FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)


"PROCESSES FOR THE PREPARATION OF BOSENTAN AND ITS INTERMEDIATES THEREOF"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenrnark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099

The following specification describes the nature of the invention:


FIELD OF THE INVENTION The present invention relates to processes for the preparation of bosentan, its structurally novel intermediates and their use for the synthesis thereof, and a pharmaceutical composition of the same
BACKGROUND OF THE INVENTION
Bosentan is an orally active dual endothelin ETA/ETB receptor antagonist and is used in the pulmonary arterial hypertension and systemic sclerosis. Bosentan is chemically described as 4-tert-Butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yI]benzene sulfonamide monohydrate and has the structural formula, as shown

U.S. Patent No. 5,292,740 (the '740 patent) describes pyrimidine sulfonamide derivatives including bosentan or a stereoisomer or salt thereof, a pharmaceutical composition and method of treatment.
The US'740 patent discloses a process for the preparation of bosentan, which is illustrated by the scheme, which follows:



U.S. Patent No. 6136971 describes a process for preparing ethylene glycol sulfonamide derivatives, including bosentan, using via formyl bosentan and pyrimidine monohalide intermediate, as illustrated by the scheme that follows :



PCT Publication WO2009/004374 describes an improved process for the preparation of bosentan using sodium hydroxide forhydrolysis and via bosentan tartaric acid salt which is illustrated by the scheme, which follows:

The present invention provides additional processes for preparation of bosentan and its intermediates which are simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of bosentan and novel intermediates thereof.
The present invention further relates to the use of the novel intermediates of bosentan in the preparation of bosentan.
In one aspect, the present invention provides a first process (process A) for preparing bosentan
comprising: reacting 4-tertiary butyl-N-[6-hydroxy-5-(0-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula 1 or a salt thereof



with ethylene oxide or 2-halo ethano] to form bosentan.
In a second aspect, the present invention provides a process for the preparation of compound of formula I or a salt thereof comprising: subjecting 4-tertiary butyl-N-[6-chloro-5-(0-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula II or a salt thereof

II to aqueous basic hydrolysis.
In a third aspect, the present invention provides a compound 4-tertiary butyl-N-[6-hydroxy-5-(0-methoxyphenoxy)[2,2'-bipyrirnidin]-4-yl]benzene sulfonamide of structural Formula I or salt thereof

I In a fourth aspect, the present invention provides a second process (Process B) for preparing bosentan comprising:


a) reacting 4-tertiary butyl-N-[6-(2-alkoxyethoxy)-5-(2-methoxyphenoxy)-2-(2-
pyrimidinyl)pyrimidin-4-yl]benzene sulfonamide compound of formula III or a salt thereof

III
where R is methyl, ethyl, benzyl, hydrogen.
with a reducing agent in the presence of an organic solvent.
In a fifth aspect, the present invention provides a process for preparing the compound of formula III or a salt thereof comprising:
reacting 4-chloro-6-alkoxyethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula IV

IV where R is same as defined for compound of formula III with 4-tertiarybutylphenyl sulfonamide compound of formula V
V
in the presence of a base and an organic solvent.
In a sixth aspect, the present invention provides a process for preparing 4-chloro-6-alkoxyethoxy-5-(O-methoxyphenoxy)~2,2'-bipyrimidine compound of formula IV

comprising:subjecting4,6-dichloro-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula VI

to basic hydrolysis to form 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula VII

a) reacting the compound of formula VII with a compound of formula VIII

where R is benzyl, benzyloxy carbonyl, methyloxymethyl, Hydrogen and X is halogen, OH. in the presence of a base and an organic solvent under phase transfer conditions.
In a seventh aspect, the present invention provides a compound 4-chloro-6-alkoxyethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine of structural formula IV

In an eighth aspect, the present invention provides a compound 4-chloro-6-hydroxy-5-(O-methoxyphenoxy)-2,2'-bipyrimidine of structural formula VII

