WO2010012637A1

WO2010012637A1 - Process for the preparation of bosentan

Info

Publication number: WO2010012637A1
Application number: PCT/EP2009/059418
Authority: WO
Inventors: Sergio Rodriguez Ropero; Juan Huguet Clotet
Original assignee: Inke, S.A.
Priority date: 2008-08-01
Filing date: 2009-07-22
Publication date: 2010-02-04

Abstract

The present invention provides a novel process for obtaining Bosentan, with few synthesis steps, by coupling the intermediate pyrimidine derivative of formula I with the sulfonamide derivative of formula II. The use of said process prevents the protection of the hydroxyl group of the sulfonamide II and thus is of considerable interest for obtaining Bosentan in a large industrial scale. The invention also refers to the intermediates of formula II and to a process for its production.

Description

PROCESS FOR THE PREPARATION OF BOSENTAN

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of Bosentan or salts thereof and to intermediates of said process.

BACKGROUND

Bosentan (1) or 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy- phenoxy)-[2,2']-bipyrimidin-4-yl]-benzene-sulfonamide has a wide variety of biological activities. It is marketed as a monohydrate under the tradename Tracleer^®.

Bosentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with World Health Organization (WHO) class III or IV symptoms to improve exercise ability and decrease the rate of clinical worsening. Bosentan is useful in treatment of a variety of illnesses including cardiovascular disorders such as hypertension, ischemia, vasospasms and angina pectoris.

1 Bosentan was first disclosed by the European patent EP 0 526 708 Bl to

Hoffmann La Roche. This patent describes the preparation of Bosentan through formation of the sulfonamide function through two different alternatives: a) condensation of a 4,6-dihalogenopyrimidine (2) and the appropriate benzenesulfonamide or b) condensation of a conveniently substituted amino- pyrimidine (4) and an appropriate benzenesulfohalogenide (see Scheme A).

When Bosentan is prepared according to alternative a) the final step of synthesis comprises the nucleophilic substitution of the halide of the pyrimidine ring (3) with a monoanion of ethylene glycol (typically, sodium ethylene glycol) and using ethylene glycol as a solvent. As known, the use of ethylene glycol as a solvent is unworkable in industrial scale synthesis because of its toxicity and its high boiling point which requires a large amount of time and high energy consumption to remove it by distillation.

Scheme A

European patent EP 1 254 121 Bl provides an improved process for the preparation of Bosentan which avoids the use of ethylene glycol. Moreover, this novel process avoids the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine monohalide (3) are coupled with one molecule of ethylene glycol. The formation of bis-sulfonamide compounds requires costly and laborious separation steps to isolate a pharmaceutically suitable pure ethylene glycol sulfonamide compound. EP 1 254 121 Bl prepares a mono-protected 1 ,2-diheteroethylene substituted sulfonamide of the formula (5), which is isolated by recrystallization :

The removal of the tert-butyi hydroxyl protecting group by means of formic acid produces the 2-(formyloxy)ethoxy derivative (6), which after being concentrated and dried is treated with NaOH to yield Bosentan. Example 5 and 7 of EP 1 254 121 Bl describe the preparation of Bosentan through isolation of ethanol solvate derivative (7). The described process involves the use of protected reagents and deprotection steps, thus increasing the cost of the final product.

EtOH

Scheme B

Therefore, there is a need for a process to prepare Bosentan which overcomes the above mentioned problems.

BRIEF DESCRIPTION OF THE INVENTION

The aim of the present invention is to provide a safe, ecological and high- yield novel process for the preparation of Bosentan and salts thereof which can be applied at an industrial level with low energy and costs.

The authors of the present invention have found that Bosentan can advantageously be prepared in high yield avoiding the use of ethylene glycol in the final step and/or its tert-butoxy monoprotected derivative, the formation of undesired ethylene glycol bis-sulfonamide and the isolation of intermediates such as the 2- (formyloxy)ethoxy derivative (6) or its monoethyl alcohol solvate (7).

Accordingly, a first aspect of the present invention is a process for the preparation of Bosentan or a pharmaceutically salt thereof characterized in that comprises the coupling reaction between a pyrimidine derivative of formula I:

I wherein A means BF3K, B(OH)₂, substituted and unsubstituted cyclic and acyclic boronic esters or SnR₃, wherein R is selected from the group consisting of a linear or branched C₁-C₅ alkyl and a sulfonamide derivative of formula II

wherein Q is a diazonium salt or a halogen and wherein the halogen is preferably selected from Cl, Br and I

A second aspect of the present invention relies on sulfonamide derivatives of formula II or salts thereof.

