WO2009095933A2

WO2009095933A2 - Improved and novel process for the preparation of bosentan

Info

Publication number: WO2009095933A2
Application number: PCT/IN2009/000032
Authority: WO
Inventors: Manne Satyanarayana Reddy; Sajja Eswaraiah; Ghojala Venkat Reddy
Original assignee: Msn Laboratories Limited
Priority date: 2008-01-10
Filing date: 2009-01-09
Publication date: 2009-08-06
Also published as: EP2240470A4; EP2240470A2; WO2009095933A3

Abstract

The present invention relates to an improved and novel process for the preparation of bosentan compound of formula (1). The present invention also relates to a crystalline form of bosentan and its intermediates.

Description

IMPROVED AND NOVEL PROCESS FORTHE PREPARATION OF

BOSENTAN

Related Applications:

This application claims the benefit of priority of our Indian patent application number 103/CHE/2008 filed on January 10, 2008 and 2334/CHE/2008 filed on September 24, 2008, which are incorporated herein by reference.

Field of Invention:

The present invention relates to an improved and novel process for the preparation of bosentan. Bosentan is chemically known as 4-(l,l-Dimethylethyl)-N-[6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide monohydrate, having structural formula- 1.

Formula- 1

Background of the Invention:

Bosentan is found to be a potential inhibitor of endothelin receptors. Endothelin has recently been shown to play a pivotal role in the development of pulmonary hypertension and elevated endothelin concentrations have been found to be strongly correlated with disease severity. Endothelin antagonists especially bosentan, are therefore considered to represent a new approach to the treatment of pulmonary hypertension. The selective nonpeptide mixed endothelin ET_A and ET_B receptor antagonist bosentan (Tracleer^®) has become the first endothelin antagonist to reach the market for pulmonary hypertension. It has a greater significance because until now only few drugs have been specifically approved for the indication of pulmonary hypertension. Bosentan can also be used for treatment of circulatory disorders such as ischemia, vasospasms and angina pectoris.

Bosentan and its analogues as potential endothelin inhibitors have been first disclosed in US patent No. 5,292,740. The patent also disclosed the methods for preparing these compounds. One of the method involves the condensation of diethyl (2- methoxyphenoxy) malonate with pyrimidine-2-carboxyamidine in presence of sodium methoxide, followed by treatment with sodium hydroxide to provide the dihydroxy derivative, which is converted into dichloro derivative by the treatment with refluxing phosphorus oxychloride. One chlorine of the dichloro derivative is replaced by 4-tert- butylbenzenesulfonamide. The remaining chlorine is replaced by ethylene glycol in presence of sodium metal to provide bosentan.

The method of preparing ethylene glycol sulfonamide derivatives involves reacting an appropriately substituted pyrimidine monohalide with a monoanion ethylene glycol (e.g., sodium ethylene glycol) typically using ethylene glycol as a solvent. The mono sodium ethylene glycol is prepared by treating ethylene glycol with sodium metal which is difficult to handle at large scale in an industrial process. However, one of the disadvantages of using a monoanion of ethylene glycol is the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine monohalide are coupled with one molecule of ethylene glycol. The removal of this bis sulfonamide requires costly and laborious separation steps to obtain a pharmaceutically suitable ethylene glycol sulfonamide compound.

In addition, the use of ethylene glycol as a solvent, which is acceptable in a small scale reaction, is impracticable in a large 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. Another drawback is the need for isolating a pyrimidine dihalide which is believed to be a potent sensitizer. This problem is further complicated by the use of a halogenated solvent e.g., methylene chloride, during the isolation of pyrimidine dihalide. Halogenated solvent is expensive to dispose off properly, thus leading to added cost. In the final stages, diisopropyl ether is used for purification by recrystallization which is not advisable to get ICH quality material. Further more the synthesis requires at least six separate isolation steps and the use of many different solvents, which makes it economically less viable at industrial level.

US Patent No 6,136,971 discloses a process which tries to overcome the disadvantages observed in the above process. It discloses a process for the preparation of 1,2-diheteroethylene sulfonamide i.e. bosentan, which involves the reaction of appropriately substituted pyrimidine monohalide intermediate with a mono protected 1 ,2- diheteroethylene anion to produce the monoprotected 1,2-diheteroethylene sulfonamide. The process involves additional steps of preparation of mono protected ethylene glycol, and removal of protecting group of mono-protected ethylene glycol sulfonamide. Hence the process is more time consuming, laborious, involves use of more reagents and solvents, decreased yields, which increases the overall cost of the product.

Therefore there is a need for a process for preparing the 1,2-diheteroethylene sulfonamide i.e., bosentan with a reduced number of reaction product isolation steps. There is a need for a process for preparing bosentan which does not produce undesired 1,2-diheteroethylene bis-sulfonamides and also provide better yields and purity and same time it can be performed at an industrial scale. Moreover, till date there is no reference of bosentan morphology. Morphology plays an important role during the formulation of an active pharmaceutical ingredient.

The present invention overcomes the major disadvantage mentioned above. In the second aspect of the present invention, in the final stage 4-tert-butyl-N-(5-(2- methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide is reduced to provide bosentan, in which there is no possibility of formation of the undesired 1,2-diheteroethylene bis-sulfonamides. In the third aspect in the final stage p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide is reacted with 2-haloethan-l-ol to provide bosentan. In this process also the formation of undesired 1,2-diheteroethylene bis-sulfonamides is controlled.

The present invention overcomes the disadvantages of the processes of prior art. It is easier to perform as it involves lesser number of steps, utilizes milder reagents and reaction conditions, which are conducive to be scaled up to an industrial level. It is cost effective and economically viable process. The present invention also provides bosentan of a morphology which is highly advantageous for formulations.