VII In a ninth aspect, the present invention provides a third process (Process C) for the
preparation of bosentan comprising: reacting 4-tertiarybutyl-N-[6-(2-
alkynoyloxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyI)pyrimidin-4-yl]benzene
sulfonamide compound of formula IX or a salt thereof

IX where R is H, methoxy, ethoxy-with a reducing agent in the presence of an organic solvent.

with a compound of formula X

In a tenth aspect, the present invention provides a process for preparing a compound of formula IX comprising: reacting 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula VII


where R is same as defined for compound of formula IX and X is halogen atom. to form 4-chloro-6-alkanoyloxy ethoxy-5-(O-methoxyphenoxy)-2,2'-bipyrimidine compound of formula XI

b) reacting the compound of formula XI with 4-tertiarybutylphenylsulfonamide compound of formula V or a salt thereof

in the presence of a base and an organic solvent.
In an eleventh aspect, the present invention provides a compound 4-tertiarybutyl-N-[6-(2-alkynoyloxyethoxy)-5-(2-metho'xyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yl]benzenesulfonamide compound of formula IX or a salt thereof.



In a twelfth aspect, the present invention provides a compound 4-chloro-6-alkanoyloxy ethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of structural formula XI

XI In another aspect, the present invention encompasses a pharmaceutical composition comprising bosentan or its pharmaceutically acceptable salts and at least a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a first process (Process A) for preparing bosentan comprising: reacting 4-tertiary butyl-N-[6-hydroxy-5-(0-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula I or a salt thereof

I
with ethylene oxide and 2-halo ethanol to form bosentan.
The reaction of Process A is effected in the presence of base and an inert solvent. Suitably the bases that can be used include but are not limited to organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; alkali metal alkoxides. such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Of these, the organic amines are preferred. The amount of base employed is not


critical, but good practice recommends that an amount of base of from an about equimolar amount to about 5 times the equimolar amount with respect to the compound of formula 1. Also, if an excess of an organic amine is employed as the base, this may additionally serve as the solvent. The reaction of Process A is normally and preferably effected in the presence of an inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents. The solvents that can be used include but are not limited to alcohols such as methanol, ethanol, isopropanol and the like; Esters such as ethyl acetate, isopropyl acetate and the like; halocarbonated solvents such as dichloromethane, chloroform and the like; hydrocarbon solvents such as toluene, n-hexane, n-heptane, cyclohexane and the like and mixtures thereof. The reaction of Process A can take place over a wide range of temperatures, from about-10°C to about 100° C. Preferably from about 0°C to about 50°C, although this may vary depending on the nature of the reactants and reagents used and on the solvents employed. The time required for the reaction of Process A may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 1 hour to about 20 hours. Preferably from about 1 hour to about 5 hours, is sufficient. The reaction of Process A can be optionally carried out in neat conditions in the absence of solvents. The molar ratio of the amounts of the respective reaction substrates to be used, generally, may be about 1.0:0.5 to about 1.0:3.0.
The present invention provides a process for the preparation of compound of formula I or a salt thereof comprising: subjecting 4-tertiary butyl-N-[6-chloro-5-(0-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula II or a salt thereof



to aqueous basic hydrolysis.
The reaction is effected by using aqueous base and an inert solvent.
The bases that can be used include, but are not limited to, inorganic bases such as alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; alkali metal carbonates, such as sodium carbonate or potassium carbonate and the like; alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide and the like. Of these, the alkali metal hydroxides are preferred. The amount of base employed is not critical, but good practice recommends an amount of base of from an about an equimolar amount to about 5 times the equimolar amount with respect to the compound of formula II .
The reaction is effected in the presence of a solvent. The solvents that can be used include, but are not limited to, halocarbonated solvent such as dichloromethane, ethylene dichloride chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof. Preferably aqueous alcohols and polar aprotic solvents.
The reaction is carried out at a temperature of from about 30°C to about 100° C or reflux temperatures of the solvents used, preferably from about 30°C to about 75°C.
The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 30 minutes to about 10 hours, preferably from about 30 minutes to about 5 hours, is sufficient. The molar ratio of the amounts of the compound of formula II and the base may be about 1:0.5 to about 1:5.
The present invention provides a compound 4-tertiary butyl-N-[6-hydroxy-5-(0-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide of structural Formula I or salt thereof

