FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF PURE BOSENTAN"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzenesulfonamide mono - hydrate of Formula I substantially free of impurities.

BACKGROUND AND PRIOR ART:
The compound 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzensulfonamide monohydrate commonly known as Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary artery hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III efficacy.
Bosentan and process for its preparation was disclosed along with several sulfonamides in US patent No. 5,292,740. The disclosed process involves reaction of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzensulfonarnide of Formula II with sodium ethylene glycolate in presence of ethylene glycol solvent at 95°C -110°C. The reaction sequence can be represented as shown in scheme I below;


The use of monoanion ethylene glycol leads to formation of undesired ethylene glycol bis-sulfonamide, in which two molecules of pyrimidine halide compound of Formula II get coupled with one molecule of ethylene glycol resulting in formation of ethylene glycol bis-sulfonamide impurity commonly known as dimer impurity of Formula III. The other major impurity formed during the reaction is deshydroxyethyl bosentan of formula IV.

The product formed is purified using column chromatography followed by crystallization to isolate pure bosentan of Formula I.
The drawback of the process is formation of the impurities and use of chromatographic technique for the purification of the product, which is impractical to use on industrial scale production of the compound.
US 6,136,971 discloses a process for the preparation of Bosentan of Formula I, wherein the compound 4-terr-butyl-N-[6-chIoro-5-(2-methoxyphenoxy)-2,2 '-bipyrimidin-4-yl] benzensulfonamide of Formula II is reacted with mono protected ethylene glycol in presence of base and nonpolar aprotic solvent to obtain monoprotected ethylene glycol sulfonamide derivative. The product obtained is further reacted with formic acid followed by reaction with base results in the compound Bosentan of Formula I.
The drawback of the process is the use of monoprotected ethylene glycol requires an additional protection and deprotection step which involves increased number of steps making the process costly and operational unfriendly.

WO2009004374 Al discloses a process for the preparation of Bosentan of Formula I, wherein the mixture of ethylene glycol and sodium hydroxide is dissolved in an tetrahydrofuran and reacted with 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl] benzensulfonamide of Formula II at a temperature of 65°C for 12 hours. The resulting mixture is cooled and reacted with tartaric acid to isolate Bosentan of Formula 1. We have found the bis-sulfonamide (Formula III) and deshydroxyethyl bosentan (Formula IV), impurities in the product, when adopted this process.
WO2011024056 A2 discloses a process for purification of Bosentan by making crystalline potassium salt of crude Bosentan, which is further converted to Bosentan of Formula I. The product obtained contains bis-sulfonamide (Formula III) and deshydroxyethyl bosentan (Formula IV), impurities to 0.2%.
The above prior arts clearly indicate the problem in removing the two impurities viz. bis-sulfonamide (Formula III) and deshydroxyethyl bosentan (Formula IV) which requires chromatographic separation and repeated purifications, which in turn increases the operational steps and affects the economy and yield of the compound Bosentan of Formula I.
Hence there is need to develop a process for purification of Bosentan which limits the impurities bis-sulfonamide (Formula III) and deshydroxyethyl bosentan (Formula IV) to less than 0.1% to meet the 1CH requirement and pharmaceutical^ acceptable grade to provide Bosentan (Formula I) of high purity and improved yield.
In the present invention the inventors have found an efficient process for purification of crude Bosentan of Formula I which selectively removes the bis-sulfonamide impurity (Formula III) to less than 0.05% to undetectable limit followed by removal of deshydroxyethyl bosentan impurity (Formula IV) to less than 0.1% to undetectable limit to obtain the compound pure Bosentan of Formula I, for which protection is sought.

OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to provide simple and cost effective process for purification of crude Bosentan.
Another objective of the present invention is to provide a process for the preparation of Bosenten of Formula I substantially free of bis-sulfonamide (Formula III) and deshydroxyethyl bosentan (Formula IV) impurities.
SUMMARY OF THE INVENTION:
The present invention provides a process for purification of Bosentan of Formula 1

Comprising the steps of;
i. treating crude Bosentan with an organic solvent selected from ethylene glycol, N,N-dimethylformamide, dimethyl sulfoxide and n-butanol to isolate Bosentan substantially free of bis-sulfonamide (Formula III) impurity.
ii. reacting isolated Bosentan substantially free of bis-sulfonamide impurity with an organic base in presence of an organic solvent to isolate pure Bosentan substantially free from deshydroxyethyl bosentan (Formula IV) impurity.
iii. optionally crystallizing the isolated pure bosentan from linear or branched Q -C4 alcohol to obtain crystalline pure Bosentan of Formula I.

