WO2009112954A2 - Processes for the preparation of bosentan and related compounds using novel intermediates - Google Patents

Abstract

Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of substantially pure ethylene glycol sulfonamide compounds such as bosentan using novel intermediates.

Description

PROCESSES FOR THE PREPARATION OF BOSENTAN AND RELATED COMPOUNDS USING NOVEL INTERMEDIATES

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of priority to Indian provisional application No.

628/CHE/2008, filed on March 13, 2008, which is incorporated herein by reference.

FIELD OF THE DISCLOSURE

Disclosed herein are novel, commercially viable and industrially advantageous processes for the preparation of substantially pure ethylene glycol sulfonamide compounds such as Bosentan using novel intermediates.

BACKGROUND

U.S. Patent No. 5,292,740 discloses a variety of sulfonamide derivatives, processes for their preparation, pharmaceutical compositions and methods of use thereof. These compounds are useful in treatment of a variety of illness including cardiovascular disorders such as hypertension, ischemia, vasospasms and angina pectoris. Among them, Bosentan, p- tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl) -4- pyrimidinyljbenzenesulfonamide monohydrate, has a wide variety of biological activities including inhibiting the renin angiotensin system and acting as an endothelin antagonist. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. Bosentan has the molecular formula of C₂₇H^N₅O₆S. H₂O, molecular weight of 569.63 and a structural formula of:

Various processes for preparation of Bosentan and related compounds are disclosed in U.S. Patent Nos. 5,292,740 and 6,136,971.

According to the U.S. Patent No. 5,292,740 (hereinafter referred to as the '740 patent), bosentan is prepared by the reaction of 5-(2-methoxyphenoxy)-2-(2-pyrimidin-2-yl)- 4,6(1 H,5H)-pyrimidinedione with phosphorous oxychloride in acetonitrile to give 4,6- dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine, which by condensation with 4-tert- butylbenzenesulfonamide potassium in dimethylsulfoxide followed by treatment with hydrochloric acid, affords p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)- 4-pyrimidinyl]benzenesulfonamide. The p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2- (2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide is then reacted with a sodium ethylene glycol, prepared by the reaction of ethylene glycol and sodium metal in ethylene glycol solvent, to produce bosentan as sodium salt (m.p. 195 - 198°C).

The '740 patent describes the use of sodium metal for the preparation of sodium ethylene glycolate. Sodium metal is an explosive and hazardous reagent and vigorously reacts with water. The use of sodium metal is not advisable for scale up operations. Moreover, the bosentan obtained by the process described in the '740 patent using sodium metal is not satisfactory from a purity perspective. Unacceptable amounts of impurities are generally formed along with bosentan using the process of the '740 patent.

According to the U.S. Patent No. 6,136,971 (hereinafter referred to as the '971 patent), bosentan is prepared by the reaction of 5-(2-methoxyphenoxy)-2-(2-pyrimidin-2-yl)- 4,6(1 H, 5H)-pyrimidinedione with phosphorous oxychloride in toluene to give 4,6-dichloro- 5-(2-methoxyphenoxy)-2,2'-bipyrimidine, which by condensation with 4-tert- butylbenzenesulfonamide in the presence of anhydrous potassium carbonate and a phase transfer catalyst (e.g., benzyltriethylammonium chloride) in toluene, provides p-tert-butyl-N- [6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide potassium salt. The p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyl] benzenesulfonamide potassium salt is then reacted with ethylene glycol mono- tert-butyl ether in toluene in the presence of granular sodium hydroxide to produce p-tert- butyl-N- [6-(2-tert-butyl-ethoxy)-5-(2-methoxyphenoxy) [2,2 ' -bipyrimidin] -4- yl]benzenesulfonamide (Bosentan tert-butyl ether). The bosentan tert-butyl ether obtained is then reacted with formic acid followed by treatment with absolute ethanol to afford bosentan formate monoethanolate. The bosentan formate monoethanolate is reacted with sodium hydroxide in absolute ethanol and water followed by acidification with hydrochloric acid and then the resulting precipitate is suction-filtered, washed with ethanol-water mixture (1 :1) to give crude bosentan. The crude bosentan obtained is then purified with mixture of ethanol and water and the resulting precipitate is suction-filtered to give bosentan.

Organic Process Research & Development 2002, 6, 120-124 discloses that the bosentan obtained as per the synthetic route described in the '740 patent is generally not of satisfactory purity. Unacceptable amounts of impurities are generally formed along with bosentan (HPLC purity: 99.3%) using the methods of the '740 patent. The product formed by this method requires three further crystallizations to provide specification grade bosentan suitable for formulation.

The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities limited to less than 0.1 percent.

Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time" ("Rt"). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRt") to identify impurities. The RRt of an impurity is its retention time divided by the retention time of a reference marker.

The prior art processes for preparing ethylene glycol sulfonamide derivatives have many drawbacks. The product obtained by the processes described in the art does not have satisfactory purity and unacceptable amounts of impurities are generally formed along with product. The major disadvantage of the prior art processes is the formation of undesired ethylene glycol bis-sulfonamide (also known as dimer impurity) in which two molecules of pyrimidine monohalide are coupled with one molecule of ethylene glycol. The formation of this bis-sulfonamide compound requires costly and laborious separation steps to obtain a substantially pure ethylene glycol sulfonamide compound.

Accordingly, there remains a need for providing improved and commercially viable processes of preparing pure ethylene glycol sulfonamide compounds, to solve the problems associated with processes described in the prior art, and that will be suitable for large-scale preparation in terms of simplicity, chemical yield and purity of the product.

SUMMARY We have now surprisingly and unexpectedly found novel processes for preparing pure ethylene glycol sulfonamide derivatives using novel intermediates. The novel intermediates can be prepared in high yields and in high purity using easy to handle reagents, thereby enabling the production of Bosentan and its pharmaceutically acceptable salts in high purity and in high yield. In one aspect, encompassed herein are novel, commercially viable and industrially advantageous processes for the preparation of highly pure ethylene glycol sulfonamide compounds such as Bosentan using novel intermediates. The novel processes solve the drawbacks associated with the prior processes and commercially viable for preparing ethylene glycol sulfonamide compounds. In another aspect, provided herein are highly pure ethylene glycol sulfonamide compounds or a pharmaceutically acceptable salt thereof substantially free of dimer impurity (i.e., undesired ethylene glycol bis-sulfonamide).

In yet another aspect, provided herein is highly pure bosentan or a pharmaceutically acceptable salt thereof substantially free of dimer impurity. As used herein, "highly pure ethylene glycol sulfonamide compounds, preferably bosentan, or a pharmaceutically acceptable salt thereof substantially free of dimer impurity" refers to ethylene glycol sulfonamide compound or a pharmaceutically acceptable salt thereof, in which ethylene glycol sulfonamide compound has a purity of about 99% to about 99.99% and further comprising dimer impurity in an amount of less than about 0.1% as measured by HPLC. Specifically, the ethylene glycol sulfonamide compound, preferably bosentan, as disclosed herein, contains less than about 0.05%, more specifically less than about 0.02%, still more specifically less than about 0.01% of dimer impurity, and most specifically essentially free of dimer impurity.

