WO2010015623A1

WO2010015623A1 - Process for the preparation of endothelin receptor antagonists

Info

Publication number: WO2010015623A1
Application number: PCT/EP2009/060085
Authority: WO
Inventors: Elena García García; Jordi Bessa Bellmunt
Original assignee: Farmaprojects, S. A.
Priority date: 2008-08-05
Filing date: 2009-08-04
Publication date: 2010-02-11

Abstract

The present invention relates to a process for the preparation of endothelin receptor antagonists, in particular bosentan, in which a compound of formula (II) reacts with an alkylating agent X-R formula (II), wherein R is either -CH₂CH₂OH or a group that can be transformed into - CH₂CH₂OH; X is a leaving group; and R₂is a 4-terf-butylbenzenesulfonamido group or a group that can be transformed into 4-terf-butylbenzenesulfonamido group; and further transforming the resulting product into bosentan. Useful intermediates are disclosed, its use for the preparation of bosentan, as well as pharmaceutical compositions comprising the product obtained by the above process.

Description

Title of invention: Process for the preparation of endothelin receptor antagonists.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of endothelin receptor antagonists, in particular bosentan. It also relates to processes for the preparation of pharmaceutical compositions, intermediates useful for the preparation of bosentan and its use.

BACKGROUND OF THE INVENTION

Bosentan is the first drug marketed of a new class of antihypertensive agents known as endothelin receptor antagonists. Bosentan belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. Its chemical name is 4-tert- butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidin-4-yl]- benzenesulfonami-de monohydrate and has the following structural formula:

Bosentan was initially developed for the treatment of hypertension, but the clinical development was redirected to the treatment of pulmonary hypertension.

Bosentan was first disclosed in EP526708-A1. The preparation disclosed therein involved the coupling of 4-te/f-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyrimidin- 2-yl)-pyrimidin-4-yl]-benzenesulphonamide and sodium ethylene glycolate in ethylene glycol as a solvent at 100 ⁰C as summarized in Scheme 1.

4-te/f-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-pyrimidin-2-yl)-pyrimidin-4-yl]-ben- zenesulfonamide was prepared starting from pyrimidine-2-carboxamidine hydrochloride via rac-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)tetrahydro-pyrimidine- 4,6-dione and 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine.

To avoid the formation of 1 ,2-diheteroethylene bis-sulfonamides, in WO2001055120 a variation of the final step was performed by using, instead of sodium ethylene glycol, a monoprotected ethylene glycol, such as (mono) te/f-butyl ether protected ethylene glycol (Scheme 2). After coupling te/f-butyl ether protected ethylene glycol with the 6-chloro intermediate (monohalide 2), te/f-butyl group is hydrolyzed with formic acid to obtain a formyl derivative, which is removed with NaOH to yield bosentan.

Scheme 2

tBuOCH₂CH₂ONa

According to WO2001055120, pyrimidine dihalide (dihalide 3 in Scheme 1 ) and/or pyrimidine monohalide (monohalide 2 in Scheme 1 ) intermediates used in the preparation of bosentan are potent sensitizers.

In WO2001055120 a process for the preparation of ethylene glycol mono-protected sulfonamides is disclosed which includes a process for preparing the pyrimidine monohalide 2 by contacting a pyrimidine dihalide 3 with te/f-butylbenzene- sulfonamide. Pyrimidine dihalide 3 is prepared by contacting pyrimidinedione 4 with a dehydrohalogenating reagent such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxybromide, phosphorus pentabromide, phosphorus tribromide, oxalyl chloride and mixtures thereof. The conversion of pyrimidinedione 4 to pyrimidine dihalide 3 using a dehydrohalogenating agent is carried out at an elevated temperature. Although the reaction can be conducted in any solvent which is substantially inert to the reaction conditions, typically the reaction is conducted in the absence of a solvent. After a sufficient amount of the pyrimidine dihalide 3 is formed, the reaction mixture is diluted with a solvent which has a boiling point of at least 80 ⁰C. The resulting reaction mixture is then quenched to destroy any remaining dehydrohalogenating agent. The quenching agent is any compound which reacts with the dehydrohalogenating agent without significantly reacting with pyrimidinedione 4 and/or pyrimidine dihalide 3. Preferably the quenching agent is selected from an alcohol, water and mixtures thereof. More preferably the quenching agent is water. The quenching agent can also contain a base to neutralize any acid that may be formed during the quenching step. Any base which can neutralize the acid that is formed in the quenching step can be used. Preferably the base is a hydroxide, and more preferably sodium hydroxide. When a phosphorus compound is used as the dehydrohalogenating agent, phosphorus by-products are produced during the quenching step. Phosphorus by-products are not desirable from an environmental point of view,and produce waste waters which have to be treated. Furthermore, due to the high molecular weight of phosphorous derivatives they are produced in huge amounts, which makes it difficult to remove them from the reaction media. Dehydrohalogenating agents, such as POCI3 (phosphorous oxichloride), PCI5 (phosphorus pentachloride) or PCI3 (phosphorus trichloride) are very toxic reagents, react violently with water and are a source of both hydrogen chloride and chlorine.

