EP2268634A2 - Procédés de préparation de bosentan et de composés apparentés à l'aide de nouveaux intermédiaires - Google Patents

Procédés de préparation de bosentan et de composés apparentés à l'aide de nouveaux intermédiaires

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Publication number
EP2268634A2
EP2268634A2 EP09718766A EP09718766A EP2268634A2 EP 2268634 A2 EP2268634 A2 EP 2268634A2 EP 09718766 A EP09718766 A EP 09718766A EP 09718766 A EP09718766 A EP 09718766A EP 2268634 A2 EP2268634 A2 EP 2268634A2
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EP
European Patent Office
Prior art keywords
formula
compound
chloride
ethylene glycol
group
Prior art date
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EP09718766A
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German (de)
English (en)
Inventor
Girish Dixit
Nandkumar Gaikwad
Hima Prasad Naidu
Nitin Sharadchandra Pradhan
Jon Valgeirsson
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Actavis Group PTC ehf
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Actavis Group PTC ehf
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Publication of EP2268634A2 publication Critical patent/EP2268634A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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.
  • cardiovascular disorders such as hypertension, ischemia, vasospasms and angina pectoris.
  • 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 C 27 H ⁇ N 5 O 6 S. H 2 O, molecular weight of 569.63 and a structural formula of:
  • 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 '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.
  • 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.
  • 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.
  • a phase transfer catalyst e.g., benzyltriethylammonium chloride
  • 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.
  • 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.
  • 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.
  • 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.
  • novel, commercially viable and industrially advantageous processes for the preparation of highly pure ethylene glycol sulfonamide compounds such as Bosentan using novel intermediates 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.
  • high pure 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.
  • 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.
  • 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.
  • R 1 is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl
  • R 2 is hydrogen, halogen, lower alkoxy, trifluoromethyl or OCH 2 COOR a ;
  • R 3 is hydrogen, halogen, lower alkyl, lower alkylthio, trifluoromethyl, cycloalkyl, lower alkoxy or trifluoromethoxy; or
  • R 2 and R together can be butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
  • R 4 , R 5 , R 6 and R 7 are independently hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulf ⁇ nyl, methylsulfonyl, methylsulfonyloxy or lower alkyloxy-carbonyloxy; or
  • R 5 together with R 4 or R 6 can be butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;
  • R a and R b each independently hydrogen or lower alkyl.
  • the process comprises: a) reacting a dihalopyrimidine compound of formula II:
  • R 4 , R 5 , R 6 , R 7 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:
  • R 1 , R 2 and R 3 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.
  • lower denotes groups with 1-7 carbon atoms, preferably 1-4 carbon atoms. Lower includes 1, 2, 3, 4, 5, 6 and 7 carbon atoms.
  • the halogen atom 'X' in the compounds of formulae II, IV & V is Cl.
  • step-(c) The highly pure ethylene glycol sulfonamide of formula I obtained in step-(c) may be converted into pharmaceutically acceptable salts by conventional methods.
  • 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 R 1 , R 2 , R 5 , R 6 and R 7 are H; R 3 is tert-butyl; R 4 is methoxy; and Z is O):
  • step-(a) is carried out in the absence of substantially any solvent or is carried out in the presence of a reaction solvent.
  • 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.
  • solvents are those that dissolve both the dichloro compounds and ethylene glycol compounds to ensure maximum contact between the reactants resulting in faster reaction.
  • 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.
  • 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.
  • 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, tetrapentylam
  • 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.
  • phase transfer catalysts are tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, and more specifically tetrabutylammonium bromide.
  • 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.
  • the reaction in step-(a) is carried out at a temperature of about
  • step-(a) 0 C 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 25 0 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-(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.
  • the protecting group 'P' in the compounds of formulae III and IV is a hydroxyl protecting group which is easily removed, such as C]-C 6 -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.
  • 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.
  • 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 protected ethylene glycol compound of formula IV prepared by the process disclosed herein is the compound of formula IV(i) (formula IV, wherein R 4 is methoxy; R 5 , R 6 and R 7 are H; and Z is O; X is Cl; and P is tert-butyl).
  • 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 R 4 is methoxy; R 5 , R 6 and R 7 are H; and Z is O; X is Cl; and P is formyl).
  • 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.
  • 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 ZnCl 2 , AlCl 3 , FeCl 3 , TiCl 4 , and Me 3 SiI. Such acids can be used individually or as a mixture.
  • 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
  • Lewis acids such as ZnCl 2 ,
  • Specific acids are trifluoroacetic acid (TFA), methanesulfonic acid (MSA), formic acid, acetic acid, sulfuric acid, hydrochloric acid, FeCl 3 , 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.
  • 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.
  • 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 0 0 C to about 125°C, specifically at a temperature of 25 0 C to about 100°C, and more specifically at a temperature of about 30°C to about 90°C.
  • 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.
  • 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.
  • 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.
  • formic acid is used for the deprotection of tert-butyl ether protected ethylene glycol compound of formula IV (i).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 15 0 C to about 75°C, and most specifically at about 6O 0 C to about 70 0 C.
  • the product formed is isolated by cooling and filtration.
  • the specific ethylene glycol compound of formula V prepared by the process disclosed herein is the compound of formula V(i) (formula V, wherein R 4 is methoxy; R 5 , R 6 and R 7 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).
  • 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.
  • 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.
  • 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.
  • 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 -
  • step-(c) 15 0 C 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 25 0 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-(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.
  • 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.
  • 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.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Z are same as defined hereinbefore; or a pharmaceutically acceptable salt thereof; comprising: a) treating a chloro compound of formula VIII:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Z are as defined in formula I; with a base to produce a hydroxy compound of formula IX:
  • '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.
  • 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.
  • 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.
  • 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.
  • the reaction is carried out at a temperature of about 5O 0 C to the reflux temperature of the solvent used, specifically at a temperature of about 80 0 C to the reflux temperature of the solvent used, more specifically at a temperature of about 100 0 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • step-(b) is carried out at a temperature of about -15 0 C to the reflux temperature of the solvent used, specifically at a temperature of about O 0 C 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.
  • step-(b) 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.
  • reaction mass obtained after completion of the reaction may be quenched with water.
  • 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.
  • 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 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 R 1 , R 2 , R 5 , R 6 and R 7 are H; R 3 is tert-butyl; R 4 is methoxy; and Z is O).
  • 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 R 1 , R 2 , R 5 , R 6 and R 7 are H; R 3 is tert-butyl; R 4 is methoxy; and Z is O):
  • 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.
  • 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.
  • ethylene glycol sulfonamide compounds substantially pure ethylene glycol sulfonamide compounds, or a pharmaceutically acceptable salt thereof, substantially free of dimer impurity (i.e., undesired ethylene glycol bis-sulfonamide).
  • provided herein is highly pure bosentan, or a pharmaceutically acceptable salt thereof, substantially free of dimer impurity.
  • 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.
  • 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.
  • Apparatus Water's HPLC system having alliance 2695 model pump and 2487 (UV) detector with Empower chromatography software or its equivalent. Chromatographic Parameters:
  • 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.
  • concentrated hydrochloric acid 5 ml
  • the resulting white colored solid was filtered and washed with water (50 ml) and then dried at 60 0 C to yield 2 gm of bosentan (HPLC Purity: 99%).
  • 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.
  • 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.
  • alkoxy includes an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge (-O-).
  • 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.