In another aspect, provided herein is bosentan or a pharmaceutically acceptable salt thereof having purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. DETAILED DESCRIPTION

According to one aspect, there is provided a process for the preparation of a substituted ethylene glycol sulfonamide of formula I:

wherein

R¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;

R² is hydrogen, halogen, lower alkoxy, trifluoromethyl or OCH₂COOR_a;

R³ is hydrogen, halogen, lower alkyl, lower alkylthio, trifluoromethyl, cycloalkyl, lower alkoxy or trifluoromethoxy; or

R² and R together can be butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfϊnyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy-carbonyloxy; or

R⁵ together with R⁴ or R⁶ can be butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

Z is O, S, ethylene, vinylene, CO=O), OCHR^b, or SCHR^b;

R^a and R^b each independently hydrogen or lower alkyl.

The process comprises: a) reacting a dihalopyrimidine compound of formula II:

wherein R⁴, R⁵, R⁶, R⁷ and Z are as defined in formula I, and X represents a halogen atom selected from the group consisting of F, Cl, Br and I; with a mono-protected ethylene glycol of formula III:

.0.

HO^' - in wherein 'P' is a protecting group; in the presence of a suitable inorganic base, optionally in the presence of a phase transfer catalyst, to provide a protected ethylene glycol compound of formula IV:

wherein R⁴, R⁵, R⁶, R⁷ and Z are as defined in formula I, X is as defined in formula II, and P is as defined in formula III; b) deprotecting the compound of formula IV using a deprotecting agent to provide the ethylene glycol compound of formula V:

wherein R⁴, R⁵, R⁶, R⁷ and Z are as defined in formula I, and X is as defined in formula II; and c) condensing the compound of formula V with a substituted benzene sulfonamide compound of formula VI:

VI

wherein R¹, R² and R³ are as defined in formula I; in the presence of a base, optionally in the presence of a phase transfer catalyst, to provide highly pure substituted ethylene glycol sulfonamide of formula I.

The term "lower", as used herein, denotes groups with 1-7 carbon atoms, preferably 1-4 carbon atoms. Lower includes 1, 2, 3, 4, 5, 6 and 7 carbon atoms.

In one embodiment, the halogen atom 'X' in the compounds of formulae II, IV & V is Cl.

The highly pure ethylene glycol sulfonamide of formula I obtained in step-(c) may be converted into pharmaceutically acceptable salts by conventional methods.

In one embodiment, the ethylene glycol sulfonamide compound of formula I prepared by the process disclosed herein is bosentan of formula I(i) or a salt or a hydrate thereof (formula I, wherein R¹, R², R⁵, R⁶ and R⁷ are H; R³ is tert-butyl; R⁴ is methoxy; and Z is O):

The reaction in step-(a) is carried out in the absence of substantially any solvent or is carried out in the presence of a reaction solvent.

In one embodiment, the reaction in step-(a) is carried out by contacting the dihalopyrimidine compound of formula II with a mono-protected ethylene glycol of formula III in a solvent or a mixture of solvents. Exemplary solvents are those that dissolve both the dichloro compounds and ethylene glycol compounds to ensure maximum contact between the reactants resulting in faster reaction. However, the process is also operable with solvents that only partially dissolve the dichloro compounds or ethylene glycol compounds. Specific solvents are toluene, xylene, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and mixtures thereof, and more specifically toluene.

Exemplary bases used in step-(a) include, but are not limited to, hydroxides, carbonates and alkoxides of alkali or alkaline earth metals. Specific alkali metals are lithium, sodium and potassium, and more specifically sodium and potassium. Specific alkaline earth metals are calcium and magnesium, and more specifically magnesium. Specific bases include sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and more specifically sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

In another embodiment, the reaction between the dihalopyrimidine compound of formula II and the mono-protected ethylene glycol of formula III in step-(a) is carried out in the presence of a phase transfer catalyst. A "phase transfer catalyst" refers to a catalyst or agent which is added to a reaction mixture of components, to transfer one or more of the reacting components to a location where it can conveniently and rapidly react with another reacting component.

Exemplary phase transfer catalysts for use herein include, but are not limited to, quaternary ammonium salts substituted with a residue such as a straight or branched alkyl group having 1 to about 18 carbon atoms, phenyl lower alkyl group including a straight or branched alkyl group having 1 to 6 carbon atoms which is substituted by an aryl group and phenyl group, e.g., tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexyl ammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammoniurn chloride, benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethyl ammonium chloride, phenyltriethylammonium chloride and the like; phosphonium salts substituted with a residue such as a straight or branched alkyl group having 1 to about 18 carbon atoms, e.g., tetrabutylphosphonium chloride and the like; and pyridinium salts substituted with a straight or branched alkyl group having 1 to about 18 carbon atoms, e.g., 1 -dodecanylpyridinium chloride and the like.

Among these phase transfer catalysts, quaternary ammonium salts substituted with a straight or branched alkyl group having 1 to about 18 carbon atoms, such as tetrabutylammonium chloride and the like, are particularly preferred.

Specific phase transfer catalysts are tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, and more specifically tetrabutylammonium bromide.

In one embodiment, the amount of the phase transfer catalyst employed is 0.5% w/w to about 10% w/w, specifically from about 1% w/w to about 5% w/w. In another embodiment, the reaction in step-(a) is carried out at a temperature of about

-15⁰C to the reflux temperature of the solvent used, specifically at a temperature of about 0°C to the reflux temperature of the solvent used, more specifically at about 25⁰C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used. The time requires for completion of the reaction in step-(a) depends on factors such as solvent used and temperature at which the reaction is carried out. For example, if the reaction is carried out in toluene under reflux conditions, about 5 hours to about 20 hours is required for the reaction completion.

In one embodiment, about 1 to 1.5 moles, specifically, about 1 to 1.2 moles of mono- protected ethylene glycol of formula III per 1 mole of the dihalopyrimidine compound of formula II is used.

In another embodiment, about 1 to 2.5 moles, specifically, about 1 to 1.5 moles, of a base per 1 mole of the mono-protected ethylene glycol of formula III is used.

The protecting group 'P' in the compounds of formulae III and IV is a hydroxyl protecting group which is easily removed, such as C]-C₆-alkyl, a trialkylsilyl, aryl, aryl alkyl or an arylsulfonyl protecting group, and the like. More specifically, the protecting group P in the compounds of formulae III and IV is tert-butyl.

The reaction mass containing the protected ethylene glycol compound of formula IV obtained in step-(a) may be subjected to usual work up such as washings, extractions etc. The reaction mass may be used directly in the next step to produce the ethylene glycol compound of formula V or the protected ethylene glycol compound of formula IV may be isolated and then used in the next step.