The presence of pyrimidinone compound (1 ) and 1 ,2-diheteroethylene bis- sulfonamides as impurities of the processes of the prior art is disclosed in Harrington, PJ. et al., Organic Process Research & Development 2002, VoI 6, No. 2, 120-124 as compounds (12) and (13).

SUMMARY OF THE INVENTION

The problem to be solved by the present invention is to provide an efficient alternative process for preparing bosentan. The solution is based on the fact that the present inventors have identified a simplified process for preparing bosentan, which provides bosentan with high purity, avoids the use intermediates which are potent sensitizers such as pyrimidine dihalide (dihalide 3), avoids or greatly reduces the presence of pyrimidinone compound (1 ) and 1 ,2-diheteroethylene bis- sulfonamides as impurities and provides an efficient and cost-effective process for preparing bosentan and its intermediates, which would be susceptible of use on an industrial scale.

The solution is based on a process for the preparation of a compound of formula (I), a solvate, including hydrates, or a pharmaceutically acceptable salt thereof

wherein R₁ is either -CH₂CH₂OH or a group that can be transformed into -CH₂CH₂OH; comprising the reaction of a compound of formula (II), or a salt thereof, with an alkylating agent X-R

wherein R is Ri or a group that can be transformed into Ri; X is a leaving group; and R₂ is a 4-te/f-butylbenzenesulfonamido group or a group that can be transformed into 4-te/f-butylbenzenesulfonamido group;

and if desired, in any order, further transforming R into R-i; Ri into -CH₂CH₂OH; and/or R₂ into a 4-te/f-butylbenzenesulfonamido group.

According to a second aspect, the invention relates to a process for the preparation of pharmaceutical composition comprising mixing bosentan prepared according to the first aspect of the invention and pharmaceutically acceptable excipients.

According to a third aspect, the invention relates to compounds of formula (Na)

wherein R₂ is -OR₃, -NR₄R₅, -NR₄SO₂Ar, -NR₄SAr, N-comprising leaving group, or halogen;

R₃ is R₉, -COOR9, -COR₉, -SO₂R₉, or -C(=NR₆)NR₇R₈; R₄ and R₅ are independently hydrogen or R₉; R₆, R₇, Re are independently hydrogen or R₉;

R₉ is a C1-C7 alkyl group, benzyl group or an aryl group, optionally substituted; Ar is an aryl group, optionally substituted; which are useful in the preparation of bosentan.

According to a fourth aspect, the invention relates to the use of compounds of formula (Na) as intermediates for the preparation of bosentan.

Definitions

In the present invention bosentan is to be understood as a 4-te/f-butyl-N-[6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidin-4-yl]- benzenesulfonamide, its solvates, including hydrates, and salts thereof, preferably bosentan monohydrate.

In the present invention a nitrogen-comprising leaving group could include diazonium salts, triazole groups, quaternary ammonium salts and others well known equivalents.

In the present invention a C1-C7 alkyl group is to be understood as being a linear or branched alkyl group which contains up to 7 carbon atoms. Thus it comprises, for instance, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, te/f-butyl, n- pentyl, 1 ,2-dimethyl propyl, 1 ,1-dimethyl propyl, 2,2-dimethyl propyl, 2-ethyl propyl, n-hexyl, 1 ,2-dimethyl butyl, 2,3-dimethyl butyl, 1 ,3-dimethylbutyl, 1 -ethyl-2- methylpropyl, and 1-methyl-2-ethyl propyl groups.

In the present invention aryl group is to be understood as an aromatic carbon-based group such as a phenyl or naphthyl group or an aromatic heterocyclic group such as a thienyl or furyl group, optionally substituted.

