WO2011024056A2 - Procédé perfectionné pour la préparation de bosentan - Google Patents

Procédé perfectionné pour la préparation de bosentan Download PDF

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Publication number
WO2011024056A2
WO2011024056A2 PCT/IB2010/002090 IB2010002090W WO2011024056A2 WO 2011024056 A2 WO2011024056 A2 WO 2011024056A2 IB 2010002090 W IB2010002090 W IB 2010002090W WO 2011024056 A2 WO2011024056 A2 WO 2011024056A2
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Prior art keywords
bosentan
potassium
process according
formula
acid
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PCT/IB2010/002090
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WO2011024056A3 (fr
Inventor
Kumar Sinha Brajesh
Rajasekhara Raju Konduru
Shankar Reddy Budidet
Pandu Rangarao Vaddi
Islam Aminul
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Limited
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Publication of WO2011024056A2 publication Critical patent/WO2011024056A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • 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

Definitions

  • the present invention relates to an improved process for the preparation of Bosentan of Formula
  • Bosentan is chemically known as 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- [2,2']-bipyrimidin-4-yl]benzenesulfonamide.
  • Bosentan is a specific competitive antagonist at endothelin receptor types ETA and ET ⁇ .
  • Endothelin (ET-I) is a neurohormone, the effects of which are mediated by binding of ETA and ET B receptors in the endothelium and vascular smooth muscle. ET-I concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role of ET-I .
  • Bosentan has a slightly higher affinity for ET A receptors than ETB receptors. Bosentan is marketed under the name Tracleer®. It has been approved for the treatment of pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • Bosentan and its pharmaceutically acceptable salts are disclosed in US 5,292,740.
  • US '740 also discloses a process for the preparation of sodium salt of Bosentan (Ia), by reacting 2- amidinopyrimidinium hydrochloride (II) with diethyl-(2-methoxyphenoxy)malonate (III) in the presence of sodium metal in methanol followed by IN sodium hydroxide to produce 5-(2- methoxyphenoxy)-2-(pyrimidin-2-yl)tetrahydropyrimidin-4,6-dione (IV), which is further reacted with phosphorus pentachloride in presence of N,N-diisopropyl-N-ethylamine to produce 4,6- dichlpro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (V).
  • WO 2009/004374 Al discloses a process for the preparation of Bosentan (I), by providing a mixture of ethylene glycol and hydroxide ions, followed by addition of 4-(l,l-dimethylethyl)-N- [6-chloro-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (VIl) and isolating Bosentan (I).
  • WO 2009/095933 Al discloses Bosentan potassium salt, which is prepared by treating Bosentan with 30% aqueous potassium hydroxide in ethanol.
  • the instant invention directed to purification of Bosentan crude by making its crystalline potassium salt, which is further converted to Bosentan (I) with bis-sulfonamide (VIII) and deshydroxyethyl (IX) impurities to less than 0.2 % by HPLC analysis.
  • the present invention also directed to a process for the preparation of Bosentan (I) by using dimethyl-(2-methoxyphenoxy)malonate (XIV).
  • the main objective of the present invention is to provide crystalline forms of Bosentan potassium Form I and Form II.
  • Another objective of the present invention is to provide a process for the preparation of crystalline Bosentan potassium Form I and Form II.
  • Another objective of the present invention is to provide a simple and cost effective process for the preparation of Bosentan using the above crystalline Bosentan potassium Form I and Form II.
  • Another objective of the present invention also provides a simple and cost effective process for the preparation of 4-( 1 , 1 -dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrirnidin]-4- yl]benzenesulfonamide (Vila).
  • the present invention provides a crystalline Bosentan potassium Form I, characterized by X-ray diffraction spectrum which shows peaks at the diffraction angles of about 5.60 ⁇ 0.2, 6.48 ⁇ 0.2, 9.67 ⁇ 0.2, 10.20 ⁇ 0.2, 1 1.16 ⁇ 0.2, 12.89 ⁇ 0.2, 14.04 ⁇ 0.2, 16.80 ⁇ 0.2, 17.89 ⁇ 0.2, 18.80 ⁇ 0.2, 22.38 ⁇ 0.2 two theta degrees.
  • Another embodiment of the present invention provides crystalline Bosentan potassium Form II, characterized by X-ray diffraction spectrum which shows peaks at the diffraction angles of about 6.64 ⁇ 0.2, 8.78 ⁇ 0.2, 9.78 ⁇ 0.2, 10.66 ⁇ 0.2, 14.71 ⁇ 0.2, 17.20 ⁇ 0.2, 17.57 ⁇ 0.2, 18.4 ⁇ 0.2, 22.33 ⁇ 0.2, 27.51 ⁇ 0.2, 29.63 ⁇ 0.2 two theta degrees.
  • Another embodiment of the present invention provides a process for the preparation of crystalline Bosentan potassium Form I,
  • step (ii) basifying the resulting solution of step (i) with aqueous potassium hydroxide
  • Another embodiment of the present invention provides substantially pure Bosentan having less than about 0.2 % of dimer impurity (VIII) and less than about 0.2 % of deshydroxy impurity (IX).
