WO2011021216A2 - Improved process for the preparation of 4-(1,1-dimethylethyl)-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide - Google Patents
Improved process for the preparation of 4-(1,1-dimethylethyl)-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide Download PDFInfo
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- WO2011021216A2 WO2011021216A2 PCT/IN2010/000525 IN2010000525W WO2011021216A2 WO 2011021216 A2 WO2011021216 A2 WO 2011021216A2 IN 2010000525 W IN2010000525 W IN 2010000525W WO 2011021216 A2 WO2011021216 A2 WO 2011021216A2
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- 0 CCCC*=C(*)C(*=C1*)=*C(*)C1Oc(cccc1)c1OC Chemical compound CCCC*=C(*)C(*=C1*)=*C(*)C1Oc(cccc1)c1OC 0.000 description 1
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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
Definitions
- the present invention relates to an improved process for the preparation of 4-(l,l- dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide monohydrate and is commonly known as bosentan.
- Bosentan is represented by the following structural formula- 1.
- the second aspect of the present invention is to provide an improved process for trie preparation of 4-tert-butyl-N-(6-hydroxy-5 -(2-methoxyphenoxy)-2,2 ' -bipyrimidin-4-yl) s benzene sulfonamide compound of formula-2, which comprises of reacting the 4-tert-butyl-N- 1 (6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3a with a base in a suitable solvent to provide the compound of formula-2.
- the fourth aspect of the present invention is to provide an improved process for the preparation of highly pure bosentan, which comprises of;
- the fifth aspect of the present invention is to provide an improved process for the preparation of bosentan compound of formula- 1, which comprises of reacting the 4-tert-butyl-
- the sixth aspect of the present invention is to provide a process for the preparation of high pure bosentan compound of formula- 1 by purification from suitable solvents particularly to reduce the amount of dimer impurities, characterized in that the purification takes place in .' presence of water.
- the present invention avoids the usage of ethylene glycol as a solvent and thereby avoids ⁇ problems associated with the prior art processes.
- phase transfer catalyst refers to reagents selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl 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 and ethyl triphenyl phosphonium - i bromide; or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
- the second aspect of the present invention provides an improved process for the preparation of 4-tert-butyl-N-(6-hydroxy-5 -(2-methoxyphenoxy)-2,2 ' -bipyrimidin-4-yl)- benzene sulfonamide compound of formula-2,
- N-alkylated impurity having the following structure formed in the ratio of 10-15% • and its has been removed by purification, whereas in the present invention N-alkylated ">; impurity is formed at the level of less than 3% and further washed out to less than 0.1% by ' * ⁇ ⁇ ' HPLC, preferably less than 0.05 % by purification of bosentan from a mixture of ethylacetate and aqueous methanol.
- the said isopropyl impurity can not be removed by any of the conventional purification technique and it should be controlled at the origin itself as there is no other way to remove this impurity. Hence it is necessary to develop a process to control this isopropyl impurity.
- the present inventor developed an improved process to control this impurity well with in the limit as per ICH guidelines in the preparation of bosentan.
- the fourth aspect of the present invention provides an improved process for the preparation of bosentan compound of formula- 1, which comprises of;
- the purification of bosentan comprises of the following steps; a) Suspending the bosentan compound of formula- 1 in a mixture of methanol and ethylacetate in the ratio of 1 :1 with respect to the bosentan and having water from 5 to 25% with respect to weight of bosentan,
- the related substances of bosentan measured by HPLC using the following chromatographic conditions Apparatus: A liquid chromatograph is equipped with variable wave length UV detector; Column : BDS hypersil C 18, 250 X 4.6 mm, 5 ⁇ m or Equivalent; Flow rate: 0.8 ml/min.; Wave length: 220 nm. ; Temperature: 30°C; Load: 20 ⁇ l using aqueous methanol and aqueous methanolic dipotassium hydrogen orthophosphate in ratio of 1 : 1 as' a diluent.
- Bosentan 25 grams was dissolved in a mixture of methanol (25 ml) and ethyl acetate (25 ml) and water (4 ml) by heated to reflux temperature and stirred for 45 minutes. The reaction mixture was cooled to 25-30 0 C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound
Abstract
An improved process for preparing 4-(l, l-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-[2, 2'-bipyπmidin]-4-yl] benzene sulfonamide monohydrate compound of formula-1 is disclosed
Description
Improved process for 4-(l,l-Dimethylethyl)-N-r6-(2-hvdroxyethoxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidinl-4-yllbeiizenesulfonamide
Related Applications:
This application claims the benefit of priority of our Indian patent application number 1889/CHE/2009 filed on 10th August 2009 and 2112/CHE/2010 filed on 26th July 2010, which are incorporated herein by reference.
Field of Invention:
The present invention relates to an improved process for the preparation of 4-(l,l- dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide monohydrate and is commonly known as bosentan. Bosentan is represented by the following structural formula- 1.
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 ETA and ETB 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.
Background of the Invention:
Bosentan and process for its preparation is disclosed in US patent No. 5,292,740. The disclosed process for the preparation of bosentan involves condensation of N-(6-chloro-5(2- methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-4-tertiarybutyl benzene sulfonamide and sodium ethylene glycolate in ethylene glycol at 110°C. The said patent involves the usage of monoanion ethylene glycol leads to the formation of undesired ethylene glycol bisulfonamide, in which two molecules of the pyrimidine monohalide coupled with one molecule of ethylene glycol. The said ethylene glycol bisulfonamide is known as dimer impurity. The other impurity is digol dimer impurity, which is formed due to the presence of digol impurity in ethylene glycol. These dimer impurities are represented by the following structural formula.
