Field of the Invention:

The present invention is directed to the novel process for preparing bosentan. Bosentan is chemically known as 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide monohydrate, having structural 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 ETA and ETB 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 methods involves the condensation of diethyl (2-methoxyphenoxy) malonate with pyrimidine-2-carboxyarmdine in presence of sodium methoxide followed by treatment with sodium hydroxide to provide the dihydroxy derivative, which is converted into dichloro derivative by 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. Another drawback is the need for isolating a pyrimidine dihalide which is believed to be a potent sensitizer.

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 in the art to develop an improved process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, which over comes all the above said problems associated with the prior processes. The present invention relates to a novel process for the preparation of bosentan which overcomes the disadvantages of the aforesaid prior-art processes. Moreover, the present process is easier to perform, 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.

Brief Description of the Invention:

The first aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula-1, which comprises of the following steps: a) Reacting the diethyl tartarate compound of formula-2 with dimethoxy propane in presence of a suitable acid in a suitable solvent to provide diethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate compound of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4,

c) condensing the compound of formula-4 with 4-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-5a in presence of a suitable base in a suitable solvent to provide N,N'-(6,6'-(2,2-dimethyl-l,3-dioxolane-4,5-diyl)bis(methylene)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-6,

d) optionally isolating the compound of formula-6 and treating it with a suitable acid in a suitable solvent to provide N,N'-(6,6'-(2,3-dihydroxybutane-l,4-diyl)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-7,

e) oxidizing the compound of formula-7 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8,

f) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

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 the following steps:

a) Reacting the propane-1,2,3-triol compound of formula-9 with acetone in presence of paratoluene sulfonic acid in a suitable solvent to provide (2,2-dimethyl-l,3-dioxolan-4-yl)methanol compound of formula-10,

b) condensing the compound of formula-10 with 4-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-5a in presence of a suitable base in a suitable solvent to provide 4-tert-butyl-N-(6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-11,

c) optionally isolating the compound of formula-11 and then treating it with a suitable acid in a suitable solvent to provide the compound of formula-12 (or) by in-situ treating the compound of formula-11 with an acid to provide the 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-12,

d) oxidizing the compound of formula-12 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yi)benzene sulfonamide compound of formula-8,

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent 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 the following steps:

a) Reacting the 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-5a, with an allyl alcohol in presence of a base in a suitable solvent, with or without using a phase transfer catalyst to provide N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzene sulfonamide compound of formula-13,

b) epoxidizing the compound of formula-13 with a suitable reagent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14,

c) opening the epoxide ring of compound of formula-14 with or without using a suitable reagent in presence or absence of a base in a suitable solvent to provide 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-12,

d) oxidizing the compound of formula-12 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8,

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

The fourth aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula-1, comprises of:

a) Reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-16 with a-halo ester compound of general formula-17 in presence of a base in a suitable solvent to provide alkyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy) acetate compound of general formula-18, b) reducing the compound of general formula-18 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

The fifth aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8, comprises of:

a) Reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5 with allyl alcohol in the presence of a base in a suitable solvent, with or without using a phase transfer catalyst to provide N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butyl benzenesulfonamide compound of formula-13,

b) oxidizing the compound of formula-13 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-8.

The sixth aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula-1, comprises of:

a) Oxidizing the N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2' -bipyrimidin-4-yl)-4-tert-butylbenzenesulfonamide compound of formula-13 with a suitable oxidizing agent in a suitable solvent to provide 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yloxy)acetic acid compound of formula-15,

b) reducing the compound of formula-15 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

The seventh aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, which comprises of reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of general formula-5 with oxiran-2-ylmethanol in presence of a base in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxy phenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14.

The eighth aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, which comprises of reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-16 with epichlorohydrin in presence of a base in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, compound of formula-14.

The ninth aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8, comprises of:

a) Reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-16 with chloroacetonitrile in presence of a suitable base in a suitable solvent to provide 4-tert-butyl-N-(6-cyanomethoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-19,

b) reducing the compound of formula-19 with a suitable reducing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8.

Advantages of the Present Invention:

• The major advantage of the present invention is that, the process does not involve a monoanion ethylene glycol (e.g. sodium ethylene glycol), which is difficult to handle on large scale synthesis.

• Use of milder reagents when compared to the processes of prior art.

• Easy to perform and economically viable process.

Detailed description of the invention:

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate* "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like methylene chloride, chloroform and ethylene dichloride; "nitrile solvents" like acetonitrile and propionitrile; polar solvents like water; and mixtures thereof.

As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of.

As used herein the present invention the term "suitable reducing agent" refers to a group which includes but is not limited to sodium borohydride, lithium tri-sec-butyl borohydride ("L-selectride"), sodium dihydro-bis-(2-methoxyethoxy) aluminate (Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, Pd/C, Raney-Ni, sodium borohydride-BF3 etherate and the like.