The present invention provides a second process (Process B) for preparing bosentan comprising: reacting 4-tertiary butyl-N-[6-(2-alkoxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yl]benzene sulfonamide compound of formula III or a salt thereof

where R is benzyl, acetyl.
The process of reduction is carried out by either using organic or inorganic acids, or using hydrogenation.
The inorganic acids that can be used include, but limited to, sulfuric acid, hydrochloric acid, hydrobromic acid and the like; organic acids such as acetic acid, formic acid, triflouroacetic acid and the like, preferably hydrochloric acid & sulfuric acid.
Alternatively, the process of reduction when carried out using hydrogenation, occurs with the use of hydrogenation "catalysts in the presence hydrogen. The hydrogenation catalysts include but are not limited to palladium-carbon, Raney nickel and the like, preferably palladium- carbon. The solvent that can be used is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate and the like; halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof, preferably alcohols, methanol. The reaction can take place over a wide range of temperatures from about 0°C to about 100° C, . preferably from about 0°C to about 50 °C. The time required for the reaction can range from about 1 hour to about 20 hours. Preferably from about I hour to about 5 hours .


The present invention provides a process for preparing the compound of formula III or a salt thereof comprising:reacting4-chloro-6-alkoxyethoxy-5-(0-methoxyphenoxy)-2,2' -bipyrimidine compound of formula IV

where R is benzyl ,alkyl and Hydrogen atom defined for compound of formula III with 4-tertiarybutylphenylsulfonamide compound of formula V

in the presence of a base and an organic solvent.
The reaction is carried out in the presence of a base and an inert solvent. The bases that can be used include but are not limited to organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and mixtures thereof or metal hydrides. Preferably sodium hydride. The mole ratios of the compounds of formula IV and V employed would generally from an equimolar amount to 5 times. The solvent that can be used is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropy! acetate and the like; halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof. Preferably aprotic polar solvents like DMF. The reaction can take place over a wide range of temperatures from about 25°C to about 150° C,. preferably from about

25°C to about 75°C. The time required for the reaction can range from about 1 hour to about 10 hours. Preferably from about 1 hour to about 5 hours. The reaction of compound of formula IV with the compound of formula V can also be carried out in neat conditions in the absence of solvents.
The present invention provides a process for preparing 4-chloro-6-alkoxyethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula IV comprising:
a) subjecting 4,6-dichloro-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of
formulaVI

VI
to basic hydrolysis to form 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine
compound of formula VII

VII b) reacting the compound of formula VII with a compound of formula VIII

where R is benzyl, benzyloxy carbonyl. methyloxymethyl-, H and X is halogen, OH. in the presence of a base and an organic solvent under phase transfer conditions.
The bases that can be used include but are not limited to organic amines, such as
triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine,
lutidine, collidine and the like; alkali metal alkoxides, such as sodium methoxide, sodium
ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or
potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium
hydroxide and mixtures thereof or alkali metal hydride preferably alkali metal hydroxide.

The mole ratios of the compounds of formula VII and VIII employed would generally be from about an equimolar amount to about 5 times, preferably 2 to 3 moles.
The solvents that can be used is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate and the like; halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane. toluene and the like and mixtures thereof, preferably alcohols. The reaction can take place over a wide range of temperatures from about 25°C to about 150° C,.preferably from about 25°C to about 75 °C. The time required for the reaction can range from about 1 hour to about 10 hours. Preferably from about 1 hour to about 5 hours.
Optionally the compound of formula VI is reacted with the compound of formula VIII to give the compound of formula IV.
The present invention provides a compound: 4-chloro-6-alkoxyethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine of structural formula IV with R as hydrogen.

