EP2049527A2

EP2049527A2 - Preparation of irbesartan

Info

Publication number: EP2049527A2
Application number: EP06700020A
Authority: EP
Inventors: Silvo Zupancic; Anica Pecavar; Rok Zupet
Original assignee: KRKA Tovarna Zdravil dd
Current assignee: KRKA dd
Priority date: 2005-01-05
Filing date: 2006-01-04
Publication date: 2009-04-22
Also published as: WO2006073376A3; EA200701433A1; WO2006073376A2; EA012852B1; NO20073984L; SI21965A

Abstract

The present invention relates to a process for the preparation of irbesartan or its pharmaceutically acceptable salts comprising a synthesis of trityl irbesartan by a reaction of 5-(4-(bromomethyl)biphenyl-2-yl)-1-(triphenylmethyl)tetrazole and 2-n-butyl-4-cyclopentane-2-imidazolin-5-one or a salt therof in an organic solvent in the presence of a phase transfer catalyst and a base, a removal of the protecting group and an isolation of irbesartan or its pharmaceutically acceptable salt.

Description

PREPARATION OF TETRAZOLE DERIVATIVE

TECHNICAL FIELD

The present invention belongs to the field of organic chemistry and relates to the synthesis of 2-butyl-l-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]spiro[2- imidazoline-4.r-cyclopentan]-5-one (in further specification named by its generic name "irbesartan").

TECHNICAL PROBLEM

Irbesartan or 2-butyl-l-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]spiro[2- imidazoline-4.1'-cyclopentan]-5-one is an angiotensin II receptor antagonist i.e. an antagonist of the so-called AT-I and AT-2 receptors. Irbesartan, by binding on these receptors instead of angiotensin II, prevents the vasoconstrictive action of angiotensin II and therefore acts as an antihypertensive agent.

There existed a need for an improved process for the synthesis of irbesartan that could be used on an industrial scale and would use known intermediates such as 5-(4- bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole and by which high yields and a high purity grade of the final product in comparison to existing processes would be achieved.

PRIOR ART

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

WO 2004/007482 describes a synthesis path, which is already comprised in the description of the basic process and whereat in the reaction of alkylating 2-«-butyl-4- cyclopentane-2-imidazolin-5-one with 5-(4-(bromomethyl)biρhenyl-2-yl)- 1 - (triphenylmethyl)tetrazole a new phase transfer catalyst (PTC catalyst) Bu₄NHSO₄ is used. The reaction takes place in two phases, in an aqueous and an organic one. In contrast to other processes this synthesis does not use azides in the last reaction step and also the conditions are milder.

EP 0 708 103 claims a process for preparation of both crystal forms of irbesartan, A and B crystal forms

SHORT DESCRIPTION OF FIGURE

Fig. 1 shows an x-ray powder diffractogram of trityl irbesartan.

SUMMARY OF THE INVENTION

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

In WO 2004/007482 a reaction of alkylating 2-w-butyl-4-cyclopentane-2-imidazolin- 5-one (1) with 5-(4-(bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole (2) by the use of a base and a PTC catalyst in two phases, an aqueous and an organic one, is described. This process does not give optimal yields of conversion, it requires high reaction temperatures and the use of several solvents. According to this process it is also necessary to separately isolate trityl irbesartan (3). In this process also the purity of the starting intermediate (2) has to be very high since otherwise the purity of the final product, irbesartan (4), and the yield are lower.

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

The synthesis of 5-(4-(biOmomethyl)biphenyl-2-yl)-l-(triphenylmethyl)-tetrazole is also known from the syntheses of other saltans and was described in EP 0253310, EP 0553879 and J. Med. Chem., 1991, 34, 2525-2547. In the present invention the drawbacks of prior art processes have been overcome.

DETAILED DESCRIPTION OF THE INVENTION

The process of synthesis of irbesartan according to the present invention comprises: a synthesis of trityl irbesartan (3) in an organic solvent in the presence of a phase transfer catalyst and a base, with a high yield, a removal of the protecting group of the formed trityl irbesartan in an organic solvent and an isolation of irbesartan or its pharmaceutically acceptable salts.

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

The syntesis of trityl irbesartan (3) is carried out by a reaction between 5-(4- (bromomethyl)biphenyl-2-yl)- 1 -(triphenylmethyl)tetrazole and 2-/z-butyl-4- cycloρentane-2-imidazolin-5-one or a salt thereof in such a manner that all reagents and catalysts are suspended or dissolved, respectively, in an organic solvent and the reaction mixture is heated. After the completed reaction the solvent is evaporated to a solid residue, which is used in the following reaction without additional isolation.