A third aspect of the present invention is the process for the preparation of the novel sulfonamide derivatives of formula II above.

A fourth aspect of the present invention is the use of the aforementioned sulfonamide derivative of formula II or its salts for the preparation of Bosentan.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the X-Ray Diffraction Pattern of Bosentan monohydrate.

DETAILED DESCRIPTION OF THE INVENTION

In the context of the present invention, the following terms have the meaning detailed below:

The term "palladium catalyst" is taken to mean a compound of palladium, which can be homogeneous and soluble in the reaction medium, such as Pd(PPtLs)₄, PdCl₂(PPh₃)₂, Pd(AcO)₂, Pd₂(dba)₃, PdCl₂(dppf), PdCl₂(CH₃CN)₂, Pd(P^lBu₃)₂ wherein Ac is acetate, Ph is phenyl, dba is dibenzylideneacetone, dppf is 1,1 '- bis(diphenylphosphino)ferrocene, and ¹Bu is tert-butyi or which can be heterogeneous and insoluble in the reaction medium, such as Pd/C.

The term "ligand" is taken to mean an organic compound of the phosphine or amine type capable of coordinating and activating the palladium species which catalyses the desired reaction, such as triphenylphosphine and tή-tert- butylphosphine. The term "linear or branched C1-C5 alkyl" relates to a linear or branched hydrocarbon radical consisting of carbon and hydrogen atoms, which does not contain unsaturation, having one to five carbon atoms and which is joined to the rest of the molecule by a single bond. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl and pentyl. Preferably, the alkyl used is butyl.

According to a first aspect, the present invention is directed to a process for the preparation of Bosentan or a pharmaceutically salt thereof characterized in that it comprises the coupling reaction between a pyrimidine derivative of formula I:

wherein A means BF3K, B(OH)₂, substituted and unsubstituted cyclic and acyclic boronic esters or SnR₃, wherein R is selected from the group consisting of a linear or branched C₁-C₅ alkyl and a sulfonamide derivative of formula II

wherein Q is a diazonium salt or a halogen and wherein the halogen is preferably selected from Cl, Br and I at a temperature comprised between 25⁰C and 200⁰C, in the presence of a palladium catalyst and in a solvent medium.

The inventors have discovered that the coupling reaction between the pyrimidines of formula I and the sulfonamides of formula II proceeds without the need to protect the hydroxyl functionality of the compound of formula II and directly yields Bosentan. These findings provide Bosentan in good yield and purity.

The coupling reaction between said compounds I and II is performed by the use of a palladium catalyst. It will be immediately apparent to the skilled person that a wide range of palladium based catalysts are suitable for this reaction. The hetereoaromatic coupling between aromatic boronic acids, esters and salts derivatives and aromatic electrophiles is commonly known by those skilled in the art as Suzuki and related reactions. The hetereoaromatic coupling between aromatic trialkyl tin derivatives and aromatic electrophiles is commonly known by those skilled in the art as Stille reaction.

In a preferred embodiment, the coupling reaction is of the Stille type. The coupling reaction is performed between compounds of formula I wherein A is SnR₃ and sulfonamides of formula II wherein Q is a halogen selected from Cl, Br and I. Preferably, the coupling reaction is performed between compounds of formula I wherein A is SnBu₃ and compounds of formula II wherein Q is Br or I. The palladium based catalyst is used in less than stechiometric amounts for economic and environmental reasons, but it is readily obvious to the skilled person that the process of the invention will also proceed by adding stechiometric amounts of the palladium based catalyst or excess of the same.

The reaction may proceed in homogenous and heterogeneous phase.

When the reaction is performed under homogeneous conditions, preferred catalysts are selected from the group consisting of Pd(PPh₃)₄, PdCl₂(PPh₃)₂,

Pd(AcO)₂, Pd₂(dba)₃, PdCl₂(dppf), PdCl₂(CH₃CN)₂ and Pd[P¹Bu₃K wherein Ac is acetate, Ph is phenyl, dba is dibenzylideneacetone, dppf is 1,1 '- bis(diphenylphosphino)ferrocene and ¹Bu is tert-butyl.