  • Formula IX Another embodiment of the present invention provides a process for the preparation of substantially pure Bosentan having less then about 0.2% of dimmer impurity (VIII) and less than about 0.2% of deshydroxy impurity (IX),
  • Another embodiment of the present invention also provides a process for the preparation of 4-( 1,1- dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) or its salt,
  • the base is not sodium mehoxide
  • the base is not sodium mehoxide
  • Figure 1 illustrates the X-ray powder diffraction pattern of crystalline Bosentan potassium Form 1.
  • Figure 2 illustrates the X-ray powder diffraction pattern of crystalline Bosentan potassium Form
  • the present invention relates to a process for the preparation of 4-(l,l-dimethylethyl)-N-[6-halo-5- (2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) or its salt.
  • the process comprises, treating 2-cyanopyrimidine (XIII) with a base selected from alkoxides such as sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide and in a solvent selected from lower alkanol such as methanol, ethanol, isopropanol or butanol.
  • a base selected from alkoxides such as sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide and in a solvent selected from lower alkanol such as methanol, ethanol, isopropanol or butanol.
  • the resulting reaction mixture is treated with ammonium chloride to produce 2-amidinopyrimidinium hydrochloride (II).
  • the reaction can be performed at a temperature ranging from about -10 0 C to about 10 0 C based on the solvents used for the reaction.
  • the compound (XVI) is prepared by reacting 2-methoxyphenol (XV),
  • XVI dimethylchloro malonate
  • a suitable solvent and a base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide to produce dimethyl-(2- methoxyphenoxy)malonate (XIV).
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide
  • alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide to produce dimethyl-(2- methoxyphenoxy)malonate (XIV).
  • the solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene
  • halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform
  • polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof.
  • Preferred solvent is the toluene.
  • the reaction can be performed at a temperature ranging from about 20°C to about 15O 0 C based on the solvents used for the reaction.
  • the compound (XVI) is added to a solution of salt of 2- methoxyphenol (XV) in the organic solvent. Preferably, after removal of water from the solution of compound (XV) by azeotropic distillation.
  • the sufficient period of time necessary for obtaining compound (XIV) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 1 to about 10 hours. More preferably, the reaction mixture is maintained for about 2 hour to about 3 hours.
  • Compound (XIV) can be isolated from the reaction mixture by adding a sufficient amount of water to the reaction mixture followed by aqueous base solution to remove unreacted 2-methoxyphenol (XV) followed by removing the solvent to produce an oily mass. Condensing the compound (XIV) with 2-amidinopyrimidinium hydrochloride (II) in the presence of a suitable base in a solvent produces 5-(2-methoxyphenoxy)-2-(pyrimidin-2- yl)tetrahydropyrimidin-4,6-dione (IV).
  • the base is selected from alkoxide such as sodium ethoxide, sodium isoproxide, sodium tert- butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert- butoxide.
  • the solvent used in the reaction is selected from lower alkanol such as methanol, ethanol, isopropanol or butanol.
  • the reaction can be performed at a temperature ranging from about -10°C to about 30 0 C based on the solvents used for the reaction.
  • a preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 5 hours.
  • Compound (IV) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, treating with a solvent and crystallizing or precipitating from the reaction medium.
  • a sufficient amount of acid is added to the reaction mixture resulting in the pH of the solution from pH of about 1 to pH of about 2, more preferably from pH of about 0.5 to pH of about 1.0. Any acid having sufficient pKa to generate the desired pH can be used.
  • the acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid, and more preferably the acid is hydrochloric acid.
  • the solvent used is selected from methylene chloride, ethyl acetate, and toluene.
  • 5-(2-Methoxyphenoxy)-2-(pyrimidine-2-yl)-tetrahydropyrimidin-4,6-dione (IV) is reacted with halogenating agent to produce 4,6-dihalo-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (Va).
  • the halogenating agent is selected from phosphorous oxychloride and phosphorous pentachloride.
  • the reaction can be performed at a temperature ranging from about 20 0 C to about 12O 0 C.
  • a preferred reaction time is from about 1 to about 10 hours, more preferably from about 3 to about 8 hours.
  • the reaction mass was added to a mixture of organic solvent and water and treated with aqueous base.
  • the solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform.
