WO2009095933A2 - Procédé perfectionné et nouveau pour la préparation de bosentan - Google Patents

Procédé perfectionné et nouveau pour la préparation de bosentan Download PDF

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WO2009095933A2
WO2009095933A2 PCT/IN2009/000032 IN2009000032W WO2009095933A2 WO 2009095933 A2 WO2009095933 A2 WO 2009095933A2 IN 2009000032 W IN2009000032 W IN 2009000032W WO 2009095933 A2 WO2009095933 A2 WO 2009095933A2
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formula
compound
butyl
tert
methoxyphenoxy
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PCT/IN2009/000032
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WO2009095933A3 (fr
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Manne Satyanarayana Reddy
Sajja Eswaraiah
Ghojala Venkat Reddy
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Msn Laboratories Limited
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Publication of WO2009095933A3 publication Critical patent/WO2009095933A3/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
    • 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
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • Bosentan is chemically known as 4-(l,l-Dimethylethyl)-N-[6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide monohydrate, having structural formula- 1.
  • Bosentan is found to be a potential inhibitor of endothelin receptors. Endothelin has recently been shown to play a pivotal role in the development of pulmonary hypertension and elevated endothelin concentrations have been found to be strongly correlated with disease severity. Endothelin antagonists especially bosentan, are therefore considered to represent a new approach to the treatment of pulmonary hypertension.
  • the selective nonpeptide mixed endothelin ET A and ET B receptor antagonist bosentan (Tracleer ® ) has become the first endothelin antagonist to reach the market for pulmonary hypertension. It has a greater significance because until now only few drugs have been specifically approved for the indication of pulmonary hypertension. Bosentan can also be used for treatment of circulatory disorders such as ischemia, vasospasms and angina pectoris.
  • Bosentan and its analogues as potential endothelin inhibitors have been first disclosed in US patent No. 5,292,740.
  • the patent also disclosed the methods for preparing these compounds.
  • One of the method involves the condensation of diethyl (2- methoxyphenoxy) malonate with pyrimidine-2-carboxyamidine in presence of sodium methoxide, followed by treatment with sodium hydroxide to provide the dihydroxy derivative, which is converted into dichloro derivative by the treatment with refluxing phosphorus oxychloride.
  • One chlorine of the dichloro derivative is replaced by 4-tert- butylbenzenesulfonamide.
  • the remaining chlorine is replaced by ethylene glycol in presence of sodium metal to provide bosentan.
  • the method of preparing ethylene glycol sulfonamide derivatives involves reacting an appropriately substituted pyrimidine monohalide with a monoanion ethylene glycol (e.g., sodium ethylene glycol) typically using ethylene glycol as a solvent.
  • a monoanion ethylene glycol e.g., sodium ethylene glycol
  • the mono sodium ethylene glycol is prepared by treating ethylene glycol with sodium metal which is difficult to handle at large scale in an industrial process.
  • one of the disadvantages of using a monoanion of ethylene glycol is the formation of undesired ethylene glycol bis-sulfonamide in which two molecules of the pyrimidine monohalide are coupled with one molecule of ethylene glycol.
  • the removal of this bis sulfonamide requires costly and laborious separation steps to obtain a pharmaceutically suitable ethylene glycol sulfonamide compound.
  • US Patent No 6,136,971 discloses a process which tries to overcome the disadvantages observed in the above process. It discloses a process for the preparation of 1,2-diheteroethylene sulfonamide i.e. bosentan, which involves the reaction of appropriately substituted pyrimidine monohalide intermediate with a mono protected 1 ,2- diheteroethylene anion to produce the monoprotected 1,2-diheteroethylene sulfonamide. The process involves additional steps of preparation of mono protected ethylene glycol, and removal of protecting group of mono-protected ethylene glycol sulfonamide. Hence the process is more time consuming, laborious, involves use of more reagents and solvents, decreased yields, which increases the overall cost of the product.
  • the present invention overcomes the major disadvantage mentioned above.
  • 4-tert-butyl-N-(5-(2- methoxyphenoxy)-6-(2-oxoethoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide is reduced to provide bosentan, in which there is no possibility of formation of the undesired 1,2-diheteroethylene bis-sulfonamides.