According to a preferred embodiment, the process of the invention is carried out in the presence of a ligand, being said ligand preferably phosphines when Pd(AcO)₂ and Pd₂(dba)₃ are used. Many phosphines may be found in the art. The election of the most suitable phosphine is a matter of routine experimentation for the skilled person and fine-tunes parameters of the reaction such as the yield, the speed or the turn over of the catalyst. According to a preferred embodiment, the reaction is carried out in the presence of triphenylphosphine or tri-te/t-butylphosphine.

Usual heterogeneous catalysts are Pd over active carbon (Pd/C) and Pd encapsulated in organic resins or inorganic ceramics.

The reaction may proceed in the presence of a solvent medium which comprises a wide variety of organic solvents and/or water. For example, polar solvents such as N,N-dimethylformamide (DMF), acetonitrile, dimethylacetamide (DMA), ethers such as 1 ,2-dimethoxyethane (DME), diethoxymethane (DEM), tetrahydrofuran (THF), dioxane; aromatic solvents such as toluene or xylene; or alcohols like methanol, ethanol, propanol or mixtures thereof. Election of the most suitable solvent requires only routine experimentation for the skilled person.

Optionally, the process of the invention may be carried out in the presence of organic bases such as tertiary amines, like triethyl amine (TEA) or N₅N- diisopropylethylamine (DIPEA), or alkaline or alkaline-earth acetates (e.g. sodium acetate); or other ammonia derivatives in which one or more hydrogen have been substituted by alkyl or aryl radicals such as ethyl, isopropyl, benzyl, phenyl or pyridine. The process of the invention may be also carried out in the presence of inorganic bases such as carbonates (e.g. sodium carbonate, potassium carbonate, cesium carbonate); or phosphates of alkaline or alkaline earth metals (e.g. potassium phosphate); metal hydroxides (sodium hydroxide, potassium hydroxide); or fluorides (potassium fluoride, cesium fluoride).

Preferably, the reaction temperature is comprised between 25⁰C and 200⁰C and when the reaction is finished, it is usually followed by purifying methods known to the skilled person (e.g. chromatography or HPLC). Normal reaction times are between 1 and 48 hours, preferably under inert atmosphere.

Pyrimidine derivatives of formula I may be prepared by methods known in the art. For example, see the experimental section of J. Org. Chem. 1995, 60, 3020- 3027, CA 2071193 and WO 2007058602.

A second aspect of the invention is directed to sulfonamide derivatives of formula II or salts thereof

wherein Q is a diazonium salt or a halogen and wherein the halogen is preferably selected from Cl, Br and I.

Said compounds of formula II are novel intermediates in the process of the invention.

The compounds of formula II may be obtained from the common intermediate of formula III:

III wherein R is H or a protective group of alcohols.

Examples of protective group of alcohols can be found in "Protective Groups in Organic Synthesis, 3^rd edition, T. W. Greene, Wiley Interscience, chapter 2". Preferably, a protective group of alcohols is of ether type such as methyl-, ethyl-, propyl-, butyl-, benzylether, all of them optionally substituted by alkyl or aryl radicals. A most preferred protective group is fert-butylether.

Another aspect of the invention relates to a process for the preparation of a sulfonamide derivative of formula II.

Compounds of formula II wherein Q is a diazonium salt may be prepared by diazotization of the primary aromatic amine of formula III. The introduction of the diazonium group is well known in the art. The method for the preparation of diazonium salts of formula III is the treatment of primary aromatic amine with organic nitrites at a temperature between O⁰C and 100⁰C. The resulting diazonium salt can be isolated as tetrafluoroborate salts which are stable at room temperature.

The preparation of compounds of formula II wherein Q is a halogen is preferable and consists of the diazotization of the primary aromatic amine and subsequent replacement of the diazonium group by the desired halogen. The process comprises the following steps: a) Diazotization of the primary amine of compound of formula III b) Replacement of the diazonium group by a halide

c) If required, eliminating the protective group of alcohol

Step a) of the process requires the use of alkyl nitrites such as isoamyl nitrite, pentyl nitrite or tert-butyi nitrite which is added to a solution of the amine in an organic solvent at 0-100⁰C. Suitable organic solvents are THF, acetonitrile and dioxane. Optionally, CuI, I₂ or mixtures thereof are added to activate the reaction.