In the present invention leaving group X is to be understood as a detachable group in the reaction conditions. The leaving group could comprise an atom of Cl, Br, I, a methanesulfonyloxy, toluensulfonyloxy, benzenesulfonyloxy or trifluoromethanesulfo-nyloxy group. Preferably X is an atom of Cl, Br, I, or a trifluoromethanesulfonyloxy group. In the present invention a group that can be transformed into 4-tert- butylbenzenesulfonamido group is to be understood such as a group that can be converted into this group after some synthetic steps and includes without limitation: -OR₃, -NR₄R₅, -NR₄SO₂Ar, -NR₄SAr, N-comprising leaving group, or halogen; wherein R₃ is hydrogen, R₉, -COOR₉, -COR₉, -SO₂R₉, or -C(=NR₆)NR₇R₈; R₄ and R₅ are independently hydrogen or R₉; R₆, R₇, Re are independently hydrogen or R₉;

R₉ is a C1-C7 alkyl group, benzyl group or an aryl group, optionally substituted; Ar is an aryl group, optionally substituted.

In the present invention a phase transfer catalyst is to be understood as a catalyst or agent which is added to a reaction mixture of components, to transfer one or more of the reacting components to a location where it can conveniently and rapidly react with another reacting component. Non-limiting examples of phase transfer catalysts or agents that may be employed are reviewed in "Phase-Transfer Catalysis" by CM. Starks et al., Chapman & Hall, New York. N.Y., 1994, which is incorporated herein by reference in its entirety.

In the present invention a base could include organic and inorganic bases such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, triethylamine and others well known equivalents.

In the present invention a group that can be transformed into OH or hydroxyl could include alcohols protected with alcohol protecting groups, halides, methanesulfonyloxy, toluensulfonyloxy, benzenesulfonyloxy or trifluoromethanesulfo-nyloxy group.

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

The first aspect of the invention involves the reaction of compound of formula (II) with an alkylating agent (X-R). Compounds of formula (lib), wherein R₂ is 4-tert- butylbenzenesulfonamido group could be obtained from their corresponding chlorides (some of them known from the cited prior art, but also from other halides or other leaving groups not containing halogen) of formula (lie) through hydrolysis in acid or basic media. Hydrolysis can take place for example using common bases such as sodium hydroxide, potassium carbonate or other bases such as DABCO (1 ,4-diazabicyclo[2.2.2]octane) in water, mixtures of water and tetrahydrofuran (THF) or mixtures of water and dioxane.

Compounds of formula (lib) could also be prepared from compound of formula (Nd) with activation of hydroxyl group (by conversion to a leaving group, carbonate, anhydride, DCC, CDIm or similar) and substitution with the sulfonamide ArSO₂NH₂ or a salt thereof. If this displacement is carried out with NH₃, the amine derivative of formula (lie) can be obtained and transformed into a compound of formula (lib) via the reaction with a sulfonyl chloride. The examples of the scheme below, Scheme 3, refer to transformations of R₂ into 4-te/f-butylbenzenesulfonamido group prior to the alkylation step. With analogous reactions, R2 could be transformed into 4-te/f- butylbenzenesulfonamido group after the alkylation reaction to yield compound of formula (I).

Compound of formula (Na), wherein R₂ is halogen could be obtained by reacting pyrimidinedione 4 with less than half of the amount of the dehydrohalogenating agents, such as POCI3 (phosphorous oxichloride), PCI5 (phosphorus pentachloride) or PCI3 (phosphorus trichloride), used to convert both dione groups into halide.

Scheme 3

(lie)

In a preferred embodiment of the first aspect of the invention, R₂ is selected from the group consisting of -OR₃, -NR₄R₅, -NR₄SO₂Ar, -NR₄SAr and N-comprising leaving group; wherein R₃ is hydrogen, R₉, -COOR₉, -COR₉ Or -SO₂R₉, -C(=NR₆)NR₇R₈; R₄ and R₅ are independently hydrogen or R₉; R₆, R₇, Re are independently hydrogen or R₉;

This embodiment is greatly advantageous since it avoids the use of pyrimidine dihalide (dihalide 3 in Scheme 1 ) and/or pyrimidine monohalide (monohalide 2 in Scheme 1 ) intermediates in the preparation of bosentan which, according to the prior art, are potent sensitizers. Furthermore, the use of the hazardous dehydrohalogenating agents, such as POCI3 (phosphorous oxichloride), PCI5 (phosphorus pentachloride) or PCI3 (phosphorus trichloride) is avoided, which greatly improves the safety and environmental characteristics of the process.