  • the present invention overcomes the disadvantages of the processes of prior art. It is easier to perform as it involves lesser number of steps, utilizes milder reagents and reaction conditions, which are conducive to be scaled up to an industrial level. It is cost effective and economically viable process.
  • the present invention also provides bosentan of a morphology which is highly advantageous for formulations.
  • the present invention relates to an improved and novel processes for the preparation of bosentan.
  • the first aspect of the invention is to provide an improved process for the preparation of bosentan compound of formula- 1, which comprises of condensing diethyl 2-(2-methoxyphenoxy)malonate compound of formula-2 with pyrimidine-2- carboximidamide hydrochloride compound of formula-3, in the presence of a base in a suitable solvent to provide 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihydroxy pyrimidine compound of formula-4, which on reaction with an halogenating agent in a suitable solvent provides 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-5; then condensing the compound of formula- 5 with 4-tert-butyl benzene sulfonamide compound of formula-6 in presence of a base in a suitable solvent provides p-tert-butyl-N-[
  • the second aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula- 1, which comprises of condensing the p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7 with a substituted allyl alcohol, compound of formula-8 (or) by condensing the 6-hydroxy sulfonamide derivative compound of formula-9, with a substituted allyl halide, compound of formula- 10 in presence of base in a suitable solvent, to provide a substituted 6-allyloxy sulfonilamide derivative compound of formula- 11.
  • the third aspect of the present invention is to provide a novel process for the preparation of bosentan compound of formula- 1, which comprises of reacting the p-tert- butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7 (or) reacting the alkoxy-sulfonamide derivative compound of formula-13, with suitable base, in a suitable solvent to provide 6-hydroxy sulfonamide derivative compound of formula-9, which on reaction with 2-halo ethan-1-ol in presence of suitable base gives bosentan, compound of formula- 1.
  • the fourth aspect of the present invention is to provide p-tert-butyl-N-[6-chloro- 5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt, compound of formula-7b as a crystalline solid.
  • the crystalline solid of the present invention is characterized by its PXRD, IR spectrum and DSC thermo gram.
  • the present invention also provides a process for the preparation of crystalline potassium salt compound of formula-7b.
  • the fifth aspect of the present invention is to provide an improved process for the preparation of high pure crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7a as a solid, which comprises of hydrolyzing the crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt compound of formula-7b with suitable aqueous acid in a suitable solvent.
  • the major advantage of the process is that it involves the condensation of mono halo sulfanilamide intermediate (7) with ethylene glycol in presence of simple base like sodium hydroxide and avoids the use of pyrophoric reagent like sodium metal with ethylene glycol, to prepare monosodium ethylene glycol prior to the condensation.
  • ethylene glycol is used in the ratio of 5-10 moles per mole of the substrate and not as a solvent. This makes the purification of the final product much easier and also the effluents will contain less amounts of toxic ethylene glycol making it a more greener and ecofriendly process.
  • Figure-1 Illustrates the powder X-ray powder diffractogram of bosentan
  • Figure-2 Illustrates the IR spectrum of bosentan.
  • Figure-3 Illustrates the DSC chromatogram of bosentan
  • Figure-4 Illustrates the photographs of bosentan recorded on a microscope.
  • Figure-5 Illustrates the X-ray powder diffraction pattern of potassium salt compound of formula-7b
  • Figure-6 Illustrates the Infrared spectrum of potassium salt compound of formula-7b
  • Figure-7 Illustrates the DSC chromatogram of potassium salt compound of formula-7b
  • Figure-8 Illustrates the HPLC cliromatogram of potassium salt compound of formula-7b
  • alkyl refers to a straight or branched or cyclic Ci to C 8 alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert- pentyl, cyclopentyl, n-hexyl, n-heptyl, octyl and isohexyl and the like.
  • alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, hydroxy and cyano.
  • alkali metal refers to lithium, sodium, potassium and cesium
  • alkaline earth metal refers to beryllium, magnesium, and calcium
  • halogen refers to chlorine, bromine and fluorine.
  • Bosentan is chemically known as 4-( 1,1 -Dimethyl ethy I)-N- [6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide monohydrate, having structural formula- 1.