Step b) of the process comprises the replacement of the diazonium salt by a halide group. Preferred halide groups are bromine and iodine. Among the reactants that can be used to perform this replacement and which are well known by the skilled man in the art are CuBr₂, CH₂I₂ and CuI.

Step c) of the process, if required, comprises the elimination of the protective group which is carried out by conventional methods. Preferably, the deprotection is carried out by hydrolysis in acid medium.

In particular, for the preparation of compounds formula II wherein Q is Br, I and Cl, good results are achieved by diazotization of compound of formula III wherein R is a protective group of alcohols, preferably tert-butyl.

Figure 1 shows the X-Ray Diffraction Pattern of the Bosentan monohydrate obtained according to the process of the present invention, and then purified. The purifying method was carried out according to the example 8 of EP 1 254 121 Bl . Bosentan obtained according to the process of the present invention can be milled or micronised to obtain a D50 and D90 particle size of less than about 400 μm, preferably less than about 200 μm, more preferably less than about 150 μm, and most preferably less than about 60 μm. It is noted the notation D_x means that X% of the particles in a composition have a diameter less than a specified diameter D. Thus, a D50 of about 400 μm means that 50% of the micronised bosentan particles have a diameter less than 400 μm.

Particles of this size are obtained by conventional methods, e.g. grinding in an air jet mill, hammer and screen mill, fine impact mill, ball mill or vibrator mill.

Micronisation is preferably effected by known methods using an ultrasonic disintegrator or by stirring a suspension with a high speed agitator. The present invention is illustrated in more detail by the following Examples but should not be construed to be limited thereto.

EXAMPLES

Example 1

7V-[2-Bromo-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-4-ført- butyl-benzenesulfonamide (9)

To a mixture Of CuBr₂ (1.63 g, 7.3 mmol) and isoamyl nitrite (1.22 mL, 9.1 mmol) in dry acetonitrile (22 mL) at O⁰C, was added dropwise, and under nitrogen, a solution of (8) (3 g, 6.1 mmol) in 30 ml of dry acetonitrile. The reaction mixture was stirred 1 h at room temperature and 90 min at 65 ⁰C. The mixture was cooled at room temperature, the solvent was evaporated, and the crude was adsorbed in silica gel and purified by column chromatography. Removal of the solvent furnished the desired compound as a yellowish solid (1.3 g, 40 %).

¹H-RMN (200 MHz, d₆-DMSO): 1.29 (s, 9H); 3.85 (m, 2H); 4.03 (s, 3H); 4.45 (m, 2H); 6.84-7.20 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H); 8.25 (d, J = 8.0 Hz, 2H) ppm.

Example 2

7V-[2-Bromo-6-(2-tert-butoxyethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-4- terf-butyl-benzenesulfonamide (11)

To a mixture Of CuBr₂ (2.04 g, 9.1 mmol) and isoamyl nitrite (1.5 rnL, 11.4 mmol) in dry THF (30 mL), was added dropwise, and under nitrogen, a solution of (10) (4.12 g, 7.6 mmol) in 40 ml of dry CH3CN. The reaction mixture was stirred at 7O⁰C for 2 h. The mixture was cooled at room temperature, the solvent was evaporated, and the crude was adsorbed in silica gel and purified by column chromatography. Removal of the solvent furnished the desired compound as a yellowish solid (2.1 g, 45 %).

¹H-RMN (200 MHz, CDCl₃): 1.16 (s, 9H); 1.33 (s, 9H); 3.63 (m, 2H); 4.03 (s, 3H); 4.45 (m, 2H); 6.84-7.38 (m, 4H), 7.51 (d, J = 8.0 Hz, 2H); 8.45 (d, J = 8.0 Hz, 2H); 9.28 (s, IH) ppm.

Example 3

4-tert-Butyl-7V-[6-(2-hydroxyethoxy)-2-iodo-5-(2-methoxyphenoxy)-pyrimidin-4- yl]-benzenesulfonamide (12)

To a mixture of compound (8) (3 g, 6.1 mmol), CuI (1.28 g, 6.7 mmol), I₂ (1.5 g, 6.1 mmol) and CH₂I₂ (6.1 mL) in dry THF (50 mL) was added dropwise, and under nitrogen, isoamyl nitrite (3.0 mL, 22.6 mmol) and the reaction was heated at 70 ⁰C for 90 min. The mixture was cooled at room temperature, the solvent was evaporated and the crude obtained was adsorbed in silica gel and purified by column chromatography. Removal of the solvent furnished the desired compound as a pale yellow solid (1.09 g, 30 %).