Preferably R₂ is -NHSO₂Ar, and more preferably 4-te/f-butylbenzenesulfonamido group.

In a preferred embodiment the alkylating agent X-R is XCH₂CH₂Y, and Y is OH or a group that can be transformed into OH. This facilitates the transformation of Ri into -CH₂CH₂OH (present in bosentan) as few synthetic steps are needed. More preferably X and Y taken together form a ring and more preferably are -OS(O)O-, - OS(O)₂O- or -0-. With these values of X and Y, specially when, X and Y are - OS(O)O- or -OS(O)₂O-, in the same step of the alkylation, R₁ is transformed into - CH₂CH₂OH without the need of any deprotection step, contrary to the process described in WO2001055120, where a complex deprotection in two steps is needed. Furthermore, the alkylating agent can be used in stoichiometric amounts, contrary to the last steps of introduction of the ethylene glycol moiety in EP526708, where the reaction was carried out in ethyleneglycol (great excess) or in WO2001055120, where the monoprotected ethyleneglycol was added in 3:1 ratio to the last intermediate. Preferably, in the processes of the above embodiments, the reaction is carried out in the presence of a base. More preferably the reaction takes place in a solvent system comprising an organic solvent. In a further preferred embodiment, the alkylation reaction takes place in the presence of a phase transfer catalyst. Preferably, the reaction is carried out between about 50 ⁰C to 100 ⁰C and, also preferably, the compound of formula (I) is bosentan.

In a preferred embodiment of the third aspect, the invention relates to compounds of formula (Na')

wherein R₂ is -OR₃, -NR₄R₅, N-comprising leaving group, -NR₄SO₂Ar Or -NR₄SAr; R₃ is R₉, -COOR₉, -COR₉, -SO₂R₉, or -C(=NR₆)NR₇R₈; R₄ and R₅ are independently hydrogen or R₉; R₆, R7, Re are independently hydrogen or R₉;

These intermediates are specially advantageous since the use of pyrimidine dihalide (dihalide 3 in Scheme 1 ) and/or pyrimidine monohalide (monohalide 2 in Scheme 1 ) intermediates is avoided in the preparation of bosentan which, according to the prior art, are potent sensitizers. Furthermore, the use of the hazardous dehydrohalogenating agents, such as POCI3 (phosphorous oxichloride), PCI5

(phosphorus pentachloride) or PCI3 (phosphorus trichloride) could be avoided by using these intermediates, which greatly improves the safety and environmental characteristics of the process.

Bosentan and the hydrates thereof, particularly bosentan monohydrate, are useful for the preparation of pharmaceutical compositions. A person skilled in the art could easily determine the particle size distribution of bosentan monohydrate for a certain pharmaceutical composition in order to obtain a suitable drug release profile, suitable handling properties during the manufacturing process and an acceptable drug product stability profile. The desired release profile could be similar to that of the product already marketed under the brand name Tracleer ® in the form of tablets, or to that of a modified release product. To obtain a larger particle size, common techniques such as controlled recrystallization can be used and to obtain smaller particles common techniques could be used such as milling, micronization and the like. Many particle size distributions would be suitable for the manufacture of pharmaceutical compositions. The particle size of bosentan monohydrate obtained in example 1 could thus be adjusted as described above and/or using other known conventional techniques to obtain the desired particle size.

Bosentan monohydrate having a mean particle size from 4 microns to 100 microns, for instance about 10 microns, could be suitable. D50 values could be from 4 to 100 microns, for example 10 microns. D90 could be from 5 to 150 microns. Other values are possible for all parameters. In particular mean particle sizes of 20, 40, 60, 80 and 100 microns could also be suitable as well as D90 below 20, 40, 60, 80, 100 or 150 microns. The relation between solubility, stability and other parameters in relation to particle size are well known for the skilled person.

Bosentan and hydrates thereof, particularly bosentan monohydrate, can be used for preparing pharmaceutical compositions including oral and parenteral compositions. Crystalline and amorphous forms could be used to this end. Crystalline forms are preferred for many uses.