Brief Description of the Invention:

The present invention relates to an improved and novel processes for the preparation of bosentan. The first aspect of the invention is to provide an improved process for the preparation of bosentan compound of formula- 1, which comprises of condensing diethyl 2-(2-methoxyphenoxy)malonate compound of formula-2 with pyrimidine-2- carboximidamide hydrochloride compound of formula-3, in the presence of a base in a suitable solvent to provide 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4, which on reaction with an halogenating agent in a suitable solvent provides 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-5; then condensing the compound of formula- 5 with 4-tert-butyl benzene sulfonamide compound of formula-6 in presence of a base in a suitable solvent provides p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide or its salt compound of formula-7, which on reaction with ethylene glycol in the presence of a base, in a suitable solvent, with or without a phase transfer catalyst provides bosentan compound of formula- 1. Optionally, the first aspect of the invention proceeds without isolation of the compound formula-5.

The second aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula- 1, which comprises of condensing the p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7 with a substituted allyl alcohol, compound of formula-8 (or) by condensing the 6-hydroxy sulfonamide derivative compound of formula-9, with a substituted allyl halide, compound of formula- 10 in presence of base in a suitable solvent, to provide a substituted 6-allyloxy sulfonilamide derivative compound of formula- 11. Treating the compound of formula- 11 with hydroxylating agent to provide a diol compound, which on subsequent oxidation in-situ with suitable oxidizing agent to provides aldehyde derivative compound of formula-12. Then reducing the compound of formula- 12 with a suitable reducing agent to provide bosentan, compound of formula- 1.

The third aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula- 1, which comprises of reacting the p-tert- butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7 (or) reacting the alkoxy-sulfonamide derivative compound of formula-13, with suitable base, in a suitable solvent to provide 6-hydroxy sulfonamide derivative compound of formula-9, which on reaction with 2-halo ethan-1-ol in presence of suitable base gives bosentan, compound of formula- 1.

The fourth aspect of the present invention is to provide p-tert-butyl-N-[6-chloro- 5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt, compound of formula-7b as a crystalline solid. The crystalline solid of the present invention is characterized by its PXRD, IR spectrum and DSC thermo gram. The present invention also provides a process for the preparation of crystalline potassium salt compound of formula-7b.

The fifth aspect of the present invention is to provide an improved process for the preparation of high pure crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7a as a solid, which comprises of hydrolyzing the crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt compound of formula-7b with suitable aqueous acid in a suitable solvent.

Advantages of the Present Invention:

• The major advantage of the process is that it involves the condensation of mono halo sulfanilamide intermediate (7) with ethylene glycol in presence of simple base like sodium hydroxide and avoids the use of pyrophoric reagent like sodium metal with ethylene glycol, to prepare monosodium ethylene glycol prior to the condensation.

• In the final stages of synthesis contrary to the methods of prior art, ethylene glycol is used in the ratio of 5-10 moles per mole of the substrate and not as a solvent. This makes the purification of the final product much easier and also the effluents will contain less amounts of toxic ethylene glycol making it a more greener and ecofriendly process.

• Formation of lower concentration of impurities. • Use of milder reagents when compared to the processes of prior art.

• Involves lesser number of steps, easy to perform and economically viable. The process can be scaled up to industrial level. • Provides a novel process which avoids the formation of dimer impurity and therefore having high purity.

• Eco-friendly and cost effective process.

Brief Description of the Drawings:

Figure-1: Illustrates the powder X-ray powder diffractogram of bosentan Figure-2: Illustrates the IR spectrum of bosentan. . Figure-3: Illustrates the DSC chromatogram of bosentan Figure-4: Illustrates the photographs of bosentan recorded on a microscope. Figure-5: Illustrates the X-ray powder diffraction pattern of potassium salt compound of formula-7b

Figure-6: Illustrates the Infrared spectrum of potassium salt compound of formula-7b Figure-7: Illustrates the DSC chromatogram of potassium salt compound of formula-7b Figure-8: Illustrates the HPLC cliromatogram of potassium salt compound of formula-7b

Detailed description of the invention:

As used herein the term "alkyl" refers to a straight or branched or cyclic Ci to C₈ alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert- pentyl, cyclopentyl, n-hexyl, n-heptyl, octyl and isohexyl and the like. Further, alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, hydroxy and cyano.

The term "alkali metal" refers to lithium, sodium, potassium and cesium, and the term "alkaline earth metal" refers to beryllium, magnesium, and calcium. The term "halogen" refers to chlorine, bromine and fluorine.

The present invention relates to an improved and novel process for the preparation of bosentan. Bosentan is chemically known as 4-( 1,1 -Dimethyl ethy I)-N- [6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide monohydrate, having structural formula- 1.

The first aspect of the present invention provides an improved process for the preparation of bosentan compound of formula- 1, which comprises of the following steps; a) Condensing diethyl 2-(2-methoxyphenoxy)malonate compound of formula-2

Formula-2 with pyrimidine-2-carboximidamide hydrochloride compound of formula- 3

Formula-3 in the presence of a suitable base in a suitable solvent to provide 5-(2- methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4,

Formula-4 b) reacting 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4 with halogenating agent in a suitable solvent to provide 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-5,

Formula-5 Wherein X is halogen; c) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-5, with 4-tert-butyl benzene sulfonamide compound of formula-6

Formula-6 in presence of a base in a suitable non polar aprotic solvent to provide p-tert-butyl- N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide or its salt compound of formula-7,

Wherein X is halogen and M is a hydrogen or alkali/alkaline earth metal ion, d) reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide or its salt compound of formula-7 with ethylene glycol in the presence of a suitable base and in a suitable aprotic solvent, with or without a phase transfer catalyst to provide bosentan compound of formula- 1.

Wherein, in the step a) the condensation of diethyl 2-(2-methoxyphenoxy) malonate compound formula-2 with pyrimidine-2-carboximidamide hydrochloride compound of formula-3, the base is selected from the group consisting of but is not limited to, hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; sodium/potassium alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; preferably sodium methoxide. The solvent used is selected from a group of alcoholic solvents which include methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol preferably methanol. In the step b) the halgenation of 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6- dihydroxy pyrimidine compound of formula-4 is carried out using a suitable halogenating agent selected from the group consisting of but is not limited to, thionyl chloride (SOCl₂), phosphorus trichloride (PCl₃), phosphorus pentachloride (PCl₅), phosphorus oxychloride (POCl₃), phosphorus tribromide (PBr₃), phosphorus pentabromide (PBr₅) and the like, preferably phosphorus oxychloride in an aprotic solvent. The suitable aprotic solvent selected from the group consisting of but is not limited to, benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably toluene.