  • the first aspect of the present invention provides an improved process for the preparation of bosentan compound of formula- 1, which comprises of the following steps; a) Condensing diethyl 2-(2-methoxyphenoxy)malonate compound of formula-2
  • X is halogen and M is a hydrogen or alkali/alkaline earth metal ion
  • the base is selected from the group consisting of but is not limited to, hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; sodium/potassium alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide; preferably sodium methoxide.
  • hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide
  • hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride
  • metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate
  • sodium/potassium alkoxides such as tert-butoxide, isopropoxide, ethoxide
  • the solvent used is selected from a group of alcoholic solvents which include methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol preferably methanol.
  • a suitable halogenating agent selected from the group consisting of but is not limited to, thionyl chloride (SOCl 2 ), phosphorus trichloride (PCl 3 ), phosphorus pentachloride (PCl 5 ), phosphorus oxychloride (POCl 3 ), phosphorus tribromide (PBr 3 ), phosphorus pentabromide (PBr 5 ) and the like, preferably phosphorus oxychloride in an aprotic solvent.
  • the suitable aprotic solvent selected from the group consisting of but is not limited to, benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably toluene.
  • the suitable bases that can be used in the reaction may include but are not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably potassium carbonate.
  • the suitable non polar aprotic solvent includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, preferably toluene.
  • bosentan is prepared by condensing p-tert-butyl-N-[6-halo-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzenesulfonamide or its salt compound of formula-7 with ethylene glycol (which is present in very low molar ratio), in the presence of a base and a suitable aprotic solvent.
  • the base is selected from the group consisting of but not limited to hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide.
  • the suitable aprotic solvent includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyltetrahydrofuran, preferably acetonitrile.
  • the phase transfer catalyst is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
  • bosentan can also be prepared as per the first aspect of the invention with out isolating the 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6- dihalopyrimidine compound of formula- 5 to further reduce the isolation steps.
  • the second aspect of the present invention provides a novel process for the preparation of bosentan which comprises of the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7,
  • R' is selected from alkyl or aryl; in the presence of suitable base and in a suitable solvent, with or without a phase transfer catalyst, to provide p-tert-butyl-N-[6-(substituted allyloxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene-sulfonamide, compound of formula-11,
  • step a) the reaction of p-tert-butyl-N-[6-halo-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide, compound of formula-7, with a substituted allyl alcohol, compound of formula-8, (OR) p-tert-butyl-N-[6-hydroxy- 5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-9, with a substituted allyl halide, compound of formula- 10, is carried out in the presence of a base selected from a group which may include but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbon
  • the phase transfer catalyst which can be used is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
  • step b) p-tert-butyl-N-[6-(substituted allyloxy)-5-(2-methoxyphenoxy)[2,2'- bi pyrimidin]-4-yl] benzene sulfonamide derivative compound of formula-11, on treatment with hydroxylating agents like OsO 4 in presence of H 2 O 2 or N-methyl morpholine N-oxide or KMnO 4 or PhCO 2 Ag/I 2 in a suitable solvents like methanol, ethanol, propanol, isopropanol and the like, preferably tert-butyl alcohol provides diol derivative, which on subsequent oxidization in-situ, in the presence of oxidizing agents like NaIO 4 or Pd(OAc) 4 provides 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2- oxoethoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide
  • step c) 4-tert-butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2, T- bipyrimidin-4-yl) benzenesulfonamide, compound of formula-12, is reduced with a reducing agent selected from a group which includes but is not limited to sodium borohydride, lithium tri-sec-butylborohydride ("L-selectride”), sodium dihydro-bis-(2- methoxyethoxy)aluminate (Vitride), bis diisobutyl aluminium hydride, lithium aluminium hydride, and the like, preferably sodium borohydride in a suitable alcoholic solvent selected from the group which may include alcohols like methanol, ethanol, propanol, isopropanol and the like to obtain bosentan, compound of formula- 1.
  • a reducing agent selected from a group which includes but is not limited to sodium borohydride, lithium tri-sec-butylborohydride (“
  • the third aspect of the present invention provides a novel process for the preparation of bosentan compound of formula- 1, which comprises of the following steps; a) Reacting p-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide, compound of formula-7
  • R is alkyl; with a suitable base, in a suitable solvent and with or without a phase transfer catalyst to provide p4ert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl]benzene sulfonamide, compound of formula-9,
  • the suitable bases that can be used in the reaction is selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide.
