SI21964A - Preparation of tetrazole derivative - Google Patents

Abstract

The submitted invention relates to a procedure for preparation of irbesartan or its pharmaceutically acceptable salts, which comprises the synthesis of trithyl irbesartan by the reaction of 5-(4-(bromomethyl)biphenyl-2-yl)-1-(triphenylmethyl)tetrazole and 2-n-butyl-4-cyclopentane-2- imidazolin-5-on or its salt in an organic solvent in the presence of a phase transfer catalyst and a base, removal of the protection group and isolation of irbesartan or its pharmaceutically acceptable salt.

Description

PREPARATION OF THE TETRAZOL DERIVATIVE

TECHNICAL FIELD

The present invention relates to the field of organic chemistry and relates to the synthesis of 2-butyl-1- [2 '- (1 H -tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazolin-4. l'-cyclopentan] -5-one (hereinafter referred to as its generic name irbesartan).

TECHNICAL PROBLEM

Irbesartan or 2-butyl-1- [2 '- (1 H -tetrazol-5-yl) biphenyl-4-yl-methyl] spiro [2-imidazolin-4-cyclopentane] -5-one is an angiotensin II receptor antagonist, respectively. you AT-1 and AT-2 receptors. By binding irbesartan to these receptors instead of angiotensin II, vasoconstrictive action of angiotensin II is prevented, therefore irbesartan acts as an antihypertensive agent.

There was a need for an improved, industrially applicable process that would use known intermediates for the synthesis of irbesartan, such as e.g. 5- (4- (Bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole, to achieve high yields and a high degree of purity of the finished product compared to existing processes.

BACKGROUND OF THE INVENTION

The synthesis of irbesartan is described in EP 0 454 511, EP 0 708 103, WO 99/06398, WO 99/38847, WO 2004/007482, WO 2004/065383, WO 2004/072064 and in articles.

The basic patent for irbesartan EP 0 454 511 describes a process for the preparation of irbesartan from basic chemicals (e.g. cyclopentanone) via seven reaction steps and intermediate 4 '- (bromo methyl) biphenyl-2-carbonitrile. The preparation of the tetrazole ring takes place in the last or last stage of synthesis with tributyltin azide as a source of azide ion, which is a very problematic reagent for use on a larger scale.

WO 2004/007482 describes a synthesis pathway already covered in the description of the basic process, wherein in the alkylation reaction of 2-n-butyl-4-cyclopentan-2-imidazolin-5-one with 5- (4- (bromomethyl) biphenyl2 -yl) -1- (triphenylmethyl) tetrazolol uses a new phase transfer catalyst (PTC catalyst), BU4NHSO4. The reaction takes place in two stages, aqueous and organic. Unlike other processes, this synthesis does not use azides in the last reaction step, and the conditions are milder.

EP 0 708 103 protects the process for the preparation of both irbesartan crystalline forms, A and B crystalline form.

SUMMARY OF THE INVENTION

The present invention relates to an improved synthesis route of irbesartan from 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole according to the following reaction scheme:

WO 2004/007482 describes the alkylation reaction of 2-n-butyl-4-cyclopentan-2-imidazolin-5-one (1) with 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole (2) using a two-phase base and PTC catalyst, aqueous and organic. This process does not give optimum conversion efficiencies, requires high reaction temperatures and the use of multiple solvents. Following this procedure, it is also necessary to separately isolate trityl irbesartan (3). Also, in this process, the purity of the intermediate 2 has to be very high, otherwise the purity of the final product and the yield are lower.

The synthesis of 2 - [- butyl-4-cyclopentan-2-imidazolin-5-one is described in J. Med. Chem., 1993, 36, 3371-3380 and in US 5,559,233.

The synthesis of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) - tetrazole is also known from the syntheses of other sartans and has been described in EP 0 253 310, EP 553879 and J. Med. Chem., 1991, 34, 2525-2547.

The present invention has eliminated the disadvantages of the prior art.

DETAILED DESCRIPTION OF THE INVENTION

The process for the synthesis of irbesartan according to the present invention comprises:

Synthesis of trityl irbesartan (3) in an organic solvent in the presence of a high transfer phase and base catalyst, removal of the protecting group of the resulting trityl irbesartan in an organic solvent, and - isolation of irbesartan or its pharmaceutically acceptable salts.