The dihalopyrimidine compound of formula II and mono-protected ethylene glycol of formula III used as starting materials in step-(a) may be obtained by processes described in the prior art, for example by the process described in the U.S. Patent Nos. 5,292,740 and 6,136,971.

The compounds of formula IV are novel and constitute another aspect of the present disclosure. In one aspect, the protected ethylene glycol compound of formula IV prepared by the process disclosed herein is the compound of formula IV(i) (formula IV, wherein R⁴ is methoxy; R⁵, R⁶ and R⁷ are H; and Z is O; X is Cl; and P is tert-butyl). The compound of formula IV (i):

is useful for the preparation of the compound of the formula I(i).

In another aspect, the specific protected ethylene glycol compound of formula IV prepared by the process disclosed herein is the compound of formula IV(ii) (formula IV, wherein R⁴ is methoxy; R⁵, R⁶ and R⁷ are H; and Z is O; X is Cl; and P is formyl). The compound of formula IV(ii):

is useful for the preparation of the compound of the formula I(i).

The step-(b) of the reaction is the removal of the protecting groups, i.e., conversion of P to hydrogen. The removal of protecting groups is performed by using suitable deprotecting agent(s) by known methods, for example as disclosed in "Protecting Groups in Organic Synthesis," T. W. Greene, John Wiley & Sons, New York, N. Y., 1981.

In one embodiment, the process for removing a protecting group of protected ethylene glycol compound of formula IV in step-(b) is illustrated with regard to removing a tert-butyl ether protecting group (i.e., conversion of P from tert-butyl to hydrogen). The removal of the tert-butyl protecting group from the tert-butyl protected ethylene glycol compound of formula IV (i) is advantageously carried out by using an acid as a deprotecting agent. An acid having a sufficient acidic strength to remove tert-butyl ether group can be used. Exemplary acids include, but are not limited to, organic acids such as toluenesulfonic acid, trifluoroacetic acid (TFA), methanesulfonic acid (MSA), formic acid, acetic acid and other carboxylic acids, and mixtures thereof; inorganic acids such as sulfuric acid, hydrobromic acid, hydroiodic acid and hydrochloric acid, and mixtures thereof; and Lewis acids such as ZnCl₂, AlCl₃, FeCl₃, TiCl₄, and Me₃SiI. Such acids can be used individually or as a mixture. Specific acids are trifluoroacetic acid (TFA), methanesulfonic acid (MSA), formic acid, acetic acid, sulfuric acid, hydrochloric acid, FeCl₃, and combinations comprising one or more of the foregoing acids; and more specifically formic acid and hydrochloric acid.

The deprotection reaction in step-(b) can be carried out in the absence of substantially any solvent or it can be carried out in the presence of a reaction solvent. In one embodiment, the deprotection in step-(b) is carried out by contacting the protected ethylene glycol compound of formula IV with an acid in a solvent or a mixture of solvents.

Exemplary solvents used for deprotection include, but are not limited to, water, alcohols, ketones, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, amyl alcohol, acetone, and mixtures thereof; and more specifically water, methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof.

The deprotection reaction in step-(b) is carried out at a temperature of about 0⁰C to about 125°C, specifically at a temperature of 25⁰C to about 100°C, and more specifically at a temperature of about 30°C to about 90°C.

The reaction mass obtained after the deprotection reaction is subjected to usual work up such as filtrations, washings, extractions, evaporations, pH adjustments, etc, and then isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum drying, spray drying, freeze drying, or a combination thereof.

The solvent used for isolating the product obtained in step-(b) is selected from the group consisting of water, alcohols, hydrocarbons, ketones, cyclic ethers, aliphatic ethers, nitriles, and the like, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert- butanol, amyl alcohol, acetone, methylene chloride, toluene, n-hexane, n-heptane, and mixtures thereof; and more specifically water, methanol, ethanol, isopropyl alcohol, acetone, methylene chloride, and mixtures thereof.

In one embodiment, the reaction mass obtained after the deprotection reaction is cooled, and a non-polar aprotic solvent is added. A substantial amount of non-polar solvent and the acid is then removed, for example, by azeotropic distillation under a reduced pressure.

In another embodiment, formic acid is used for the deprotection of tert-butyl ether protected ethylene glycol compound of formula IV (i). When formic acid is used for the deprotection, the initial product can be a formyloxy-protected ethylene glycol compound of formula IV(ii). The formyloxy group can then be removed by contacting the formyloxy- protected ethylene glycol compound of formula IV(ii) with a base.

A base which can hydrolyze the formyloxy group is used. Specifically, the base is selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide; carbonates such as sodium carbonate, lithium carbonate, potassium carbonate and calcium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate.

More specifically, the base is selected from the group consisting of hydroxide, and most specifically sodium hydroxide. The deprotection of the formyloxy group is performed in the presence of a solvent.

Specifically, the solvent is a protic solvent such as water, alcohol and a mixture thereof, more preferably the solvent is water, ethanol and a mixture thereof.

In another embodiment, hydrochloric acid is used for the deprotection of tert-butyl ether protected ethylene glycol compound of formula IV(i). The deprotection reaction with hydrochloric acid in isopropyl alcohol solvent is specifically carried out at a temperature of about 0°C to about 80°C, more specifically at about 15⁰C to about 75°C, and most specifically at about 6O⁰C to about 70⁰C. The product formed is isolated by cooling and filtration. By using this method of deprotection of tert-butyl ether protected ethylene glycol compound of formula IV(i), the formation of the intermediate compound of formula IV(ii) can be avoided.

The compounds of formula V are novel and constitute another aspect of the disclosure.

In another aspect, the specific ethylene glycol compound of formula V prepared by the process disclosed herein is the compound of formula V(i) (formula V, wherein R⁴ is methoxy; R⁵, R⁶ and R⁷ are H; X is Cl; and Z is O). The compound of formula V(i):

is useful for the preparation of bosentan of formula I(i).

The reaction in step-(c) is carried out by contacting the ethylene glycol compound of formula V with a substituted benzene sulfonamide compound of formula VI in a solvent or a mixture of solvents .

Exemplary solvents are those that dissolve both the ethylene glycol compounds and benzene sulfonamide compounds to ensure maximum contact between the reactants, resulting in faster reaction. However, the process is also operable with solvents that only partially dissolve the ethylene glycol compounds or benzene sulfonamide compounds. Specific solvents are selected from the group consisting of toluene, xylene, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and mixtures thereof, and more specifically toluene.

Exemplary bases used in step-(c) include, but are not limited to, hydroxides, carbonates and alkoxides of alkali or alkaline earth metals. Specific alkali metals are lithium, sodium and potassium, more specifically sodium and potassium. Specific alkaline earth metals are calcium and magnesium, and more specifically magnesium.

Specific bases are calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert- butoxide, sodium isopropoxide and potassium tert-butoxide, and more specifically sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. In an embodiment, the reaction between the ethylene glycol compound of formula V with a substituted benzene sulfonamide compound of formula VI in step-(c) is carried out in the presence of a phase transfer catalyst as described above.