DESCRIPTION OF THE INVENTION:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows:
The term substantially free in the context of the present invention means the stated product is free from contamination of stated impurities preferably less than 0.1% and most preferably less than 0.05% to undetectable limits.
The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Accordingly the present invention provides an efficient, economic and convenient process for purification of crude Bosentan to obtain pure Bosentan of Formula I substantially free of bis-sulfonamide impurity to less than 0.05% to undetectable limit and substantially free of deshydroxyethyl bosentan impurity to less than 0.1% to undetectable limit.
In an embodiment of the present invention the compound crude Bosentan is taken in an organic solvent and stirred under heating to get the compound Bosentan substantially free of bis-sulfonamide impurity, in the present invention substantially free means, after the reaction the bis-sulfonamide impurity in the isolated Bosentan reduces to less than 0.05% to undetectable limit.
According to the literature procedures the bis-sulfonamide impurity of Formula III is removed by carrying out chromatographic separation or repeated purification which increases the operational costs and loss in yield of the final product.
Surprisingly the present inventors found tha.t the bis-sulfonamide impurity of Formula III can be easily removed by heating in presence of an organic solvent of higher boiling

point. During heating the bis-sulfonamide impurity present breaks in two, resulting in corresponding increase in compound Bosentan and deshydroxyethyl bosentan.
The organic solvent used for the above reaction is selected from ethylene glycol, N,N-dimethylformamide, dimethyl sulfoxide and n-butanol or mixture thereof. The preferred solvent used for the reaction is selected among ethylene glycol and dimethyl sulfoxide or mixture thereof, wherein the most preferred solvent used for the reaction is ethylene glycol. The ratio of crude Bosentan to the solvent used is 2 volumes to 6 volumes based on the crude Bosentan, wherein the preferred volume of the solvent used is 3 volumes based on the crude Bosentan.
The stirring of the reaction mixture is performed at temperature in the range of 70°C to 130°C, wherein the preferred temperature for the reaction is 100°C to 125°C and the most preferred temperature to perform the reaction is 120°C to 125°C. The time required for reducing the level of bis-sulfonamide impurity is 5 to 8 hours. The isolated compound has the bis-sulfonamide impurity in the range of 0.05% to undetectable level when analysed by HPLC.
Accordingly the compound crude Bosentan is charged in ethylene glycol and stirred. Applied heating and raised the temperature of the reaction mixture slowly to 120°C and maintained at 120 - 125°C for 6 hours. Stopped heating and brought the temperature of the reaction mixture to 85°C, maintaining the temperature at 80 to 85°C, slowly charged sufficient amount of water (5 volume to 7 volume water) to make the reaction mixture freely stirrable. Maintained under stirring at 80 - 85°C for 30 minutes and applied cooling to take the temperature of the reaction mixture to 20 to 30°C. Maintained under stirring for one hour and filtered the mass to isolate the compound Bosentan substantially free of bis-sulfonamide impurity.
The compound crude Bosentan used for the present invention is prepared as per the process disclosed in prior art or as per the process disclosed in the US patent No. 5,292,740 which is incorporated herein by reference.