The first object of the invention is the synthesis of trityl irbesartan intermediates.

The synthesis of trityl irbesartan (3) is carried out by the reaction between 5- (4- (bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole and 2-n-butyl-4-cyclopentan-2-imidazolin-5-one or its salt by suspending or dissolving all reagents and catalysts in an organic solvent and heating the reaction mixture. After completion of the reaction, the solvent was evaporated to a solid residue which was used in the next reaction without further isolation.

Organic miscible water miscible solvents such as DMSO, DMF, DMA or nitriles are used as the solvent in the reaction. Acetonitrile is preferably used.

Reaction catalysts (PTC catalysts) are tetraalkylammonium salts such as e.g. tetrabutylammonium bromide, crown ethers such as e.g. 18-Crown-6, cryptandi, tris (3,6 dioxaheptyl) amine (TDA) or pyridyl sulfoxide. Preferably, the catalyst is tetrabutylammonium bromide.

Synthesis of trityl irbesartan is carried out at a temperature from 15 ° C to the reflux temperature of the solvent, preferably at a temperature between 25 ° C and 45 ° C. The reaction proceeds within up to 6 hours, preferably up to 3 hours.

Alkali metal hydroxides such as LiOH, NaOH or KOH, preferably KOH, are used as the base for the reaction.

The 2-n-butyl-4-cyclopentan-2-imidazolin-5-one intermediate can be used in any form, preferably in the form of salts with mineral acids.

An advantage of the process described is that the output intermediate 5- (4 (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole does not require absolute purity, but a lower purity intermediate, preferably above 80, can be used % (HPLC area% method). Nevertheless, its conversion to trityl irbesartan is above 95% at this rate.

A further object of the present invention is the cleavage of the trityl irbesartan protecting group.

Removal of the trityl protecting group of trityl irbesartan can be performed as described in T W. Greene's and PGM Wuts 'Protective Groups in Organic Synthesys', published by John Wiley and Sons (1981), or in Protective Groups in Organic Chemistry, published by JF McOmie in Plenum Press.

Surprisingly, we found that, unlike the known processes where the cleavage takes place in an acidic medium, the removal of the trityl protecting group is also carried out in alkaline conditions in high efficiency. Trityl irbesartan is dissolved or suspended in alcohol, a solid mineral base is added, and the mixture is heated at elevated temperature, between room temperature and the solvent reflux temperature, preferably at the solvent reflux temperature. After the reaction lasts up to 6 hours, preferably up to 3 hours, the reaction mixture is evaporated.

In the removal of the trityl protecting group, various alcohols, such as e.g. methanol, ethanol, isopropanol, propanol or butanol, preferably methanol. The mineral base may be KOH, NaOH or LiOH, preferably KOH.

The conversion of trityl irbesartan to irbesartan is practically 100%, the by-product is methyl trityl ether, or alkyl trityl ether, which is removed by extraction.

A further object of the present invention is also a method of isolating irbesartan and its pharmaceutically acceptable salts.

Isolation of irbesartan is carried out by adding water to the residue after evaporation and extracting the aqueous phase with a suitable organic solvent. Suitable organic solvents are esters, methylene chloride, heptane, hexane or toluene, preferably tert-butyl methyl ether. Subsequently, the aqueous phase is acidified with HCl to a pH of between 1.2 and 7, preferably up to a pH of between 3 and 5. If the aqueous phase is acidified with HCI below pH 1.2, the hydrochloride salt of irbesartan can also be prepared by isolation from the reaction mixture is carried out according to the procedures described in SI P-200400220 or SI P-200400292.

If the separated aqueous phase is acidified with HCl to a pH of between 1.2 and 7, preferably to a pH of between 3 and 5, the crude irbesartan recovered from the water can be further filtered or extracted into an organic solvent. It is extracted with an organic solvent in which irbesartan dissolves and is immiscible with water, such as e.g. methylene chloride. The organic phase was washed with water, dried with a suitable desiccant and evaporated to a solid residue to give crude irbesartan.

The yield of the entire synthesis of irbesartan from 5- (4- (bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole by this process is above 95%.