Dimer Impurity Digol dimer impurity
The removal of bis-sulfonamide compound required costly and laborious separation steps to obtain a pharmaceutically suitable pure ethylene glycol sulfonamide compound i.e., : bosentan. Generally the use of ethylene glycol as a solvent, which is acceptable in a small scale reaction, is impracticable in a large industrial scale synthesis because of its toxicity and its high boiling point which requires a large amount of time and high energy consumption to remove it by distillation. Hence this process is commercially not suitable.
US 6136971 disclose a process for the preparation of ethylene glycol sulfonamide derivatives including bosentan. The disclosed process involves the reaction of p-tert-butyl-N- [6-chloro-5-(O-methoxy-phenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide potassium salt with ethylene glycol mono-tert-butyl ether in presence of a base provides the p-tert-butyl-N[6- (2-tert-buyl-ethoxy)-5 -(O-methoxy-phenoxy) [2,2 ' -bipyrimidin] -4-yl]benzenesulfonamide, which on hydrolysis with formic acid to provide bosentan formate. Thus obtained bosentan
formyl derivative on treatment with a base to provide bosentan. The main disadvantage of this process is that, the usage of mono-protected ethylene glycol sulfonamide requires additional deprotection step so that number of reaction steps are increased. Hence the process is more time consuming, laborious, involves the usage of more reagents & solvents as well as decreased yields, which increases the overall cost of the product.
WO 2009/95933 discloses a process for the preparation of bosentan, which involves the reaction of p-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene- sulfonamide with sodium hydroxide in ethylene glycol at 160-165°C for longer hours to provide the p-tert-butyl-N-[6-(hydroxyl)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl]benzene-sulfonamide, which on reaction with 2-choroethanol in dimethyl formamide in presence of sodium carbonate to provide bosentan. The said process involves the usage of ethylene glycol as well as reaction carried out at 160-165°C and hence commercially not recommendable. Even though the said application disclose the use of toluene in place of ethylene glycol it does not specifically exemplified the process parameters and has been" carried out in analogous manner to the one exemplified in ethylene glycol. Hence there is a" need in the art for an improved process for bosentan which avoids the usage of ethylene glycol * or its protected derivative and to perform in an industrial scale having less number of steps and? isolation.
Like any chemical compound, bosentan can contain extraneous compounds or'"' impurities that can come from many sources. In general the product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products 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 the preparation process, it should be analyzed for the purity by HPLC or TLC analysis to determine if it is desirable for continue the process or need to purified further to continue the process especially for use in a pharmaceutical product. The active pharmaceutical ingredient need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather the purity standards are set with the intention of ensuring that an active pharmaceutical ingredient is as free of impurities as possible, and thus, is as safe as possible for clinical use.
It is known to a person skilled in art that an impurity can be controlled by knowing the structure of the impurity, the process parameters, and the interaction of the impurity with other reagents, solvents, intermediates etc. as well as the final pharmaceutical drug. When we prepared bosentan as per the prior art process, in some of the experiments it was observed that an impurity at 0.8 RRT was present in substantial proportions. This impurity could not be removed from the final product by the conventional methods of purification like crystallization etc due to its similarity in structure, as well as physical properties when compared with bosentan. So in order to develop a technique to remove/control this particular impurity, we have identified the same using LC-MS and prepare the identified compound, characterized and confirmed that impurity formed at 0.8RRT is 4-isopropyl-N-(6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide (herein designated as "isopropyl impurity"). Hence there is a need in the art to control the 4-isopropyl- N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide in the preparation of bosentan.
Organic Process Research & Development 2002, 6, 120-124 disclosed that the bosentan - prepared by the prior art process contains high levels of dimer impurity and pyrimidinone - impurity and the same can be reduced by recrystallisation of bosentan from methanol-isopropyl acetate, followed by ethanol-water purification to provide bosentan with purity of 99.3% by ■
HPLC. The said pyrimidinone impurity was represented by the following structural formula. °*
Pyrim Λidinon He Impurity
The said article disclosed the second generation process for the preparation of high pure bosentan through monoprotected ethylene glycol providing bosentan with the purity of 99.70 % containing low level of dimer and pyrimidinone impurities.
The prior art data base article IPCOMOOO 185691 also disclosed the process for the crystallization of bosentan from a mixture of methanol and isopropyl acetate and provides the
PXRD of obtained bosentan, which is designated as form X. However the purity of the bosentan obtained by the above processes is not satisfactory. Hence there is a need in art to develop an improved process which can provide better yields and high purity and which can be performed at an industrial scale.
There is a need in the art for an improved process for the preparation of bosentan which avoids the above mentioned prior art problems and also to provide a process for the preparation of bosentan to control the formation of isopropyl impurity. Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of bosentan compound of formula- 1, which comprises of reacting the 4-tert-butyl-
N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2 with 2-chloroethan-l-ol or 2-bromoethanol in the presence of suitable base, in a suitable solvent to provide the bosentan compound of formula- 1.
