SI22126A - Procedure of preparation of candesartan cilexetil - Google Patents

Abstract

The present invention provides an improved synthesis for the manufacture of candesartan and pharmaceutically acceptable salts and esters thereof as active ingredients of a medicament for treatment of hypertension and related diseases and conditions, which comprises the removal of a tetrazolyl protective group in an organic solvent and in the presence of Lewis acid.

Description

PROCEDURE FOR THE PREPARATION OF CANDESARTAN CELEXETIL

FIELD OF THE INVENTION

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

A technical problem

Candesartan cilexetil of formula (I) is chemically described as (+/-) - 1 [[(cyclohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) ) -1,1'-biphenyl-4-ylmethyl] -L-N-benzimidazole-7-carboxylate. Due to its ability to inhibit the angiotensin converting enzyme, it is widely used to treat hypertension and related diseases and conditions. Candesartan cilexetil as an angiotensin receptor antagonist avoids the side effects of calcium antagonists, but has high stability and obvious curative effects. Currently sold as a racemic mixture. It is prepared according to published patents, e.g. EP 0 720 982 BI and EP 0 459 136.

(I)

As outlined below, it would be very useful to provide a more efficient and economical technological process for the manufacture of candesartan cilexetil.

BACKGROUND OF THE INVENTION

EP 0 720 982 Bi describes the preparation, candesartan cilexetil, by deprotection of triphenylmethyl (solid) moiety in methanol and in the presence of hydrochloric acid. The disadvantages of this process are very low yields and the product must be purified by chromatography. EP 0 668 272 further describes an improved process for removing a protecting group using anhydrous hydrogen chloride in methanol. The yields are slightly improved compared to EP 0 720 982 BI, but the share of decomposition products is still quite high. The disadvantages of the above mentioned processes are that they involve the use of highly corrosive acids and there is also a need for the reaction mixture to be treated by complex extractions or chromatographic purification.

WO 2005/021535 describes the preparation of candesartan cilexetil by the deprotection of a solid with solvolysis at reflux temperatures in anhydrous Cl to C5 alcohol under neutral or slightly basic conditions. Conversion to candesartan cilexetil is between 76% and 91%, which is still not optimal in industrial production, and the reaction time is 24 hours, which is another downside from an industry use standpoint. Further, longer reaction times at reflux temperatures usually lead to higher levels of decay products.

WO 2005/037821 describes the deprotection of a tetrazolyl group with (+/-) - 1 [[(cydohexyloxy) carbonyloxy] ethyl-2-ethoxy-N [[2 '- (7''phenylmethyltetrazol-5-yl) -1. r'biphenyl-4-yl] methyl-1H-benzimidazole-7-carboxylate (trityl candesartan cilexetil) using methanesulfonic, toluene sulfonic, formic and trifluoroacetic acid or simply by refluxing trityl candesartan cilexetil in a mixture of toluene, methanol and methanol. The disadvantages of these processes are that the deprotection reaction of the protecting group is not complete and that the product is mostly isolated in the form of viscous oil due to impurities present.

WO 2005/051928 describes methods for the preparation of tetrazolyl compounds, which include the removal of the protecting groups of the? / V-protected tetrazolyl compounds, in particular candesartan cilexetil, with organic acids. Because they use low reaction temperatures of 30 ° C to 35 ° C, the efficiencies are no higher than 60% and use additional extractions and purification with activated carbon and celite, which is a clear indication of the presence of unwanted by-products and / or the presence of starting material .

Summary of the Invention

The present invention provides an improved synthesis for the preparation of candesartan and its pharmaceutically acceptable salts and esters as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions comprising the removal of a tetrazolyl protecting group in an organic solvent and in the presence of Lewis acid. Normally, Lewis species is intended to mean all species having an empty orbit and / or accessible LUMO and all species with full or partial positive charge. Usually, Lewis acids such as boron trifluoride, aluminum trihalide and / or zinc dihalide are used.

A preferred embodiment of the present invention is an improved deprotection reaction leading to candesartan and its pharmaceutically acceptable salts and esters comprising removing the triphenylmethyl (trityl) protecting group from the tetrazolyl moiety in a polar organic solvent and in the presence of Lev / isoic acid. Zinc dihalide, including zinc difluoid, dichloride, dibromide or diiodide, is preferably used as Levvis acid. Most preferably, zinc dichloride is used.

