pressure to a dry residue. The amorphous form of olmesartan medoxomil (0.43 g) was obtained.

Example 8 g of olmesartan medoxomil is dissolved in 20 ml of heptane at reflux temperature. The solution was slowly cooled to room temperature and stirred at this temperature for 3 hours. During this process, olmesartan medoxomil is slowly precipitated. The product was filtered and dried for 18 hours at room temperature. The amorphous form of olmesartan medoxomil (0.45 g) was obtained.

T = 120-140 ° C.

Example 9 g of olmesartan medoxomil is dissolved in 45 ml of isopropanol at reflux temperature. The solution was slowly cooled to room temperature and stirred at this temperature for 3 hours. During this process, olmesartan medoxomil is slowly precipitated. The product was filtered and dried for 18 hours at room temperature. 1.96 g of olmesartan medoxomil are obtained.

Average particle size: 40 pm.

The crystalline form of the product is the same as described in the Annual Report of Sankyo Research Laboratories Vol. 55 (2003).

Example 10 Dissolve 10 g of olmesartan medoxomil in 140 ml of ethanol at reflux temperature. The solution was slowly cooled to room temperature without stirring. The mixture was allowed to stand at room temperature overnight (18 hours). The product was filtered and dried for 3 hours in a vacuum oven. 7.3 g of olmesartan medoxomil are obtained.

Average particle size: 253 pm.

The crystalline form of the product is the same as described in the Annual Report of Sankyo Research Laboratories Vol. 55 (2003).

Olmesartan medoxomil pharmaceutical formulation

Example 11 g of olmesartan medoxomil, 104 g of microcrystalline cellulose, 230 g of lactose monohydrate and 40 g of low substituted hydroxypropylcellulose are homogenized. Finally, 6 g of magnesium stearate are mixed to prepare the compressed mixture. The compressed mixture is compressed into cores of a theoretical weight of 210 mg. The cores were coated with a film-coated suspension containing (calculated on the dry part of the film-coated suspension) hydroxypropylcellulose (43.75% by weight), hydroxypropylcellulose (37.5% by weight), talc (6.25% by weight) and titanium dioxide (12.5% by weight). The theoretical weight of the film-coated tablet is 218 mg.

Example 12

The cores of Example 1 were coated with a pre-prepared film coating suspension containing (calculated on the dry part of the film coating suspension) partially hydrolyzed polyvinyl alcohol (40% by weight), titanium dioxide (25% by weight), macrogol (20.2% by weight) and talc (14.8% by weight). The theoretical weight of the film-coated tablet is 218 mg.

Example 13 g of microcrystalline cellulose, 114 g of lactose monohydrate, 20 g of low-substituted hydroxypropyl cellulose and 2 g of sodium lauryl sulfate are homogenized and sprayed with purified water in a fluidized bed granulator. Sift the granulate. 40 g of olmesartan medoxomil, 52 g of microcrystalline cellulose, 114 g of lactose monohydrate and 20 g of low substituted hydroxypropyl cellulose are added to the granulate and mixed. Finally 6 g of magnesium stearate are added to prepare the compressed mixture. The compressed mixture is compressed into cores of a theoretical weight of 210 mg.

The cores were coated with a case suspension of Example 11 or 12

Claims (27)