The present invention provides a process for the preparation of the compound IV with R as hydrogen comprising the reaction of 4,6-dichloro-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula VI with ethylene glycol in the presence of base such as Hydroxide ion bases and hydride ion bases, preferably sodium hydride.
The solvent that can be used is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate and the like; halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), THF, acetonitrile and the like; hydrocarbon solvents


such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof. Preferably THF.
The present invention provides a compound: 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine of structural formula VII.

The present invention provides a third process (Process C) for the preparation of bosentan comprising: reacting 4-tertiarybutyl-N-[6-(2-alkynoy!oxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yl] benzene sulfonamide compound of formula IX or a salt thereof

with a reducing agent in the presence of an organic solvent; where R is H, methoxy, ethoxy-
The process of reduction is carried out by hydrogenation.
The process of reduction is used, it is carried out using hydrogenation catalysts in the presence of hydrogen. The hydrogenation catalysts include but are not limited to palladium-carbon, Raney nickel and the like, preferably palladium- carbon.
The solvent that can be used is selected from the group alcohols such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate and the like; halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like and


mixtures thereof. Preferably alcohols. The reaction can take place over a wide range of temperatures from about 0°C to about 100° C, preferably from about 0°C to about 50°C.
The time required for the reaction can range from about 1 hour to about 20 hours. Preferably from about 1 hour to about 5 hours.
The present invention provides a process for preparing compound of formula IX comprising: reacting 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula VII

VII
with a compound of formula X

X
where R is same as defined for compound of formula IX and X is halogen atom.
to form 4-chloro-6-alkanoyloxy ethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound of formula XI

b) reacting the compound of formula XI with 4-tertiarybutylphenylsulfonamide compound of formula V or a salt thereof



V in the presence of a base and an organic solvent.
The reaction, previously described above, is carried out in the presence of a base and an inert solvent. The bases that can be used include but are not limited to organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and mixtures thereof alkali metal hydride, preferably sodiumhydride.
The solvent that can be used is selected from the group alcohols such as methanol, ethanol, isopropyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate and the like; halocarbonated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), THF, acetonitrile and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof, preferably THF.The reaction can take place over a wide range of temperatures from about 25°C to about 150° C, preferably from about 25°C to about 75 °C. The time required for the reaction can range from about 1 hour to about 10 hours. Preferably from about 1 hour to about 5 hours. The reactions, previously described, of a) a compound of formula VII with the compound of formula X; b) compound of formula XI with the compound of formula V can also be carried out in neat conditions in the absence of solvents. The mole ratios of the compounds of formula VII arid X employed would generally be from about an equimolar amount to about 5 times, preferably 2 to 3.
The mole ratios of the compounds of formula [2-2] and [8-1] employed would generally be from about an equimolar amount to about 5 times.
The present invention provides a compound 4- tertiarybutyl N-[6-(2-alkynoyloxyethoxy)-5-(2-methoxyphenoxy)-2-(2- pyrimidinyl)pyrimidin-4-yl] benzenesulfonamide compound of formula IX or a salt thereof.



IX The present invention provides a compound 4-chloro-6-alkanoyloxy ethoxy-5-(0-methoxyphenoxy)-2,2,-bipyrimidine compound of structural formula XI

XI
The isolation of the desired target compounds from the reaction mixtures in all of the above previously described processes can be carried out by methods known in the art, but in consideration of the physical properties of the desired compound, crystallization, extraction, washing, column chromatography, etc. may be combined, preferably extraction and crystallization.
The present invention provides that in the processes previously described, the intermediate compounds are optionally isolated and can be obtained by the so-called one pot reaction.
The target compound, bosentan, is optionally purified by recrystallisation usinga solvent or mixture of solvents or alternatively, by converting into a pharmaceutically acceptable salt and back to bosentan.
In one embodiment, bosentan or a pharmaceutically acceptable salt thereof obtained by the processes described above has the following impurities namely: 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ol of formula A