Crude irbesartan can be further recrystallized. Methods for crystallizing irbesartan are described in the patent literature, for example, in EP 0 454 511, EP 0 708 103, WO 99/67236 or WO 03/050110.

It can be crystallized from solvents such as: alcohols such as methanol, ethanol, isopropanol, npropanol, butanol, isobutanol; fer / -butanol, DMF, DMSO, dioxane, THF, 3-pentanone, 2-butanone, 4-methyl-2-pentanone, or combinations of solvents with water.

Furthermore, pharmaceutically acceptable salts thereof are prepared from irbesartan synthesized according to the present invention. The latter may be alkali salts (e.g., sodium, potassium, calcium or magnesium salts) or acid addition salts such as hydrochloride, oxalate, citrate, acetate, lactate, and the like.

Hydrochloride is preferably referred to as the pharmaceutically acceptable salt of the present invention, which can also be prepared by isolation from the reaction mixture according to the procedures described in SI P-200400220 or SI P-200400292.

Irbesartan hydrochloride can also be prepared by:

- acidify the basic salt of irbesartan or a solution of this salt in water or another polar solvent with HCI to a pH below 1.2, if the irbesartan solution in an organic solvent or mixture of organic solvent and water is acidified with HCI to a pH below 1.2.

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

EXAMPLES Example 1

Weigh 0.83 g (3.6 mmol) of 2 - [- butyl-4-cyclopentan-2-imidazolin-5-one hydrochloride, 15 ml of acetonitrile, 1.84 g (2.94 mmol) of 5- (4) - (Bromomethyl) biphenyl-2-yl) -1 (triphenylmethyl) tetrazole, 1.3 ml of IM tetrabutylammonium bromide (in acetonitrile) and 1.1 g (20 mmol) of crushed KOH. The mixture was stirred at 40 ° C under an inert atmosphere for 2.5 hours. The conversion of the starting compound 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole to tritylirbesartan is 96%. The mixture was cooled, evaporated and 17 ml of methanol and 0.33 g (5.9 mmol) of crushed KOH were added. The reaction mixture was refluxed for 2.5 hours and then evaporated again. Conversion to irbesartan is practically 100%. 17 ml of water and 50 ml / erc-butyl methyl ether are added, stirred and the phase separated. The aqueous phase is re-extracted with 50 ml of tert-butyl methyl ether and then the aqueous phase is acidified with 2 M HCl to pH = 4.5. The suspension was cooled to 5 ° C and the precipitate was filtered off. 1.34 g (96%) of crude irbesartan are obtained.

Example 2

0.79 g (3.4 mmol) of 2-n-butyl-4-cyclopentan-2-imidazolin-5-one hydrochloride, 15 ml of acetonitrile, 1.84 g (2.94 mmol) of 5- (4) are added to the flask. - (Bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole, 0.31 g of tetrabutylammonium bromide and 1.32 g (23.5 mmol) of crushed KOH. The mixture was stirred at 31 ° C under an inert atmosphere for 2.5 hours. The conversion of the starting compound 5- (4 (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole to tritylirbesartan is 95%. The mixture was cooled, evaporated and 17 ml of methanol and 0.33 g (5.9 mmol) of crushed KOH were added. The reaction mixture was refluxed for 2.5 hours and then evaporated again. Conversion to irbesartan is practically 100%. 17 ml of water and 50 ml of tert-butyl methyl ether are added, stirred and the phase is separated. The aqueous phase is re-extracted with 50 ml / erc-butyl methyl ether and then the aqueous phase is acidified with 2 M HCl to pH = 2. 40 ml of methylene chloride are added, the mixture is stirred and separated. The aqueous phase is re-extracted with 10 ml of methylene chloride. The combined organic phases are washed twice with 20 ml of water, dried with Na ₂ SO4 and evaporated to dryness. 1.4 g (96%) of crude irbesartan are obtained.

Example 3 G of irbesartan was suspended at room temperature in 20 ml of water and 2 ml of methanol were added. The suspension was then acidified with 2M HCl to pH 1.03. The mixture was refluxed for 10 minutes, stirred at room temperature at luro and 30 minutes on ice. The precipitate was filtered off and the product was dried in a vacuum oven at 50 ° C for 1 hour. 2.25 g of the sesquihydrate hydrochloride salt of irbesartan is isolated.