As used here in the present invention the term "suitable oxidizing agent" refers to a group which includes but is not limited to nitric acid, hydrogen peroxide, per acids such as per acetic acid, trifluoro per acetic acid, per benzoic acid, m-chloro per benzoic acid and the like, ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metaperiodate, ruthenium trichloride and the like

As used herein the present invention the term "peroxy acid" refers to a group which includes but is not limited to hydrogen peroxide; alkyl hydro peroxide such as tertiary butyl hydroperoxide, ethyl benzene hydroperoxide; peroxy carboxylic acid such as peroxy acetic acid, trifluoro peroxy acetic acid, perbenzoic acid, m-chloroperbenzoic acid; Mn-salen catalyst/aq. Sodium hypo chlorite and dimethyldioxirane.

As used herein the present invention the term "the suitable acid" refers to a group which includes but is not limited to inorganic acids such as hydrochloric acid, hydro bromic acid, sulfuric acid, nitric acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluene sulfonic acid and malic acid.

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, lithium iodide and like.

The first aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula-1, which comprises of the following steps:

a) Reacting the diethyl tartarate compound of formula-2 with dimethoxy propane in presence of an acid in a suitable solvent to provide diethyl 2,2-dimethyl-l,3-dioxolane-4,5-dicarboxylate compound of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4,

c) condensing the compound of formula-4 with 4-tert-butyl-N-(6-halo-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5 in presence of a suitable base in a suitable solvent to provide N,N'-(6,6'-(2,2-dimethyl-l,3-dioxolane-4,5-diyl)bis(methylene)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-6,

d) optionally isolating the compound of formula-6 and treating it with a suitable acid in a suitable solvent to provide the compound of formula-7 (or) by in-situ treating the compound of formula-6 with a suitable acid in a suitable solvent to provide the N,N-(6,6'-(2,3-dihydroxybutane-l,4-diyl)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-7,

e) oxidizing the compound of formula-7 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8,

f) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

Wherein in step a) the suitable solvent is selected from ketone solvents, ester solvents, ether solvents and alcohol solvents or mixtures thereof, preferably acetone.

In step b) the suitable solvent is selected from alcohol solvents, ether solvents, diglyme, and water or mixtures thereof, preferably methanol.

In step c) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium tertiary butoxide; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents, preferably acetonitrile.

In step c) & d) the suitable acid is selected from inorganic acids, preferably hydrochloric acid; and the suitable solvent is selected from alcohol solvents, polar solvents, ester solvents, ketone solvents or mixtures thereof, preferably methanol.

In step e) the suitable oxidizing agent is preferably sodium metaperiodate; and the suitable solvent is selected from chloro solvents, ketone solvents, polar solvents, nitrile solvents or their mixtures thereof, preferably acetone/water mixture.

In step f) the suitable reducing agent is preferably sodium borohydride; and the suitable solvent is selected from alcohol solvents, ether solvents, preferably tetrahydrofuran.

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 the following steps:

a) Reacting the propane-1,2,3-triol compound of formula-9 with acetone in presence of paratoluene sulfonic acid or other dehydrating agent in a suitable solvent to provide (2,2-dimethyl-l,3-dioxolan-4-yl) methanol compound of formula-10,

b) condensing the compound of formula-10 with 4-tert-butyl-N-(6-halo-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of general formula-5 in presence of a suitable base in a suitable solvent to provide 4-tert-butyl-N-(6-((2,2- dimethyl-l,3-dioxolan-4-yl)methoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-11,

c) optionally isolating the compound of formula-11 and then treating it with a suitable acid in a suitable solvent to provide the compound of formula-12 (or) by in-situ treating the compound of formula-11 with an acid to provide the 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-12,

d) oxidizing the compound of formula-12 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8,

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

Wherein in step a) the suitable solvent is selected from ketone solvents, ester solvents, ether solvents and alcohol solvents, hydrocarbon solvents or mixtures thereof; preferably pet ether.

In step b) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, and nitrile solvents, preferably acetonitrile; the suitable acid is selected from inorganic acids, preferably hydrochloric acid.

In step c) the suitable acid is selected from inorganic acids, preferably hydrochloric acid; and the suitable solvent is selected from alcohol solvents, polar solvents, ester solvents, ketone solvents or mixtures thereof, preferably methanol.

In step d) the suitable oxidizing agent is preferably sodium metaperiodate; and the suitable solvent is selected from chloro solvents, ketone solvents, polar solvents, or their mixtures thereof, preferably acetone/water mixture.

In step e) the suitable reducing agent is preferably sodium borohydride; and the suitable solvent is selected from alcohol solvents, ether solvents, preferably tetrahydrofuran.

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 the 4-tert-butyl-N-(6-halo-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5 with allyl alcohol in the presence of a base in a suitable solvent, with or without using a phase transfer catalyst provides N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2,-bipyrimidin-4-yl)-4-tert-butyl benzenesulfonamide compound of formula-13,

b) epoxidizing the compound of formula-13 with a suitable reagent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, Formula-14

c) opening the epoxide ring of compound of formula-14 with or without using a suitable reagent in a suitable solvent to provide 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-12,

d) oxidizing the compound of formula-12 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8,

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

Wherein in step a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile.

In step b) the suitable reagent for epoxidation is selected from per acids, preferably metachloro perbenzoic acid; and the suitable solvent is selected from chloro solvents, ether solvents, preferably methylene chloride.