In another embodiment of the present invention the compound Bosentan substantially free of the bis-sulfonamide impurity is reacted with an amine in presence of base and polar aprotic solvent to isolate Bosentan of Formula 1 substantially free of bis-sulfonamide and substantially free of deshydroxyethyl bosentan impurity.
The amine used in the reaction reacts with the deshydroxyethyl bosentan impurity to give the corresponding amino ether compound which on workup with an acid results in the formation of acid addition salt which is water soluble and get removed along with the filtrate.
The amine used for the reaction is halo alkyl amine selected from chloroalkyl amine, bromoalkyl amine or iodoalkyl amine. The preferred haloalkyl amine used for the reaction is selected from N,N-diethylaminoethyl chloride, N,N-diethylaminopropyl chloride, N,N-diethylaminobutyl chloride, N,N-diethylaminopentyl chloride, N,N-dimethylaminoethy] chloride, N,N-dimethylaminopropyl chloride, 3-chloropropyl amine, 2-chloroethyl amine, 3-chloroN-methyIpropyl amine, 3-chloro-N-ethylpropyl amine, 2-chloro-N-ethyl amine, 2-chloro-N-methyl amine and the salts, wherein the preferred amine used for the reaction is N,N-dirnethylaminoethyl chloride, N,N-dimerhylaminopropyl chloride and the salts. The most preferred amine used is N,N-dimethylaminopropyl chloride and its salts. The preferred salt of amine used is hydrochloride salt.
The base used for the reaction is selected from alkali metal carbonates and alkaline earth metal carbonates. The preferred alkali metal carbonates are potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate whereas the alkaline earth metal carbonates used are magnesium carbonate, calcium carbonate or mixture thereof. The most preferred base used for the reaction is potassium carbonate.
The polar aprotic solvent used for the reaction is selected from N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone. The preferred polar aprotic solvent used is N,N-dimethylformamide and dimethylsulfoxide, wherein the most preferred solvent used for the reaction is dimethylsulfoxide. The preferred volume of the solvent used is 3 volumes to 10 volumes of the charged compound Bosentan

substantially free of the bis-sulfonamide impurity, wherein the most preferred volume of the solvent used is 5 volumes of the charged compound Bosentan substantially free of the bis-sulfonamide impurity.
The reaction is carried out at temperature in the range of 50°C to 80°C, wherein the preferred temperature to perform the reaction is at 60° to 65°C.
Accordingly the compound Bosentan substantially free of the bis-sulfonamide impurity is charged in the solvent dimethyl sulfoxide containing the base potassium carbonate. Stirred the reaction mass and raised the temperature to 60°C and maintained the reaction at 60 - 65°C for one to two hours. Charged amino compound N,N-dimethyIaminopropyl chloride hydrochloride maintaining the temperature at 60 - 65°C and maintained the reaction mixture for 7 - 10 hours. After completion of the reaction, the reaction mass was quenched with dilute hydrochloric acid maintaining the temperature at 60 - 65°C, stirred the reaction mixture for 15 - 30 minutes at 60 - 65°C and cooled slowly to 20°C. Stirred the reaction mass at 20 - 30°C for one hour. Filtered and washed the solid compound separated with water to isolate the product Bosentan of Formula I substantially free of bis-sulfonamide and substantially free of deshydroxyethyl bosentan impurity.
The isolated compound Bosentan of Formula I substantially free of bis-sulfonamide and substantially free of deshydroxyethyl bosentan if required is crystallized from C1 - C4 alcohols to isolate crystalline bosentan of Formula I.
The present invention is further illustrated in detail with reference to the following examples. It is desired that the example be considered in all respect as illustrative and are not intended to limit the scope of the processed invention.
EXAMPLES: Example 1:
Crude Bosentan (105.0 gm, having bis-sulfonamide impurity 0.59% and deshydroxyethyl bosentan impurity 0.44%) was added to ethylene glycol (315 ml). The resulting reaction mass was slowly heated under stirring to 120°C and maintained at 120 - 125°C for 6

hours. Applied cooling and cooled the reaction mass to 80°C. Slowly added water (525ml) to the reaction mass maintaining the temperature at 80 - 85°C and stirred for 1.0 hour. Applied cooling to bring the temperature of the reaction mass to 25°C and stirred for 1.0 hour at 25 - 30°C. Filtered the solid product and washed with water to isolate crude Bosentan substantially free of bis-sulfonamide impurity. Dried the compound at 50 - 55°C till constant weight.
Result:
Weight = 99.75 gm
% Yield = 95.0%;
Bis-sulfonamide impurity = Not detected;
Deshydroxyethyl bosentan impurity = 0.87%.
Example 2:
Charged crude Bosentan substantially free of bis-sulfonamide impurity (95.0 gm, having
deshydroxyethyl bosentan impurity 0.87%), to the flask having dimethylsulfoxide (475
ml) and potassium carbonate (69. 1 gm). The resulting reaction mass was slowly heated
under stirring to 60-65°C and maintained for 1.0 hour. Slowly charged N,N-
dimethylaminopropyl chloride hydrochloride (13.61 gm) maintaining the temperature at
60 - 65°C. Stirred and maintained the reaction mass at 60 - 65°C for 8 hrs. Charged dil.
hydrochloric acid solution (concentrated hydrochloric acid 142.5 ml + water 807.5 ml)
maintaining the reaction mass at 60 - 65°C and stirred for 15 minutes. Cooled the reaction
mass to 25°C and maintained for 1.0 hour at 25 - 30°C. Filtered the solid mass and
washed with water (2*95 ml) to isolate the compound pure Bosentan of Formula I
substantially free of bis-sulfonamide and deshydroxyethyl bosentan impurity. Dried the
product at 50 - 55°C till constant weight.
Result:
Weight = 90.25 gm
% Yield = 95.0%;
Bis-sulfonamide impurity = Not detected;
Deshydroxyethyl bosentan impurity = 0.02%.
HPLC Purity =99.24%;