Claims (28)

REQUIREMENTS 1. A process for the preparation of irbesartan or its pharmaceutically acceptable salts, characterized in that a) synthesis of trityl irbesartan by reaction of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole and 2 - [- butyl-4-cyclopentan-2-imidazolin-5-one or its salts in an organic solvent in the presence of a phase transfer catalyst and a base, b) remove the protecting group of the resulting trityl irbesartan in the organic solvent; and c) isolate irbesartan or its pharmaceutically acceptable salts. 2. A process for removing the trityl irbesartan protecting group, characterized in that the reaction is carried out in alcohol, with the addition of a mineral base and at elevated temperature. Process according to claim 1a), characterized in that the phase transfer catalyst is tetraalkylammonium salt, crown ether, cryptand, tris (3,6-dioxaheptyl) amine or pyridyl sulfoxide. Process according to claim 3, characterized in that the catalyst is preferably tetrabutylammonium bromide. A process according to claim 1a), characterized in that the organic solvent in which the reaction is carried out is a water miscible solvent such as DMSO, DMF, DMA or nitriles. Process according to claim 5, characterized in that the organic solvent is preferably acetonitrile. A process according to claim 1a), characterized in that the reaction is carried out at a temperature from 15 ° C to the reflux temperature of the solvent. Process according to claim 7, characterized in that the reaction is preferably carried out at a temperature between 25 ° C and 45 ° C. Process according to claim 1a), characterized in that alkali metal hydroxides are used as the base. 10. The method of claim 9, wherein the base is preferably KOH. Process according to claim 1a), characterized in that 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole of lower purity levels, preferably above 80%, can be used. Process according to claim 1b) and 2, characterized in that the base is KOH, NaOH or LiOH and that methanol, ethanol, isopropanol, propanol or butanol are used as alcohol. 13. The method of claim 12, wherein the base is preferably KOH. Process according to claim 12, characterized in that methanol is preferably used as an alcohol. A process according to claim 1b) and 2, characterized in that the reaction takes place at elevated temperature, between room temperature and the reflux temperature of the solvent. A process according to claim 15, characterized in that the reaction is preferably carried out at the reflux temperature of the solvent. Process according to claim 1c), characterized in that isolated irbesartan is in any form, such as a polymorph, hydrate or salt. 18. The isolation process according to claim 1c), characterized in that water is added to the residue after evaporation of the reaction mixture and the aqueous phase is extracted with an organic solvent which is little or no miscible with water. Process according to claim 18, characterized in that organic solvents such as esters, tert-butyl methyl ether, methylene chloride, heptane, hexane or toluene are used for the extraction. Process according to claim 19, characterized in that tertbutyl methyl ether is preferably used for the extraction. 21. The method of claim 18, wherein the separated aqueous phase is acidified with HCl to a pH of between 1.2 and 7, preferably to a pH of between 3 and 5. Process according to claim 18, characterized in that the separated aqueous phase is acidified with HCl to a pH below pH 1.2 and the hydrochloride salt of irbesartan is isolated. 23. A process according to claim 21, characterized in that the crude irbesartan recovered from the water is further filtered or extracted into a suitable organic solvent in which irbesartan dissolves and is immiscible with water. Process according to claim 23, characterized in that methylene chloride is used as the solvent for extraction. Process according to claim 23, characterized in that the organic phase is washed with water, dried with a suitable drying agent and evaporated to a solid residue to give crude irbesartan. 26. The process of claim 23, wherein the organic phase is extracted with HCl after extraction to a pH below 1.2 and the hydrochloride salt of irbesartan is isolated. A process according to claim 23, characterized in that the filtered effluent irbesartan is recrystallized from solvents such as: alcohols such as methanol, ethanol, isopropanol, N-propanol, butanol, isobutanol, / er / -butanol; DMF, DMSO, dioxane, THF, 3-pentanone, 2-butanone, 4methyl-2-pentanone, or combinations thereof with water. Process according to claim 18, characterized in that the basic salt of irbesartan or a solution of this salt in water or an organic solvent or a mixture of both are acidified to a pH below 1.2 and the hydrochloride salt of irbesartan is isolated.