In the step c) the coupling of the 5-(2-methoxyphenoxy)~2-(2'-pyrimidinyl)-4,6- dihalopyrimidine compound of formula-5 with 4-tert-butyl benzene sulfonamide compound of formula-6, the suitable bases that can be used in the reaction may include but are not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably potassium carbonate. The suitable non polar aprotic solvent includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably toluene.

In the step d) bosentan is prepared by condensing p-tert-butyl-N-[6-halo-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt compound of formula-7 with ethylene glycol (which is present in very low molar ratio), in the presence of a base and a suitable aprotic solvent. The base is selected from the group consisting of but not limited to hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide. The suitable aprotic solvent includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyltetrahydrofuran, preferably acetonitrile.

The phase transfer catalyst is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide. The use of ethylene glycol in presence of a base in a suitable solvent not only reduced the number of steps but also the formation of impurities was arrested. The processes disclosed in prior art either utilize monoanion of ethylene glycol or monoprotected ethylene glycol leads to the formation of dimmers and other impurities.

Optionally the bosentan can also be prepared as per the first aspect of the invention with out isolating the 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6- dihalopyrimidine compound of formula- 5 to further reduce the isolation steps.

The second aspect of the present invention provides a novel process for the preparation of bosentan which comprises of the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7,

Formula-7 with a substituted allylalcohol, compound of formula-8, . H(X ^^ R'

Formula-8

Wherein R' is selected from alkyl or aryl; in the presence of suitable base and in a suitable solvent, with or without a phase transfer catalyst, to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide, compound of formula-11,

(OR) by reacting p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)[2,2'- bipyrimidin] -4-yl] benzene sulfonamide derivative of formula-9,

with a substituted allylhalide, compound of formula- 10,

Formula- 10 wherein X is halogen and R' is defined as above; in the presence of suitable base and in a suitable solvent, with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-11,

Formula-11 b) treating p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy){2,2'- bipyrimidin)-4-yl] benzene sulfonamide, compound of formula-11, with a hydroxylating agent provides dihydroxy derivative, which upon subsequent oxidation in-situ with suitable oxidizing agent, provides an aldehyde derivative 4-tert- butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzene^' sulfonamide, compound of formula- 12,

Formula 12 c) reducing the 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'- bipyrimidin-4-yl) benzene sulfonamide, compound of formula- 12, with a suitable reducing agent in a suitable solvent to provide bosentan, compound of formula -1.

Wherein, in the step a) the reaction of p-tert-butyl-N-[6-halo-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide, compound of formula-7, with a substituted allyl alcohol, compound of formula-8, (OR) p-tert-butyl-N-[6-hydroxy- 5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-9, with a substituted allyl halide, compound of formula- 10, is carried out in the presence of a base selected from a group which may include but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide and in the suitable solvent selected from a group which may include but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitirle, preferably acetonitrile to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-11. The phase transfer catalyst which can be used is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

In the step b) p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxyphenoxy)[2,2'- bi pyrimidin]-4-yl] benzene sulfonamide derivative compound of formula-11, on treatment with hydroxylating agents like OsO₄ in presence of H₂O₂ or N-methyl morpholine N-oxide or KMnO₄ or PhCO₂Ag/I₂ in a suitable solvents like methanol, ethanol, propanol, isopropanol and the like, preferably tert-butyl alcohol provides diol derivative, which on subsequent oxidization in-situ, in the presence of oxidizing agents like NaIO₄ or Pd(OAc)₄ provides 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2- oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, compound of formula-12.

In step c) 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2, T- bipyrimidin-4-yl) benzenesulfonamide, compound of formula-12, is reduced with a reducing agent selected from a group which includes but is not limited to sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride"), sodium dihydro-bis-(2- methoxyethoxy)aluminate (Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, and the like, preferably sodium borohydride in a suitable alcoholic solvent selected from the group which may include alcohols like methanol, ethanol, propanol, isopropanol and the like to obtain bosentan, compound of formula- 1.

The third aspect of the present invention provides a novel process for the preparation of bosentan compound of formula- 1, which comprises of the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-7

Formula-7 with a suitable base, in a suitable solvent and with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yljbenzene sulfonamide, compound of formula-9, (or) reacting p-tert-butyl-N-[6-alkoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide derivative of formula- 13,

Formula- 13 wherein R is alkyl; with a suitable base, in a suitable solvent and with or without a phase transfer catalyst to provide p4ert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl]benzene sulfonamide, compound of formula-9,

Formula-9 b) p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-9, upon treating with 2-halo-ethan-l-ol, wherein halogen is either chlorine or bromine; in presence of suitable base, in a aprotic solvent and with or without a phase transfer catalyst, provides bosentan compound of formula- 1.

Wherein, in the step a) the suitable bases that can be used in the reaction is selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide. The suitable solvent which is used is selected from a group which includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, ethylene glycol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran. The phase transfer catalyst is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

In the step b) the compound of formula- 1 is obtained by the reaction of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula- 9 with 2-halo-ethan-l-ol, in presence of suitable base selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably sodium carbonate. The phase transfer catalyst which can be used is selected from the group consisting of but is not limited to terra butyl ammonium bromide, terra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

The fourth aspect of the present invention is to provide p-tert-butyl-N-[6-chloro-

5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt, compound of formula-7b as a crystalline solid.