A process for the preparation of olmesartan medoxomil comprising an alkylation reaction between ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylate (III) and 4- [2 (triethyltetrazol-5-yl) phenyl] -benzyl bromide (IVa) or 4'-bromomethylbiphenyl-2 carbonitrile (IVb) in an organic solvent and in the presence of a base where the same organic solvent is used as the reaction and crystallization solvent to give the compound of formula (V); and converting the resulting compound (V) to olmesartan medoxomil. The process for the preparation of olmesartan medoxomil according to claim 1, wherein the organic solvent used as the reaction and crystallization solvent is acetonitrile. The process of claim 1, wherein the alkylation step is carried out with 4'-bromomethylbiphenyl 2-carbonitrile (IVb), followed by a cycloaddition reaction to the tetrazole moiety, and wherein the cycloaddition reaction can be carried out before or after hydrolysis of the ethyl ester and esterification with 4-substituted methyl-5- methyl-2-oxo-1,3-dioxolene derivative (VI). The process for the preparation of olmesartan medoxomil according to claim 1, wherein the organic solvent used as the reaction and crystallization solvent is partially distilled off. The process for the preparation of olmesartan medoxomil according to claims 1 and 2, wherein the product of the alkylation reaction between ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (II) and 4- [2- (trityltetrazole-5- yl) phenyl] benzyl bromide (IVa) or 4'bromomethylbiphenyl-2-carbonitrile (IVb) was crystallized from the reaction mixture. The process for the preparation of olmesartan medoxomil according to claim 1, wherein the product of the alkylation reaction between ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) and 4- [2- (triethyltetrazol-5-yl) phenyl] benzyl bromide (IVa) or 4'bromomethylbiphenyl-2-carbonitrile (IVb) was suspended in water after filtration and recrystallized from the same solvent as used in the alkylation reaction. The process for the preparation of olmesartan medoxomil according to claim 1 or 2, wherein the potassium carbonate base is used. The process for the preparation of olmesartan medoxomil according to claim 7, wherein the product of the alkylation reaction between ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) and 4- [2- (triethyltetrazol-5-yl) phenyl] benzyl bromide (IVa) or 4'bromomethylbiphenyl-2-carbonitrile (IVb) was suspended in water after filtration and recrystallized from acetonitrile. 9. A process for the preparation of olmesartan medoxomil comprising a one-pot process comprising the hydrolysis of ethyl ester (V), esterification with 4-substituted methyl-5-methyl-2-oxo-l, 3dioxolene (VI), preferably 4-chloromethyl -5-methyl-2-oxo-1,3-dioxolene and subsequent deprotection of the trityl protecting group without any isolation during the process. 10. A process for the preparation of olmesartan medoxomil comprising: i. ) the alkylation step of ethyl 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5carboxylate (III) with 4- [2- (triethyltetrazol-5-yl) phenyl] benzyl bromide (IVa) in acetonitrile and in the presence of potassium of carbonate as base, and ii. ) a one-pot process comprising the hydrolysis of ethyl ester, esterification with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene and subsequent deprotection of the trityl protecting group without any isolation during the process. The process according to claims 9 and 10, wherein the hydrolysis of ethyl ester and esterification with 4-chloromethyl 5-methyl-2-oxo-1,3-dioxolene are carried out in dimethylacetamide. The process of claims 9 and 10, wherein the deprotection of the trityl protecting group with the trityl olmesartan medoxomil is carried out in the presence of an acid selected from organic acid, inorganic acid, their derivatives and mixtures thereof, and a co-solvent. The process of claim 12, wherein the co-solvent can be selected from alcohols, ketones, nitriles or water. The process of claim 13, wherein the co-solvent concentration is up to 30% (v / v), preferably up to 20% (v / v). The method of claims 10 and 12, wherein the deprotection of the trityl protecting group with the trityl olmesartan medoxomil is carried out in ethyl acetate and in the presence of hydrochloric acid. 16. A process for the preparation of olmesartan medoxomil, characterized in that after the deprotection of the tetrazole moiety in ethyl acetate is complete, the reaction mixture is cooled, preferably to room temperature, and neutralized with an aqueous solution of the inorganic base to a pH of 6, preferably to a pH between 3 and 5, and the product is isolated. Process according to claim 16, characterized in that the solvent phases are separated, where the aqueous phase can be extracted with an organic solvent, preferably ethyl acetate, the concentrated organic phases are concentrated and cooled and the colored olmesartan medoxomil is isolated. Process according to claim 16, characterized in that the trityl alcohol remains dissolved in the reaction mixture and does not precipitate. The method of claims 9 and 10, wherein the reaction mixture is neutralized to pH 6 after deprotection. 20. Olmesartan medoxomil essentially free of dehydro and / V-alkylated impurities. 21. Olmesartan medoxomil according to claim 20, wherein the amount of dehydro olmesartan medoxomil and the amount of A-alkylated impurities is less than 0.2%, preferably less than 0.1%. Use of a 4-substituted methyl-5-methyl-2-oxo-1,3-dioxolene derivative with a content of more than 90%, preferably more than 95%, for the preparation of olmesartan medoxomil according to claims 20 and 21. 23. A new form of olmesartan medoxomil, characterized by a melting point of 182-184 ° C. Process for the preparation of a new form of olmesartan medoxomil according to claim 23, characterized in that olmesartan medoxomil is slowly crystallized from isobutanol or THF. 25. Amorphous form of olmesartan medoxomil, characterized by a glass transition temperature of about 120-140 ° C. 26. A process for the preparation of the amorphous form of olmesartan medoxomil according to claim 25, characterized in that the solution of olmesartan medoxomil in an organic solvent such as ethers, halogenated hydrocarbons and alcohols is evaporated, spray dried or lyophilized. Process according to claim 26, characterized in that the solution of olmesartan medoxomil in methylene chloride or heptane is evaporated.