¹H-RMN (200 MHz, de-DMSO): 1.27 (s, 9H); 3.86 (m, 2H); 4.05 (s, 3H); 4.45 (m, 2H); 6.90-7.22 (m, 4H), 7.46 (d, J = 8.5 Hz, 2H); 8.35 (d, J = 8.0 Hz, 2H) ppm.

Example 4

4-tert-Butyl-7V-[6-(2-tert-butoxyhydroxyethoxy)-2-iodo-5-(2-methoxyphenoxy)- pyrimidin-4-yl]-benzenesulfonamide (13)

To a mixture of compound (10) (3 g, 5.5 mmol), CuI (1.1 g, 5.7 mmol), I₂ (1.4 g, 5.5 mmol) and CH₂I₂ (4.4 mL, 55 mmol) in dry THF (30 mL) was added dropwise, and under nitrogen, isoamyl nitrite (2.3 mL, 17.0 mmol) and the reaction was heated at 70 ⁰C for 90 min. The mixture was cooled at room temperature, the solvent was evaporated and the crude obtained was adsorbed in silica gel and purified by column chromatography. Removal of the solvent furnished the desired compound as a pale yellow solid (1.62 g, 45 %).

Example 5

To a mixture of compound (10) (2 g, 3.6 mmol), in 25 mL of CH₂I₂ was added dropwise, and under nitrogen, isoamyl nitrite (9.8 mL, 73.4 mmol) and the reaction was heated at 85 ⁰C for 90 min. The mixture was cooled at room temperature, the mass reaction was partitioned with CH₂Cl₂ and IM aqueous solution of Na₂SO₃, dried, the solvent was evaporated and the crude obtained was adsorbed in silica gel and purified by column chromatography. Removal of the solvent furnished the desired compound as a pale yellow solid (1.0 g, 44%).

Example 6

4-tert-butyl-7V-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2']bipyrimi(iinyl- 4-yl] -benzenesu lfonam ide (Bosentan)

To a solution of 13 (3 g, 5 mmol), dry cesium fluoride (1.7 g, 11 mmol) and bis(tri-t-butylphosphine)palladium (0) (255 mg, 0.5 mmol) in dry 1,4-dioxane (60 mL) was added 2-tributylstannyl pyrimidine (2.2 g, 6.0 mmol). The reaction mixture was stirred at 100-110 ⁰C for 16 h under a stream of nitrogen, then cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated and the resulting residue was purified by column chromatography on silica gel. The title compound (2.23 g, 81 %) was obtained as a pale yellow solid. The crude bosentan was taken up in 6.7 mL of absolute ethanol at reflux. Water (6.7 mL) was added dropwise at reflux. The resulting suspension was allowed to slowly cool to 20-25⁰C. The precipitate was filtered and air-dried at 25⁰C to afford 2.0 g of bosentan monohydrate (70 % yield) as a white solid.

¹H-RMN (200 MHz, de-DMSO): 1.29 (s, 9H); 3.85 (m, 2H); 3.93 (s, 3H); 4.59 (m, 2H); 6.81-7.18 (m, 4H), 7.43 (d, J = 8.0 Hz, 3H); 8.45 (d, J = 8.0 Hz, 2H); 9.01 (s, 2H) ppm.

DSC-TG: endothermic peak at 116.53 ⁰C, with a loss of weight of 3.1 % (monohydrate).

D₁₀: 1.36 μm, D50: 20.32 μm, D90: 56.64 μm

Example 7

4-førM)utyl-7V-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2,2']bipyrimidinyl-

4-yl] -benzenesu lfonam ide (Bosentan)

To a solution of 9 (1.5 g, 2.7 mmol), dry cesium fluoride (0.91 g, 5.9 mmol) and bis(tri-t-butylphosphine)palladium (0) (140 mg, 0.27 mmol) in dry DMF (20 mL) was added 2-tributylstannyl pyrimidine (1.2 g, 3.2 mmol). The reaction mixture was stirred at 140-150 ⁰C for 16 h under a stream of nitrogen, then cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated and the resulting residue was purified by column chromatography on silica gel. The title compound (0.8 g, 53 %) was obtained as a pale yellow solid.