Formula-7b The crystalline solid of the present invention is characterized by the following a) It's XRD wherein peaks were observed at about 4.2, 8.3, 9.6, 15.6, 16.3, 18.3, 19.3, 20.5, 21.0, 22.1, 26.0, 27.5, and 28.4 ± 0.2 degrees two theta. b) It's IR whe.rein peaks were observed at 3467.4, 3062.8, 2960.9, 1662.9, 1591.9, 1551.4, 1501.0, 1448.5, 1249.3, 858.7, 795.0, 719.8, 694.4, 586.0, and 540.6 cm^"1. c) It's DSC thermo gram having endothermic peak at about 201.14°C and exothermic peak at about 306.17⁰C.

The present invention also provides a process for the preparation of crystalline potassium salt compound of formula-7b, which comprises of reacting 4,6-dichloro-5-(2- methoxyphenoxy)-2,2'-bipyrimidine compound of formula-5a

Formula-5a with 4-tert-butyl benzene sulfonamide compound of formula-6 in the presence of potassium carbonate and a suitable aprotic solvent, with or without a phase transfer catalyst, to provide p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl] benzene sulfonamide potassium salt, compound of formula-7b.

Wherein the above condensation reaction of formula-5a and formula-6, the suitable solvent is selected from the group which may include but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethylsulfoxide, and the phase transfer catalyst used in step a) is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide, and lithium iodide.

US patent 6,136,971 discloses the compound of formula-7b, but it is not isolated and is used in the next step as a suspension in toluene. US patent 5,292,740 also described the formation of potassium salt of the above intermediate in the synthesis of bosentan and its analogues but is silent about its isolation and its nature. The present inventors isolated the p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]- 4-yl] benzene sulfonamide potassium salt compound of formula- 7b as highly pure crystalline solid, which when used for the preparation of p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyramidin]-4-yl]benzene sulfonamide, compound of formula-7a gave a product with high purity (i.e., >99%). The fifth aspect of the present invention is to provide an improved process for the preparation of high pure crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7a as a solid, which comprises of hydrolyzing the crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt compound of formula- 7b with suitable aqueous acid like hydrochloric acid in a suitable solvent.

The present invention provides crystalline bosentan with rod shaped morphology, which is highly pure, free flowing solid and easy to handle during formulation as an active pharmaceutical ingredient. It has a greater advantage over the prior art forms.

The p-tert-butyl-N-[6-(methoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide 13a is an impurity formed in the present invention which was isolated and characterized. The said impurity compound of formula- 13a is formed due to the presence of methanol traces in the reaction medium and the process is represented as below.

Methanol,

Sodium hydroxide

Toluene

Formula- 13a Wherein M= H

General Experimental Conditions

XRD analysis of bosentan and its salts was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FI-IR spectrum of bosentan and impurity compound of formula-13a was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of bosentan and its salt was carried out on Waters DSC Q-IO model differential scanning calorimeter.

The mass spectrum of impurity was recorded on positive Ql MS by mass spectrometer and the ¹H NMR data was recorded in CDCl₃ solvent on Avance 300 MHz spectrometer using TMS as internal standard. The present invention is schematically represented by the following schemes: Scheme-1:

Formula-2 Formula-3

Formula-5 a, wherein X=C

wherein X= Halogen and F^=C₁-C₈ branched striaght chain alkyl group or an aryl group Scheme-2:

Bosentan is also prepared by the novel processes which are represented in the following reaction schemes: Scheme-3:

metal ion

Scheme-4:

wherein R is C,.₆ alkyl group which may be straight chain /branched and which may be substituted/unsubstituted; or is an aryl group; or is an substituted aryl group, wherein M is a hydrogen or akali or alkaline earth metal ion wherein X is a halogen

Scheme-5:

wherein R is C_|._β alkyl group which may be straight chain /branched and which may be substituted/unsubstituted; or is an aryl group; or is an substituted aryl group. wherein M is a hydrogen or akali or alkaline earth metal ion The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example 1: 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4:

To a solution of diethyl 2-(2-methoxyphenoxy)malonate compound of formula-2 (289 g) in methanol (400 ml) sodium methoxide (100 ml) was added slowly within 20 min and then stirred for 30 min. A solution of pyrimidine-2-carboximidamide hydrochloride compound of formula-3 (100 g) dissolved in methanol (750 ml) was added to the reaction mixture and stirred at 25- 3O⁰C for 25 hrs. The reaction mixture was concentrated in vacuum to get a solid residue. The obtained residue was dissolved in 1000 ml water and pH was adjusted to 5-6 with dilute HCl. The precipitated product was filtered, washed with water and dried at 50⁰C. The title compound was obtained as a pale yellowish powder. Yield: 19O g

Example 2: Preparation of 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dichloro pyrimidine compound of formula-5a:

To 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4 (100 g), POCl₃ (500 ml) was added. Heated the reaction mixture to 9O⁰C and stirred for 30 min. The temperature of the reaction mixture was raised to 105°C and was stirred for 8 hrs. The reaction mixture was cooled to 6O⁰C and concentrated to obtain a residue. The reaction mixture was quenched with ice water and toluene was added to it. The pH was adjusted to 8-9 with 30% sodium hydroxide solution. The organic and the aqueous layers were separated. The aqueous layer was extracted with toluene. The organic layers were combined, washed with water and dried. The solvent was distilled off to provide the title compound as a solid. Yield: 96_.g

Melting range: 138-140⁰C Example 3: p-tert-butyI-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide formula-7a:

To a solution of 4-tert-butyl benzene sulfonamide compound of formula-6 (48 g) in toluene (600 ml), potassium carbonate (35 g) and tetra butyl ammonium bromide (10 g) was added and the reaction mixture was heated to 50°C. A solution of 5-(2- methoxyphenoxy)-2-(2'pyrimidinyl)-4,6-dichloro pyrimidine compound of formula- 5 (60 g) in toluene (1200 ml) was added slowly to the reaction mixture and it was refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25°C and acidified with aqueous hydrochloric acid. The reaction mixture was stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 87 g