The second aspect of the present invention is to provide an improved process for trie preparation of 4-tert-butyl-N-(6-hydroxy-5 -(2-methoxyphenoxy)-2,2 ' -bipyrimidin-4-yl)s benzene sulfonamide compound of formula-2, which comprises of reacting the 4-tert-butyl-N-1 (6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3a with a base in a suitable solvent to provide the compound of formula-2. r
The third aspect of the present invention is to provide preparation, isolation, and characterization of an "Isopropyl impurity" and its alkali metal salt as well as process to control its formation in the preparation of bosentan.
The fourth aspect of the present invention is to provide an improved process for the preparation of highly pure bosentan, which comprises of;
a) Condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4 with 4-tert-butylbenzene sulfonamide having less than 0.15% of
4-isopropylbenzene sulfonamide in the presence of a base, in a suitable non polar aprotic solvent provides 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3,
b) reacting the 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3 with ethylene glycol in the presence of a suitable base in a suitable solvent to provide bosentan compound of formula- 1,
c) purifying the obtained bosentan compound of formula- 1 using a suitable solvent to provide pure bosentan compound of formula- 1.
The fifth aspect of the present invention is to provide an improved process for the preparation of bosentan compound of formula- 1, which comprises of reacting the 4-tert-butyl-
N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3a with ethylene glycol in the presence of alkoxide base in a suitable solvent to provide bosentan compound of formula- 1.
The sixth aspect of the present invention is to provide a process for the preparation of high pure bosentan compound of formula- 1 by purification from suitable solvents particularly to reduce the amount of dimer impurities, characterized in that the purification takes place in .' presence of water.
Advantages of the Present Invention:
• The present invention avoids the usage of ethylene glycol as a solvent and thereby avoids \ϊ problems associated with the prior art processes.
• Involves the usage of toluene/DMSO/DMF in place of ethylene glycol reduces amount of v heat required for its removal and also reduces the cost of production.
• The present invention avoids the formation of dimer & digol dimer impurities and therefore having high purity.
• The major advantage of the process is that it involves the usage of base like sodium tert-butoxide avoids the use of pyrophoric reagent like sodium metal with ethylene glycol, to prepare monosodium ethylene glycol prior to the condensation.
• Provides preparation, isolation, characterization and control of the "Isopropyl impurity".
• Involves the use of milder reagents when compared to the processes of prior art.
• Provides bosentan free of 4-Isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl)benzene sulfonamide (isopropyl impurity) or its alkali metal salt & dimer impurities.
Detailed description of the invention:
Unless otherwise specified, as used herein the present invention, the term "suitable base" refers to the base and 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; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides of alkalimetal such as tert- butoxide, isopropoxide, ethoxide and methoxides of sodium and potassium; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride.
Unless otherwise specified, as used herein the present invention, the term "phase transfer catalyst" refers to reagents selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl 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 and ethyl triphenyl phosphonium - i bromide; or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
The present invention relates to an improved process for the preparation of bosentan. *'• Bosentan is chemically known as 4-(l,l-dimethylethyl)-N-[6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide monohydrate and is- '• represented by the following structural formula- 1.
Formula- 1
Accordingly the first aspect of the present invention provides an improved process for the preparation of bosentan compound of formula- 1, which comprises of reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2
Formula-2
with 2-chloroethan-l-ol or 2-bromoethan-l-ol in the presence of base and in a suitable solvent to provide bosentan compound of formula- 1, characterized in that the suitable solvent used is selected from a mixture of toluene/DMSO or toluene/DMF. The reaction has been carried out at a temperature ranges from 50°C to reflux temperature of the solvent.
The second aspect of the present invention provides an improved process for the preparation of 4-tert-butyl-N-(6-hydroxy-5 -(2-methoxyphenoxy)-2,2 ' -bipyrimidin-4-yl)- benzene sulfonamide compound of formula-2,
Formula-2
which comprises of reacting the 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'- "■* bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3a
Formula-3a
with a suitable base selected from sodium hydroxide, potassium hydroxide preferably sodium hydroxide in a suitable solvent provides the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2, characterized in that the suitable solvent is a mixture of toluene, dimethyl sulfoxide and water or mixture of dimethyl
sulfoxide and water. The said reaction has been carried out at a temperature ranges from 50°C to reflux temperature of the solvent. The base used in the reaction is about 2-7 moles w.r.to 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzenesulfonamide compound of formula-3a.
In the reported process of WO 2009/095933, the conversion of 4-tert-butyl-N-(6- chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide to 4-tert-butyl-N- (6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide involves the usage of ethylene glycol as a solvent, which leads to the formation of dimer & digol dimer impurities. Where as in the present invention process of bosentan, ethylene glycol is replaced with a mixture of toluene, dimethylsulfoxide and water. Hence the present invention avoids the formation of dimer impurity, digol dimer impurity and other possible degradation impurities formed due to the high temperature required for the removal of ethylene glycol. Hence the compound of formula-2 is free of said dimer and digol dimer impurities and using the same in the preparation of bosentan leads to the high pure bosentan substantially free of dimer impurity *v and digol dimer impurity.
Moreover as per the process disclosed in the above application for the preparation of -^ bosentan, N-alkylated impurity having the following structure formed in the ratio of 10-15% • and its has been removed by purification, whereas in the present invention N-alkylated ">; impurity is formed at the level of less than 3% and further washed out to less than 0.1% by '*■■' HPLC, preferably less than 0.05 % by purification of bosentan from a mixture of ethylacetate and aqueous methanol.