As the reaction solvent there are used organic solvents that are miscible with water such as DMSO, DMF, DMA and nitriles. Preferably, acetonitrile is used.

Reaction catalysts (PTC catalysts) are tetralkylammonium salts such as tetrabuylammonium bromide, crown ethers such as 18-crown-6, cryptands, tris(3,6- dioxaheptyl)amine (TDA) or pyridyl sulfoxide. Preferably, the catalyst is tetrabutylammonium bromide. The synthesis of trityl irbesartan is carried out at a temperature from 15⁰C to reflux temperature of the solvent, preferably at a temperature between 25°C to 45⁰C. The reaction is completed within up to 6 hours, preferably within up to 3 hours.

As the base in the reaction alkali metal hydroxides such as LiOH, NaOH or KOH are used, preferably KOH.

The intermediate 2-«-butyl-4-cyclopentane-2-imidazolin-5-one can be used in any form, preferably in the form of a salt with mineral acids.

An advantage of the described process is also that for the starting intermediate 5-(4- (bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole no absolute purity is required, but an intermediate with a lower degree of purity can be used, yet preferably above 80 % (HPLC area % method). Nevertheless, its conversion to trityl irbesartan in this step is above 95 %.

The isolated trityl irbesartan may be, if necessary, recrystallized from organic solvents such as DMA, DMF, esters, alcohols, nitriles or mixtures of these solvents or mixtures of these solvents with non-polar solvents.

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

A removal of the trityl protecting group of trityl irbesartan can be carried out as described in the article T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, published by John Wiley and Sons (1981) or in Protective Groups in Organic Chemistry, ed. J. F. McOmie, published by Plenum Press.

We have surprisingly found that the reaction of removal of the trityl protecting group, in contrast to known processes wherein the cleavage takes place in an acidic medium, can also be carried out with a high yield in alkaline conditions. Trityl irbesartan is dissolved or suspended in an alcohol, a solid mineral base is added and the mixture is heated at an elevated temperature between room temperature and the reflux temperature of the solvent, preferably at the reflux temperature of the solvent. After completed reaction lasting up to 6 hours, preferably up to 3 hours, the reaction mixture is evaporated.

In the reaction of removing the trityl protecting group different alcohols such as e.g. methanol, ethanol, isopropanol, propanol or butanol, preferably methanol may be used. The mineral base may be KOH, NaOH or LiOH, preferably KOH. Also alcoholates NaOR, KOR, LiOR can be used.

The conversion of trityl irbesartan to irbesartan is practically 100%, the side product is methyl trityl ether i.e. an alkyl trityl ether, which is removed by extraction.

A further object of the present invention is a process of isolation of irbesartan and its pharmaceutically acceptable salts.

The isolation of irbesartan is carried in such a manner that water is added to the evaporation residue and the aqueous phase is extracted with a suitable organic solvent. Suitable organic solvents are esters, methylene chloride, heptane, hexane or toulene, preferably tert-butyl methyl ether. Then the separated aqueous phase is acidified with HCl to a pH value between 1.2 and 7, preferably to a pH between 3 and 5. If the separated aqueous phase is acidified with HCl under pH 1.2, the hydrochloride salt of irbesartan is obtained, which can also be prepared by carrying out the isolation from the reaction mixture according to processes described in SI P-200400220 or SI P-200400292. Alternatively, the hydrochloride salt of irbesartan can also be obtained in such a manner that the separated aqueous phase is not acidified, but directly poured into an aqueous HCl solution with pH value under 1.2.

If the separated aqueous phase is acidified with HCl to a pH value between 1.2 and 7, preferably to a pH between 3 and 5, the crude irbesartan, which precipitated from water, may be further filtered off or extracted into an organic solvent. It is extracted with an organic solvent in which irbesartan is soluble and which is not miscible with water, such as methylene chloride. The organic phase is washed with water, dried with a suitable drying agent and evaporated to a solid residue in order to obtain crude irbesartan.

The yield of the complete irbesartan synthesis from 5-(4~(bromomethyl)biphenyl-2- yl)-l-(triphenylmethyl)tetrazole according to this process is above 95 %.