  • the aqueous base used is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxides, calcium hydroxide.
  • the suitable base is selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate or mixtures thereof.
  • the solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene
  • halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform
  • polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof.
  • Preferred solvent is the toluene.
  • phase transfer catalyst which is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate.
  • phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate.
  • phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltri
  • the reaction is performed at a temperature ranging from about 3O 0 C to about 150 0 C based on the solvents used for the reaction. More preferably, from about 25 0 C to about 120 0 C.
  • a preferred reaction time is from about 1 to about 7 hours, more preferably from about 1 to about 5 hours. Water formed during the reaction is separated by azeotropically.
  • Vila 4-(l ,l-dimethylethyl)-N-[6-halo- 5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonamide (Vila) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, extracting with a solvent and removing the solvent and crystallizing or precipitating it from a crystallization solvent.
  • a sufficient amount of acid is added to the reaction mixture resulting in the pH of the solution from pH of about 0.5 to pH of about 4, more preferably, from pH of about 0.5 to pH of about 1. Any acid having sufficient pKa to generate the desired pH can be used.
  • the acid is selected from the group consisting of inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid and sulfuric acid, and more preferably the acid is hydrochloric acid.
  • the solvent used in the extraction is selected from methylene chloride, ethyl acetate, and toluene.
  • Compound (Vila) can be converted to its salts selected from hydrochloride, hydrobromide.
  • Bosentan (I) The reaction of 4-(l,l-dimethylethyl)-N-[6-halo-5-(2-methoxyphenoxy)-[2,2'-bipyrimidin]-4- yl]benzenesulfonamide (Vila) or its salt with ethylene glycol to produce Bosentan (I) is carried out in the presence of a base selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate or mixtures there of and in a solvent.
  • alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate
  • alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate or mixtures there of and in a solvent.
  • the solvent is selected from aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform, polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof.
  • aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene
  • halogenated hydrocarbon solvents such as methylene chloride, dichloro ethane, chloroform
  • polar aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, sulfolane or mixtures thereof.
  • Preferred solvent is toluene.
  • phase transfer catalyst is a catalyst or agent added to the reaction mixture of components, where it can conveniently and rapidly react with another reacting component.
  • the phase transfer catalyst used is selected from tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate.
  • tetrabutylammonium bromide tetrabutylammonium bromide.
  • the reaction can be performed at a temperature ranging from about 15°C to about 130 0 C based on the solvents used for the reaction. More preferably, from about 25°C to about 120 0 C.
  • a preferred reaction time is from about 10 to about 30 hours, more preferably from about 15 to about 24 hours, and most preferably from about 13 to about 24 hours.
  • Preferably from about 10 equivalents to about 130 equivalents of ethylene glycol relative to the 4-(l ,l -dimethylethyl)-N-[6-halo-5-(2- methoxyphenoxy)-[2,2'-bipyrimidin]-4-yl]benzenesulfonarnide (Vila) is used in the reaction, more preferably from about 50 equivalents to about 120 equivalents.
  • Bosentan (I) can be isolated from the reaction mixture by adding a sufficient amount of acid to the reaction mixture to neutralize any base that may be present, extracting with a solvent and removing the solvent and crystallizing or precipitating it from a solvent.
  • Another embodiment of the present invention relates to the purification of Bosentan of formula I.
  • Bosentan potassium Form I having X-ray diffraction characteristic peaks at about 5.60 ⁇ 0.2, 6.48 ⁇ 0.2, 9.67 ⁇ 0.2, 10.20 ⁇ 0.2, 1 1.16 ⁇ 0.2, 12.89 ⁇ 0.2, 14.04 ⁇ 0.2, 16.80 ⁇ 0.2, 17.89 ⁇ 0.2, 18.80 ⁇ 0.2, 22.38 ⁇ 0.2 two theta degrees, is prepared by treating crude Bosentan with potassium hydroxide in aqueous alcohol to produce crystalline Bosentan potassium Form I.
  • the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet- butanol, preferably isopropanol.
  • the salt formation can be carried out at temperature of about 10 to 100 0 C, preferably between 55 to 60 0 C.
  • the crystalline Bosentan potassium Form I is isolated by filtration.
  • the crystalline Bosentan potassium Form I obtained by the above process contains less than 0.2 % bis-sulfonamide (VIII) impurity by HPLC.