N-alkylated impurity
Further bosentan prepared by the present invention is substantially free of dimer impurities i.e. dimer impurity and digol dimer impurity as measured by HPLC.
The third aspect of the present invention provides the 4-isopropyl-N-(6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide compound of formula-5a. The said compound is an impurity which is formed during the preparation of bosentan, and it was isolated, characterized and prepared and having the following general structural formula-5a.
Isopropyl impurity of the present invention is characterized by 1H NMR (300 MHz) δ(ppm): 9.00-8.99 (d, J=4.74 Hz, 2H), 8.72 (b, IH), 8.45-8.43 (d, J=8.22 Hz, 2H), 7.42-7.39 (m, 3H), 7.15-6.85 (m, 4H), 4.84 (s, IH), 4.58 (s, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 2.92 (m, IH), ' 1.22 (d, J=6.81 Hz, 6H) ; Mass spectra m/z = 560 (M+Na)+.
The present invention is also relates to an alkali metal salts of compound of formula-5' represented by the following structural formula-5
Formula-5
Wherein M is an alkali metal ion.
Extensive research on this impurity formation revealed that the origin of "Isopropyl impurity" is the presence of 4-isopropyl benzene sulfonamide as an impurity in 4-tertiary butyl benzene sulfonamide, the key raw material used in the preparation of bosentan. The 4-isopropyl benzene sulfonamide impurity present in the stating material reacts with 5-(2- methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4 and then subsequently reacts with ethylene glycol to provide 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)-2,2'-bipyrimidin-4-yl) benzene sulfonamide compound of formula-5a i.e. the isopropyl impurity.
The present invention also provides a process for the preparation of isopropyl impurity compound of formula-5a or its alkali metal salt compound of formula-5, which comprises of the following steps;
a) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4
Formula-4
wherein X is a halogen;
with 4-isopropyl benzene sulfonamide,
in the presence of a base and in a suitable solvent in the presence or absence of a phase >• transfer catalyst, to provide 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'- '" bipyrimidin]-4-yl] benzene sulfonamide compound of formula-6, ■
Formula-6
wherein X is a halogen and M is H or alkali metal ion,
b) reacting 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-6, with ethylene glycol in the presence of a base in a
i
suitable solvent provides 4-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl]benzene sulfonamide (isopropyl impurity) or its alkali metal salt compound of formula-5.
In step a) the coupling of 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalo pyrimidine compound of formula-4 with 4-isopropyl benzene sulfonamide, the suitable base is as defined above, preferably potassium carbonate. The suitable solvent includes but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and their mixtures thereof, preferably toluene;
In step b) 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide is reacted with ethylene glycol in the presence of a base and a suitable aprotic solvent, with or without a phase transfer catalyst to obtain 4-isopropyl-N-[6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzene sulfonamide or its alkali metal salt compound of formula-5 (isopropyl impurity). The suitable solvent includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2- methyltetrahydrofuran, dimethylformamide, alcohols like methanol, ethanol, propanol, isopropanol and the like and their mixtures thereof; and the base is as defined above. The formation of isopropyl impurity is schematically represented by the following scheme: !"?
wherein X = halogen
The process for the preparation of isopropyl impurity of the present invention is represented by the following scheme:
a) X=Cl
Ethylene glycol
Base
Solvent
wherein X is a halogen and
M is H or an alkali metal ion
The said isopropyl impurity can not be removed by any of the conventional purification technique and it should be controlled at the origin itself as there is no other way to remove this impurity. Hence it is necessary to develop a process to control this isopropyl impurity. The present inventor developed an improved process to control this impurity well with in the limit as per ICH guidelines in the preparation of bosentan.
The fourth aspect of the present invention provides an improved process for the preparation of bosentan compound of formula- 1, which comprises of;
a) Condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4,
3
Formula-4
Wherein X is halogen
with 4-tert-butylbenzene sulfonamide having less than 0.15%, preferably less than 0.10% of 4-isopropylbenzene sulfonamide impurity, in the presence of a suitable base in a suitable solvent and in presence or absence of a phase transfer catalyst to provide 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-3,
b) reacting the 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3
Formula-3
Wherein X is halogen,
with ethylene glycol in the presence a suitable base in a suitable solvent to provide * bosentan compound of formula- 1 ,
c) purifying the obtained bosentan compound of formula- 1 using a suitable solvents selected - from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol and ester ' solvents like ethyl acetate and isopropyl acetate and their mixtures or their aqueous mixtures to provide pure bosentan compound of formula- 1.
In step a) the coupling of the 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6- dihalopyrimidine compound of formula-4 with 4-tert-butylbenzene sulfonamide, the suitable base is as defined and the suitable solvent includes but is not limited to benzene, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran and their mixtures thereof.
In step b) 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide is reacted with ethylene glycol in the presence of a base and in a suitable aprotic solvent, with or without a phase transfer catalyst to obtain bosentan compound of formula- 1. The suitable base is as defined and the suitable solvent includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, alcohols like methanol, ethanol, n-propanol, isopropanol and the like or their mixtures thereof.
The process for the preparation of bosentan compound of formula- 1 free of isopropyl impurity is represented by the following scheme.