Parenteral compositions include injections or infusions to be administered intravenously. These preparations could be prepared by freeze-drying aqueous solutions containing bosentan, preferably in one of its salt forms.

Oral compositions could be prepared for example in the form of capsules, granules, pellets or tablets, preferably film-coated tablets. The person skilled in the art could easily adapt pharmaceutical compositions developed for other products to bosentan compositions, taking into account its properties. Film-coated tablets are the preferred oral dosage form. Tablet cores could be obtained by direct compression or by granulation, using either wet or dry granulation, including both aqueous and non- aqueous wet granulation techniques, well known in the art, of bosentan or its salts or hydrates, particularly bosentan monohydrate, together with pharmaceutically acceptable excipients.

The following are examples of wet granulation. Percentages relate to the weight of the final film-coated tablet.

Bosentan monohydrate (10-70 % w/w), maize starch (5-80 % w/w), pregelatinised starch (1-30 % w/w), sodium starch glycolate (0.2-20% w/w) and optionally 0.2-3 % w/w of glycerol dibehenate were blended in a fluidized air bed (FAB). 0.5-15 % of povidone dissolved in water (alternatively in water/alcohol mixtures) was added to the mixture by spraying it onto the mixture. After that, the granulate was dried for at 60 ⁰C until a suitable water content is obtained. Then, the granulate was mixed glycerol dibehenate (0.1-5 % w/w) and magnesium stearate (0.3-5 % w/w), blended and the mixture was compressed to form tablets using a rotary tabletting machine.

Tablets were then film coated using conventional drum coating equipment with an aqueous suspension (alternatively with an organic solvent such as an alcohol or acetone or mixtures thereof with water) of the film coating comprising hydroxypropyl methylcellulose (0.2-10 % w/w), ethylcellulose (0.2-10 % w/w), glycerol triacetate, talc, titanium dioxide (E171 ), iron oxide yellow (E172) and iron oxide red (E172).

The following is another example of wet granulation. Bosentan monohydrate (10-70 % w/w), maize starch (5-80 % w/w), pregelatinised starch (1-30 % w/w), sodium starch glycolate (0.2-20% w/w) and povidone (0.5-15 %) were dry blended. Water was sprayed into the blend and the mixture kneaded to granules in a high shear granulator. After that, the granulate was dried until a suitable water content is obtained, sieved and mixed with glycerol dibehenate (0.1-5 % w/w) and magnesium stearate (0.3-5 % w/w), blended and the mixture was compressed to form tablets using a rotary tabletting machine. Tablets were then film coated as in the previous example.

The following is another example of wet granulation. 64.5 g of bosentan monohydrate, 50 g of maize Storch, 10 g of pregelatinised starch, 8 g of sodium starch glycolate and 10 g of povidone were dry blended. Water was sprayed into the blend and the mixture kneaded to granules in a high shear granulator. After that, the granulate was dried until a suitable water content is obtained, sieved and mixed with 4 g of glycerol dibehenate and 4 g of magnesium stearate, blended and the mixture was compressed to form tablets using a rotary tabletting machine. Tablets were then film coated as in the previous example.

Alternatively, bosentan monohydrate could be prepared by direct compression using the same excipients or other fillers such as microcrystalline cellulose, mannitol, lactose or isomalt and conventional excipients such as binders, disintegrants, lubricants, glidants or in the absence of some of them if not needed.

Also alternatively, bosentan monohydrate could be prepared by dry granulation techniques known in the art, using the same excipients or other fillers such as microcrystalline cellulose, mannitol or isomalt and conventional excipients such as binders, disintegrants, lubricants, glidants or in the absence of some of them if not needed.

The purification of all intermediates and final products by methods known in the art should be considered as included in the scope of the invention. One of the standard purification methods is the preparation of intermediates in its solid state, preferably in crystalline form by conventional crystallisation and recrystallisation techniques using solvents that a person skilled in the art considers to be the most suitable.

Throughout the description and claims the word "comprise" and variations of the word, such as "comprising", are not intended to exclude other technical features, additives, components or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

EXAMPLES Example 1 : Preparation of 4-tert-butyl-N-(6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide, Bosentan by coupling with ethylene sulphite.