In one embodiment, the amount of the phase transfer catalyst employed is about 0.5% w/w to about 10% w/w, specifically about 1% w/w to about 5% w/w. In one embodiment, the reaction in step-(c) is carried out at a temperature of about -

15⁰C to the reflux temperature of the solvent used, specifically at a temperature of about 0°C to the reflux temperature of the solvent used, more specifically at about 25⁰C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used. The time requires for completion of the reaction in step-(c) depends on factors such as solvent used and temperature at which the reaction is carried out. For example, if the reaction is carried out in toluene under reflux conditions, about 5 hours to about 18 hours is required for the reaction completion.

In one embodiment, about 1 to 1.5 moles, specifically, about 1 to 1.2 moles of benzene sulfonamide compound of formula VI per 1 mole of the ethylene glycol compound of formula V is used.

In another embodiment, about 1 to 5 moles, specifically, about 2 to 3 moles, of a base per 1 mole of the benzene sulfonamide compound of formula VI is used.

The reaction mass containing the compound of formula I obtained in step-(c) may be subjected to usual work up such as washings, extractions, evaporations etc., followed by isolation as solid from a suitable organic solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum drying, spray drying, freeze drying, or a combination thereof.

The pure ethylene glycol sulfonamide compound of formula I, specifically bosentan of formula I(i), or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein is having a purity of about 99% to about 99.99% and further comprising dimer impurity in an amount of less than about 0.1% as measured by HPLC. In one embodiment, the ethylene glycol sulfonamide compound, specifically bosentan, as disclosed herein, contains less than about 0.05%, more specifically less than about 0.02%, still more specifically less than about 0.01% of dimer impurity, and most specifically essentially free of dimer impurity.

According to another aspect, there is provided a process for preparing a substituted ethylene glycol sulfonamide of formula I:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and Z are same as defined hereinbefore; or a pharmaceutically acceptable salt thereof; comprising: a) treating a chloro compound of formula VIII:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and Z are as defined in formula I; with a base to produce a hydroxy compound of formula IX:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and Z are as defined in formula I; b) reacting the hydroxy compound of formula IX with a 2-haloethanol compound of formula X:

wherein 'Hal' represents a halogen atom selected from the group consisting of F, Cl, Br and I; in the presence of a base, optionally in the presence of a phase transfer catalyst, to provide substantially pure substituted ethylene glycol sulfonamide of formula I.

Specifically, the halogen atom 'Hal' in the compounds of formula X is Cl. The reaction in step-(a) is carried out by contacting the chloro compound of formula VIII with a suitable base in a solvent or a mixture of solvents. Exemplary solvents are those that dissolve the chloro compound to ensure maximum contact between the reactants resulting in faster reaction. However, the process is also operable with solvents that only partially dissolve the chloro compound. Specific solvents are toluene, ethylene glycol, xylene, tetrahydrofuran, dimethylformamide, diphenyl ether, and the like, and mixtures thereof; and more specifically ethylene glycol and diphenyl ether. In one embodiment, the base used in step-(a) is a strong alkali base, selected from the group consisting of hydroxides of alkali metals. Specific bases are sodium hydroxide and potassium hydroxide, and more specifically potassium hydroxide.

In one embodiment, the reaction is carried out at a temperature of about 5O⁰C to the reflux temperature of the solvent used, specifically at a temperature of about 80⁰C to the reflux temperature of the solvent used, more specifically at a temperature of about 100⁰C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.

The time requires for completion of the reaction depends on factors such as solvent used and temperature at which the reaction is carried out. For example, if the reaction is carried out in diphenyl ether under reflux conditions, from about 15 minutes to 5 hours is required for the reaction completion. The reaction mass obtained after completion of the reaction may be quenched with water.

In one embodiment, about 1 to 15 moles, specifically about 11 moles of base per 1 mole of chloro compound of formula VIII is used.

The reaction mass containing the hydroxy compound of formula IX obtained in step- (a) is optionally treated with an acid, for example hydrochloric acid, followed by usual work up such as washings, extractions etc, and then isolated as a solid from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum drying, spray drying, freeze drying, or a combination thereof. The reaction mass may be used directly in the next step to produce the ethylene glycol sulfonamide of formula I or the hydroxy compound of formula IX may be isolated and then used in the next step.

The solvent used for isolating the hydroxy compound of formula IX is selected from the group consisting of water, acetone, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, methylene chloride, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, and mixtures thereof.

The reaction in step-(b) is carried out by contacting the hydroxy compound of formula IX with a 2-haloethanol compound of formula X in a solvent or a mixture of solvents. Exemplary solvents include, but are not limited to, ethers, aromatic hydrocarbon solvents, chlorinated solvents, aprotic solvents, and mixtures thereof. Specific solvents are tetrahydrofuran, diphenyl ether, petroleum ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, dimethylsulfoxide, dimethylacetamide, and mixtures thereof, and more specifically dimethylformamide. The base used in step-(b) is an organic or inorganic base. Exemplary organic bases are triethyl amine, diisopropyl amine, dimethyl amine, monomethyl amine (gas or aqueous solution) and diisopropyl ethyl amine. In one embodiment, the organic base is triethylamine.

Exemplary inorganic bases include, but are not limited to, hydroxides, carbonates and alkoxides of alkali or alkaline earth metals. Specific alkali metals are lithium, sodium and potassium, more specifically sodium and potassium. Specific alkaline earth metals are calcium and magnesium, and more specifically magnesium.

Specific inorganic bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and more specifically sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

In an embodiment, the reaction between the hydroxy compound of formula EX and 2- haloethanol compound of formula X in step-(b) is preferably carried out in the presence of a phase transfer catalyst as described above.

In one embodiment, the amount of the phase transfer catalyst employed is about 0.5% w/w to about 10% w/w, specifically from about 1 % w/w to about 5% w/w.

The reaction in step-(b) is carried out at a temperature of about -15⁰C to the reflux temperature of the solvent used, specifically at a temperature of about O⁰C to the reflux temperature of the solvent used, more specifically at about 25°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.

The time requires for completion of the reaction in step-(b) depends on factors such as solvent used and temperature at which the reaction is carried out. For example, if the reaction is carried out in dimethylformamide under reflux conditions, about 5 to 20 hours is required for the reaction completion.

In one embodiment, about 1 to 1.7 moles, specifically 1.6 moles of 2-haloethanol compound of formula X per 1 mole of the hydroxy compound of formula IX is used.

In one embodiment, about 1 to 5 moles, specifically, about 5 moles of a base per 1 mole of 2-haloethanol compound of formula X is used. The reaction mass obtained after completion of the reaction may be quenched with water. The reaction mass containing the compound of formula I obtained in step-(b) may be subjected to usual work up such as washings, extractions, evaporations, pH adjustments etc., followed by isolation as solid from a suitable organic solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti- solvent to the solution, evaporation, vacuum drying, spray drying, freeze drying, or a combination thereof.