  • the suitable solvent which is used is selected from a group which includes but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, ethylene glycol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran.
  • the phase transfer catalyst is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
  • the compound of formula- 1 is obtained by the reaction of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula- 9 with 2-halo-ethan-l-ol, in presence of suitable base selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, preferably sodium carbonate.
  • suitable base selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the
  • the phase transfer catalyst which can be used is selected from the group consisting of but is not limited to terra butyl ammonium bromide, terra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
  • the fourth aspect of the present invention is to provide p-tert-butyl-N-[6-chloro-
  • the crystalline solid of the present invention is characterized by the following a) It's XRD wherein peaks were observed at about 4.2, 8.3, 9.6, 15.6, 16.3, 18.3, 19.3, 20.5, 21.0, 22.1, 26.0, 27.5, and 28.4 ⁇ 0.2 degrees two theta. b) It's IR whe.rein peaks were observed at 3467.4, 3062.8, 2960.9, 1662.9, 1591.9, 1551.4, 1501.0, 1448.5, 1249.3, 858.7, 795.0, 719.8, 694.4, 586.0, and 540.6 cm “1 . c) It's DSC thermo gram having endothermic peak at about 201.14°C and exothermic peak at about 306.17 0 C.
  • the present invention also provides a process for the preparation of crystalline potassium salt compound of formula-7b, which comprises of reacting 4,6-dichloro-5-(2- methoxyphenoxy)-2,2'-bipyrimidine compound of formula-5a
  • the suitable solvent is selected from the group which may include but is not limited to benzene, toluene, xylene, tetrahydofuran, 2-methyltetrahydrofuran, dimethylformamide, dimethylsulfoxide, and the phase transfer catalyst used in step a) is selected from the group consisting of but is not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide,
  • US patent 6,136,971 discloses the compound of formula-7b, but it is not isolated and is used in the next step as a suspension in toluene.
  • US patent 5,292,740 also described the formation of potassium salt of the above intermediate in the synthesis of bosentan and its analogues but is silent about its isolation and its nature.
  • the present inventors isolated the p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]- 4-yl] benzene sulfonamide potassium salt compound of formula- 7b as highly pure crystalline solid, which when used for the preparation of p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyramidin]-4-yl]benzene sulfonamide, compound of formula-7a gave a product with high purity (i.e., >99%).
  • the fifth aspect of the present invention is to provide an improved process for the preparation of high pure crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-7a as a solid, which comprises of hydrolyzing the crystalline p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide potassium salt compound of formula- 7b with suitable aqueous acid like hydrochloric acid in a suitable solvent.
  • the present invention provides crystalline bosentan with rod shaped morphology, which is highly pure, free flowing solid and easy to handle during formulation as an active pharmaceutical ingredient. It has a greater advantage over the prior art forms.
  • the p-tert-butyl-N-[6-(methoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide 13a is an impurity formed in the present invention which was isolated and characterized.
  • the said impurity compound of formula- 13a is formed due to the presence of methanol traces in the reaction medium and the process is represented as below.
  • XRD analysis of bosentan and its salts was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.
  • FI-IR spectrum of bosentan and impurity compound of formula-13a was recorded on Thermo model Nicolet-380 as KBr pellet.
  • the thermal analysis of bosentan and its salt was carried out on Waters DSC Q-IO model differential scanning calorimeter.
  • R is C,. 6 alkyl group which may be straight chain /branched and which may be substituted/unsubstituted; or is an aryl group; or is an substituted aryl group, wherein M is a hydrogen or akali or alkaline earth metal ion wherein X is a halogen
  • R is C
  • M is a hydrogen or akali or alkaline earth metal ion
  • Example 4 p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt compound of formula-7b: To a solution of 4-tert-butyl benzene sulfonamide compound of formula-6 (48 g) in toluene (600 ml), potassium carbonate (35 g) and tetra butyl ammonium bromide (10 g) was added and the reaction mixture was heated to 50 0 C.