It has been unexpectedly found that in the preparation of candesartan and its pharmaceutically active esters and salts, preferably candesartan cilexetil, the deprotection reaction of the tetrazolyl protecting group, especially when the teitrazolyl protecting group is trityl, leads to much higher yields, when carried out in a polar organic solvent and in the presence Lewis acids. Reaction times are shorter compared to deprotection procedures in the prior art and therefore candesartan cilexetil is prepared with lower impurity levels.

A further aspect of the present invention is candesartan cilexetil, substantially free of 2-oxo impurities, having the structural formula (Π)

H wherein R1 is alkyl or alkylaryl such as methyl, ethyl, benzyl, etc .; and R _{2 is} H or a tetrazolyl protecting group, such as e.g. triphenyneethyl (trityl) protecting group.

Preferred embodiments are described below; of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved synthesis for the preparation of candesartan cilexetil comprising removing the trifeuylmethyl (trityl) protecting group in an organic solvent and in the presence of Lewis acid.

Starting material being a candesartan derivative or free acid, preferably candesartan ester, most preferably (+/-) - 7 - [[(cyclohexyloxy) carbonyloxy] ethyl] 2ethoxy-1 - [[2 - (// - triphenylmethyltetrazol-5 -yl) -1,1'-biphenyl-4-ylmethyl] -1H-benzimidazole-7carboxylate (trityl candesartan cilexetil) can be prepared as described e.g. in J. Med. Chem. 1993, 36, 2343-2349 or by any other method of preparation known in the art and can be used in its solid or dissolved form. Thus, trityl candesartan cilexetil can be used as an isolated compound, as a solution or as an uninsulated reaction mixture.

The first embodiment of the present invention is an improved deprotection reaction leading to candesartan and its pharmaceutically acceptable salts and esters, comprising removing the protecting group from the tetrazolyl moiety in a polar organic solvent and in the presence of Lewis acid, which is a classical electron-deficient species, such as e.g. boron trifluoride, aluminum trihalide, zinc dihalide, etc. Preferably zinc dihalide and most preferably zinc dichloride are used. In a preferred embodiment, the tetrazolyl protecting group is a triphenylmethyl (trityl) protecting group.

Process for the preparation of (+/-) - 1- [[(cyclohexyloxy) carbonyl].] Oxyethyl-2-ethoxy "1 - [[2 '- (\ Hetrazol-5" yl) -1,1-biphenyl-4- yl] raelyl] -lT-benzimidazole-7-carboxylate (candesartan cilexetil) comprises:

i. transesterification or esterification of a tetrazolyl protected candesartan derivative or tetrazolyl protected candesartan in its acid form into tetrazolyl protected candesartan cilexetil, ii. treatment of tetrazolyl protected candesartan cilexetil with Lewis acid in a suitable organic solvent, iii. addition of another solvent, preferably water, and heating of the reaction mixture, iv. isolation of the obtained candesartan cilexetil.

In a preferred embodiment, the process comprises preparing (+/-) - 1 [f (cyclohexyloxy) carbonyl] oxy] ethyl'2-ethoxy-1 · - [[2 '- (1H-tetazazol-5-yl) -1,, -biphenyl-4yl] methyl] -1H-benzimidazole-7-carboxylate (candesartan cilexetil):

i. treatment of 1 - [[(cyldohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1 - [[(2- (77thiphenylmethyltetrazol-5-yl) -1,1-biphenyl4 <1] methyl] -1H-benzimidazole-76 carboxylate (trityl candesartan cilexetil) with Levvis acid in a suitable organic solvent, ii) addition of another solvent, preferably water, and heating of the reaction mixture, iii) isolation of the resulting candesartan cilexetil.

A preferred process for the preparation of caudesartan cilexetil is one in which zinc dichloride is preferred by Lewis acid. Lewis acid is added in an amount of between 0.4 and 1.5 equivalents, preferably in an amount of between 0.6 and 1.2 equivalents, most preferably in an amount of between 0.7 and 1.0 equivalents.