To a mixture of 0.98 g (1.93 mmol) of 4-tert-butyl-N-(6-hydroxy-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide (lib), 0.30 g (2.15 mmol) of K2CO3 and 30 mg (0.09 mmol) of tetrabutylammonium bromide in 5 ml. of methylethylketone was added 0.18 ml. (2.33 mmol, 1.2 equiv) of ethylene sulphite. The suspension was heated to reflux and stirred until no starting material was observed by TLC. The solvent was eliminated at reduced pressure and the residue dissolved in ethyl acetate. The product was extracted with a solution of NaOH 1 M and the aqueous phase neutralized with acetic acid, extracted to ethyl acetate and washed with NaHCO3 and diluted acetic acid. The organic extracts were dried with anhydrous Na2SO4, filtered and the solvent evaporated under reduced pressure. The product was recrystallised from ethanol/water.

Example 2: Preparation of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)benzenesulfonamide (2) by hydrolysis of chloride (lie)

A suspension of 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4- yl)benzenesulfonamide, (lie) (1.6 g, 3.04 mmol) in 30 ml. of mixture of aqueous sodium hydroxide (1 N) and DMF (1 :1 ) was stirred at reflux until no starting material was observed by TLC (CH2CI2/MeOH/NH3 6:1 :0.1 ). The mixture was poured into ice-water and acidified with 1 N aqueous HCI. The crude is purified by column chromatography through silica gel obtaining the intermediate of formula (lib). 1 H- NMR (CDCI3, 250 MHz): δ 8.88 (d, J=4.85 Hz, 2H), 8.21 (br d, J=7.53 Hz, 2H), 7.42 (t, J=4.85 Hz, 1 H), 7.33 (d, J=8.53 Hz, 2H), 6.96 (m, 3H), 6.71 (t, J=7.9 Hz, 1 H), 3.86 (s, 3H), 1.17 (s, 9H).

Claims

1. A process for the preparation of a compound of formula (I), a solvate, including hydrates, or a pharmaceutically acceptable salt thereof

wherein R is Ri or a group that can be transformed into Ri; X is a leaving group; and

R₂ is a 4-te/f-butylbenzenesulfonamido group or a group that can be transformed into 4-te/f-butylbenzenesulfonamido group;

2. The process according to claim 1 , wherein R₂ is selected from the group consisting of -OR₃, -NR₄R₅, -NR₄SO₂Ar, -NR₄SAr and N-comprising leaving group; wherein R₃ is hydrogen, R₉, -COOR₉, -COR₉ Or -SO₂R₉, -C(=NR₆)NR₇R₈; R₄ and R₅ are independently hydrogen or R₉; R₆, R₇, Re are independently hydrogen or R₉;

3. The process according to claim 1 or 2, wherein R₂ is -NHSO₂Ar, preferably 4-tert- butylbenzenesulfonamido group.

4. The process according to any of the preceding claims, wherein X-R is XCH₂CH₂Y and Y is OH or a group that can be transformed into OH.

5. The process according to claim 4, wherein X and Y taken together form a ring and preferably are -OS(O)O-, -OS(O)₂O- or -0-.

6. The process according to claim 5, wherein X and Y are -OS(O)O- Or -OS(O)₂O-

7. The process according to any of the preceding claims, wherein the reaction is carried out in the presence of a base.

8. The process according to any of the preceding claims, wherein the reaction takes place in a solvent system comprising an organic solvent.

9. The process according to any of the preceding claims, wherein the reaction takes place in the presence of a phase transfer catalyst.

10. The process according to any of the preceding claims, wherein the reaction is carried out between about 50 ⁰C to 100 ⁰C.

1 1. The process according to any of the preceding claims wherein the compound of formula (I) is bosentan.

12. A process for the preparation of pharmaceutical composition comprising mixing bosentan prepared according to claim 1 1 and pharmaceutically acceptable excipients.

13. Compounds of formula (Na)

(Ha)

wherein R₂ is -OR₃, -NR₄R₅, N-comprising leaving group, -NR₄SO₂Ar, -NR₄SAr, or halogen;

R₃ is R₉, -COOR9, -COR₉, -SO₂R₉, or -C(=NR₆)NR₇R₈;

R₄ and R₅ are independently hydrogen or R₉;

R₆, R₇, Re are independently hydrogen or R₉;

14. The compounds of formula (Na) according to claim 13, wherein R₂ is -OR3, - NR₄R₅, N-comprising leaving group, -NR₄SO₂Ar Or -NR₄SAr.

15. The use of compounds of formula (Na) according to claims 13 and 14 as intermediates for the preparation of bosentan.