The crude bosentan was taken up in 2.4 mL of absolute ethanol at reflux. Water (2.4 mL) was added dropwise at reflux. The resulting suspension was allowed to slowly cool to 20-25⁰C. The precipitate was filtered and air-dried at 25⁰C to afford 0.7 g of bosentan monohydrate (47 % yield) as a white solid.

¹H-RMN (200 MHz, de-DMSO): 1.29 (s, 9H); 3.85 (m, 2H); 3.93 (s, 3H); 4.59 (m, 2H); 6.81-7.18 (m, 4H), 7.43 (d, J = 8.0 Hz, 3H); 8.45 (d, J = 8.0 Hz, 2H); 9.01 (s,

2H) ppm.

D₁₀: 1.36 μm, D50: 20.32 μm, D90: 56.64 μm

Claims

1. A process for the preparation of Bosentan or a pharmaceutically salt thereof

characterized in that comprises a coupling reaction between a pyrimidine derivative of formula I:

wherein A means BF3K, B(OH)₂, substituted and unsubstituted cyclic and acyclic boronic esters or SnR₃, wherein R is selected from the group consisting of a linear or branched C₁-C₅ alkyl

and a sulfonamide derivative of formula II

wherein Q is a diazonium salt or a halogen, and wherein the halogen is

preferably selected from Cl, Br and I, in the presence of a palladium catalyst and in a solvent medium.

2. The process according to claim 1 characterised in that A in compound of formula I

is SnR₃, preferably SnBu₃ and Q in compound of formula II is Br or I.

3. The process according to claim 1 and 2, characterised in that being the reaction performed in homogeneous conditions, the palladium catalyst is selected from Pd(PPh₃)₄, PdCl₂(PPh₃)₂, Pd(AcO)₂, Pd₂(dba)₃, PdCl₂(dppf), PdCl₂(CH₃CN)₂ and Pd[P^lBu₃]₂, wherein Ac is acetate, Ph is phenyl, dba is dibenzylideneacetone, dppf is 1,1 '-bis(diphenylphosphino)ferrocene and ¹Bu is tert-butyi.

4. The process according to claim 1 and 2, characterised in that being the palladium catalyst selected from Pd(AcO)₂ and Pd₂(dba)₃ the coupling reaction is carried out in the presence of a ligand.

5. The process according to claim 4, characterised in that said ligand is of the phosphine type, preferably triphenylphosphine or tri-te/t-butylphosphine.

6. The process according to claim 1 and 2, characterised in that being the reaction performed in heterogeneous conditions, the palladium catalyst used is Pd/C.

7. The process according to claim 1 characterized in that the reaction medium is water or/and an organic solvent selected from the solvents THF, DME, DEM, toluene, xylene, methanol, ethanol, propanol, dioxane, acetonitrile, DMF, DMA and water, or mixtures thereof.

8. The process according to claim 1 characterised in that it further comprises an organic or inorganic base.

9. The process according to claim 8 characterised in that said organic base is selected from tertiary amines, like triethyl amine (TEA) or N,N-diisopropylethylamine (DIPEA), or acetates; or other ammonia derivatives in which one or more hydrogen have been substituted by alkyl or aryl radicals such as ethyl, isopropyl, benzyl, phenyl or pyridine.

10. The process according to claim 8 characterised in that said inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium fluoride, cesium fluoride or potassium phosphate.

11. A sulfonamide derivative of formula II or salts thereof:

wherein Q is a diazonium salt or a halogen, preferably Cl, Br and I

12. A process for the preparation of a sulfonamide derivative of formula II according to claim 11, wherein being Q a halogen, the reaction comprises the following steps: a) diazotization of the primary amine of compound of formula III

III wherein R is H or a protective group of alcohols b) replacement of the diazonium group by a halide c) if required, eliminating the protective group of alcohols

13. The process according to claim 12 wherein the protective group of alcohols of compound of formula III is of ether type such as methyl-, ethyl-, propyl-, butyl-, benzylether, all of them optionally substituted by alkyl or aryl radicals, preferably, the protective group of alcohols is te/t-butylether

14. Use of a sulfonamide intermediate of formula II or salts thereof according to claim 11 for the preparation of Bosentan.