Another solvent, preferably water, can be added in an amount of between 0.5% (v / v) and 10% (v / v), preferably between 1 and 5%.

Organic solvents may be added as a second solvent, before or during heating. Preferably, the second solvent is water.

The reaction mixture is heated at a temperature between 0 ° C and 120 ° C, preferably at reflux temperature, for 0.5 to 10 hours, preferably for 2 to 4 hours.

Alcohols, acetates, ethers, amides, nitriles and mixtures thereof are thinly used as suitable organic reaction solvents. In a preferred embodiment, the organic solvent is alcohol and in the most preferred embodiment, the organic solvent is methanol.

The conversion of the starting material is almost complete because less than 2% of the starting compound (trityl candesartan cilexetil) remains in the reaction mixture. The by-product of 2-oxo-candesartan cilexetil in the reaction mixture is less than 2%.

Isolation of the resulting candesartan cilexetil involves crystallization, precipitation, lyophilization, extraction, including extraction under super-critical conditions, or use of compressed gases, spray drying or any other process known to one skilled in the art.

In the preferred process, after completion of the deprotection step, cool the reaction mixture to a temperature below 30 ° C, neutralize to a pH between 5 and 8, preferably to a pH between 6 and 7, with a solution of a base which may be an inorganic base such as NaOH, KOH, LiOH , Ca (OH) ₂ , Na ₂ CO ₃ , NaHCO ₃ , K ₂ CO ₃ , KHCO ₃ , inorganic phosphates, ah organic base, such as amines. Preferably carbonates and phosphates are used, and most preferably hydrogen carbonates are used as bases to neutralize the reaction mixture.

After neutralization, the volatile components of the reaction mixture were evaporated in vacuo, the water-immiscible solvent was added to the reaction mixture, together with some water, and candesartan cilexetil was extracted into the organic phase. The organic fractions were collected, washed with water or brine and dried over desiccant, e.g. anhydrous sodium or magnesium sulfate (VI), the Extractions are carried out at a temperature below 50 ° C, preferably below 30 ° C and most preferably below 20 ° C.

Acetates (e.g., ethyl acetate, methyl acetate, isopropyl acetate, propyl acetate, butyl acetate, isobutyl acetate), ethers (e.g. diethyl ether, drosopropyl ether, tert- butyl methyl ether), halogenated hydrocarbons (such as methylene chloride), toluene and hydrocarbons (heptane, hexane, cyclohexane).

The organic phase was partially evaporated in vacuo until there remained between 1/2 and 1/5 of the output volume in the vessel, and a non-polar solvent was added to the concentrate. Hydrocarbons (heptane, hexane, cyclohexane), toluene and ethers can be added as non-polar solvents. After the addition of the non-polar solvent, the mixture was stirred and cooled below 20 ° C for 2 to 24 hours.

The crystallized or crystallized product was collected and dried for 10 hours at a temperature between 10 ° C and 50 ° C until candesartan cilexetil containing less than about 5000 ppm slice of dual solvents was obtained. For drying the obtained candesartan cilexetil, all drying methods known to the average person, such as e.g. air drying, vacuum drying, fiuid bed drying, including fluid bed drying with moist air, and spray drying. Vacuum drying is preferred.

The crude product may be recrystallized from organic solvents such as alcohol, ketone and nitrites and / or mixtures thereof. Mixtures of the above solvents with ethers, halogenated hydrocarbons and hydrocarbons may also be used. The crystalline forms of the products crystallized from the above solvents were the same as described in Chem. Pharm. Buli. 47 (2) J82-186 (1999).

Candesartan cilexetil solvates may form during the crystallization process and during filtration.

It is important to control the particle size of candesartan cilexetil during its preparation. The average particle size used in our work is 10 to 100 µm, preferably below 50 µm, usually obtained by crystallization of candesartan cilexetil from organic solvents or mixtures thereof with water with stirring. In the absence of mixing, crystallization from organic solvents or mixtures thereof with water can also yield larger particles, e.g. having an average diameter of more than 100 µm, which must 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.

Average particle size and particle size distribution are important to ensure that the process process is industrially suitable, i.e., that it does not cause segregation of the components of the tabletting compound unless tableted / Isompressed immediately after preparation of the tabletting mixture.