The crude irbesartan may be additionally recrystallized. Processes for crystallization of irbesartan are described in the patent literature such as in EP 0454511, EP 0708103, WO 99/67236 or WO 03/050110.

It can be recrystallized from solvents such as alcohols e.g. methanol, ethanol, isopropanol, w-propanol, butanol, isobutanol, tert-butanol; DMF, DMSO, dioxan, THF, 3-pentanone, 2-butanone, 4-methyl-2-pentanone or combinations of these solvents with water.

From irbesartan synthesized according to the present invention, there can be further prepared its pharmaceutically acceptable salts. They can 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. As a pharmaceutically acceptable salt according to this invention preferably hydrochloride is mentioned, which can also be prepared in such a manner that the isolation from the reaction mixture is carried out according to the processes described in SI P-200400220 or SI P-200400292.

Irbesartan hydrochloride can also be prepared in such a manner that a basic salt of irbesartan or a solution of this salt in water or some other polar solvent is acidified with HCl to a pH under 1.2; an irbesartan solution in an organic solvent or a mixture of an organic solvent and water is acidified with HCl to a pH under 1.2. a solution of a basic salt of irbesartan is poured directly into an aqueous HCl solution with pH value under 1.2.

Irbesartan hydrochloride can optionally be recrystallized from organic solvents such as ketones, esters, alcohols or nitriles under the addition of HCl. The particle size of irbesartan hydrochloride, in sesquihydrate form as well as in anhydrous form, was measured by means of laser diffraction on Malvern-Mastersizer Apparatus MS 2000. The average diameter of particles was from 10 to 150 microns.

X-ray powder diffractograms of trityl irbesartan were recorded with diffractometer Phillips PW3040/60 X'Pert PRO; CuK₀₆ radiation 0.1541874 nm.

Herein the following abbreviated terms are used: "m" relates to a strong relative intensity from 30 to 100 % and "s" relates to medium relative intensity from 10 to 30 %.

Trityl irbesartan is characterized by the following data:

A typical x-ray powder diffractogram is represented by the following 2-theta values accompanied by the intensities: 2Θ(°) (± 0.1) Intensity

6.47 m

8.14 m

11.14 S

12.03 S

13.51 m

15.71 S

19.00 m

20.87 m

23.13 m

27.95 S

28.93 S

Preferably trityl irbesartan is characterized by the following degrees 2-theta: 6.47; 8.14; 13.51; 19.00; 20.87; 23.13 ± 0.1.

The DSC curve of crystal trityl irbesartan was recorded by means of differential scanning calorimeter DSC 822 Mettler Toledo. Samples with a weight of about 3 mg were recorded with a heating rate of 10 °C/min in nitrogen atmosphere and in open aluminum pots. The onset temperature was measured at about 148°C. The onset temperature means the beginning of the endothermal change of melting, which means that the beginning of the melting interval (melting point) of crystal trityl irbesartan is at this temperature.

The present invention is illustrated but in no way limited by the following examples. EXAMPLES

Example 1

Into a flask there were weighed 2-n-butyl-4-cyclopentane-2-imidazolin-5-one hydrochloride (0.83 g, 3.6 mmole), acetonitrile (15 ml), 5-(4-(bromomethyl)biρhenyl- 2-yl)-l-(tiϊphenylmethyl)tetrazole (1.84 g, 2.94 mmole), IM tetrabutylammonium bromide (in acetonitrile) (1.3 ml) and crushed KOH (1.1 g, 20 mmole). The mixture was stirred at 40⁰C in an inert atmosphere for 2.5 hours. The conversion of the starting compound 5-(4-(bromomethyl)biρhenyl-2-yl)-l-(triphenylmethyl)tetrazole to trityl irbesartan was 96 %. The mixture was cooled, evaporated and methanol (17 ml) and crushed KOH (0.33 g, 5.9 mmole) were added. The reaction mixture was refluxed for 2.5 hours and then again evaporated. The conversion to irbesartan was practically 100 %. Water (17 ml) and tert-butyl methyl ether (50 ml) were added, it was stirred and the phases were separated. The aqueous phase was again extracted with 50 ml of tert-butyl methyl ether and then the aqueous phase was acidified with 2 M HCl to pH = 4.5. The suspension was cooled to 5⁰C and the precipitate was filtered off. 1.34 g (96 %) of crude irbesartan were obtained.