Example 4: p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt compound of formula-7b: To a solution of 4-tert-butyl benzene sulfonamide compound of formula-6 (48 g) in toluene (600 ml), potassium carbonate (35 g) and tetra butyl ammonium bromide (10 g) was added and the reaction mixture was heated to 50⁰C. A solution of 5-(2- methoxyphenoxy)-2-(2'pyrimidinyl)-4,6-dichloro ' pyrimidine compound of formula-5 (60 g) in toluene (1200 ml) was added slowly to the reaction mixture and it was refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25°C.The solid obtained slurried in water and then filtered, washed with water and then dried to get the title compound. Yield: 90 g

Example 5: p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzenesulfonamide potassium salt compound of formula-7b:

To 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4 (100 g), POCI₃ (500 ml) was added. Heated the reaction mixture to 90°C and stirred for 30 min. The temperature of the reaction mixture was raised to 105°C and was stirred for 8 hrs. The reaction mixture was cooled to 6O⁰C and concentrated to obtain a residue. The reaction mixture was quenched with ice water and toluene (1200 ml) was added to it. The pH was adjusted to 8-9 with 30% sodium hydroxide solution. The organic and the aqueous layers were separated. The aqueous layer was extracted with toluene (200 ml). The organic layers were combined, washed with water and dried. The solvent was concentrated to 1200 ml and a solution of 4-tert- butyl benzene sulfonamide (6) (48 g) in toluene (600 ml), potassium carbonate (35 g) and tetra butyl ammonium bromide (10 g) was added and the reaction mixture was heated to 50°C. The reaction mixture was heated to refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25°C.The solid obtained was filtered and made slurry in water. The solid was filtered, washed with water and dried. Yield: 92 g

Example-6: Preparation of crystalline p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt compound of formula-7b:

To a solution of 4-tert-butyl benzene sulfonamide compound of formula-6 (61.3 grams) in toluene (1500 ml), potassium carbonate (77.93 grams) and tetra butyl ammonium bromide (2.77 grams) was added and the reaction mixture was heated to 50°C. A solution of 5-(2-methoxyphenoxy)-2-(2'pyrimidmyl)-4,6-dichloro pyrimidine compound of formula-5a (100 grams) in toluene (1500 ml) was added slowly to the reaction mixture and it was refluxed for 10 hrs. The reaction mixture was cooled to 25°C.The solid obtained was filtered and made slurry in water. The solid was filtered, washed with water followed by acetonitrile and dried. Yield: 116 grams, HPLC purity: 99.3%, MR: 202-205°C.

Example-7: Preparation of high pure • p-tert-butyI-N-[6-chloro-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula -7a:

Water (100 ml) was added to potassium salt of p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7b (50 grams) and the pH of the mixture was adjusted to 2 with hydrochloric acid and stirred for lhr. The obtained solid is filtered off and washed with acetonitrile. Dried the solid to get the title compound. Yield: 42 grams Example 8: Preparation of bosentan.

A mixture of ethylene glycol (5.5 g), acetonitrile (130 ml), and sodium hydroxide (2.8 g) was heated to 75-80°C and the reaction mixture was stirred for 8-12 hrs. p-tert- butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide potassium salt-7b (5 g) was a added to the reaction mixture and stirred for 12 -14 hrs. The reaction mixture was cooled to 25°C, quenched with water and the pH was adjusted to 2- 3 with IN HCl. Toluene was added to the reaction mixture and stirred for 10 min. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with water, dried over sodium sulfate. The solvent was distilled off to provide a residue. The residue was taken in ethanol (15 ml) and heated to 60-65⁰C and stirred for 30 min. Water (15 ml) was added drop wise to the reaction mixture, then cooled to 25⁰C and it was stirred at this temperature for 2 hrs. The solid formed was filtered and washed with a mixture of chilled ethanol and water (1 :1). The compound was air dried to provide the title compound. Yield: 4.2 g

MR: 138-140⁰C

HPLC Purity: 99.70 %

Water content: 3.2 % (w/w)

Particle size distribution: D(0.1):9.677; D(0.5):37,410; D(0.9):122.534; D [4,3]: 53.49; (Bosentan prepared above was micronized to provide bosentan with mean particle size in the range of below 20 microns, which on further micronization provided bosentan with a mean particle size in the range of below 10 microns.)

Example 9: Preparation of bosentan. A mixture of ethylene glycol (5.5 g), acetonitrile (130 ml), sodium hydroxide

(2.8 g) and tetra butyl ammonium bromide (0.5 g) was heated to 75-80°C and the reaction mixture was stirred for 8-12 hrs. p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide potassium salt-7b (5 g) was a added to the reaction mixture and stirred for 12 -14 hrs. The reaction mixture was cooled to 25°C, quenched with water and the pH was adjusted to 2-3 with IN HCl. Toluene was added to the reaction mixture and stirred for 10 min. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with water, dried over sodium sulfate. The solvent was distilled off to provide a residue. The residue was taken in ethanol (15 ml) and heated to 60-65°Cand stirred for 30 min. Water (15 ml) was added drop wise to the reaction mixture, then cooled to 25°C and it was stirred at this temperature for 2 hrs. The solid formed was filtered and washed with a mixture of chilled ethanol and water (1 :1). The compound was air dried to provide the title compound. Yield: 4.0 g

Example 10: Preparation of bosentan.

A mixture of ethylene glycol (6 g), acetonitrile (30 ml), and potassium carbonate (5 g) was heated to 75-80°C and the reaction mixture was stirred for 8-12 hrs. p-tert- butyl-N-[6-chloiO-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt-7b (500 mg) was added to the reaction mixture and stirred for 12 -14 hrs. The reaction mixture was cooled to 25⁰C, quenched with water and the pH was adjusted to 2-3 with IN HCl. Toluene (20 ml) was added to the reaction mixture and stirred for 10 min. The organic and aqueous layers were separated. The aqueous layer was extracted with toluene (10 ml). The combined organic layers were washed with water, dried over sodium sulfate. The solvent was distilled off to provide a residue. The residue was taken in ethanol (2ml) and heated to 60-65°Cand stirred for 30 min. Water (3 ml) was added drop wise to the reaction mixture, then cooled to 25⁰C and it was stirred at this temperature for 2 hrs. The solid formed was filtered and washed with a mixture of chilled ethanol and water (1 :1). The compound was air dried to provide the title compound. Yield: 250 mg

Example 11: Preparation of bosentan sodium.