The solvent used for isolating the pure substituted ethylene glycol sulfonamide of formula I is selected from the group consisting of water, acetone, methanol, ethanol, n- propanol, isopropanol, ethyl acetate, methylene chloride, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, and mixtures thereof.

If required, the pure ethylene glycol sulfonamide of formula I obtained by the processes disclosed herein may be converted into pharmaceutically acceptable salts by conventional methods.

The chloro compound of formula VIII used as starting material in step-(a) may be obtained by processes described in the prior art, for example by the process described in the U.S. Patent No. 5,292,740.

The compounds of formula IX are novel and constitute another aspect of the present disclosure.

In another aspect, the hydroxy compound of formula IX prepared by the process disclosed herein is the compound of formula IX(i) or a salt thereof (formula IX, wherein R¹, R², R⁵, R⁶ and R⁷ are H; R³ is tert-butyl; R⁴ is methoxy; and Z is O). The compound of formula IX(i) or a salt thereof:

is useful for the preparation of the compound of the formula I(i).

In particular, the preferred ethylene glycol sulfonamide compound of formula I prepared by the process described herein is bosentan of formula I(i) or a salt or a hydrate thereof (formula I, wherein R¹, R², R⁵, R⁶ and R⁷ are H; R³ is tert-butyl; R⁴ is methoxy; and Z is O):

Pharmaceutically acceptable salts of the substituted ethylene glycol sulfonamide of formula I can be prepared in high purity by using the substantially pure compound of formula I obtained by the methods disclosed herein, by known methods, for example as described in U.S. Patent No. 5,292,740.

Specific pharmaceutically acceptable salts of the substituted ethylene glycol sulfonamide of formula I are obtained from alkali or alkaline earth metals include the sodium, calcium, potassium and magnesium, and more preferable salt being sodium.

The purity of the substituted ethylene glycol sulfonamide of formula I or their pharmaceutical acceptable salts thereof obtained according to the methods disclosed herein is greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% measured by HPLC.

The pure ethylene glycol sulfonamide compound of formula I, specifically bosentan of formula I(i), or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein is having a purity of about 99% to about 99.99% and further comprising dimer impurity in an amount of less than about 0.1% as measured by HPLC. In one embodiment, the ethylene glycol sulfonamide compound, specifically bosentan, as disclosed herein, contains less than about 0.05%, more specifically less than about 0.02%, still more specifically less than about 0.01% of dimer impurity, and most specifically essentially free of dimer impurity.

According to another aspect, provided herein are highly pure ethylene glycol sulfonamide compounds, or a pharmaceutically acceptable salt thereof, substantially free of dimer impurity (i.e., undesired ethylene glycol bis-sulfonamide).

According to another aspect, provided herein is highly pure bosentan, or a pharmaceutically acceptable salt thereof, substantially free of dimer impurity.

As used herein, "highly pure ethylene glycol sulfonamide compounds, preferably bosentan, or a pharmaceutically acceptable salt thereof substantially free of dimer impurity" refers to ethylene glycol sulfonamide compound or a pharmaceutically acceptable salt thereof, in which ethylene glycol sulfonamide compound has a purity of about 99% to about 99.99% and further comprising dimer impurity in an amount of less than about 0.1% as measured by HPLC. Specifically, the ethylene glycol sulfonamide compound, preferably bosentan, as disclosed herein, contains less than about 0.05%, more specifically less than about 0.02%, still more specifically less than about 0.01% of dimer impurity, and most specifically essentially free of dimer impurity. Instrumental Details:

High Performance Liquid Chromatography (HPLC):

The purity was measured by high performance liquid chromatography under the following conditions:

Apparatus: Water's HPLC system having alliance 2695 model pump and 2487 (UV) detector with Empower chromatography software or its equivalent. Chromatographic Parameters:

Column Zorbax SB-Phenyl 150 x 4.6 mm x 3.5 μm Detector UV at 220nm Flow rate 1.OmI / min

Injection volume 10.0 μL Run time 50 min

Column temperature 3O⁰C Sample temperature Ambient Diluent Water: Acetonitrile-50:50(% v/v)

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES Example 1

Preparation of 4-(2-terf-Butoxyethoxy)-5-(2-methoxyphenoxy)-6-chloro-2,2'- bipyrimidine

4,6-Dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (50 gm), ethylene glycol mono-tert- butyl ether (18.4 gm), anhydrous powdered potassium carbonate (30.9 gm), tetra- butylammonium bromide (33.5 gm) and toluene (500 ml) were taken into a reaction flask and the resulting mixture was refluxed (100-HO⁰C) for 9 hours. After completion of the reaction, toluene was distilled out completely under reduced pressure. Methylene chloride (100 ml) and water (50 ml) were added to the residue, the resulting two layers were separated and the organic layer was washed with water (50 ml). The organic layer was dried over anhydrous sodium sulfate (10 gm) and distilled out methylene chloride under vacuum at 30-35°C. After completion of distillation, isopropyl alcohol (75 ml) was added to the residue and cooled to 0- 5⁰C. The resulting solid was filtered and dried at 60⁰C to yield 36 gm of 4-(2-tert- butoxyethoxy)-5-(2-methoxyphenoxy)-6-chloro-2,2'-bipyrimidine (Purity by HPLC: 97%). Example 2

Preparation of 4-(2-Formyloxyethoxy)-5-(2-methoxyphenoxy)-6-chIoro-2,2'- bipyrimidine

A mixture of 4-(2-tert~butoxyethoxy)-5-(2-methoxyphenoxy)-6-chloro-2,2'-bipyrimidine (4 gm) and formic acid (40 ml, purity: 97-99%) was heated at 85°C for 4 hours. The resulted solution was cooled to 25-30°C and poured into 5% sodium bicarbonate solution (150 ml). The resulting solution was extracted with methylene chloride (40 ml). The organic layer was washed with water (25 ml) and dried over sodium sulfate (10 gm). Methylene chloride layer was distilled out under vacuum at 4O⁰C and the resulting residue was dissolved in isopropyl alcohol (6 ml) at reflux temperature (75-8O⁰C). The clear solution was further cooled to 10- 15°C, filtered the solid and washed with isopropyl alcohol (2 ml) to get yellow colored solid. The resulting solid was dried at 50-55⁰C to give 3.3 gm of 4-(2-formyloxyethoxy)-5-(2- methoxyphenoxy)-6-chloro-2,2'-bipyrimidine (Purity by HPLC: 95%).

Example 3

Preparation of 2-[[6-Chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]oxy] ethanol

30% Sodium hydroxide solution (1 ml) was added to the suspension of 4-(2- formyloxyethoxy)-5-(2-methoxyphenoxy)-6-chloro-2,2'-bipyrimidine (2 gm), water (2 ml) and absolute ethanol (15 ml) at 25 - 30⁰C. The reaction mixture was stirred for 1 hour at 25 - 3O⁰C. After completion of reaction, the suspension was slowly acidified with 0.5 ml concentrated hydrochloric acid and adjusted the pH to 4 - 5. The reaction mass was cooled to 10 - 15⁰C and stirred for 1 hour. The resulting solid was filtered, washed with chilled ethanol (2 ml) and the white colored solid was dried at 50-55⁰C to yield 1.7 gm of 2-[[6- chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]oxy]ethanol (Purity by HPLC: 95%).