  • Bosentan potassium Form II having X-ray diffraction characteristic peaks at about 6.64 ⁇ 0.2, 8.78 ⁇ 0.2, 9.78 ⁇ 0.2, 10.66 ⁇ 0.2, 14.71 ⁇ 0.2, 17.20 ⁇ 0.2, 17.57 ⁇ 0.2, 18.4 ⁇ 0.2, 22.33 ⁇ 0.2, 27.51 ⁇ 0.2, 29.63 ⁇ 0.2 two theta degrees, is prepared by treating crystalline Bosentan potassium Form I with an acid in a solvent followed by treating with aqueous potassium hydroxide.
  • the acid used for acidification is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid etc.
  • the solvent used is selected from water.
  • Acidification is carried out at a temperature of about 10 to 100 0 C, preferably between 55 to 60°C.
  • Aqueous potassium hydroxide is added at a temperature of about 10 to 100°C, preferably 55 to 60°C.
  • Crystalline Bosentan potassium Form Il is isolated after cooling the solution to room temperature by filtration and optionally dried.
  • the crystalline Bosentan potassium Form II obtained by the above process contains less than 0.2% of deshydroxy impurity (IX) by HPLC.
  • Bosentan potassium Form I or Form II is treated with an acid, in a solvent or mixture of solvents to produce Bosentan substantially free from bis-sulfonamide impurity (VIII) and deshydroxy impurity (IX).
  • the acid used is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid etc.
  • the solvent used is selected from water; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride, chloroform; esters such as methyl acetate, ethyl acetate; aromatic hydrocarbons such as toluene, xylene or mixtures thereof.
  • Acid is added to a pH of about 0.5 to 1.0 at temperature of about 0 to 7O 0 C, preferably at about 20 to 5O 0 C.
  • the organic layer is separated and removed the solvent to produce the residue.
  • the residue containing Bosentan is dissolved in a solvent selected from alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, tet-butanol, preferably ethanol, at a temperature of about 20 to 100 0 C, preferably 55 to 60 0 C.
  • Treating the resulting solution with carbon enoantichromas and filtered through hyflo bed and the filtrate is heated to reflux temperature and DM water is added at reflux temperature.
  • the resulting reaction mass is cooled to room temperature over a period of 4 to 7 hours to crystallize the Bosentan pure, which is filtered and dried.
  • Bosentan (I) prepared by the process of the present invention includes its hydrates and solvates.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of substantially pure Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX) in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients and the quantity of the compound or composition of the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.
  • compositions of the present invention are prepared using conventional materials and techniques, such as mixing, blending and the like.
  • composition comprising Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX) also include, suitable adjuvants, carriers, excipients, or stabilizers, etc. and can be in solid or liquid form such as, tablets.
  • the present invention further provides Bosentan having less than about 0.2% of bis-sulfonamide impurity (VIII) and less than about 0.2 % of deshydroxyethyl impurity (IX), for use in the manufacture of a medicament for the treatment in hypertension.
  • VIII bis-sulfonamide impurity
  • IX deshydroxyethyl impurity
  • Dimethyl(2-methoxyphenoxy)malonate (XIV) was added to the reaction mass containing 2- aminopyrimidinium hydrochloride (II) prepared in stage-2 at 0-5 0 C.
  • Sodium ethoxide (106.76g, 1570 mmol) was added to the reaction mass at 0-5°C in 1 hrs and maintain at 35°C for 5hrs. Thereafter, the reaction mass was concentrated, dissolved in mixture of DM water (500ml) and toluene (150mi) and acidified to pH 0.5-0.7 with dilute hydrochloric acid at 20-30 0 C.
  • the precipitated product was filtered, washed with toluene followed by water and dried at 75-8O 0 C to yield 129.3g of title compound.
  • Bosentan crude obtained in example- l(step-5) was added to the 8% w/w aqueous isopropyl alcohol (28 liter) at room temperature and heated the slurry to 55-60 0 C.
  • Potassium hydroxide 421.5 g, 6.38 moles was added to the slurry and heated to 75-85°C and maintained for 1 h. Thereafter the reaction mass was cooled to ambient temperature and isolated wet Bosentan potassium (3.9 Kg). Chromatographic purity (By HPLC): 93.58%
  • Bosentan potassium (2.7 Kg, 4.23 mol) isolated in Example-3 was added to mixture of DM water (10 liter) and methylene chloride (22.5 liter) and acidified to pH 0.5-1.0 with concentrated hydrochloric acid at 20-30 0 C. The organic layer was separated, washed with DM water and concentrated. The concentrated mass was dissolved in ethanol (6.75 liter) at 60-65°C, treated with carbon enoantichromos (190 g), filtered through hyflo bed and washed with hot ethanol (1.35 liter). The total filtrate was collected, heated to reflux temperature and added DM water (8 liter) at reflux temperature. The resulting reaction mass was allowed to ambient temperature over a period of 6 h to crystallize the product. The product was filtered and dried to yield Bosentan Monohydrate 2.45 Kg (80.8%).