In step c) the suitable reagent for opening the epoxide ring is carbon tetrabromide;

In step d) the suitable oxidizing agent is preferably sodium metaperiodate; and the suitable solvent is selected from ether solvents, nitrile solvents, ketone solvents, polar solvents or their mixtures thereof, preferably acetone/water mixture.

In step e) the suitable reducing agent is preferably sodium borohydride; and the suitable solvent is selected from alcoholic solvents, ether solvents, chloro solvents, preferably tetrahydrofuran.

The fourth aspect of the present invention provides a novel process for the preparation of bosentan compound of formula-1, comprises of:

a) Reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-16 Formula-16 with a-halo ester compounds of general formula-17

XCH2COOR Formula-17

where X is a halogen and R is H or C1-C9 alkyl

in presence of a suitable base in a suitable solvent to provide alkyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetate compound of general formula-18 Formula-18 wherein R = H or C1 to C9 alkyl

b) reducing the compound of general formula-18 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

Wherein in step a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium carbonate; and the suitable solvent is selected from hydrocarbon solvents, polar aprotic solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably toluene/dimethyl sulfoxide mixture.

In the step b) the suitable reducing agent is preferably sodium borohydride; and the suitable solvent is selected from alcohol solvents, ether solvents, preferably tetrahydrofuran.

During the preparation of bosentan by the above aspect of the invention, we have observed that the N-alkylated compound (herein designated as "N-alkyl ester impurity) having the following structural formula is formed as an impurity.

N-alkyl ester impurity The said N-alkyl ester impurity has been removed during further purifications using suitable solvents in final stages.

The fifth aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8, comprises of:

a) Reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5, with allyl alcohol in the presence of a base in a suitable solvent, with or without using a phase transfer catalyst to provide N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butyl benzenesulfonamide compound of formula-13,

b) oxidizing the compound of formula-13 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, compound of formula-8.

Wherein in step a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile.

In step b) the suitable oxidizing agent is ruthenium chloride in presence of sodium metaperiodate; and the suitable solvent is selected from ketone solvents, ether solvents, polar solvents and their mixtures thereof, preferably acetonitrile/water mixture. Potassium permanganate in presence of tetrahydrofuran is also used as an oxidizing agent.

The sixth aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula-1, comprises of:

a) Oxidizing the N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2' -bipyrimidin-4-yi)-4-tert-butylbenzenesulfonamide compound of formula-13 with a suitable oxidizing agent in a suitable solvent to provide 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yloxy)acetic acid compound of formula-15,

Formula-15 b) reducing the compound of formula-15 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

Wherein in step a) the suitable oxidizing agent is potassium permanganate in presence of acid; and the suitable solvent is selected from ketone solvents, nitrile solvents, ether solvents, polar solvents and their mixtures thereof, preferably tetrahydrofuran.

In step b) the suitable reducing agent is preferably sodium borohydride-BF3 etherate; and the suitable solvent is selected from alcohol solvents, ether solvents, preferably tetrahydrofuran.

The seventh aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'- bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, which comprises of reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5 with oxiran-2-ylmethanol in presence of a base in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxy phenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, compound of formula-14.

The eighth aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, which comprises of reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-16 with epichlorohydrine in presence of a base in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14.

Wherein in the above aspects of 7 & 8, the suitable base used is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile.

The ninth aspect of the present invention is to provide a novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8, comprises of:

a) Reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-16 with chloroacetonitrile in presence of a suitable base in a suitable solvent to provide 4-tert-butyl-N-(6-cyanomethoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-19, Formula-19 b) reducing the compound of formula-19 with a suitable reducing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'- bipyrimidin-4-yl)benzenesulfonamide compound of formula-8.

Wherein in step-a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium carbonate; the suitable solvent is selected from polar aprotic solvents like dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, preferably dimethyl formamide.

In step-b) the suitable reducing agent is preferably DIBAL; the suitable solvent is selected from hydrocarbon solvents like toluene, hexane, heptane and cyclohexane, preferably toluene.

The present invention can be represented schematically by the following schemes: Scheme-1:

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: Preparation of diethyl 2,2-dimethyl-l,3-dioxolane-4,5-dicarboxylate compound of formula-3.

Para-toluene sulfonic acid monohydrate ( 4.68 g) followed by 2,2-dimethoxy propane (50.48 g) was added to a solution of diethyl tartarate compound of formula-2 (50 g) in acetone ( 400 ml) at 25-30°C. The reaction mixture was heated to 50-55°C and stirred for 10 hours and concentrated the reaction mixture to remove acetone. Ethyl acetate and water were added to the above reaction mixture and both the organic and aqueous layers were separated. Extracted the aqueous layer with ethyl acetate. Both the organic layers were combined, dried, filtered and distilled to get the title compound. Yield: 56 grams Example 2: Preparation of (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4.

Sodium borohydride (30.08 g) was added to diethyl 2,2-dimethyl-l,3-dioxolane-4,5-dicarboxylate compound of formula-3 (40 g) in anhydrous methanol (640 ml) at 0°C. The reaction mixture temperature was raised to 25-30°C and stirred for 4 hours. After the reaction was completed, ethyl acetate and water were added to the reaction mixture and both the organic and aqueous layers were separated. Extracted the aqueous layer with ethyl acetate. Both the organic layers were combined, dried, filtered and distilled to get the title compound. Yield: 22.5 grams

Example-3: Preparation of N,N'-(6,6'-(2,2-dimethyl-l,3-dioxolane-4,5-diyl)bis (methylene)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butyl benzene sulfonamide) compound of formuIa-6.