Example 4 Preparation of 2-[[6-Chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]oxy] ethanol

4-(2-tert-Butoxyethoxy)-5-(2-methoxyphenoxy)-6-chloro-2,2'-bipyrimidine (25 gm) was added to 18% isopropyl alcoholic hydrochloride (250 ml) and the resulting mixture was heated to 60-65⁰C. The reaction mass was cooled to 0 to 5⁰C and maintained for 1 hour. The resulting solid was filtered and transferred the wet solid into a flask containing water (100 ml) and adjusted pH to 7 by using liquid ammonia. The resulting slurry was filtered and dried at 60°C to yield 18.5 gm of 2-[[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4- yl]oxy]ethanol (Purity by HPLC: 97%).

Example 5 Preparation of p-tert-Butyl-Λ^r-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2- pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide monohydrate (Bosentan)

A mixture of 2-[[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]oxy]ethanol (5 gm), tert-butyl benzene sulfonamide (2.8 gm), anhydrous powdered potassium carbonate (4.6 gm), tetrabutyl ammonium bromide (3 gm) and toluene (50 ml) was taken into a reaction flask and refluxed (100-110°C) for 15 hours. After completion of the reaction, toluene was distilled out completely under reduced pressure followed by the addition of methylene chloride (50 ml) and water (25 ml). The resulting two layers were separated and the organic layer was washed with water (50 ml). The organic layer was dried over anhydrous sodium sulfate (5 gm) and distilled out the organic solvent under vacuum at 30°C. The resulting residue was dissolved in a mixture of ethyl acetate (15 ml) and methanol (35 ml) to get a clear solution. The solution was allowed to cool to 25°C over 1 hour and stirred at 25°C for 18 hours. The precipitated solid was filtered and dried at 60°C to produce 2.7 gm of crude Bosentan (Purity by HPLC: 99.0%).

Example 6

Preparation of p-tert-Butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyl]benzenesulfonamide (Deshydroxy ethyl Bosentan)

A mixture of p-tert-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyl]benzenesulfonamide (2 gm) and potassium hydroxide pellets (2.5 gm) was heated to 150°C to produce a suspension followed by the addition of diphenyl ether (10 ml) at 15O⁰C. The reaction mass temperature was increased to 175°C and stirred till completion of reaction (1 to 2 hours). The resulting mass was cooled to 25-30⁰C followed by addition of water (50 ml) and toluene (25 ml) at 25-3O⁰C. The resulting two layers were separated and the aqueous layer was washed with toluene (50 ml) at 25-3O⁰C. The aqueous layer was cooled to 15⁰C followed by the addition of concentrated hydrochloric acid (1.5 ml) and adjusted the pH to 2 at 10-15⁰C. The resulting solid was filtered and washed with water (50 ml). The white colored solid was dried at 50-55 ⁰C to yield 1.2 gm of p-/ert-Butyl-N-[6- hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] benzenesulfonamide. Example 7

Preparation of p-tert-Butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyI)-4- pyrimidinyl] benzenesulfonamide (Deshydroxy ethyl Bosentan) p-/ert-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] benzenesulfonamide (10 gm) was added to the mixture of sodium hydroxide pellets (3.04 gm), ethylene glycol (100 ml) and water (5 ml) at 100°C and maintained for 3 hours to 5 hours to get complete conversion. The resulting mass was cooled to 25-30°C and quenched with water (50 ml). The resulting mass was extracted with methylene chloride (100 ml) in acidic pH. The resulting layers were separated and the methylene chloride layer was concentrated completely on rotavapour. Ethyl acetate (30 ml) and methanol (70 ml) were added to the residue and then heated to form a clear solution. The solution was gradually cooled at 20 to 30°C, filtered and dried at 50-55 ⁰C to yield 5.5 gm of p-ter/-Butyl-N-[6- hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide

(Purity by HPLC: 99.1%).

Example 8

Preparation of p-ter/-Butyl-7V-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2- pyrimidinyl)-4-pyrimidinyl] benzenesulfonamide monohydrate (Bosentan Crude) p-ter^-Butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl] benzenesulfonamide (5 gm), potassium tertiary-butoxide (1.6 gm), 2-chloroethanol (1 gm) and dimethylformamide (50 ml) were taken into a reaction flask and the mixture was heated to 120°C for 15 hours. The reaction mass was poured into water (100 ml) followed by adjustment of pH to 2 using concentrated hydrochloric acid (5 ml) at 20-25°C. The resulting white colored solid was filtered and washed with water (50 ml) and then dried at 60⁰C to yield 2 gm of bosentan (HPLC Purity: 99%).

Example 9 Purification of crude Bosentan (Pure Bosentan) p-terr-Butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4- pyrimidinyljbenzenesulfonamide monohydrate crude (20 gm) was dissolved in the mixture of ethyl acetate (60 ml) and methanol (140 ml) to produce a clear solution. The solution was allowed to cool to 25⁰C over 1 hour and then stirred for 18 hours at 25⁰C. The resulting precipitated solid was filtered and dried at 60⁰C to produce 11 grams of pure bosentan (HPLC Purity: 99.8%; Content of dimer impurity: 0.05%; deshydroxyethyl bosentan impurity: 0.03%).

As used herein, "alkyl" includes straight chain, branched, and cyclic saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms for the straight chain and generally from 3 to about 12 carbon atoms for the branched and cyclic. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, sec-pentyl, cyclopentyl, cyclohexyl, and octyl.

"Cycloalkyl" indicates saturated hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane.

As used herein, "alkoxy" includes an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3- hexoxy, and 3-methylpentoxy.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, or iodo. Compounds are described using standard nomenclature. For example, any position not substituted by any indicated group is understood to have its valency filled by a bond as indicated, or a hydrogen atom. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CHO is attached through carbon of the carbonyl group.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

We claim:

1. A process for the preparation of a substituted ethylene glycol sulfonamide compound of formula I:

wherein

R¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;

R² is hydrogen, halogen, lower alkoxy, trifluoromethyl or OCH₂COOR_a;

R³ is hydrogen, halogen, lower alkyl, lower alkylthio, trifluoromethyl, cycloalkyl, lower alkoxy or trifluoromethoxy; or

R² and R³ together are butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy-carbonyloxy; or

R⁵ together with R⁴ or R⁶ are butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

Z is O, S, ethylene, vinylene, C(=O), OCHR^b, or SCHR^b;

R^a and R^b are each independently hydrogen or lower alkyl; the process comprising: a) reacting a dihalopyrimidine compound of formula II:

with a mono-protected ethylene glycol of formula III: HI

in the presence of a suitable inorganic base, optionally in the presence of a phase transfer catalyst; wherein X is a halogen atom selected from the group consisting of F, Cl, Br and I' and wherein 'P' is a protecting group; to provide a protected ethylene glycol compound of formula IV:

b) deprotecting the compound of formula IV using a deprotecting agent to provide the ethylene glycol compound of formula V:

; and c) condensing the compound of formula V with a substituted benzene sulfonamide compound of formula VI:

in the presence of a base, optionally in the presence of a phase transfer catalyst, to provide the substituted ethylene glycol sulfonamide of formula I; and optionally converting the compound of formula I into a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein R¹, R², R⁵, R⁶ and R⁷ in the compound of formula I are H; R³ is tert-butyl; R⁴ is methoxy; and Z is O.