  • Example-6 Preparation of crystalline p-tert-butyl-N-[6-chloro-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide potassium salt compound of formula-7b:
  • Example-7 Preparation of high pure • p-tert-butyI-N-[6-chloro-5-(2-methoxy phenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula -7a:
  • Example 9 Preparation of bosentan. A mixture of ethylene glycol (5.5 g), acetonitrile (130 ml), sodium hydroxide
  • Example 12 Preparation of bosentan potassium. To a solution of bosentan (3 g) in ethanol (15 ml), 30% potassium hydroxide was added drop wise at 25-30°C and stirred the solution slowly until a solid was formed. The reaction mixture was stirred for one hour at 25-30°C. Filtered the solid formed and washed with ethanol. The solid was dried to obtain the title compound. Yield: 1.2 g Water content: 3.5 %;
  • Example-13 Preparation of p-tert-butyI-N-[6-(prop-2-enyI-oxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yI] benzene sulfonamide compound of formula- 11:
  • Example-16 Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-9:
  • Example-17 Preparation of p-tert-butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-y IJ benzene sulfonamide compound of formula-9:
  • the title compound is prepared analogous manner to example-15 using toluene as a solvent in place of ethylene glycol. Yield: 45 g
  • Example-18 Preparation of p-tert-butyI-N-[6-(hydroxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-9:
  • HPLC High Performance Liquid Chromatography
  • a liquid chromatograph is equipped with variable wave length UV detector; Column: Inertsil ODS 3 V, 250 X 4, 6mm, 5 ⁇ m or Equivalent; Flow rate : 1.0 ml/min.; Wave length : 220 nm. ; Temperature: 25° C; Load : 20 ⁇ l

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Abstract

La présente invention porte sur un procédé perfectionné et nouveau pour la préparation du composé bosentan de formule (1). La présente invention porte également sur une forme cristalline de bosentan et sur ses intermédiaires.
PCT/IN2009/000032 2008-01-10 2009-01-09 Procédé perfectionné et nouveau pour la préparation de bosentan WO2009095933A2 (fr)

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EP09705099A EP2240470A4 (fr) 2008-01-10 2009-01-09 Procédé perfectionné et nouveau pour la préparation de bosentan

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Cited By (16)

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WO2010015623A1 (fr) * 2008-08-05 2010-02-11 Farmaprojects, S. A. Procédé pour la fabrication d'antagonistes des récepteurs de l'endothéline
WO2010032261A1 (fr) * 2008-08-12 2010-03-25 Cadila Healthcare Limited Procédé pour la préparation de bosentan
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
WO2009093127A3 (fr) * 2008-01-24 2010-07-22 Actavis Group Ptc Ehf Forme cristallisée stable et sensiblement pure de bosentan
ITMI20090361A1 (it) * 2009-03-11 2010-09-12 Sifa Vitor S R L Procedimento per la preparazione delbonsentan
WO2010118992A1 (fr) 2009-04-13 2010-10-21 Sandoz Ag Procédé de préparation d'un antagoniste du récepteur endothélial (bosentan)
WO2011021216A2 (fr) * 2009-08-10 2011-02-24 Msn Laboratories Limited Procédé amélioré pour la préparation de 4-(1,1-diméthyléthyl)-n-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy) [2,2'-bipyrimidin]-4-yl] benzènesulfonamide
WO2011024056A2 (fr) 2009-08-27 2011-03-03 Aurobindo Pharma Limited Procédé perfectionné pour la préparation de bosentan
WO2011058524A3 (fr) * 2009-11-12 2011-08-11 Ranbaxy Laboratories Limited Formes cristallines du sel de bosentan et leurs procédés de préparation
WO2012020421A1 (fr) 2010-08-11 2012-02-16 Megafine Pharma (P) Ltd. Nouveau procédé de préparation de bosentan
CN103153964A (zh) * 2010-10-01 2013-06-12 Zach***股份公司 制备波生坦一水合物及其中间体的方法
US8530488B2 (en) 2007-10-24 2013-09-10 Generics [Uk] Limited Crystalline forms of bosentan
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