A B
where R is alkyl, benzyl,
2-{[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]oxy}ethanol of formula B 6-hydroxy 2-sulfonamide impurity of formula C

Bosentan-dimer impurity of formula D
6,6'-ethoxy -2-chloro impurity of formula E

6,6'-ethoxy -2- sulfonamide impurity of formula F
Desmethyl Bosentan Impurity G

G

H

Hydroxy Bosentan Impurity J

Hydroxy desmethyl Bosentan Impurity H


Each one the above described impurities are present in an amount of less than about 0.15%. The total purity of the bosentan or a pharmaceutically acceptable salt thereof obtained by the above described processes has the purity by HPLC of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.5%.
Preferably, the chemical purity of the bosentan or a pharmaceutically acceptable salt thereof is about 99% or more, more preferably about 99.5% or more, more preferably about 99.8% or more, more preferably about 99.9% or more, as measured by area under HPLC. In one embodiment, the present invention encompasses bosentan or a pharmaceutically acceptable salt thereof having less than about 0.20% of any single impurity as measured by area under HPLC peaks. Preferably, the bosentan or a


pharmaceutical!)/ acceptable salt thereof has less than about 0.15% of any single chemical impurity as measured by area under HPLC peaks.
In yet another embodiment, bosentan or its pharmaceutically acceptable salts obtained by the processes described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 600ppm of dichloromethane, less than about 800ppm of N,N-dimethylformamide (DMF), less than about 3000ppm of methanol, 5000ppm of acetone, ethyl acetate, isopropyl alcohol, and tetrahydrofuran (THF), less than about 890 ppm of toluene.
In one embodiment, Bosentan or its pharmaceutically acceptable salts obtained by
the process of the present invention can have a D50 and D90 particle size of less than about
400 microns, preferably less than about 200 microns, more preferably less than about 150
microns, still-more preferably less than about 50 microns and most preferably less than
about 15 microns. The particle size can be determined by such techniques as, for example,
Malvern light scattering, a laser light scattering technique, etc., using, e.g., a Malvern
Mastersizer 2000. It is noted the notation Dx means that X% of the particles have a
diameter less than a specified diameter D. Thus, a D50 of about 250 microns means that
50% of the particles composition comprising of Bosentan or its pharmaceutically
acceptable salts have a diameter less than about 250 microns. The particle sizes of the
Bosentan or its pharmaceutically acceptable salts obtained by, for example, any milling,
grinding, micronizing or other particle size reduction method known in the art to bring the
solid state Bosentan or its pharmaceutically acceptable salts any of the foregoing desired
particle size range. . '
The advantage of above method is that costly 4-tert butyl benzenesulphonamide is used in later stage resulting in reduction in cost. Use of hazardous sodium metal is avoided. Some of the impurities like dimer reported to be formed by innovator route is not likely to be formed.
The present invention also provides pharmaceutical compositions comprising bosentan or its pharmaceutically acceptable salts obtained by the processes of present invention. Such pharmaceutical compositions may be administered to a mammalian patient


in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The bosentan or its pharmaceuticaliy acceptable salts obtained by the process disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the bosentan or its pharmaceuticaliy acceptable salts is oral. The dosage forms may contain the bosentan or its pharmaceuticaliy acceptable salts as part of a composition. The pharmaceutical compositions may further contain one or more pharmaceuticaliy acceptable excipients.
The processes for the preparation of bosentan or its intermediates thereof of the present invention are simple, eco-friendly and easily scahable.
The present invention particularly provides: A) A process for the preparation of bosentan


with ethylene oxide or 2-halo ethanol.
comprising: reacting 4-tertiary butyl-N-[6-hydroxy-5-(O-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl]benzenesulfonamide compound, I, or a salt thereof