Another embodiment of the present invention relates to candesartan cilexetil, substantially free of 2-oxo impurities, having the structural formula (TT)

wherein R1 is alkyl or alkylaryl such as methyl, ethyl, benzyl, etc .; and R _{2 is} H or a tetrazolyl protecting group, such as e.g. triphenylmethyl protecting group.

The first preferred embodiment of the present invention is candesartan cilexetil, substantially free of 2-oxo impurities. The present invention also provides a method for synthesizing candesartan cilexetil comprising an amount of 2-oxo impurities of not more than 0.10%, preferably not more than 0.05%.

The 2-oxo impurity was determined by HPLC method, ld comprising:

Equipment

HPLC: Agilent 1100

Data evaluation: ChemStatiom

Chromatographic conditions:

Column;

Zorbax Eclipse XDB C-l 8, 1.8 pm, 50 x 4.6 mm

Mobile Phase:

solvent A: 0.0IM sodium dihydrogen phosphate, pH 2.5 solvent B: acetonitrile

Gradient:

Time (min) % A % B 0 55 45 16 5 95 18 5 95 19 55 45

Follow-up:

Column temperature: Flow rate:

Detection:

Injection:

min ° C 1.0 ml / min

UV, 225 nm μΐ

Reference solution (RS)

RSl: Dissolve 5 mg of candasartan cilexetil standard and 5 mg of each of the candesartan intermediates of trityl candesartan cilexetil and trityl candesartan in acetonitrile and dilute to 10.0 ml. RS2: Dilute 1.0 ml of this solution to 100.0 ml with acetonitrile.

Test solutions (TS)

TS1: Dilute 20.0 μΐ of the reaction solution to 20.0 ml with acetonitrile.

TS2: Dissolved about 10 mg of the substance to be investigated in acetonitrile and diluted to 25.0 ml with acetonitrile.

When chromatograms are recorded under the prescribed conditions, the retention time of candesartan is about 7 minutes, the relative retention time of trityl candesartan cilexetil is about 1.2, the relative retention time of trityl candesartan is about 2.1, and the relative retention times are 2 ~ oxo candesartan cilexetil, Ph ₃ COH , Ph ₃ COMe, Ph ₃ COEt are about 0.6, 0.8, 1.3, 1.4. The evaluation process is surface%.

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

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

Examples

Comparative Example (WO 2005/021535, Example 12)

A mixture of trityl candesartan cilexetil (0.43 g) and methanol (8.6 ml) was stirred and refluxed for 24 hours. After this time, the reaction mixture was analyzed by HPLC.

Candesartan Cilexetil: 64.9%

Trityl candesartan cilexetil: 0.64%

2-oxo candesartan cilexetil: 8.0%.

The mixture was evaporated to 1/4 and the precipitated crystals were filtered off after cooling. The filtrate was evaporated and crystallized from cyclohexane. White crystals were obtained (HPLC surface%: candesartan cilexetil: 76.1%, trityl candesartan cilexetil: 1.2%, 2-oxo candesartan cilexetil: 10.9%.

Comparative Example (WO 2005/037821. Example 5)

A solution of trityl candesartan cilexetil (0.43 g), formic acid (0.38 ml), methylene chloride (1.7 ml) and methanol (0.9 ml) was stirred for 5 hours at 25 ° C. After this time, the reaction mixture is analyzed:

HPLC surface%, 5h: candesartan cilexetil: 68.1%, trityl candesartan cilexetil:

12.4%, 2-oxo candesartan cilexetil: 0.5%

HPLC surface%, 7h: candesartan cilexetil: 64.6%. trityl candesartan cilexetil: 14.9%, 2-oxo candesartan cilexetil: 1.7%

HPLC surface%, 23h: candesartan cilexetil: 61.6%, trityl candesartan cilexetil:

18.4%, 2-oxo candesartan cilexetil: 2.2%.