(having <0.15% of4-isopropyl
benzene sulfonamide)
Solvent, Base,
Formula-4
HO OH
Base
Solvent
Ester
H7O Alcohol
Water
Formula- 1 Formula- 1
The fifth aspect of the present invention provides an improved process for the preparation of bosentan compound of formula- 1, which comprises of reacting the 4-tert-butyl- N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3
Formula-3
Wherein X is halogen and is selected from chlorine or bromine
with ethylene glycol in the presence alkoxide base like sodium tertiary butoxide or potassium tertiary butoxide in a suitable aprotic solvent which includes but is not limited to benzene, toluene, xylene, acetonitrile, tetrahydofuran, 2-methyl tetrahydrofuran, preferably tetrahydrofuran to provide bosentan compound of formula- 1.
The sixth aspect of the present invention provides a process for the preparation of high pure bosentan by purification from a suitable solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol, ethylacetate or isopropyl acetate or mixtures thereof, characterized in that the purification is carried out in presence of water.
The purification process of the present invention comprises of the following steps;
a) Suspending the bosentan compound of formula- 1 in a mixture of solvents selected from alcohols like methanol, ethanol, isopropanol, n-propanol, butanol and aqueous ester solvents like aqueous ethylacetate and aqueous isopropylacetate,
b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with a suitable hydrocarbon solvent selected from toluene, heptane, hexane and cyclohexane, and dried to get the pure bosentan compound of formula- 1.
The prior art process involves the recrystallisation of bosentan from a mixture of isopropyl acetate and methanol to remove the dimer impurity. However the purity of the obtained bosentan is not satisfactory after the first purification, four or five repeated purifications are required to attain a desired purity of bosentan according to ICH guidelines. The repeated purification leads to increase in processing time and loss in the yield of the final product and hence increases the overall cost of production. In order to reduce the number of purifications, we carried out number of recrystallisation of bosentan using a mixture of alcohol and ester solvents in different ratio with respect to the weight of the bosentan and surprisingly found that the usage of water along with mixture of alcohol and ester solvent leads to the maximum purity in single purification. The preferable ratio of alcohol and ester solvent is 1 : 1 with respect to the weight of the bosentan and having water content up to 5 to 25 % with respect to weight of the bosentan (for example: for 25 grams of bosentan, a mixture of 25 ml of alcohol and 25 ml of ester solvent and 2 ml of water is used).
In a preferred embodiment, the purification of bosentan comprises of the following steps;
a) Suspending the bosentan compound of formula- 1 in a mixture of methanol and ethylacetate in the ratio of 1 :1 with respect to the bosentan and having water from 5 to 25% with respect to weight of bosentan,
b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with a suitable hydrocarbon solvent selected from toluene, heptane, hexane and cyclohexane, and drying to get the pure bosentan compound of formula- 1.
The starting material of the present invention can be prepared by the process known in the art or can be prepared from the process disclosed in US 5292740 & WO 2009/095933.
The 1H NMR data of isopropyl impurity was recorded in CDCl3 solvent on BRUKER 300 MHz spectrometer using TMS as internal standard. The mass spectrum of isopropyl impurity was recorded on positive Ql MS by mass spectrometer.
The related substances of bosentan measured by HPLC using the following chromatographic conditions: Apparatus: A liquid chromatograph is equipped with variable wave length UV detector; Column : BDS hypersil C 18, 250 X 4.6 mm, 5μm or Equivalent; Flow rate: 0.8 ml/min.; Wave length: 220 nm. ; Temperature: 30°C; Load: 20 μl using aqueous methanol and aqueous methanolic dipotassium hydrogen orthophosphate in ratio of 1 : 1 as' a diluent.
The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as a limitation of the scope of the invention.
Examples:
Example 1: Preparation of 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-beπzene sulfonamide compound of formula-2:
A mixture of toluene (175 ml), DMSO (75 ml), water (50ml), Sodium hydroxide (15.2 grams) and 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)- benzene sulfonamide (50 grams) was heated to 105-110°C and the reaction mixture stirred for 12-13 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Water (400 ml) was added to the reaction mixture and stirred for 10 minutes. Acidified the reaction mixture with concentrate hydrochloric acid and filtered the obtained solid, washed the solid with water. Methanol (75 ml) was added to the obtained solid at 25-300C and stirred for an hour. Filtered the solid, washed with methanol and dried to get the title compound.
Yield: 38 grams
Example-2: Preparation of bosentan compound of formula-1:
A mixture of DMSO (125 ml), toluene (125 ml), sodium carbonate (20.9 grams) "and 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide
(25 grams) was heated to 105-1100C and stirred for 3.5-4 hours at same temperature. 2-chloro ethanol (35.72 grams) was added to the reaction mixture at 105-1100C and stirred it for 12-13 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 300 ml of water was added to it. Acidified the reaction mixture with Conc.HCl at room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and distilled off the organic layer under reduced pressure. Methanol (25 ml) was added to the obtained residue at 25-30°C and stirred the reaction mixture for 30 minutes.
Filtered the obtained solid, washed with methanol and dried to get the title compound.
Yield: 20.5 grams; Purity by HPLC: 97.15%; N-alkylated impurity: 1.46%
Example-3: Purification of Bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml), ethyl acetate (25 ml) and water (4 ml) by heated to reflux temperature and stirred at reflux for 45 minutes. The
reaction mixture was cooled to 25-30°C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound.