B) The process as described in A, wherein the compound, I, or a salt thereof is prepared by the process comprising:
subjecting 4-tertiary buty]-N-[6-chloro-5-(0-methoxyphenoxy)[2,2'-bipyrimidin]-4-
yl]benzenesulfonamide compound, II, or a salt thereof

to aqueous basic hydrolysis.
C) The process as described in B above, wherein hydrolysis is carried out in the presence of sodium hydroxide.
D) A compound 4-tertiary butyl-N-[6-hydroxy-5-(0-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl]benzene sulfonamide, I, or salt thereof

E) A process for the preparation of bosentan

comprising:
b) reacting 4-tertiary buty]-N-[6-(2-alkoxyethoxy)-5-{2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-y]]benzene sulfonamide compound, III, or a salt thereof

where R is benzyl, alkyl and Hydrogen atom with a reducing agent in the presence of an organic solvent.
F) The process as described in E above, wherein the reducing agent is hydrogen and
palladium -carbon as catalyst.
G) The process as described in E, wherein the compound, III or a salt thereof is prepared
by the process comprising:
reacting 4-chloro-6-alkoxyethoxy-5-(0-metrioxyphenoxy)-2,2'-bipyrimidine compound ,IV,

where R is same as defined for compound, III with 4-tertiarybutylphenylsulfonamide compound, V

in the presence of a base and an organic solvent. H] The process as described in G above, wherein the base is sodium hydride.
I] The process as described in G, wherein the compound, IV, is prepared by the process comprising: a) subjecting 4,6-dichioro-5-(0-methoxyphenoxy)-2,2'-bipynmidine compound, VI,

to basic hydrolysis to form 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound , VII,

b) reacting the compound, VII, with a compound, VIII

where R is benzyl, benzyloxy carbonyl, methyloxymethyl-, H and X is halogen atom, OH.
in the presence of a base and an organic solvent under phase transfer conditions.
J) A compound 4-chloro-6-aIkoxyethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine, IV,

K.] A compound 4-chloro-6-hydroxy-5-(0-methoxyphenoxy)-2,2,-bipyrimidine, VII,

L] A process for the preparation of bosentan




comprising: reacting 4-tertiarybutyl-N-[6-(2-alkynoyloxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-4-yl]benzenesulfonamide compound, IX, or a salt thereof
where R is benzyl, alkyl and hydrogen atom with a reducing agent in the presence of an organic solvent.
M] The process as described in L, wherein the reducing agent is sodium borohydride. N] The process as described in L, wherein the compound, IX, is prepared by the
process comprising:
a) reacting 4-chIoro-6-hydroxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound, VII



with a compound, X,
where R is same as defined for compound, IX, and X is halogen atom to form 4-chloro-6-alkanoyloxy ethoxy-5-(O-methoxyphenoxy)-2,2'-bipyrimidine, XI,

b) reacting the compound , XI, with 4-tertiarybutylphenylsulfonamide compound, V, or a salt thereof
in the presence of a base and an organic solvent. O] A compound 4-tertiarybutyl-N-[6-(2-alkynoyloxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl) pyrimidin-4-yl]benzenesuIfonamide compound , IX, or a salt thereof

P] A compound 4-chIoro-6-alkanoy!oxy ethoxy-5-(0-methoxyphenoxy)-2,2'-bipyrimidine compound , XI,

Q) The bosentan or a pharmaceutically acceptable salt thereof has a chemical purity of about 95 area % or more by HPLC .
R) The process of Q, wherein the bosentan or a pharmaceutically acceptable salt thereof has a chemical purity of about 98 area % or more by HPLC .


S) The process of R, wherein the bosentan or a pharmaceutically acceptable salt thereof has a chemical purity of about 99 area % or more by HPLC .
T) The bosentan or a pharmaceutically acceptable salt thereof obtained has about 0.5 area % or less of total impurities as measured by HPLC .
U) The bosentan or a pharmaceutically acceptable salt thereof obtained has less than about 0.15 area % of any individual impurity as measured by HPLC.
Dated this Second (2nd) day of April, 2009

(Signed)
DR.MADHAVI KARNIK
DEPUTY GENERAL MANAGER-IPM
GLENMARK GENERICS LIMITED