To a solution of bosentan (3 g) in ethanol (15 ml), 30% sodium hydroxide was added drop wise at 25-30°C and stirred the solution slowly until a solid was formed. The reaction mixture was stirred for one hour at 25-30⁰C. Filtered the solid formed and washed with ethanol. The solid was dried to obtain the title compound. Yield: 1.5 g Water content: 2.7 %; Assay: 95.66 % MR: 215 -218°C

Example 12: Preparation of bosentan potassium. To a solution of bosentan (3 g) in ethanol (15 ml), 30% potassium hydroxide was added drop wise at 25-30°C and stirred the solution slowly until a solid was formed. The reaction mixture was stirred for one hour at 25-30°C. Filtered the solid formed and washed with ethanol. The solid was dried to obtain the title compound. Yield: 1.2 g Water content: 3.5 %;

Assay: 100 %; MR: 218 -22O⁰C

Example-13: Preparation of p-tert-butyI-N-[6-(prop-2-enyI-oxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yI] benzene sulfonamide compound of formula- 11:

To a solution of prop-2-en-l-ol (51.4 grams) in acetonitrile (350 ml), sodium hydroxide(14.18 grams) was added and heated to 80-85°C for 4 hrs. The reaction mixture was cooled to 25-3O⁰C and p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl]benzene sulfonamide compound of formula-7a (50 grams) was added followed by heating to 80-85⁰C for 14 hrs. Then water (600 ml) was added and the pH was adjusted to 2.0 by using hydrochloric acid. The reaction mixture was maintained at 27°C for 40 min, the solid formed was filtered and washed with water. The compound was dried for 2 hrs at 60-65⁰C. Yield: 43 g

Example-14: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-

2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-12:

To a solution of p-tert-butyl-N-[6-(prop-2-enyl-oxy)-5-(2-methoxyphenoxy) [2,2'- bipyrimidin]-4-yl] benzene sulfonamide (25 grams) in methanol (350 ml), OsO₄ (0.1 gm), H₂O₂ (75 ml), and water (200 ml) were added. The reaction mixture was stirred for 24 hrs at 25-35°C. The solvent was distilled off from reaction mixture and dichloromethane was added and stirred for 15 min. The organic layer was separated and washed with water. The solvent was distilled off from filtrate and residue dissolved in acetone. Aqueous sodium periodate was added to the reaction mixture and stirred for 7 hrs at 25-3O⁰C temperature and filtered. The solvent was distilled off from the filtrate and the residue, extracted with chloroform. The organic layer was washed with water, the solvent was distilled off to provide the title compound as a solid. Yield: 20 g

Example-15: Preparation of bosentan compound of formula-l:

A solution of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'- bipyrimidin-4-yl)benzene sulfonamide compound of formula- 12 (10 grams) in methanol (100 ml) was cooled to 0-5°C and sodium borohydride (0.69 grams) was slowly added in portions. Stirred the reaction mixture for 2 hr. The reaction mixture was poured into crushed ice and the pH adjusted to 2.0 with HCl. The solid precipitated was filtered, washed with water and dried. Yield: 8 g

Example-16: Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-9:

To a solution of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl]benzene-sulfonamide compound of formula-7a (50 grams) in ethylene glycol (329.7 grams), sodium hydroxide (10.6 grams) was added and heated to 160- 165°C for 10 hours. The reaction was quenched with water and the pH was adjusted to 2.0 with hydrochloric acid. The reaction mixture was stirred at room temperature for 40 min'. The precipitated solid was filtered and washed with water. The compound is dried at 70-75⁰C for 10 hours. Yield: 41 g

Example-17: Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-y IJ benzene sulfonamide compound of formula-9: The title compound is prepared analogous manner to example-15 using toluene as a solvent in place of ethylene glycol. Yield: 45 g Example-18: Preparation of p-tert-butyI-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-9:

To a solution of p-tert-butyI-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl]benzene-sulfonamide compound of formula-13a (50 grams) in ethylene glycol (329.7 grams), sodium hydroxide (10.6 grams) was added and heated to 160- 165⁰C for 10 hours. The reaction was quenched with water and the pH was adjusted to 2.0 with hydrochloric acid. The reaction mixture was stirred at room temperature for 40 min. The precipitated solid was filtered and washed with water. The compound is dried at 70-75°C for 10 hours. Yield: 42 g

ExampIe-19: Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-9:

The title compound is prepared analogous manner to example- 17 using toluene as a solvent in place of ethylene glycol. Yield: 39 g

Example-20: Preparation of bosentan compound of formula-l:

To a solution of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-9 (38.5 grams) in dimethylformamide (450 ml), sodium carbonate (32.16 grams) was added and heated to

110-115⁰C for 4 hrs. 2- Chloroethanol (54.96 grams) (50 ml) was added to the reaction mixture and stirred for 16 hrs. Water was added to the reaction mixture and the pH was adjusted to 2 with hydrochloric acid. Dichloromethane (700 ml) was added to the reaction mixture. The aqueous and organic layers were separated. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off from organic layer and residue was taken in methanol (150 ml) and stirred for 30 min. Water (200 ml) was added to the reaction mixture and stirred for 4 hrs. The precipitated solid was filtered, washed with water and air dried. Yield: 36 g Example 21: Preparation of p-tert-butyI-N-[6-(methoxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide salt (13a)( impurity).

To a solution of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide potassium salt (7) (0.5 g) in toluene (8 ml), sodium hydroxide (0.07 g) and methanol (2 ml) was added and the reaction mixture was heated to 50- 55°C and stirred for 6 hrs. Cooled the reaction mixture to 10-15°C and adjusted the pH to 3-4 with hydrochloric acid. The reaction mixture was extracted with dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulfate and distilled off to obtain the title compound as a solid. Yield: 0.4 g

Mass spectrum: [M⁺+ 1] Peak at m/z 522

IR (cm^"1): 3420 (NH str); 1375 (SO₂ str).