Example 3: Crystallisation of Pure Bosentan:
Pure Bosentan (85 gm) was added to methanol (595 ml). The resulting reaction mass was slowly heated under stirring to 60 - 65°C and maintained for 30 minutes. Charged activated charcoal (3.45 gm) and maintained at 60 - 65°C for 30 minutes. Filtered the reaction mixture through hy-flow bed at 60 - 65°C and washed with hot methanol (170 ml). The Filtrate was taken in flask and under stirring heated to 60 - 65°C for 10 minutes. Reaction mixture cooled to 20 - 30°C and maintained for 1.0 hour. Filtered the reaction mixture and washed with methanol (85 ml) to isolate crystalline Bosentan of Formula I. Dried the product at 50 - 55°C till constant weight.
Result:
Weight = 76.50 gm
% Yield = 90.0%;
Bis-sulfonamide impurity = Not detected;
Deshydroxyethyl bosentan impurity = Not detected;
HPLC Purity = 99.84%;

We Claim,
1. A process for the preparation of pure Bosentan of Formula I,

Comprising the steps of,
i. treating crude bosentan with an organic solvent at temperature of 70 - 130°C
to isolate crude bosentan substantially free of bis-sulfonamide impurity of
Formula III.

ii. reacting the isolated bosentan substantially free of bis-sulfonamide impurity with an amine in presence of a polar aprotic solvent and base to isolate pure bosentan substantially free of deshydroxyethyl bosentan impurity of Formula IV.


iii. optionally crystallizing the isolated pure bosentan from C1 - C4 alcohol to get crystalline bosentan of Formula I.
2. The process according to claim 1, wherein the organic solvent in step (i) is selected from the group consisting of ethylene glycol, N,N-dimethylforrnamide, dimethyl sulfoxide and n-butanol.
3. The process according to claim 2, wherein the organic solvent is ethylene glycol.
4. The process according to claim 4, wherein the reaction is carried out at temperature of 120°C to 125°C.
5. The process according to claim 1, wherein the amine in step (ii) is haloalkyl amine.
6. The process according to claim 1, wherein the amine in step (ii) is chloroalkyl amine, bomoalkyl amine or iodoalkyl amine.
7. The process according to claim 6, wherein the amine in step (ii) is selected from the group consisting of N,N-diethylaminoethyl chloride, N,N-diethylaminopropyl chloride, N,N-diethylaminobutyl chloride, N,N-diethylaminopentyl chloride, N,N-dimethylaminoethyl chloride, N,N-dimethylaminopropyl chloride, 3-chloropropyl amine, 2-chlooethyl amine, 3-chloro-N-methylpropyl amine, 3-chloro-N-ethylpropyl amine, 2-chloro-N-ethyl amine, 2-chloro-N-methyl amine and the salts thereof.

8. The process according to claim 8, wherein the amine is N,N-dimethylaminopropyl chloride hydrochloride.
9. The process according to claim 1, wherein the base in step (ii) is selected from alkali metal and alkaline earth metal carbonates.
10. The process according to claim 8, wherein the alkali metal and alkaline earth metal carbonates are selected from the group consisting of potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate or mixture thereof.
11. The process according to claim 10, wherein the base in step (ii) is potassium carbonate.
12. The process according to claim 1, wherein the polar aprotic solvent in step (ii) is selected from the group consisting of N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone.
13. The process according to claim 13, wherein the polar aprotic solvent in step (ii) is dimethylsulfoxide.
14. The process according to claim 1, wherein the reaction in step (ii) is carried out at temperature of 50°C to 80°C.
15. The process according to claim 15, wherein the reaction is carried out at temperature of 60° to 65 °C.