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Abstract

La présente invention porte sur la purification de Bosentan brut par la formation de son sel de potassium cristallin, qui est encore converti en Bosentan (I) comprenant des impuretés bis-sulfonamide (VIII) et déhydroxyéthyle (IX) à hauteur inférieure à 0,2 % par analyse par HPLC.
PCT/IB2010/002090 2009-08-27 2010-08-27 Procédé perfectionné pour la préparation de bosentan WO2011024056A2 (fr)

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WO2013136110A1 (fr) * 2012-03-16 2013-09-19 Natco Pharma Limited Procédé pour la préparation de bosentan monohydrate
WO2013186706A1 (fr) * 2012-06-12 2013-12-19 Cadila Pharmaceuticals Ltd Procédé pour la préparation de bosentan
CN104193687B (zh) * 2014-07-01 2017-09-26 上海天慈国际药业有限公司 一种治疗肺动脉高压药物的制备方法
WO2020069851A1 (fr) 2018-10-03 2020-04-09 Huntsman Advanced Materials (Switzerland) Gmbh Nouveaux absorbeurs uv à base de triazine substitués par pyridine et pyrimidine

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WO2009095933A2 (fr) 2008-01-10 2009-08-06 Msn Laboratories Limited Procédé perfectionné et nouveau pour la préparation de bosentan

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WO2009004374A1 (fr) 2007-06-29 2009-01-08 Generics [Uk] Limited Procédé d'introduction d'une chaîne latérale hydroxyéthoxy dans le bosentan
WO2009095933A2 (fr) 2008-01-10 2009-08-06 Msn Laboratories Limited Procédé perfectionné et nouveau pour la préparation de bosentan

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WO2013136110A1 (fr) * 2012-03-16 2013-09-19 Natco Pharma Limited Procédé pour la préparation de bosentan monohydrate
WO2013186706A1 (fr) * 2012-06-12 2013-12-19 Cadila Pharmaceuticals Ltd Procédé pour la préparation de bosentan
JP2015521594A (ja) * 2012-06-12 2015-07-30 カディラ ファーマシューティカルズ リミテッド ボセンタンの製造方法
CN104193687B (zh) * 2014-07-01 2017-09-26 上海天慈国际药业有限公司 一种治疗肺动脉高压药物的制备方法
WO2020069851A1 (fr) 2018-10-03 2020-04-09 Huntsman Advanced Materials (Switzerland) Gmbh Nouveaux absorbeurs uv à base de triazine substitués par pyridine et pyrimidine
US11840804B2 (en) 2018-10-03 2023-12-12 Huntsman Textile Effects (Switzerland) Gmbh Pyridine and pyrimidine substituted triazine UV absorbers

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