¹H NMR (δ): 1.25 (s, 9H); 3.78 (s, 3H), 3.83(s, 3H); 6.55-7.08 (m, 4H), 7.41-7.45 (m,

3H); 8.25-8.27 (d, 2H); 9.09-9.13 (d, 2H); 11.4 (br, IH)

Method of Analysis:

Analysis of particle size distribution of bosentan: A Malvern laser diffraction instrument (Malvern Mastersizer 2000) was used to characterize the particle size distribution of bosentan. The technique used is wet method and the instrument parameters are as follows: Material RI: 1.65; Dispersant RI: 1.468; Dispersant: Light liquid paraffin; Sensitivity: Normal; Particle shape: Irregular; Stirrer speed: 2600 rpm

High Performance Liquid Chromatography (HPLC) method Of Analysis:

The related substances of bosentan, its salts as well as its intermediates were analyzed by HPLC using the following conditions:

Apparatus : A liquid chromatograph is equipped with variable wave length UV detector; Column: Inertsil ODS 3 V, 250 X 4, 6mm, 5μm or Equivalent; Flow rate : 1.0 ml/min.; Wave length : 220 nm. ; Temperature: 25° C; Load : 20 μl

Claims

We Claim:

1. A process for the preparation of bosentan compound of formula- 1,

Formula- 1 which comprises of the following steps; a) Condensing diethyl 2-(2-methoxyphenoxy)malonate compound of formula-2

Formula-2 with pyrimidine-2-carboximidamide hydrochloride compound of formula-3

Foπmιla-5 wherein X is halogen; c) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-5, with 4-tert-butyl benzene sulfonamide compound of formula-6

H₂NO₂S- <1 >— t-Bu

Formula-6 in presence of a base in a suitable non polar aprotic solvent to provide p-tert- butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide or its salt compound of formula-7,

Formula-7 wherein X is halogen and M is a hydrogen or alkali/alkaline earth metal ion, d) reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide or its salt compound of formula-7 with ethylene glycol in the presence of a suitable base and in a suitable aprotic solvent, with or without a phase transfer catalyst to provide bosentan compound of formula- 1.

2. A process for the preparation of bosentan comprising the condensation of p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfon- amide or its salt compound of formula-7 with ethylene glycol, in presence of a base and a suitable aprotic solvent with or without a phase transfer catalyst to provide bosentan.

3. The process according to claim 2, wherein the base is selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; sodium/potassium alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; the suitable aprotic solvent is selected from a group consisting of benzene, toluene, xylene, acetonitrile, tetrahydofuran and 2-methyltetrahydrofuran and the phase transfer catalyst is selected from a group consisting of tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.

4. The use of alkali or alkaline earth metal hydroxides or their carbonates as a base in the condensation of p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]- 4-yl]benzene sulfonamide or its salt compound of formula-7 with ethylene glycol to provide bosentan.

5. The use of sodium hydroxide as a base in the condensation of p-tert-butyl-N-[6-halo-

5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide or its salt compound of formula-7 with ethylene glycol to provide bosentan.

6. The use of acetonitrile as a solvent in the condensation of p-tert-butyl-N-[6-halo-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt compound of formula-7 with ethylene glycol, to provide bosentan.

7. A process for the preparation of bosentan compound of formula- 1, which comprises of the following steps; a) Condensing diethyl 2-(2-methoxyphenoxy)malonate compound of formula- 2

Formula-3 in the presence of sodium methoxide in methanol to provide 5-(2- methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4,

Formula-4 b) reacting 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4 with phosphorous oxychloride to provide 5-(2-methoxy phenoxy)-2-(2'-pyrimidinyl)-4,6-dichloropyrimidine compound of formula-5a,

Formula-5a c) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dichloro pyrimidine compound of formula-5, with 4-tert-butyl benzene sulfonamide compound of formula-6

H₂NO₂S→k /) — t-Bu

Formula-6 in presence of potassium carbonate in toluene without presence of phase transfer catalyst, followed by treatment with aqueous hydrochloric acid to provide p-tert- butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-7a,

Formula-7a d) reacting p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7a with ethylene glycol in the presence of sodium hydroxide in acetonitrile, without the presence of a phase transfer catalyst to provide bosentan compound of formula- 1.

8. The process according to any proceeding claims, wherein the obtained bosentan is having purity of > 99.70 % area by HPLC.

9. The process according to any proceeding claims, wherein the obtained bosentan has a mean particle size in the range of 30-100 microns and D (v 0.9) in the range of

70-180 microns.

10. The process according to any proceeding claim, wherein obtained bosentan having a morphology as shown in figure-4.

11. A process for the preparation of bosentan compound of formula- 1, which comprises of the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7,

Formula-7 with a substituted allylalcohol, compound of formula-8,

HO ^^ R'

Formula-8 wherein R' is selected from alkyl or aryl; in the presence of a suitable base and in a suitable solvent, with or without a phase transfer catalyst, to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide, compound of formula-11,

Formula- 11 b) treating p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy){2,2'- biρyrimidin)-4-yl]benzene sulfonamide, compound of formula-11, with a hydroxylating agent provides dihydroxy derivative, which upon subsequent oxidation in-situ with suitable oxidizing agent, provides an aldehyde derivative 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide, compound of formula- 12,

12. A process for the synthesis of bosentan which comprises of; a) Reacting p-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl] benzene sulfonamide derivative of formula-9,

Formula-9 with a substituted allylhalide, compound of formula- 10,

Formula- 10 wherein X is halogen and R' is defined as above; in the presence of suitable base and in a suitable solvent, with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-11,

Formula-11 b) treating p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy){2,2'- bipyrimidin)-4-yl]benzene sulfonamide, compound of formula-11, with a hydroxylating agent provides dihydroxy derivative, which upon subsequent oxidation in-situ with suitable oxidizing agent, provides an aldehyde derivative 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide, compound of formula- 12,

Formulal2 c) reducing the 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'- bipyrimidin-4-yl) benzene sulfonamide, compound of formula- 12, with a suitable reducing agent in a suitable solvent to provide bosentan, compound of formula -1.