Yield: 10 grams; Purity by HPLC: 99.82%; N-alkylated impurity: 0.01%
Example-4: Preparation of 4-isopropyI-N-[6-chloro-5-(2-methoxyphenoxy) (2,2'- bipyrimidin)-4-yl] benzene sulfonamide compound of formula-6a:
Potassium carbonate (3.5 grams) and tetra butyl ammonium bromide (1.0 grams) was added to a solution of 4-isopropyl benzene sulfonamide (4.8 grams) in toluene (60 ml) and then heated it into 50°C. A solution of 5-(2-methoxyphenoxy)-2-(2'pyrimidinyl)-4,6-dichloro pyrimidine (formula-4a) (6.0 grams) in toluene (120 ml) was slowly added to the reaction mixture and it was refluxed using dean stark apparatus for 10 hrs. The reaction mixture was cooled to 25°C and acidified with aqueous hydrochloric acid. The reaction mixture was stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 8.7 grams
ExampIe-5: Preparation of 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-
2,2'-bipyrimidin-4-yl)benzene sulfonamide ( formula-5, isopropyl impurity):
A mixture of ethylene glycol (30.27 grams), sodium tertiary butoxide (3.75 grams), and tetrahydrofuran (20 ml) was heated to 70-75°C and stirred for four hours. The reaction mixture was cooled to 50°C and 4-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4- yl] benzene sulfonamide (5.0 grams) was added to the reaction mixture. The reaction mixture was heated to 70-75°C and stirred for 12 hours. The reaction mixture was cooled to 25°C, quenched with water and the reaction mixture acidified with aqueous hydrochloric acid. The solid obtained was filtered, washed with water and dried to get the title compound.
Yield: 4.5 grams
ExampIe-6: Preparation of 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3a:
A mixture of 4-teritary butyl benzene sulfonamide (15.2 grams) having 0.11% of 4-isopropyl benzene sulfonamide, potassium carbonate (19.77 grams), tetrabutylammonium bromide (0.7 grams) in toluene (750 ml) was heated to 45-50°C and stirred for 30 minutes.
4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (25 grams) was added the above mixture and heated to reflux temperature then stirred for 12 hours. The reaction mixture was
cooled and then quenched with water. The reaction mixture was filtered and washed the solid with water. Acetonitrile (300 ml) was added to wet solid and heated to reflux temperature then stirred for 2 hours. Water (50 ml) was added to the above wet solid and acidified with hydrochloric acid. The solid was filtered, washed with water and dried to get the title compound.
Yield: 80 grams; Purity by HPLC: 98.97 %; isopropyl derivative: 0.11%
Example-7: Preparation of bosentan compound of formula-1:
A mixture of ethylene glycol (301 grams), sodium tertiary butoxide (37.3 grams), and tetrahydrofuran (200 ml) was heated to 70-75 °C and stirred for four hours. 4-tert-butyl-N-[6- chloro-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide (formula-3a) (50 grams) having less than 0.11 % of 4-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide was added to the reaction mixture at 25-30°C and heated to 70-750C then stirred for 12 hours. The reaction mixture was cooled to 25°C, quenched with water and then acidified with aqueous hydrochloric acid. The solid obtained was filtered, washed with water and dried to get the title compound.
Yield: 44 grams; Purity by HPLC: 99.64 %; Isopropyl impurity: 0.10%
Examples 8 to 11: Preparation of bosentan compound of formula-1 :
Bosentan monohydrate compound of formula-1 is prepared analogues to the exmple-6 *& 7, except that 4-tertiary butyl benzene sulfonamide with different levels of 4-isopropyl benzene sulfonamide impurity is used as input. The purity results of the experiments are tabulated in the following table, which shows the level of 4-isopropyl benzene sulfonamide in the starting 4-tertiary butyl benzene sulfonamide and corresponding isopropyl derivative formed in the final bosentan compound.
A mixture of ethylene glycol (300 grams), sodium tertiary butoxide (37.3 grams) and tetrahydrofuran (200 ml) was heated to 70-75 °C and stirred for four hours. The reaction mixture was cooled to 25-300C and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide (formula-3a) (50 grams) was added to it. The reaction mixture was heated to 70-75°C and stirred for 10.5 hours. The reaction mixture was cooled to 25-30°C, quenched with water and acidified with aqueous hydrochloric acid then stirred for 2 hours. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 45 grams
Purity by HPLC: 98.40%; 6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-ol (monochloro impurity): 0.1 1%; Pyrimidinone impurity: 0.22%; dimer impurity: 0.62%; formula-3a:0.13%; 0.53 RRT impurity: 0.20%
Reference Example-1: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and isopfopyl acetate (25 ml) by heated to reflux temperature and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3 hours. The solid obtained was filtered, washed with ethyl acetate and dried to get the pure title compound
Yield: 13 grams; Purity by HPLC after 3 purifications: 99.72 %; dimer impurity: 0.07 % "'• * Reference Example-2: Purification of bosentan compound of formula-1:
Bosentan (44 grams) was dissolved in a mixture of methanol (44 ml) and ethyl acetate (44 ml) by heated to reflux temperature and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3 hours. The solid obtained was filtered, washed with ethyl acetate and dried to get the pure title compound
Yield: 40 grams
Purity by HPLC after 4 repeated purifications: 99.73 %; dimer impurity: 0.05 % by HPLC
Example-13: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and ethyl acetate (25 ml) and water (2 ml) by heated to reflux temperature and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3.5 hours. The solid obtained was filtered, washed with ethylacetate and dried to get the pure title compound. Yield: 11 grams
Purity by HPLC after 2 purifications: 99.83 %; 6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-ol (monochloro impurity): Not Detected ; Pyrimidinone impurity: 0.04%; dimer impurity: 0.06%; formula-3a: Not Detected; 0.53 RRT impurity: Not detected
Example-14: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and ethyl acetate (25 ml) and water (4 ml) by heated to reflux temperature and stirred for 45 minutes. The reaction mixture was cooled to 25-300C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound
Yield: 10 grams; Purity by HPLC after 2 purifications: 99.85 %; dimer impurity: 0.02 %
Example-15: Purification of bosentan compound of formula-1:
Bosentan (25 grams) was dissolved in a mixture of methanol (25 ml) and ethyl acetate (20 ml) isopropylacetate (5 ml) and water (2 ml) by heated to reflux temperature and stirred for 45 minutes. The reaction mixture was cooled to 25-30°C and stirred for 3.5 hours. The solid obtained was filtered, washed with cyclohexane and dried to get the pure title compound Yield: 10 grams; Purity by HPLC after 2 purifications: 99.87 %; dimer impurity: 0.04 %'.