A mixture of (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4 (0.77 g), acetonitrile (50 ml) and sodium tertiary butoxide (2.73 g) was heated to 80-85°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-3 0°C, added 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-5a (5 g) to it. Heated the reaction mixture to 80-85°C and stirred for 8 hours at the same temperature. Water (50 ml) and ethylacetate were added to the reaction mixture. Separated the both aqueous and organic layers and
the organic layer was distilled off completely under reduced pressure to get the title compound. Yield: 4.5 grams

Example-4: Preparation of N,N'-(6,6'-(l,2-dihydroxyethane-l,2-diyI)bis(oxy) bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-burylbenzene sulfonamide) compound of formula-7.

To a solution of N,N'-(6,6'-(2,2-dimethyl-l,3-dioxolane-4,5-diyl)bis(methylene) bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzene sulfonamide) compound of formula-6 (10 g) in methanol (50 ml) conc.HCl was added at 25-30°C untill the pH reached to 2. Stirred the reaction mixture for 1 hour at same temperature. Distilled off the solvent from the reaction mixture and added water and ethyl acetate to the obtained compound. Separated the both aqueous and organic layers and extracted the aqueous layer with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 8.5 grams

Example 5: Preparation of N,N'-(6,6'-(l,2-dihydroxyethane-l,2-diyl)bis(oxy) bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzene sulfonamide) compound of formula-7.

A mixture of (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4 (0.77 g), acetonitrile (50 ml) and sodium tertiary butoxide (5.47 g) was heated to 80-85°C and stirred for 4 hours. 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-5 (5 g) was added to the above reaction mixture and stirred for 12 hours at 80-85°C and then cooled to 25-30°C. Water and cone. HC1 were added to the above reaction mixture and stirred for 1 hour at 25-3 0°C. Ethyl acetate was added and both the organic and aqueous layers were separated. Extracted the aqueous layer with ethyl acetate. Both the organic layers were combined, dried, filtered and distilled to get the title compound. Yield: 5 grams Example 6: Preparation of N,N'-(6,6'-(l,2-dihydroxyethane-l,2-diyl)bis(oxy) bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzene sulfonamide) compound of formula-7.

A mixture of (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4 (0.77 g), tetra hydro furan (50 ml) and sodium hydroxide(1.00 g) was heated to 70-75°C and stirred for 4 hours. 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-5 (5 g) was added to the above reaction mixture and stirred for 12 hours at 70-75°C and then cooled to 25-30°C. Water and cone. HC1 were added to the above reaction mixture and stirred for 1 hour at 25-30°C. Ethyl acetate was added and both the organic and aqueous layers were separated. Extracted the aqueous layer with ethyl acetate. Both the organic layers were combined, dried, filtered and distilled to get the title compound. Yield: 5 grams Example 7: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bi pyrimidin-4-yl)benzenesulfonamide compound of formula-8.

A mixture of N,N'-(6,6'-(l,2-dihydroxyethane-l,2-diyl)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-7(5 g), acetone (35 ml), water (15 ml) and sodium metaperiodate (2.8 g) was stirred for 2 hours at 25-30°C. After completion of the reaction, distilled off the solvent from the reaction mixture. Water followed by ethyl acetate was added to the reaction mixture and separated the both aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Combined the organic layers, and distilled off the solvent completely under reduced pressure to get the title compound.Yield: 4.2 grams Example 8: Preparation of bosentan compound of formula-1.

A solution of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8 (10 g) in methanol (100 ml) was cooled to 0-5°C and sodium borohydride (0.69 g) was slowly added in portions. Stirred the reaction mixture for 2 hr. The reaction mixture was poured into crushed ice and acidified with hydrochloric acid. Ethyl acetate was added to the reaction mixture and separated the both aqueous and organic layers. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 8 grams. Example 9: Preparation of (2,2-dimethyl-l,3-dioxolan-4-yl)methanol compound of formula-10.

To a solution of propane-1,2,3-triol compound of formula-9 (25 g) in pet ether (250 ml), acetone (100 ml) and para-toluene sulfonic acid monohydrate (3.0 g) were added at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 40 hours at the same temperature. Cooled the reaction mixture to 25-30°C added sodium acetate(3 g) and stirred for 30 minutes. Filtered the reaction mixture and the filtrate was distilled off completely under reduced pressure to get the title compound. Yield: 29 grams Example 10: Preparation of 4-tert-butyl-N-(6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-ll.

A mixture of (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-10 (0.627 g), acetonitrile (50 ml) and sodium tertiary butoxide (5.47 g) was heated to 80-85°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30°C, 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-5 (5 g) was added to it. Heated the reaction mixture to 80-85°C and stirred for 8 hours at same temperature. Cooled the reaction mixture to 25-30°C, water followed by ethyl acetate were added. Separated the both aqueous and organic layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 4.8 grams

Example 11: Preparation of 4-tert-butyl-N-(6-(l,2-dihydroxyethoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-12.