Example 2

Into a flask there were added 2-n-butyl-4-cyclopentane-2-imidazolin-5-one hydrochloride (0.79 g, 3.4 mmole), acetonitrile (15 ml), 5-(4-(bromomethyl)biphenyl- 2-yl)-l-(triphenylmethyl)tetrazole (1.84 g, 2.94 mmole), tetrabutylammonium bromide (0.31 g) and crushed KOH (1.32 g, 23.5 mmole). The mixture was stirred at 31⁰C in an inert atmosphere for 2.5 hours. The conversion of the starting compound 5-(4-(bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole to trityl irbesartan was 95 %. The mixture was cooled, evaporated and methanol (17 ml) and crashed KOH (0.33 g, 5.9 mmole) were added. The reaction mixture was refluxed for 2.5 hours and then again evaporated. The conversion to irbesartan was practically 100 %. Water (17 ml) and tert-butyl methyl ether (50 ml) were added, it was stirred and the phases were separated. The aqueous phase was again extracted with 50 ml of tert- butyl methyl ether and then the aqueous phase was acidified with 2 M HCl to pH = 2. Methylene chloride (40 ml) was added, the mixture was stirred and separated. The aqueous phase was again extracted with 10 ml of methylene chloride. The combined organic phases were washed twice with water (20 ml), dried with Na₂SO₄ and evaporated to dryness. 1.4 g (96 %) of crude irbesartan were obtained.

Example 3

Irbesartan (2 g) was suspended at room temperature in water (20 ml) and methanol (2 ml) was added. Then the suspension was acidified with 2M HCl to pH 1.03. The mixture was heated under reflux for 10 minutes, stirred at room temperature for one hour and on ice for 30 minutes. The precipitate was filtered off and the product was dried in a vacuum dryer at 5O⁰C for one hour. 2.25 g of sesquihydrate hydrochloride salt of irbesartan were isolated.

Example 4

Into a flask there were added trityl irbesartan (11.5 g, 17.1 mmole), methanol (140 ml) and crushed KOH (3.07 g, 54.8 mmole). The reaction mixture was refluxed for 2.5 hours and evaporated, and water (170 ml) and tert-butyl methyl ether (170 ml) were added. The phases were stirred, separated and the organic phase was discarded. The aqueous phase was acidified with 1 M HCl to pH = 0.99. The precipitate was stirred at room temperature for 4 hours and then filtered off. 7.55 g (90 %) of crude irbesartan hydrochloride sesquihydrate were obtained. Example 5: Recrystallization of irbesartan hydrochloride sesquihydrate.

Irbesartan hydrochloride sesquihydrate (7.4 g) was dissolved at an elevated temperature in 18 ml of a mixture ethyl methyl ketone/3M HCl (10: 1). The mixture was then cooled and stirred at room temperature for 1 hour and at 0⁰C for 30 minutes. The precipitate was filtered off and dried at 40⁰C for 2 hours. 5.3 g (75 %) of irbesartan hydrochloride sesquihydrate were obtained.

Example 6

Trityl irbesartan (28 g) was dissolved in DMF (25 ml) at an elevated temperature. The mixture was cooled to room temperature and then the formed suspension was stirred for 30 minutes on ice. The obtained product was filtered off and washed with fresh DMF. 26 g (93 %) of the product were obtained.

Claims

1. A process for the preparation of irbesartan or its pharmaceutically acceptable salts, characterized in that the following steps are carried out: a) a synthesis of trityl irbesartan by a reaction between 5-(4- (bromomethyl)biphenyl-2-yl)~ 1 -(triphenylmethyl)tetrazole and 2-«-butyl-4- cyclopentane-2-imidazolin-5-one or a salt thereof in an organic solvent in the presence of a phase transfer catalyst and a base, b) a removal of the protecting group of the formed trityl irbesartan in an organic solvent and c) an isolation of irbesartan or its pharmaceutically acceptable salts.

2. A process of the removal of the protecting group of trityl irbesartan, characterized in that the reaction is carried out in an alcohol with an addition of a mineral base and at an elevated temperature.

3. A process according to claim Ia), characterized in that the phase transfer catalyst is a tetraalkylammonium salt, crown ether, cryptand, tris(3,6-dioxaheptyl)amine or pyridyl sulfoxide.

4. A process according to claim 3, characterized in that the catalyst is preferably tetrabutylammonium bromide.

5. A process according to claim Ia), characterized in that the organic solvent wherein the reaction is perfomed is a water-miscible solvent such as DMSO, DMF, DMA or nitriles.