US8785461B2 (en) 2008-02-08 2014-07-22 Generics [Uk] Limited Process for preparing bosentan
WO2022108572A1 (fr) * 2020-11-23 2022-05-27 Gazi University Formulations de systèmes d'administration de médicament auto-nanoémulsifiants chargés de bosentan monohydraté (snedds) préparés avec des mélanges de mono et diglycérides à longue chaîne

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Cited By (29)

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US8530488B2 (en) 2007-10-24 2013-09-10 Generics [Uk] Limited Crystalline forms of bosentan
WO2009093127A3 (fr) * 2008-01-24 2010-07-22 Actavis Group Ptc Ehf Forme cristallisée stable et sensiblement pure de bosentan
US8785461B2 (en) 2008-02-08 2014-07-22 Generics [Uk] Limited Process for preparing bosentan
WO2010015623A1 (fr) * 2008-08-05 2010-02-11 Farmaprojects, S. A. Procédé pour la fabrication d'antagonistes des récepteurs de l'endothéline
WO2010032261A1 (fr) * 2008-08-12 2010-03-25 Cadila Healthcare Limited Procédé pour la préparation de bosentan
US8975402B2 (en) 2008-11-03 2015-03-10 Generics [Uk] Limited HPLC method for the analysis of bosetan and related substances and use of these substances as reference standards and markers
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
JP2012507497A (ja) * 2008-11-03 2012-03-29 ジェネリクス・（ユーケー）・リミテッド ボセンタンおよび関連物質のｈｐｌｃ分析方法、ならびに参照スタンダードまたはマーカーとしてのこれら物質の使用
WO2010103362A3 (fr) * 2009-03-11 2010-11-04 Sifavitor S.R.L. Procédé pour la préparation du bosentan
AU2010222683B2 (en) * 2009-03-11 2015-04-02 Sifavitor S.R.L. Process for the preparation of bosentan
US9233936B2 (en) 2009-03-11 2016-01-12 Sifavitor S.R.L. Process for the preparation of bosentan
EP2406235A2 (fr) 2009-03-11 2012-01-18 Sifavitor S.r.l. Procédé pour la préparation du bosentan
US20120041200A1 (en) * 2009-03-11 2012-02-16 Giancarlo Biffi Process for the preparation of bosentan
ITMI20090361A1 (it) * 2009-03-11 2010-09-12 Sifa Vitor S R L Procedimento per la preparazione delbonsentan
WO2010118992A1 (fr) 2009-04-13 2010-10-21 Sandoz Ag Procédé de préparation d'un antagoniste du récepteur endothélial (bosentan)
WO2011021216A2 (fr) * 2009-08-10 2011-02-24 Msn Laboratories Limited Procédé amélioré pour la préparation de 4-(1,1-diméthyléthyl)-n-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy) [2,2'-bipyrimidin]-4-yl] benzènesulfonamide
WO2011021216A3 (fr) * 2009-08-10 2011-04-28 Msn Laboratories Limited Procédé amélioré pour la préparation de 4-(1,1-diméthyléthyl)-n-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy) [2,2'-bipyrimidin]-4-yl] benzènesulfonamide
WO2011024056A2 (fr) 2009-08-27 2011-03-03 Aurobindo Pharma Limited Procédé perfectionné pour la préparation de bosentan
WO2011024056A3 (fr) * 2009-08-27 2011-05-19 Aurobindo Pharma Limited Procédé perfectionné pour la préparation de bosentan
AU2010317410B2 (en) * 2009-11-12 2014-10-02 Sun Pharmaceutical Industries Limited Crystalline forms of bosentan salts and processes for their preparation
US8716477B2 (en) 2009-11-12 2014-05-06 Ranbaxy Laboratories Limited Crystalline forms of bosentan salts and processes for their preparation
WO2011058524A3 (fr) * 2009-11-12 2011-08-11 Ranbaxy Laboratories Limited Formes cristallines du sel de bosentan et leurs procédés de préparation
US9139537B2 (en) 2010-08-11 2015-09-22 Megafine Pharma(P) Ltd. Process for preparation of bosentan
WO2012020421A1 (fr) 2010-08-11 2012-02-16 Megafine Pharma (P) Ltd. Nouveau procédé de préparation de bosentan
CN103153964A (zh) * 2010-10-01 2013-06-12 Zach***股份公司 制备波生坦一水合物及其中间体的方法
CN103153964B (zh) * 2010-10-01 2016-10-05 Zach***股份公司 制备波生坦一水合物及其中间体的方法
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
WO2022108572A1 (fr) * 2020-11-23 2022-05-27 Gazi University Formulations de systèmes d'administration de médicament auto-nanoémulsifiants chargés de bosentan monohydraté (snedds) préparés avec des mélanges de mono et diglycérides à longue chaîne

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