13. The process according to claim 11 & 12, wherein i) in step a) base is selected from the group which may include but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like; and the suitable solvent is selected from a group which may include but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and acetonitrile; and the phase transfer catalyst is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide; ii) ii) in step b) the hydroxylating agent is selected from OsO₄ in presence of H₂O₂ or N-methyl morpholine N-oxide or KMnO₄ or PhCO₂Ag/I₂ in a suitable solvents like methanol, ethanol, propanol, isopropanol and the like; and the oxidizing agent is selected from NaIO₄ or Pd(OAc)₄; iii) in step c), the reducing agent is selected from a group which includes but is not limited to sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride"), sodiumdihydro^Jbis-(2-methoxyethoxy)aluminate (Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, and the like; and suitable solvent is alcoholic solvent selected from the group which may include alcohols like methanol, ethanol, propanol, isopropanol and the like.

14. p-tert-butyl-N-[6-(substitutedallyloxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of general formula- 11.

Formula- 11 wherein R' is alkyl or aryl;

15. p-tert-butyl-N-[6-(piOp-2-enyloxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yljbenzene sulfonamide, compound of formula- 1 Ia.

Forraula-l la

16. 4-tert-butyl-N-(5-(2-memoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4- yl)benzene sulfonamide, compound of formula- 12.

Formula- 12

17. A process for the preparation of bosentan comprising the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene-sulfonamide compound of formula-7,

Formula-7 wherein X is halogen, with a base, in a suitable solvent and with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yljbenzene sulfonamide, compound of formula-9,

Fomula-9 b) p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-9, upon treating with 2-halo-ethan-l- ol, wherein halogen is either chlorine or bromine; in presence of suitable base, in an aprotic solvent and with or without a phase transfer catalyst, provides bosentan, compound of formula -1.

18. A process for the preparation of bosentan comprising the following steps; a) reacting p-tert-butyl-N-[6-alkoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide derivative of formula-13,

Formula-13 wherein R is alkyl, with a base, in a suitable solvent and with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4- yl]benzene sulfonamide, compound of formula-9, b) p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-9, upon treating with 2-halo-ethan-l- ol, wherein halogen is either chlorine or bromine; in presence of suitable base and in an aprotic solvent with or without a phase transfer catalyst, provides bosentan, compound of formula -1.

19. The process according to claim 17 & 18, wherein the base used is selected from the group which may include but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like; and the suitable solvent is used is selected from a group which includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, ethylene glycol, dimethylformamide and dimethylsulfoxide..

20. Crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt, compound of formula-7b, characterized by any one of the following, a) It's XRD wherein peaks were observed at about 4.2, 8.3, 9.6, 15.6, 16.3, 18.3, 19.3, 20.5, 21.0, 22.1, 26.0, 27.5, and 28.4 ± 0.2 degrees two theta. b) It's IR wherein peaks were observed at 3467.4, 3062.8, 2960.9, 1662.9, 1591.9, 1551.4, 1501.0, 1448.5, 1249.3, 858.7, 795.0, 719.8, 694.4, 586.0, and 540.6 cm^"1. c) It's DSC thermo gram having endothermic peak at about 201.14⁰C and exothermic peak at about 306.17°C.

21. A process for the preparation of crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxy phenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt, compound of formula-7b, which comprises of reacting 4,6-dichloro-5-(2-methoxyphenoxy)- 2,2'-bipyrimidine compound of formula-5a with 4-tert-butyl benzene sulfonamide compound of formula-6 in the presence of potassium carbonate and a suitable aprotic solvent like toluene, with or without a phase transfer catalyst like tetrabutyl ammonium bromide to provide crystalline p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt, compound of formula-7b.

22. A process for the preparation of high pure p-tert-butyl-N-[6-chloro-5-(2-methoxy phenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide of formula-7a, which comprises of hydrolyzing crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxy phenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt compound of formula-7b with aqueous hydrochloric acid followed by washing with acetonitrile.

23. A process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxo ethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide, compound of formula- 12, which comprise of treating p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy){2,2'-bipyrimidin)-4-yl]benzene sulfonamide, compound of formula-11, with a hydroxylating agent provides dihydroxy derivative, which upon subsequent oxidation in-situ with a suitable oxidizing agent to provide compound of formula- 12.

24. A process for the preparation of bosentan compound of formula- 1, which comprises of reducing the 4-tert-butyl-N-(5-(2-methoxyphenoxy)~6-(2-oxoethoxy)-2,2'- bipyrimidin-4-yl) benzene sulfonamide, compound of formula- 12, with a suitable reducing agent in a suitable solvent to provide bosentan, compound of formula - 1.

25. A process for the preparation of p-tert-butyl-N-[6-(substituted allyloxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-11, which comprise of reacting p-tert-butyl-N-[6-halo-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7, with a substituted allylalcohol, compound of formula-8,

Formula-8

Wherein R' is selected from alkyl or aryl ; in the presence of a suitable base and in a suitable solvent, with or without a phase transfer catalyst, (OR) by reacting p-tert-butyl-N-[6-hydroxy-5-(2- methoxyphenoxy)[2,2'-bipyrimidin] -4-yl] benzene sulfonamide compound of formula-9, with a substituted allylhalide, compound of formula- 10,

X ^^ R¹ Formula- 10 wherein X is halogen and R' is defined as above; in the presence of a suitable base and in a suitable solvent, with or without a phase transfer catalyst to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide, compound of formula-11.

26. p-tert-butyl-N-[6-(alkoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-13:

Formula- 13 wherein R is alkyl.

27. p-tert-butyl-N-[6-(methoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula- 13 a.

Formula- 13a

28. Bosentan containing the impurity p-tert-butyl-N-[6-(methoxy)-5-(2-methoxy phenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula- 13 a, in a concentration of less than 0.1 % area by HPLC.