6. A process according to claim 5, characterized in that the organic solvent is preferably acetonitrile.

7. A process according to claim Ia), characterized in that the reaction takes place at a temperature from 15⁰C to the reflux temperature of the solvent.

8. A process according to claim 7, characterized in that the reaction takes place preferably at a temperature between 25⁰C and 45⁰C.

9. A process according to claim Ia), characterized in that as the base alkali metal hydroxides are used.

10. A process according to claim 9, characterized in that the base is preferably KOH.

11. A process according to claim Ia), characterized in that 5-(4- (bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole of a lower purity grade, preferably above 80 % is used.

12. A process according to claim Ib) and 2, characterized in that the base is KOH, NaOH or LiOH and as the alcohol methanol, ethanol, isopropanol, propanol or butanol is used.

13. A process according to claim 12, characterized in that the base is preferably KOH.

14. A process according to claim 12, characterized in that as the alcohol preferably methanol is used.

15. A process according to claim Ib) and 2, characterized in that the reaction takes place at an elevated temperature, between room temperature and the reflux temperature of the solvent.

16. A process according to claim 15, characterized in that the reaction takes place preferably at the reflux temperature of the solvent.

17. A process according to claim Ic), characterized in that the isolated irbesartan is in any form, as an polymorph, a hydrate or a salt.

18. An isolation process according to claim Ic), characterized in that after the evaporation of the reaction mixture water is added to the residue and the aqueous phase is extracted with an organic solvent that is poorly or not at all miscible with water.

19. A 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 extraction.

20. A process according to claim 19, characterized in that preferably tert-butyl methyl ether is used for extraction.

21. A process according to claim 18, characterized in that the separated aqueous phase is acidified with HCl to a pH value between 1.2 and 7, preferably to a pH between 3 and 5.

22. A process according to claim 18, characterized in that the separated aqueous phase is acidified with HCl to a pH value under pH 1.2 and a hydrochloride salt of irbesartan is isolated.

23. A process according to claim 18, characterized in that the separated aqueous phase of irbesartan is poured directly into an aqueous HCl solution with pH value under 1.2.

24. A process according to claim 21, characterized in that the crude irbesartan precipitated from water is further filtered off or extracted into a suitable organic solvent wherein irbesartan is soluble and which is not miscible with water.

25. A process according to claim 24, characterized in that methylene chloride is used as the solvent for extraction.

26. A process according to claim 24, characterized in that the organic phase is washed with water, dried with a suitable drying agent and evaporated to a solid residue to obtain crude irbesartan.

27. A process according to claim 24, characterized in that after extraction the organic phase is acidified with HCl to a pH value under 1.2 and irbesartan hydrochloride salt is isolated.

28. A process according to claim 24, characterized in that the filtered-off precipitated irbesartan is recrystallized from solvents such as alcohols such as methanol, ethanol, isopropanol, «-propanol, butanol, isobutanol, tert-butanol; DMF, DMSO, dioxan, THF, 3-pentanone, 2-butanone, 4-methyl-2-pentanone, or combinations of these solvents with water.

29. A process according to claim 18, characterized in that a basic salt of irbesartan or a solution of this salt in water or an organic solvent or a mixture of both is acidified to a pH value under 1.2 and irbesartan hydrochloride salt is isolated.

30. Solid trityl irbesartan, characterized by the temperature of the melting point of about 148°C.

31. Solid trityl irbesartan, characterized by an onset temperature at about 148°C.

32. Solid trityl irbesartan, characterized by an x-ray powder diffractogram with peaks at 6.47; 8.14; 11.14; 12.03; 13.51; 15.71; 19.00; 20.87; 23.13; 27.95; 28.93 ± 0.1 degrees 2-theta.

33. Solid trityl irbesartan according to claim 32, preferably characterized by x-ray powder diffractogram with peaks at 6.47; 8.14; 13.51; 19.00; 20.87; 23.13 ± 0.1 degrees 2-theta.

34. Use of trityl irbesartan for the preparation of irbesartan hydrochloride.

35. A process for the preparation of irbesartan hydrochloride, characterized in that a solution of an alkaline salt of irbesartan is acidified to a pH under 1.2.

36. A process for the preparation of irbesartan hydrochloride, characterized in that a solution of a basic salt of irbesartan in poured directly into an aqueous HCl solution with pH value under 1.2.