Example-16: Purification of bosentan compound of formula-1:
A mixture of bosentan (10 grams) and ethanol (20 ml) was heated to reflux temperature
(80-85°C) and stirred for 30 minutes. Water (30 ml) was added to the reaction mixture'at 80- 85°C. The reaction mixture was cooled to 25-30°C and stirred for 8 hours. The solid obtained was filtered, washed with water and then dried to get the pure title compound:
Yield: 9.5 grams; Purity by HPLC: 99.90%
Claims
1. An improved process for the preparation of bosentan compound of formula- 1,
Formula- 1
which comprises of reacting the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2
Formula-2
with 2-chloroethan-l-ol or 2-bromoethan-l-ol in the presence of base and in a suitable solvent to provide bosentan compound of formula- 1, characterized in that the suitable solvent used is selected from a mixture of toluene/DMSO or toluene/DMF.
2. An improved process for the preparation of 4-tert-butyl-N-(6-hydroxy-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide compound of formula-2,
Formula-2
which comprises of reacting the 4-tert-butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidin-4-yl)-benzene sulfonamide compound of formula-3a 
Formula-3a
with a suitable base selected from sodium hydroxide or potassium hydroxide in a suitable solvent to provide the 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin- 4-yl)-benzene sulfonamide compound of formula-2, characterized in that the suitable solvent is selected from a mixture of toluene, dimethyl sulfoxide and water or mixture of dimethyl sulfoxide and water.
3. A process according to any of the preceding claims, wherein the reaction has been carried out at a temperature ranges from 50°C to reflux temperature of the solvent used.
4. A process for the preparation of bosentan of claim 1, further comprises of slurrying the bosentan in a suitable alcoholic solvent to reduce the amount of N-alkylated impurity.
5. A process according to claim 2, wherein the base used in the reaction is about to 2 to 7 moles w.r.to 4-tert-butyl-N-(6-chloro-5 -(2-methoxyphenoxy)-2,2 ' -bipyrimidin-4-yl)- benzene sulfonamide compound of formula-3a.
6. The use of mixture of toluene, dimethylsulfoxide and water for the conversion of 4-tert- butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide in to 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)-benzene sulfonamide.
7. A process for the preparation of bosentan compound of formula-1, which comprises of preparing the compound of formula-2 according to claim-2, and converting the same into bosentan.
8. A process according to any of the preceding claims, wherein the obtained bosentan is substantially free of dimer and digol dimer impurities and having purity greater than 99.50% by HPLC.
9. Bosentan and 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)- benzene sulfonamide substantially free of dimer impurity and digol dimer impurity.
10. A process according to claim 1 or 7, wherein the bosentan is further purified using ethanol/water and the obtained bosentan containing less than 0.05% of N-alkyl impurity; preferably less than 0.02% by HPLC and free of dimer and digol dimer impurities.
11. 4-Isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)
benzene sulfonamide or its salt compound represented by the following general structural formula
Wherein M is hydrogen or alkali metal ion.
12. 4-Isopropyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)
benzene sulfonamide compound represented by the following structural formula
characterized by at least one of 1H NMR (300 MHz) δ(ppm): 9-8.99 (d, J=4.74 Hz, 2H), 8.72 (b, IH), 8.45-4.43 (d, J=8.22 Hz, 2H), 7.42-7.39 (m, 3H), 7.15-6.85 (m, 4H), 4.84 (s, IH), 4.58 (s, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 2.92 (m, IH), 1.22 (d, J=6.81 Hz, 6H) & Mass spectra m/z=560 (M+Na)+.
13. A process for the preparation of 4-isopropyl-N-(6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzene sulfonamide or its salt compound of formula-5, which comprises of the following steps;
a) condensing 5-(2-methoxyphenoxy)-2-(2'-pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4
Formula-4
wherein X is a halogen;
with 4-isopropyl benzene sulfonamide,
■" ^— SO2NH2 in presence of a base in a suitable solvent and in the presence or absence of a phase transfer catalyst, to provide 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'* bipyrimidin]-4-yl] benzene sulfonamide compound of formula-6,
Formula-6
wherein X is a halogen and M is an alkali metal ion,
b) reacting 4-isopropyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-6, with ethylene glycol in the presence of a base in presence of a suitable solvent to provide 4-isopropyl-N-[6-(2-hydroxyethoxy)-5-(2- methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benzene sulfonamide (isopropyl impurity) or its alkali metal salt compound of formula-5.