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Abstract

L'invention porte sur de nouveaux procédés, commercialement viables et industriellement avantageux pour la préparation de composés d'éthylène glycol sulfonamide sensiblement purs, tels que le bosentan, à l'aide de nouveaux intermédiaires.
EP09718766A 2008-03-13 2009-03-12 Procédés de préparation de bosentan et de composés apparentés à l'aide de nouveaux intermédiaires Withdrawn EP2268634A2 (fr)

Applications Claiming Priority (2)

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IN628CH2008 2008-03-13
PCT/IB2009/005454 WO2009112954A2 (fr) 2008-03-13 2009-03-12 Procédés de préparation de bosentan et de composés apparentés à l'aide de nouveaux intermédiaires

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US8664390B2 (en) 2007-06-29 2014-03-04 Generics (Uk) Limited Process for the introduction of hydroxyethoxy side chain in bosentan
JP2011500780A (ja) 2007-10-24 2011-01-06 ジェネリクス・（ユーケー）・リミテッド 新規結晶形
JP5683276B2 (ja) 2008-02-08 2015-03-11 ジェネリクス・［ユーケー］・リミテッド ボセンタンの製造方法
WO2010015623A1 (fr) * 2008-08-05 2010-02-11 Farmaprojects, S. A. Procédé pour la fabrication d'antagonistes des récepteurs de l'endothéline
WO2010061210A1 (fr) * 2008-11-03 2010-06-03 Generics [Uk] Limited Procédé clhp pour l’analyse de bosentan et de substances apparentées et utilisation de ces substances en tant que standards de référence et marqueurs
CN102421770A (zh) 2009-04-13 2012-04-18 桑多斯股份公司 制备内皮素受体拮抗剂(波生坦)的方法
US9139537B2 (en) 2010-08-11 2015-09-22 Megafine Pharma(P) Ltd. Process for preparation of bosentan
US20130245259A1 (en) 2012-03-16 2013-09-19 Natco Pharma Limited Process for the preparation of bosentan monohydrate
EP2738165B1 (fr) * 2012-12-03 2016-10-12 WÖRWAG PHARMA GmbH & Co. KG Procédé au moyen d'une catalyse par transfert de phase

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US5739333A (en) * 1995-05-16 1998-04-14 Tanabe Seiyaku Co., Ltd. Sulfonamide derivative and process for preparing the same
US6136971A (en) * 1998-07-17 2000-10-24 Roche Colorado Corporation Preparation of sulfonamides
US8664390B2 (en) * 2007-06-29 2014-03-04 Generics (Uk) Limited Process for the introduction of hydroxyethoxy side chain in bosentan
ES2376375T3 (es) * 2007-12-18 2012-03-13 Dipharma Francis S.R.L. Procedimiento para la preparación de bosent�?n.

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