Example 1

A mixture of 0.43 g (0.5 mmol) of trityl candesartan cilexetil, 15 ml of methanol, ZnCl ₂ (0.05 g; 0.37 mmol) and water (0.4 ml) was stirred at reflux for 2.5 hours. The reaction mixture was analyzed (surface% HPLC: candesartan cilexetil: 75.5%, trityl candesartan cilexetil: 1.2%, 2-oxo candesartan cilexetil: 1.6%) and cooled to room temperature. The mixture was then neutralized to pH 6.11 by the addition of saturated NaHCO3 solution and the methanol was evaporated. Ethyl acetate (15 ml) and water (10 ml) were added and the mixture stirred. After separation of the phases, the organic phase was washed with water (10 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to 1/4 of the output volume. Heptane (10 ml) was added to the oil residue and cooled to 0 ° C. The precipitated product was collected by filtration and dried.

Claims (18)

Patent claims A process for the preparation of candesartan cilexetil, comprising removing the tetrazolyl protecting group in an organic solvent and in the presence of Levris acid. Process according to claim 1, characterized in that the tetrazole protecting group is triphenylmethane. (tritium) protecting group. Process according to claim 1, characterized in that the organic solvent is a solvent or a mixture of solvents selected from the group of alcohols, acetates, ethers, amides and nitriles. Process according to claim 3, characterized in that the organic solvent is methanol. 5. A process according to claim 1, characterized in that the Lewis acid is boron trifluoride, aluminum trihalide and / or cyan dihalide. Process according to claim 5, characterized in that the Lewis acid is zinc dichloride. Process according to claim 1, characterized in that Lewis acid is added in an amount of between 0.4 and 1.5 equivalents, preferably in an amount of between 0.6 and 1.2 equivalents, most preferably in an amount of between 0.7 and 1 , 0 equivalents. 8. A process for the preparation of candesartan cilexetil comprising: i. transesterification ah esterification of the tetrazolyl protected candesartan derivative ah tetrazolyl protected candesartan in its acid form in tetrazolyl protected candesartan cilexetil, ii. treatment of tetrazolyl protected candesartan cilexetil with Lewis acid in a suitable organic solvent, iii. addition of another solvent, preferably water, and heating of the reaction mixture, iv. isolation of the obtained candesartan cilexetil. 9. A process for the preparation of candesartan cilexetil comprising: i. treatment of (+/-) - 1 - [[(cyclohexylcarbonyl) carbonyl] oxy.] ethyl-2-ethoxy-1 - [[(2 '- (2V-phenylmethyltetrazol-5-yl) -1,1-biphenyl-4 -yl3niethyl] -1H''beiisinidazole-7carboxylate (trityl candesartan cilexetil) with Lewis acid in a suitable organic solvent, ii) addition of another solvent, preferably water, and heating of the reaction mixture, iii) isolation of the resulting candesartan cilexetil. The process according to claims 8 and 9, characterized in that another solvent, preferably water, in amounts of between 0.5% (v / v) and 10% (v / v), preferably between 1 and 5%, is added. Process according to claims 8 and 9, characterized in that the reaction mixture is heated at a temperature between 0 ° C and 120 ° C, preferably at reflux temperature, for 0.5 to 10 hours, preferably for 2 to 4 hours. Process according to claims 1, 8 and 9, characterized in that alcohols, acetates, ethers, amides, nitriles and mixtures thereof are used as suitable organic reaction solvents. Process according to claim 12, characterized in that methanol is used as the reaction solvent. A method according to claims 1, 8 and 9, characterized in that. the isolation of candesartan cilexetil obtained involves crystallization, precipitation, lyophilization, extraction, including extraction under super-critical conditions, or the use of compressed gases, spray drying or any other process known to the person skilled in the art. Process according to claims 1, 8 and 9, characterized in that candesartan cilexetil containing less than about 5000 ppm residual solvents is obtained. 16. Candesartan cilexetil, substantially free of 2-oxo impurities of structural formula (Π) wherein R1 is alkyl or alkylaryl such as methyl, ethyl, benzyl, etc .; and R _{2 is} H or a tetrazolyl protecting group, such as e.g. triphenylmethyl protecting group. Candesartan cilexetil according to claim 16, characterized in that it comprises an amount of 2-oxo impurities of not more than 0.10%, preferably nc; greater than 0.05%. 18. The method according to claims 1, 8 and 9, characterized in that the amount of 2-oxo candesartan cilexetil in the reaction mixture is less than 2%.