14. An improved process for the preparation of highly pure bosentan monohydrate compound of formula- 1 ,
Formula- 1
which comprise of the following steps;
a. Condensing 5 -(2-methoxyphenoxy)-2-(2 ' -pyrimidinyl)-4,6-dihalopyrimidine compound of formula-4,
Formula-4
wherein X is halogen,
with 4-tert-butylbenzene sulfonamide having less than 0.15% of 4-isoprόpyϊbenzene sulfonamide impurity, in presence of a suitable base in a suitable solvent and in presence or absence of a phase transfer catalyst to proivde p-tert-butyl-N-[6-halo- 5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzene sulfonamide compound of formula-3,
b. reacting the 4-tert-butyl-N-[6-halo-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3
Formula-3
Wherein X is halogen,
with ethylene glycol in the presence of a suitable base in a suitable solvent to provide bosentan compound of formula- 1, c. purifying the obtained bosentan compound of formula- 1 using a suitable solvents to provide pure bosentan compound of formula- 1.
15. The process according to claim 13 & 14) wherein;
In step a) the suitable base used is selected from the group consisting of 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; and the suitable solvent selected from benzene, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran and their mixtures thereof; and a 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. ■ •
In step b) the base used is selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides of alkalimetal such as tert-butoxide, isopropoxide, ethoxide and methoxides of sodium and potassium; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; and the suitable solvent used is selected from benzene, toluene, xylene, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, alcohols like methanol, ethanol, propanol, isopropanol and the like or their mixtures thereof.
16. A process for the preparation of highly pure bosentan comprise of the following steps; a) Suspending the bosentan compound of formula- 1 in a mixture of solvents selected from alcohols like methanol, ethanol, isopropanol, n-propanol, butanol and ester solvents like ethylacetate, isopropylacetate and water or mixtures thereof,
b) heating the reaction mixture to reflux temperature, c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with a suitable hydrocarbon solvent selected from toluene, heptane, hexane and cyclohexane, and dried to get the pure bosentan compound of formula- 1.
17. A process for the preparation of highly pure bosentan comprises of the following steps; a) Suspending the bosentan compound of formula- 1 in a mixture of water, methanol and ethylacetate,
b) heating the reaction mixture to reflux temperature,
c) stirring the reaction mixture at reflux temperature,
d) cooling the reaction mixture to 25-30°C,
e) filtering and washing the solid with cyclohexane and dried to get the pure bosentan compound of formula- 1.
18. A process according to claim 16, wherein in step a) the alcohol or ester solvent is used in an amount of about 1 ml to about 2 ml per 1 gram of bosentan and water is used in an amount about 5 to about 25% with respect to the weight of bosentan.
19. An improved process for the preparation of bosentan monohydrate compound of formula- 1 ,
Formula- 1
which comprises reacting the 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2'- bipyrimidin]-4-yl] benzene sulfonamide compound of formula-3a
Formula-3a with ethylene glycol in the presence of alkoxide base like sodium tertiary butoxide or potassium tertiary butoxide in a suitable aprotic solvent like benzene, toluene, xylene, acetonitrile, tetrahydrofuran and 2-methyl tetrahydrofuran, to provide bosentan compound of formula- 1.
20. Bosentan compound of formula- 1, having the impurity 4-isopropyl-N-(6-(2 -hydroxy ethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-y])benzene sulfonamide compound of formula-5a (isopropyl impurity) in a concentration less than 0.15%, preferably 0.10%, more preferably 0.05% by HPLC.
21. Bosentan compound of formula- 1 according to claim 20 is substantially free of isopropyl impurity.
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| IN2112/CHE/2010 | 2010-07-26 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013186706A1 (en) * | 2012-06-12 | 2013-12-19 | Cadila Pharmaceuticals Ltd | Process for the preparation of bosentan |
| WO2014104904A1 (en) * | 2012-12-30 | 2014-07-03 | Instytut Farmaceutyczny | Process for preparation of bosentan monohydrate of pharmaceutical purity |
| CN114907275A (en) * | 2022-04-29 | 2022-08-16 | 武汉工程大学 | Preparation method of bosentan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6136971A (en) * | 1998-07-17 | 2000-10-24 | Roche Colorado Corporation | Preparation of sulfonamides |
| WO2009095933A2 (en) * | 2008-01-10 | 2009-08-06 | Msn Laboratories Limited | Improved and novel process for the preparation of bosentan |
-
2010
- 2010-08-09 WO PCT/IN2010/000525 patent/WO2011021216A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6136971A (en) * | 1998-07-17 | 2000-10-24 | Roche Colorado Corporation | Preparation of sulfonamides |
| WO2009095933A2 (en) * | 2008-01-10 | 2009-08-06 | Msn Laboratories Limited | Improved and novel process for the preparation of bosentan |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013186706A1 (en) * | 2012-06-12 | 2013-12-19 | Cadila Pharmaceuticals Ltd | Process for the preparation of bosentan |
| JP2015521594A (en) * | 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 | Method for producing bosentan |
| WO2014104904A1 (en) * | 2012-12-30 | 2014-07-03 | Instytut Farmaceutyczny | Process for preparation of bosentan monohydrate of pharmaceutical purity |
| CN114907275A (en) * | 2022-04-29 | 2022-08-16 | 武汉工程大学 | Preparation method of bosentan |
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