To the solution of 4-tert-butyl-N-(6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-ll (10 g) in methanol (50 ml) conc.HCl was added at 25-30°C until the pH reached to 2. Stirred the reaction mixture for 1 hour at same temperature. Distilled off the solvent from the reaction mixture and added water and ethyl acetate to the obtained compound. Separated the both aqueous and organic layers and extracted the aqueous layer with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 7.5 grams

Example 12: Preparation of 4-tert-butyl-N-(6-(l,2-dihydroxyethoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-12.

A mixture of (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-10 (0.627 g), acetonitrile (50 ml) and sodium tertiary butoxide (5.47 g) was heated to 80-85°C and stirred for 4 hours at same temperature. Cooled the reaction mixture to 25-30°C, 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4- )benzenesulfonamide compound of formula-5a (5 g) was added to it. Heated the reaction mixture to 80-85°C and stirred for 8 hours at same temperature. Cooled the reaction mixture to 25-30°C, water (50 ml) was added to it. Acidified the reaction mixture with cone, hydrochloric acid and stirred the reaction mixture for lhour at 25-30°C. Ethylacetate was added to the reaction mixture, separated the both aqueous and organic layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 4.5 grams

Example 13: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bi pyrimidin-4-yl)benzenesuIfonamide compound of formula-8.

A mixture of 4-tert-butyl-N-(6-(l,2-dihydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide

compound of formula-12 (5 g), acetone (35 ml), water (15 ml) and sodium metaperiodate (5.5 g) was stirred for 2 hours at 25-30°C. After the reaction completed, distilled off the solvent completely. Ethyl acetate was added to the reaction mixture and separated the both aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Combined the organic layers and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 4.1 grams Example 14: Preparation of N-(6-(alIyIoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzenesulfonamide compound of formula-13:

A mixture of prop-2-en-l-ol (2.1 g), acetonitrile (50 ml) and sodium hydroxide (0.76 g) was heated to 80-85°C. Stirred the reaction mixture for 3-4 hours at the same temperature. The reaction mixture was cooled to 25-30°C and added 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-5a (5 g) to it. Heated the reaction mixture to 80-85°C and stirred for 8 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C and water (50 ml) was added to it. Acidified the reaction mixture with cone, hydrochloric acid. Filtered the precipitated solid and dried the material to get the title compound. Yield: 4.7 grams

Example 15: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-yImethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-14:

A solution of meta chloro perbenzoic acid (0.7 g) in dichloromethane (20 ml) was slowly added to the mixture of N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzenesulfonamide compound of formula-13 (2 g) in dichloromethane (40 ml) at 0-5°C. The reaction mixture was stirred for 30 minutes at 0-5°C and then washed with 10% sodium carbonate solution followed by saturated sodium chloride solution. The solvent was distilled off completely to get the title compound. Yield: 1.5 grams

Example 16: Preparation of 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yI)benzenesulfonamide compound of formula-12:

A mixture of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-14 (2 g), carbon tetrabromide (0.1 g) and water (10 ml) was heated to 60°C. The reaction mixture was stirred for 10 hours. After completion of the reaction the reaction mixture was cooled to 20-25°C. Water was added to the reaction mixture followed by dichloromethane and both the organic and aqueous layers were separated. The organic layer was distilled off completely under reduced pressure to get the title compound. Yield:

1.34 grams Example 17: Preparation of 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-12:

A mixture of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-14 (2 g) and water (100 ml) was heated to 100°C and then stirred for 12 hours at 100°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and the solvent was extracted with ethyl acetate. The organic layer was dried and distilled off completely under reduced pressure to get the title compound. Yield: 1.6 grams

Example 18: Preparation of 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yloxy)acetic acid compound of formula-15:

To a solution of N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzene sulfonamide compound of formula-13 (5 g) in methanol (150 ml)was slowly added to a mixture of potassium permanganate (2.89 g) and water (50 ml). The reaction mixture was heated to 50°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture and the filtrate was extracted with ethyl acetate. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 3.8 grams Example 19: Preparation of 4-tert-buryl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8:

To a solution of N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzene sulfonamide compound of formula-13 (1 g) in tetrahydrofuran (30 ml) was slowly added potassium permanganate(0.504 g) dissolved in water (10 ml). The reaction mixture was heated to 40°C and then stirred for 1 hour at the same temperature. Filtered the reaction mixture to remove the unwanted precipitates and the filtrate was extracted with ethyl acetate. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 0.6 grams

Example 20: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8:

To a solution of N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzene sulfonamide compound of formula-13 (2 g) in acetonitrile (180 ml), ruthenium chloride stock solution (10 ml) and sodium metaperiodate (1.56 g) in water (20 ml) were added. The reaction mixture was stirred for 1.5 hrs at 25-30°C. Filtered the reaction mixture and the filtrate was extracted with ethyl acetate. Separated the both aqueous and organic layers and washed the organic layer with 10% sodium thiosulphate solution. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 1.3 grams

Example 21: Preparation of Bosentan compound of formula-1

A solution of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8 (10 g) in tetrahydrofuran (100 ml) was cooled to 0-5°C and sodium borohydride (0.69 g) was slowly added in portions. Stirred the reaction mixture for 2 hr. The reaction mixture was poured into crushed ice and then acidified with hydrochloric acid. Added ethyl acetate to the reaction mixture and separated the both aqueous and organic layers. Distilled off the solvent completely from organic layer under reduced pressure to get the title compound. Yield: 8 grams