3. The process of claim 1, wherein the compound of formula I obtained is bosentan of formula I(i) or a salt or a hydrate thereof:

4. The process of claim 1, wherein the halogen atom 'X' in the compounds of formulae II, IV & V is Cl.

5. The process of claim 1 , wherein the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents.

6. The process of claim 5, wherein the solvent is selected from the group consisting of toluene, xylene, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and mixtures thereof.

7. The process of claim 1, wherein the base used in step-(a) comprises a hydroxide, a carbonate, or an alkoxide of alkali or alkaline earth metals.

8. The process of claim 7, wherein the base is selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert- butoxide, sodium isopropoxide and potassium tert-butoxide.

9. The process of claim 1, wherein the reaction in step-(a) is carried out in the presence of a phase transfer catalyst.

10. The process of claim 9, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetraethylammonium chloride, tetramethyl ammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyl trihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyl tridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethyl ammonium chloride, phenyltriethylammonium chloride, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, and dodecanylpyridinium chloride.

11. The process of claim 10, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethyl ammonium chloride, and tetrabutylammonium hydrogen sulfate.

12. The process of claim 1, wherein the mono-protected ethylene glycol of formula III in step-(a) is used in a molar ratio of about 1 to 1.5 moles relative to 1 mole of the dihalopyrimidine compound of formula II.

13. The process of claim 12, wherein the mono-protected ethylene glycol of formula III is used in a molar ratio of about 1 to 1.2 moles relative to 1 mole of the dihalopyrimidine compound of formula II.

14. The process of claim 1, wherein the base in step-(a) is used in a molar ratio of about 1 to 2.5 moles relative to 1 mole of the mono-protected ethylene glycol of formula III.

15. The process of claim 1, wherein the protecting group 'P' in the compounds of formulae III and IV is a hydroxyl protecting group selected from the group consisting of Cj-C₆- alkyl, trialkylsilyl, aryl, aryl alkyl, formyl, and arylsulfonyl protecting group.

16. The process of claim 15, wherein the protecting group 'P' is tert-butyl.

17. The process of claim 1, wherein the deprotecting agent used in step-(b) is an acid, a base, or a combination thereof.

18. The process of claim 17, wherein the acid comprises an organic acid, an inorganic acid, a Lewis acid, or a mixture thereof.

19. The process of claim 18, wherein the acid is selected from the group consisting of toluenesulfonic acid, trifluoroacetic acid (TFA), methanesulfonic acid (MSA), formic acid, acetic acid, sulfuric acid, hydrobromic acid, hydriodic acid, hydrochloric acid,

ZnCl₂, AlCl₃, FeCl₃, TiCl₄, Me₃SiI, and a combination of two or more of the foregoing acids.

20. The process of claim 19, wherein the acid is formic acid or hydrochloric acid.

21. The process of claim 17, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate.

22. The process of claim 1, wherein the reaction in step-(b) is carried out in the presence of a solvent selected from the group consisting of water, alcohols, ketones, and mixtures thereof.

23. The process of claim 22, wherein the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, amyl alcohol, acetone, and mixtures thereof.

24. The process of claim 1, wherein the reaction in step-(c) is carried out by contacting the ethylene glycol compound of formula V with a substituted benzene sulfonamide compound of formula VI in a solvent or a mixture of solvents.

25. The process of claim 24, wherein the solvent is selected from the group consisting of toluene, xylene, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and mixtures thereof.

26. The process of claim 1, wherein the base used in step-(c) comprises a hydroxide, a carbonate, or an alkoxide of alkali or alkaline earth metals.

27. The process of claim 26, wherein the base is selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert- butoxide, sodium isopropoxide, and potassium tert-butoxide.

28. The process of claim 1, wherein the reaction in step-(c) is carried out in the presence of a phase transfer catalyst.

29. The process of claim 28, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetraethylammonium chloride, tetramethyl ammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyl trihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyl tridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethyl ammonium chloride, phenyltriethylammonium chloride, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, and dodecanylpyridinium chloride.

30. The process of claim 29, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethyl ammonium chloride, and tetrabutylammonium hydrogen sulfate.

31. The process of claim 1 , wherein the benzene sulfonamide compound of formula VI in step-(c) is used in a molar ratio of about 1 to 1.5 moles relative to 1 mole of the ethylene glycol compound of formula V.

32. The process of claim 1, wherein the base in step-(c) is used in a molar ratio of about 1 to 5 moles relative to 1 mole of the benzene sulfonamide compound of formula VI.

33. A process for preparing a substituted ethylene glycol sulfonamide of formula I:

wherein

R¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;

R is hydrogen, halogen, lower alkoxy, trifluoromethyl or OCH₂COOR_a;

R³ is hydrogen, halogen, lower alkyl, lower alkylthio, trifluoromethyl, cycloalkyl, lower alkoxy or trifiuoromethoxy; or

R² and R³ together are butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy-carbonyloxy; or

R⁵ together with R⁴ or R⁶ are butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy

Z is O, S, ethylene, vinylene, C(=O), OCHR^b, or SCHR^b; R^a and R each independently hydrogen or lower alkyl; the process comprising: a) treating a chloro compound of formula VIII:

with a base to produce a hydroxy compound of formula IX:

b) reacting the hydroxy compound of formula IX with 2-haloethanol compound of formula X:

in the presence of a base, optionally in the presence of a phase transfer catalyst, to provide the substituted ethylene glycol sulfonamide of formula I; and optionally converting the compound of formula I into a pharmaceutically acceptable salt thereof; wherein 'Hal' is a halogen atom selected from the group consisting of F, Cl, Br and I;

34. The process of claim 33, wherein the reaction in step-(a) is carried out by contacting the chloro compound of formula VIII with an alkali metal hydroxide base in a solvent or a mixture of solvents at a temperature of about 5O⁰C to the reflux temperature of the solvent used.

35. The process of claim 34, wherein the solvent is selected from the group consisting of toluene, ethylene glycol, xylene, tetrahydrofuran, dimethylformamide, diphenyl ether, and mixtures thereof.

36. The process of claim 33, wherein the base used in step-(a) is sodium hydroxide or potassium hydroxide.

37. The process of claim 33, wherein the base in step-(a) is used in a molar ratio of about 1 to 15 moles relative to 1 mole of the chloro compound of formula VIII.