Example 22: Preparation of Bosentan compound of formula-1

Sodiumborohydride (0.13 gram) was added to the solution of 2-(6-(4-tert- butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetic acid compound of formula-15 (2 g) in tetrahydrofuran (20 ml) at 0-5°C. The reaction mixture was stirred for one hour and then BF3-etherate (0.59 g) was added to the reaction mixture at 0-5°C. After completion of the addition raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours. Quenched the reaction mixture with aqueous hydrochloric acid and methylene chloride was added. Separated the both aqueous and organic layers and aqueous layer was extracted with dichloromethane and combined the organic layers. Washed the organic layer with 10% sodium bicarbonate solution. Distilled off the solvent completely under reduced pressure to get title compound. Yield: 1.26 gms. Example 23: Preparation of 4-tert-butyI-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-ipyrimidin-4-yl)benzenesulfonamide compound of formula-14

A mixture of oxiran-2-ylmethanol (1.4 g), acetonitrile (50 ml) and sodium hydroxide (0.76 g) was heated to 80-85°C and the reaction mixture was stirred for 3-4 hours at the same temperature. Cooled the reaction mixture to 25-30°C, added 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-5a (5 g) to it. Heated the reaction mixture to 80-85°C and stirred for 8 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C and added water (50 ml). Acidified the reaction mixture with hydrochloric acid. Filtered the precipitated solid and dried the material to get the title compound. Yield: 4.75 grams

Example 24: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-14

A mixture of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-16 (4 g), acetonitrile (40 ml) and sodium hydroxide (0.63 g) was heated to 80-85°C and the reaction mixture was stirred for 3-4 hours at the same temperature. Cooled the reaction mixture to 25-30°C and then 2-(chloromethyl)oxirane (0.73 g) was added to it. Heated the reaction mixture to 80-85°C and stirred for 8 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C, water (50 ml) was added to it. Acidified the reaction mixture with hydrochloric acid. Filtered the precipitated solid to get the title compound. Yield: 4.1 grams

Example 25: Preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8

A mixture of 4-tert-butyl-N-(6-(2,3-dmydroxypropoxy)-5-(2-memoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-12 (5 g), acetone (35 ml), water (15 ml) and sodium metaperiodate (3.67 g) was stirred for 3 hours at 25-30°C. After the completion of the reaction, distilled off the solvent from the reaction mixture. Ethyl acetate was added to the reaction mixture and separated the both aqueous and organic layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers, dried with sodium sulphate and then distilled off the solvent completely under reduced pressure to get the title compound. Yield: 3.5 grams

Example 26: Preparation of ethyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetate compound of formula-18

A mixture of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-16 (10 g), sodium carbonate (8.35 g), toluene (50 ml) and dimethyl sulfoxide (50 ml) was heated to 110-115°C and the reaction mixture was stirred for 4 hours. Ethyl 2-bromoacetate (6.54 g) was added slowly to the reaction mixture at 110-115°C and the reaction mixture was stirred for 3 hours at the same temperature. The reaction mixture was cooled to 25-30°C and water was added to it. Acidified the reaction mixture with hydrochloric acid. Ethyl acetate was added to the reaction mixture and separated the both aqueous and organic layers. The organic layer was distilled off completely under reduced pressure to get the title compound. Yield: 9.35 grams; M.R:178- 182°C

Example 27: Preparation of Bosentan of formula-1

A solution of ethyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy)acetate compound of formula-18 (1.5 g) in tetrahydrofuran (15 ml) was cooled to 0-5°C and sodium borohydride (0.69 g) was slowly added in portions. Stirred the reaction mixture for 1 hour at 0-5°C. The reaction mixture was poured into crushed ice and acidified with hydrochloric acid. The reaction mixture was extracted with ethyl acetate. Distilled off the ethyl acetate layer completely under reduced pressure to get the title compound.Yield: 1.1 grams

Example 28: Preparation of N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzenesulfonamide compound of formula-13:

A mixture of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-16 (5 g), acetonitrile (50 ml) and sodium hydroxide (0.78 g) was heated to 80-85°C and the reaction mixture was stirred for 3-4 hours at same temperature. The reaction mixture was cooled to 25-30°C and then 3-chloroprop-1-ene (0.75 g) was added to it. Heated the reaction mixture to 80-85°C and the reaction mixture was stirred for 8 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C and then water (50 ml) was added to the reaction mixture. Acidified the reaction mixture with hydrochloric acid. Filtered the precipitated solid and dried to get the title compound. Yield: 3.7 grams

Example 29: Preparation of 4-tert-butyI-N-(6-cyanomethoxy-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-19 10 grams of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-16 was dissolved in 100 ml of dimethylformamide and added 8.35 grams of sodium carbonate. Heated the reaction mixture to reflux temperature. Cooled the reaction mixture to 50°C and added 4.5 grams of chloro acetonitrile to it. Heated the reaction mixture to reflux temperature and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture and acidified with aqueous hydrochloric acid. Ethyl acetate was added to the reaction mixture and separate the both aqueous and organic layers. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 9.0 grams.