38. The process of claim 33, wherein the halogen atom 'Hal' in the compound of formula X is Cl.

39. The process of claim 33, wherein the reaction in step-(b) is carried in a solvent selected from the group consisting of ethers, aromatic hydrocarbon solvents, chlorinated solvents, aprotic solvents, and mixtures thereof.

40. The process of claim 39, wherein the solvent is selected from the group consisting of tetrahydrofuran, diphenyl ether, petroleum ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, dimethylsulfoxide, dimethylacetamide, and mixtures thereof.

41. The process of claim 33, wherein the base used in step-(b) is an organic or inorganic base.

42. The process of claim 41, wherein the organic base is selected from the group consisting of tri ethyl amine, diisopropyl amine, dimethyl amine, monomethyl amine, (gas or aqueous solution) and diisopropyl ethyl amine.

43. The process of claim 41, wherein the inorganic base comprises a hydroxide, a carbonates, or an alkoxide of alkali or alkaline earth metals.

44. The process of claim 43, wherein the inorganic base is selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide, and potassium tert-butoxide.

45. The process of claim 33, wherein the reaction in step-(b) is carried out in the presence of a phase transfer catalyst.

46. The process of claim 45, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetraethylammonium chloride, tetramethyl ammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyl trihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyl tridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethyl ammonium chloride, phenyltriethylammonium chloride, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide and dodecanylpyridinium chloride

47. The process of claim 46, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethyl ammonium chloride, and tetrabutylammonium hydrogen sulfate.

48. The process of claim 33, wherein the 2-haloethanol compound of formula X in step-(b) is used in a molar ratio of 1 to 1.7 moles relative to 1 mole of the hydroxy compound of formula IX.

49. The process of claim 33, wherein the base in step-(b) is used in a molar ratio of 1 to 5 moles relative to 1 mole of 2-haloethanol compound of formula X.

50. The process of any one of claims 1 and 33, wherein the substituted ethylene glycol sulfonamide of formula I obtained has a purity of greater than about 99% as measured by HPLC.

51. The process of any one of claims 1 and 33, wherein the substituted ethylene glycol sulfonamide of formula I or a pharmaceutically acceptable salt thereof obtained has a purity of about 99% to about 99.99%, and a dimer impurity in an amount of less than about 0.1% as measured by HPLC.

52. The process of claim 51, wherein the substituted ethylene glycol sulfonamide of formula I or a pharmaceutically acceptable salt thereof comprising the dimer impurity in an amount of less than about 0.05%.

53. The process of claim 52, wherein the substituted ethylene glycol sulfonamide of formula I or a pharmaceutically acceptable salt thereof comprises the dimer impurity in an amount of less than about 0.02%.

54. The process of claim 51, wherein the substituted ethylene glycol sulfonamide of formula I or a pharmaceutically acceptable salt thereof, is essentially free of dimer impurity.

55. A protected ethylene glycol compound of formula IV:

wherein R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, halogen, lower alkyl, trifiuoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy- carbonyloxy; or

R⁵ together with R⁴ or R⁶ is butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Z is O, S, ethylene, vinylene, C(=O), OCHR^b, or SCHR^b; R^b is hydrogen or lower alkyl; and P is a protecting group; and X represents a halogen atom selected from the group consisting of F, Cl, Br and I.

56. The compound of formula IV as defined in claim 55, wherein the protecting group 'P' is a hydroxyl protecting group selected from the group consisting of C]-C₆-alkyl, trialkylsilyl, aryl, aryl alkyl, formyl, and arylsulfonyl.

57. The compound of formula IV as defined in claim 55, wherein R⁴ is methoxy; R⁵, R⁶ and R⁷ are H; and Z is O; X is Cl; and P is tert-butyl; as represented by the compound of formula IV(i):

58. Use of the compound of formula IV of claim 55 in the process for manufacture of the ethylene glycol sulfonamide of formula I and pharmaceutically acceptable salts thereof.

59. Use of the compound of formula IV(i) of claim 57 in the process for manufacture of bosentan of formula I(i) or a pharmaceutically acceptable salt thereof.

60. The compound of formula IV as defined in claim 55, wherein R⁴ is methoxy; R⁵, R⁶ and R⁷ are H; and Z is O; X is Cl; and P is formyl; as represented by the compound of formula IV(ii):

61. Use of the compound of formula IV(ii) of claim 60 in the process for manufacture of bosentan of formula I(i) or a pharmaceutically acceptable salt thereof.

62. An ethylene glycol compound of formula V:

wherein R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy- carbonyloxy; or

R⁵ together with R⁴ or R⁶ is butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

Z is O, S, ethylene, vinylene, C(=O), OCHR^b, or SCHR^b; R^b is hydrogen or lower alkyl; and X represents a halogen atom selected from the group consisting of F, Cl, Br and I.

63. The compound of formula V as defined in claim 62, wherein the protecting group 'P' is a hydroxyl protecting group selected from the group consisting of Ci-C₆-alkyl, trialkylsilyl, aryl, aryl alkyl, formyl, and arylsulfonyl.

64. Use of the compound of formula V of claim 62 in the process for manufacture of the ethylene glycol sulfonamide of formula I and pharmaceutically acceptable salts thereof.

65. The compound of formula V as defined in claim 62, wherein R⁴ is methoxy; R⁵, R⁶ and R⁷ are H; X is Cl; and Z is O; as represented by the compound of formula V(i):

66. Use of the compound of formula V(i) of claim 65 in the process for manufacture of bosentan of formula I(i) or a pharmaceutically acceptable salt thereof.

67. A hydroxy compound of formula IX:

wherein

R¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;

R² is hydrogen, halogen, lower alkoxy, trifluoromethyl or OCH₂COOR_a;

R³ is hydrogen, halogen, lower alkyl, lower alkylthio, trifluoromethyl, cycloalkyl, lower alkoxy or trifluoromethoxy; or

R² and R³ together are butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

R⁴, R⁵, R⁶ and R⁷ are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy-carbonyloxy; or

R⁵ together with R⁴ or R⁶ is butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

Z is O, S, ethylene, vinylene, C(=O), OCHR^b, or SCHR^b;

R^a and R^b each independently hydrogen or lower alkyl.

68. The compound of formula IX as defined in claim 67, wherein the protecting group 'P' is a hydroxyl protecting group selected from the group consisting of CrCβ-alkyl, trialkylsilyl, aryl, aryl alkyl, formyl, and arylsulfonyl.

69. Use of the compound of formula IX of claim 67 in the process for manufacture of the ethylene glycol sulfonamide of formula I and pharmaceutically acceptable salts thereof

70. The compound of formula IX as defined in claim 67, wherein R¹, R², R⁵, R⁶ and R⁷ are H; R³ is tert-butyl; R⁴ is methoxy; and Z is O; as represented by the compound of formula IX(i):

71. Use of the compound of formula IX(i) of claim 70 in the process for manufacture of bosentan of formula I(i) or a pharmaceutically acceptable salt thereof.