Example 30: Preparation of 4-tert-butyI-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyriniidin-4-yl)benzenesulfonamide compound of formula-8

10 grams of 4-tert-butyl-N-(6-cyanomethoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-19 was dissolved in 100 ml of toluene. Cooled the reaction mixture to -40°C to -60°C. 19 ml of DIBAL was added to the reaction mixture and stirred for 2 hours at the same temperature. Quenched the reaction mixture with aqueous hydrochloric acid. Separated the both aqueous and organic layers. Organic layer was washed with water. Distilled off the solvent completely to get the title compound. Yield: 8.0 grams.

We Claim:

1. A novel process for the preparation of bosentan compound of formula-1, which comprises of the following steps:

a) Reacting the diethyl tartarate compound of formula-2

Formula-2 with dimethoxy propane in presence of a acid in a suitable solvent to provide diethyl 2,2-dimethyl-l,3-dioxolane-4,5-dicarboxylate compound of formula-3,

Formula-3

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide (2,2-dimethyl-l,3-dioxolane-4,5-diyl)dimethanol compound of formula-4,

Formula-4

c) condensing the compound of formula-4 with 4-tert-butyl-N-(6-halo-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5

Formula-5

Wherein X is halogen in presence of a suitable base in a suitable solvent to provide N,N'-(6,6'-(2,2-dimethyl-l,3-dioxolane-4,5-diyl)bis(methylene)bis(oxy)bis(5-(2-methoxy phenoxy)-2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-6

Formula-6

d) optionally isolating the compound of formula-6 and treating it with a suitable acid in a suitable solvent to provide compound of formula-7 (or) by in-situ treating the compound of formula-6 with a suitable acid in a suitable solvent to provide the N,N'-(6,6'-(2,3-dihydroxybutane-l,4-diyl)bis(oxy)bis(5-(2-methoxyphenoxy)- 2,2'-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) compound of formula-7

Formula-7

e) oxidizing the compound of formula-7 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'- bipyrimidin-4-yl)benzenesulfonamide compound of formula-8,

Formula-8

f) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

2. A process according to claim-1, wherein, in step a) the suitable solvent is selected from ketone solvents, ester solvents, ether solvents and alcohol solvents or mixtures thereof, preferably acetone.

in step b) the suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, Pd/C, Raney-Ni, sodium borohydride-BF3 etherate, preferably sodium borohydride; and the suitable solvent is selected from alcohol solvents, ether solvents, diglyme and water or mixtures thereof, preferably methanol.

in step c) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium tertiary butoxide; the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents, preferably acetonitrile; and the suitable acid is selected from inorganic acid such as hydrochloric acid, hydro bromic acid, sulfuric acid and nitric acid.

in step d) the suitable acid is selected from inorganic acids, preferably hydrochloric acid; and the suitable solvent is selected from alcohol solvents, polar solvents, ester solvents, ketone solvents or mixtures thereof, preferably methanol.

in step e) the suitable oxidising agent is preferably sodium metaperiodate; and the suitable solvent is selected from chloro solvents, ketone solvents, polar solvents, nitrile solvents or their mixtures thereof, preferably acetone/water mixture.

in step f) the suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, Pd/C, Raney-Ni, sodium borohydride-BF3 etherate, preferably sodium borohydride; and the suitable solvent is selected from alcohol solvents, ether solvents, preferably tetrahydrofuran.

3. A novel process for the preparation of bosentan compound of formula-1, which comprises of the following steps:

a) Reacting the propane-1,2,3-triol compound of formula-9

Formula-9 with acetone in presence of paratoluenesulfonic acid or other dehydrating agent in a suitable solvent to provide (2,2-dimethyl-l,3-dioxolan-4-yl)methanol compound of formula-10,

Formula-10

b) condensing the compound of formula-10 with 4-tert-butyl-N-(6-halo-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5 in presence of a suitable base in a suitable solvent to provide 4-tert-butyl-N-(6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-11,

Formula-11

c) optionally isolating the compound of formula-11 and then treating it with a suitable acid in a suitable solvent to provide the compound of formula-12 (or) by in-situ treating the compound of formula-11 with an acid to provide the 4-tert- butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2,-bipyrimidin-4- l)benzene sulfonamide compound of formula-12,

Formula-12

d) oxidizing the compound of formula-12 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2- oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8,

Formula-8

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

4. A process according to claim-3, wherein,

in step a) the suitable solvent is selected from ketone solvents, ester solvents, ether solvents and alcohol solvents, hydrocarbon solvents or mixtures thereof, preferably pet ether.

in step b) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide; the suitable solvent is selected from hydrocarbon solvents, ether solvents, and nitrile solvents, preferably acetonitrile; and the suitable acid is selected from inorganic acids, preferably hydrochloric acid.

in step c) the suitable acid is selected from inorganic acids, preferably hydrochloric acid; and the suitable solvent is selected from alcohol solvents, polar solvents, ester solvents, ketone solvents or mixtures thereof, preferably methanol.

in step d) the suitable oxidizing agent is preferably sodium metaperiodate; and the suitable solvent is selected from chloro solvents, ketone solvents, polar solvents, or their mixtures thereof, preferably acetone/water mixture.

in step e) the suitable reducing agent is preferably sodium borohydride; and the suitable solvent is selected from alcohol solvents, ether solvents, preferably tetrahydrofuran.

5. A novel process for the preparation of bosentan compound of formula-1, which comprises of the following steps:

a) Reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of general formula-5, with allyl alcohol in the presence of a base in a suitable solvent, with or without using a phase transfer catalyst to provide N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butylbenzene sulfonamide compound of formula-13,

b) epoxidizing the compound of formula-13 with a suitable reagent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14,

c) opening the epoxide ring of compound of formula-14 with or without using a suitable reagent in a suitable solvent to provide 4-tert-butyl-N-(6-(2,3-dihydroxypropoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-12,

d) oxidizing the compound of formula-12 with a suitable oxidizing agent in a suitable solvent to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8,

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide bosentan compound of formula-1.

6. A process according to claim-5, wherein,
in step a) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile.

in step b) the suitable reagent for epoxidation is selected from per acids such as m-chloroperbenzoic acid, peroxy acetic acid, trifluoro peroxy acetic acid, perbenzoic acid, preferably m-chloroperbenzoic acid; and the suitable solvent is selected from chloro solvents, ether solvents, preferably methylene chloride.

in step c) the suitable reagent for opening the epoxide ring is carbon tetrabromide and the suitable solvent is selected from polar solvents and alcohol solvents.

in step d) the suitable oxidizing agent is preferably sodium metaperiodate; and the suitable solvent is selected from ether solvents, nitrile solvents, ketone solvents, polar solvents or their mixtures thereof, preferably acetone/water mixture.

in step e) the suitable reducing agent is selected from sodium borohydride, lithium aluminium hydride, Pd/C, Raney-Ni, sodium borohydride-BF3 etherate, preferably sodium borohydride; and the suitable solvent is selected from alcoholic solvents, ether solvents, chloro solvents, preferably tetrahydrofuran. 7. A novel process for the preparation of bosentan compound of formula-1, which comprises of the following steps:

a) Reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzenesulfonamide compound of formula-16

Formula-16

with a-halo ester compounds of general formula-17

XCH2COOR Formula-17

wherein, X is a halogen and R is H or C1-C9 alkyl;

in presence of a suitable base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium carbonate in a suitable solvent selected from hydrocarbon solvents, polar aprotic solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably mixture of toluene/dimethyl sulfoxide to provide alkyl 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yloxy)acetate compound of general formula-18

Formula-18 wherein R = H or C1 to C9 alkyl; b) reducing the compound of general formula-18 with a suitable reducing agent preferably sodium borohydride in a suitable solvent selected from alcohol solvents, ether solvents, preferably tetrahydrofuran to provide bosentan compound of formula-1.

8. A novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2- oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8, comprises of:

a) Reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of general formula-5, with allyl alcohol in the presence of a base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide in a suitable solvent selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile with or without a phase transfer catalyst to provide N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butyl benzenesulfonamide compound of formula-13,

b) oxidizing the compound of formula-13 with a suitable oxidizing agent selected from ruthenium chloride in presence of sodium metaperiodate or potassium permanganate in presence of tetrahydrofuran in a suitable solvent selected from ketone solvents, ether solvents, polar solvents and their mixtures thereof, preferably acetonitrile/water mixture to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide, compound of formula-8.

9. A novel process for the preparation of bosentan compound of formula-1, comprises of:

a) Oxidizing the N-(6-(allyloxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-4-tert-butyl benzenesulfonamide compound of formula-13 with a suitable oxidizing agent selected from potassium permanganate in presence of acid in a suitable solvent selected from ketone solvents, nitrile solvents, ether solvents, polar solvents and their mixtures thereof, preferably tetrahydrofuran to provide 2-(6-(4-tert-butylphenylsulfonamido)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yloxy) acetic acid compound of formula-15,

b) reducing the compound of formula-15 with a suitable reducing agent preferably sodium borohydride-BF3 etherate in a suitable solvent selected from alcohol solvents, ether solvents, preferably tetrahydrofuran to provide bosentan compound of formula-1.

10. A novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, which comprises of reacting the 4-tert-butyl-N-(6-halo-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of general formula-5 with oxiran-2-ylmethanol in presence of a suitable base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide in a suitable solvent selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-14.

11. A novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-14, which comprises of reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-16 with epichlorohydrine in presence of a base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, preferably sodium hydroxide in a suitable solvent selected from hydrocarbon solvents, ether solvents, nitrile solvents and their mixtures thereof, preferably acetonitrile to provide 4-tert-butyl-N-(5-(2-methoxy phenoxy)-6-(oxiran-2-ylmethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-14.

12. A novel process for the preparation of 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-8, comprises of:

a) Reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin- 4-yl) benzenesulfonamide compound of formula-16 with chloroacetonitrile in presence of sodium carbonate in dimethylformamide to provide 4-tert-butyl-N-(6- cyanomethoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-19, Formula-19

b) reducing the compound of formula-19 with diisobutylaluminium hydride (DIBAL) in toluene to provide 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide compound of formula-8.

13. The compounds having the following structures: