TECHNICAL FIELD
The present invention describes an efficient process for the preparation of salts of Bosentan and isolation of substantially pure base thereof and also the isolation of substantially pure crystalline intermediates involved in the process.

BACKGROUND AND PRIOR ART OF THE INVENTION
The present invention relates to acid addition salts of Bosentan  methods of purifying Bosentan base using the salts and amorphous Bosentan. The acid addition salts are useful for the purification of Bosentan base. Further  the acid addition Bosentan salts of the invention can be obtained in a stable solid-state form making them useful for purification and bulk storage.
Bosentan is chemically known as 4-(l l-Dimethylethyl)-N-[6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)[2 2""-bipyrimidin]-4-yl]benzenesulfonamide  having the structural formula- 1.

Formula- 1

Bosentan is a pharmaceutically active compound (an endothelin receptor antagonist) useful for the treatment of pulmonary arterial hypertension and is represented by the formula (I).
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 methods involves the condensation of diethyl (2- methoxyphenoxy) malonate with pyrimidine-2-carboxyamidine in the presence of sodium methoxide  to provide the dihydroxy derivative  which is converted into dichloro derivative by the treatment with refluxing phosphorus oxychloride. One of the chlorine of the dichloro derivative is replaced by 4-tert- butylbenzenesulfonamide. The remaining chlorine is replaced by ethylene glycol using monosodium ethylene glycolate to provide Bosentan as illustrated in Scheme-1.
Scheme-1:

Stage-1

Stage 2:

Stage 3:


Stage-4

STATEMENT OF THE INVENTION
Accordingly  the present invention relates to acid addition salts of Bosentan; a method of making an acid addition salt of Bosentan  which comprises: a) combining Bosentan base and an acid having a pKa higher than 3 in an organic solvent to form a solution; b) precipitating a Bosentan acid addition salt from said solution and c) isolating the precipitated Bosentan acid addition salt; a method of purifying Bosentan  which comprises: a) preparation of an acid addition salt of Bosentan by following any mehod discussed in earlier claims  b) isolation of said acid addition salt of Bosentan from organic solvent c) optionally re crystallizing by using an organic solvent d) converting Bosentan acid addition salt into Bosentan base and e) isolation of Bosentan base; a process which comprises dissolving a solid Bosentan acid addition salt as above in an organic solvent  and precipitating said salt to obtain a purified solid Bosentan acid addition salt; Bosentan citrate salt; and Bosentan tartarate salt.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
In order that the invention may be readily understood and put into practical effect  reference will now be made to exemplary embodiments as illustrated with reference to the accompanying figures. The figure together with a detailed description below  are incorporated in and form part of the specification  and serve to further illustrate the embodiments and explain various principles and advantages  in accordance with the present disclosure where:
FIG. 1 is an XRPD pattern for the crystalline Bosentan citrate salt.
FIG. 2 is an XRPD pattern for the crystalline Bosentan tartarate salt.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to acid addition salts of Bosentan.
In an embodiment of the present invention the said acid has a pKa higher than 3.
In another embodiment of the present invention the said salts are in solid form.

In yet another embodiment of the present invention the said salts are in crystalline form.
In still another embodiment of the present invention the said acid addition salt is selected from Bosentan citrate and Bosentan tartarate.
In still another embodiment the said salt is selected from crystalline Bosentan citrate and crystalline Bosentan tartarate.
The present invention further relates to a method of making an acid addition salt of Bosentan  which comprises: a) combining Bosentan base and an acid having a pKa higher than 3 in an organic solvent to form a solution; b) precipitating a Bosentan acid addition salt from said solution and c) isolating the precipitated Bosentan acid addition salt.
In an embodiment the said acid is selected from the group of citric acid and tartaric acid.
In another embodiment the said organic solvent is selected from the group consisting of ketones  chlorinated hydrocarbons  hydrocarbons  alcohols  esters; aliphatic nitriles; ethers and mixtures thereof.
In yet another embodiment the said organic solvent is selected from the group consisting of acetone  methyl tert.butyl ketone  dichloromethane  methanol  ethanol  isopropanol  ethyl acetate  butyl acetate  acetonitrile  di-isopropyl ether  methyl tertiary butyl ether tetrahydrofuran  and mixtures thereof.
The present invention further relates to a method of purifying Bosentan  which comprises: a) preparation of an acid addition salt of Bosentan by following any mehod discussed in earlier claims  b) isolation of said acid addition salt of Bosentan from organic solvent c) optionally re crystallizing by using an organic solvent d) converting Bosentan acid addition salt into Bosentan base and e) isolation of Bosentan base.
In an embodiment the Bosentan base is amorphous in nature
In another embodiment the said organic solvent is selected from the group consisting of ketones  chlorinated hydrocarbons  hydrocarbons  alcohols  esters  aliphatic nitrites  ethers and mixtures thereof.
In yet another embodiment said organic solvent is selected from the group consisting of acetone  methyl tert.butyl ketone  dichloromethane  methanol  ethanol  isopropanol  ethyl acetate  butyl acetate  acetonitrile  di-isopropyl ether  methyl tertiary butyl ether tetrahydrofuran  and mixtures thereof.
In still another embodiment said converting step comprises contacting said Bosentan acid addition salt with an organic or inorganic base in organic solvent.
In still another embodiment the method further comprises recrystallizing said isolated acid addition salt of Bosentan prior to said converting step.
The present invention further relates to a process which comprises dissolving a solid Bosentan acid addition salt as above in an organic solvent  and precipitating said salt to obtain a purified solid Bosentan acid addition salt.
The present invention further relates to Bosentan citrate salt.
The present invention further relates to Bosentan tartarate salt.
The present invention relates to the discovery of stable acid addition salts of Bosentan that are useful for the purification of Bosentan base. Accordingly  a first aspect of the invention relates to an acid addition salt of Bosentan  wherein said salt is in the solid state and wherein said acid has a pKa values higher than 3. The acid can be selected from organic acids preferably tartaric acid and citric acid. The solid form obtained is crystalline in nature. In particular  the Bosentan acid additional salt is selected from Bosentan citrate and Bosentan tartarate  preferably from crystalline Bosentan citrate and crystalline Bosentan tartarate.
Yet another aspect of the present invention relates to a method of making an acid addition salt of Bosentan  which comprises combining Bosentan base and an acid having a pKa higher than 3 in an organic solvent  preferably a polar organic solvent  to form a solution; precipitating a Bosentan acid addition salt from said solution; and optionally purifying the precipitated Bosentan acid addition salt.
A further aspect of the present invention relates to a method of purifying Bosentan  which comprises combining crude Bosentan and an acid having a pKa more than 3 in a first solvent to obtain an acid addition salt of Bosentan; isolating said acid addition salt of Bosentan from said first solvent; optionally purifying the acid addition salt in the second solvent  converting said pure Bosentan acid addition salt into Bosentan base in a third solvent; and isolating said Bosentan base from said third solvent.
Another aspect of the invention relates to a process of purifying Bosentan salt that comprises dissolving a solid Bosentan acid addition salt in an organic solvent and precipitating said salt to obtain a purified solid Bosentan acid addition salt.
Another aspect of the invention is to provide the crystalline form of the Bosentan Intermediates 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl diol compound of formula-2  4 6- dichloro 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl compound of formula-3  4-tert-Butyl-N-[6-chloro5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl-4-yl]-benzene sulfonamide compound of formula-4  4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide citrate salt compound of formula-5  4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide citrate salt compound of formula-6 in the solid state with good yield  high purity and ease of operations. The intermediate is further characterized by well established techniques like XRD  DSC and FTIR.

In another embodiment  the present invention provides a crystalline form of Formula- 2 having the X-ray diffraction pattern with peaks at 9.815  11.685  11.980  12.587  14.664  15.016  16.261  19.591  20.435 21.387 22.371  23.412  24.184  24.904  25.312  25.944  26.591  27327  28.047  28.708  29.139  29.605  30.384  30.896  31.220  32.339  32.717  33.381  34.113  34.511  34.958  35.399  35.92  37.188  37.768  38.340  39.323  39.838  40.197  42.013  43.466  44.384  45.412  46.138  47.837  48.344  49.542  50.932  51.866  52.967  54.077  54.830  58.510  59.565  ± 0.2 degrees two theta values.
In another embodiment the present invention provides FTIR spectra of crystalline form of Formula-2 with peaks at 3254  3151  2842  1796  1663  1619  1603  1578 1565  1516  1501  1472 1448  1434  1402  1357  1322  1298  1253  1232  1213  1180 1166  1156  1148  1114  1088  1058  1052  1022  946  835  817  807  763  723  713  687  677  644  635  598  555  506  458 cm-1.
In another embodiment the present invention provides DSC thermogram of crystalline form of Formula- 2 with endothermic peak at 170.34°C.
In another embodiment  the present invention provides a crystalline form of Formula- 3 having the X-ray diffraction pattern with peaks at6.394  8.610  9.877  11.068  11.969  13.907  14.752  15.547  17.255  18.485  19.824  20.473  22.213  22.718  23.577  24.106  24.823  25.893  26.307  26.578  27.295  27.532  27.790  28.211  29.315  30.064  30.792  31.490  32.028  32.415  33.594  34.273  34.851  35.208  35.681  36.444  37.417  38.545  39.016  40.266  40.638  41.551  41.918  43.093  43.458  43.811  44.393  45.265  47.350  45.995  49.012  49.426  ± 0.2 degrees two theta values.
In another embodiment the present invention provides FTIR spectra of crystalline form of Compound-2 with peaks at 1722  1587  1578  1566  15.37  1501  1475  1456  1428  1390  1359  1348  1329  1319  1295  1288  1276  1255  1221  1199  1187  1178  1165  1157  1114  1058  1048  1036 1022  873  840  828  815  796  781  773  765  758  752  709  700  670  661 648  632cm-1.
In another embodiment the present invention provides DSC thermogram of crystalline form of Formula- 3 with endothermic peak at 160.18°C.
In another embodiment  the present invention provides a crystalline form of crude Formula- 4 having the X-ray diffraction pattern with peaks at 6.580  7.586  9.299  12.006  13.172  13.688  14.746  15.197  17.862  18.671  19.054  19.873  20.182  20.877  22.252  22.894  23.201  23.910  24.175  24.822  25.032  25.921  26.530  26.797  27.394  28.242  29.244  29.718  30.710  31.207  32.135  33.368  34.921  35.522  36.170  36.754  38.697  40.513  43.189  44.331  44.907  45.414  46.457  49.512 ± 0.2 degrees two theta values.
In another embodiment the present invention provides FTIR spectra of crystalline form of Compound-2 with peaks at 2967  1850  1593  1584  1546  1514  1500  1485  1460  1425  1392  1359  1342  1303  1281  1276  1253  1227  1220 1205 1190 1168  1133  1112  1094  1084  1060  1010  1004  949  901  882  868  849  815  782  771  724  699  678  630  605  587  576  566  552  545  533  517 cm-1.
In another embodiment the present invention provides DSC thermogram of crystalline form of crude Formula- 4 with endothermic peak at 231.17°C.
In another embodiment  the present invention provides a crystalline form of purified Formula- 5 having the X-ray diffraction pattern with peaks at 3.357  6.726  8.330  8.735  9.219  10.313  13.560  15.248  15.504  15.990  16.434  16.769  17.550  17.788  18.337  18.647  19.407  20.231  20.716  21.373  21.746  22.577  22.969  23.771  24.253  24.561  25.120  25.731  26.249  26.574  27.138  27.891  28.933  31.748  32.366  33.626  36.043  37.369  37.756 ± 0.2 degrees two theta values.
In another embodiment the present invention provides FTIR spectra of crystalline form of purified Formula- 5 with peaks at 2960  2152  1714  1665  1620  1606  1578  1520  1501  1477  1405  1370  1342  1299  1256  1187  1172  1154  1142  912.78  827  802  751  740  716  706  659  625  608  570 cm-1.
In another embodiment the present invention provides DSC thermogram of crystalline form of purified Formula- 6 with endothermic peak at 150.97°C.
In another embodiment  the present invention provides a crystalline form of purified Formula- 6 having the X-ray diffraction pattern with peaks at 3.357  6.726  8.330  8.735  9.219  10.313  13.560  15.248  15.504  15.990  16.434  16.769  17.550  17.788  18.337  18.647  19.407  20.231  20.716  21.373  21.746  22.577  22.969  23.771  24.253  24.561  25.120  25.731  26.249  26.574  27.138  27.891  28.933  31.748  32.366  33.626  36.043  37.369  37.756 ± 0.2 degrees two theta values.
In another embodiment the present invention provides FTIR spectra of crystalline form of purified Formula- 6 with peaks at 2960  2152  1714  1665  1620  1606  1578  1520  1501  1477  1405  1370  1342  1299  1256  1187  1172  1154  1142  912.78  827  802  751  740  716  706  659  625  608  570 cm-1.
In another embodiment the present invention provides DSC thermogram of crystalline form of purified Formula- 6 with endothermic peak at 150.97°C.
The present invention relates to the discovery of stable acid addition salts of Bosentan. These acid addition salts are useful for the purification of Bosentan base. The Bosentan acid addition salts of the invention are made from fairly mild acids having a pKa of more than 3. The “pKa” refers to the pKa of the starting acid; hence as used herein reference to the pKa even in the context of the addition salt is referring to the pKa of the starting acid. Suitable acids include  for example  tartaric acid and citric acid.
The Bosentan acid addition salts of the invention are isolatable in a solid state  which can be advantageous. The “solid state” obtained is crystalline. Generally the acid addition Bosentan salts of the invention can be obtained in a stable solid state form making them useful for purification  bulk storage.
The Bosentan acid addition salts of the present invention are typically monovalent salts  i.e.  having an acid: base ratio of about 1:1. Analytical methods  such as titration or ionic chromatography  may show a ratio of acid: base of 0.8:1 to 1:1.2 in the isolated solid form of the salt as a result of  e.g.  traces of unbound acid and/or base and inherent variance associated with the analytical method. Such variation in the acid: base ratio is encompassed by an acid: base ratio of “about 1:1.”
Exemplary Bosentan acid addition salts according to the present invention include Bosentan citrate and Bosentan tartarate. In a preferred embodiment  the Bosentan acid addition salts of the present invention are Bosentan citrate and Bosentan tartarate. Each of these salts is isolatable in a crystalline solid state with a molar ratio of Bosentan to acid moieties of about 1:1.
The Bosentan acid addition salts of the present invention can be made by combining Bosentan base and an acid having a pKa higher than 3 in an organic solvent  preferably a polar organic solvent  to form a solution  and then precipitating a Bosentan acid addition salt from said solution. Optionally the precipitated Bosentan acid addition salt can be isolated.
A molar equivalent or a slight excess of the starting acid with reference to the Bosentan base is typically used in order to form a Bosentan acid addition salt having an acid: base ratio of about 1:1.
The Bosentan base used in forming the Bosentan acid addition salt (i.e.  the starting Bosentan base) is amorphous  in any degree of purity. The starting Bosentan base can also be crude Bosentan that is present in the reaction mixtures obtained after the chemical synthesis of Bosentan.
The organic solvent used is typically a polar organic solvent  which includes both protic and aprotic solvents. Generally  the dielectric constant of a solvent provides a rough measure of a solvent""s polarity; solvents with a dielectric constant of less than 15 are typically considered nonpolar. Examples of suitable polar solvents include C3-C10 aliphatic ketones (e.g.  acetone  methyl ter.butyl ketone  etc.)  C1-C6 chlorinated hydrocarbons (e.g.  dichloromethane)  C1-C6 aliphatic alcohols (e.g.  methanol  ethanol  isopropanol)  C3-C10 aliphatic esters (e.g.  ethyl acetate)  C2-C5 aliphatic nitriles (e.g.  acetonitrile)  and ethers  including cyclic ethers (e.g.  di-isopropyl ether  tetrahydrofuran)  as well as mixtures thereof.
There is no specific order in which the Bosentan base and the acid must be combined in the solvent to form the solution. Generally the conditions are such that all of the Bosentan (and all of the acid) is dissolved in the solvent  though strictly speaking such is not required; i.e.  some amount of solid or immiscible Bosentan may be present in the solution. The dissolution of Bosentan base in the solvent is advantageously performed at an enhanced temperature  which includes the reflux temperature of the solvent. The contacting or combining of the Bosentan-containing solvent with the acid is advantageously performed at an ambient or higher than ambient temperature  including the reflux temperature of the solvent. In other embodiments  the acid can be added  e.g.  substantially at the same time as the base  before the base  etc.
The precipitation of the Bosentan acid addition salt can be carried out in various ways. For example  the precipitation can occur spontaneously upon the contacting of the Bosentan with the acid in the organic solvent. Precipitating of the Bosentan acid addition salt can also be induced by seeding the solution  cooling the solution  evaporating at least part of the solvent  adding an antisolvent  and by combining one or more of these techniques.
The precipitated Bosentan acid addition salt can be isolated from the solution by conventional techniques  e.g. filtering or centrifugation  and can be washed and dried.
The isolated Bosentan acid addition salt can  however  be purified if desired. For example  the isolated salt is recrystallized or reprecipitated by dissolving (at least partially  e.g.  suspending) the isolated salt in a solvent  such as any of the above defined polar organic solvents  at an enhanced temperature (which includes a reflux temperature of the solvent)  and then crystallizing or precipitating the salt from the solvent. The recrystallization (reprecipitation) process may be repeated until a desired purity of the isolated Bosentan acid addition salt is obtained. For clarity  the terms “purify ” “purification ” “purified ” and variations thereof are used herein to indicate an improvement in the quality or purity of the substance and are not meant in the narrow sense of obtaining near absolute purity. Hence reducing the impurities from 2.0% to 1.5% represents a “purification” of the substance.
The solid state Bosentan acid addition salts of the present invention can be advantageously used to obtain purified Bosentan. In general  crude Bosentan can be purified by converting it to a Bosentan acid addition salt as described above and then converting the Bosentan salt back into Bosentan base. For example  a purification process can comprise (i) combining crude Bosentan and an acid having a pKa more than 3 in a first solvent or solvent mixture  preferably from polar organic solvents  to obtain an acid addition salt of Bosentan; (ii) isolating the acid addition salt of Bosentan in solid state from the first solvent or solvent mixture; (iii)preferably purifying the acid addition salt of Bosentan using second solvent or solvent mixture till the required purity is attained(iv) converting the Bosentan acid addition salt into Bosentan base in a third solvent  preferably an polar organic solvent in presence of a base such as alkali and alkali metal hydroxides alkali metal carbonate; and (iv) isolating the Bosentan base from said third solvent by evaporation to get amorphous Bosentan. Because structurally related impurities present in the crude Bosentan are generally soluble in the organic solvents used to form the salt  these impurities generally remain in the first solution during the isolation of the solid Bosentan acid addition salt; thereby separating these impurities from the Bosentan moiety. The conversion to Bosentan base  especially in an polar organic solvent and water in presence of a base  can likewise provide a further purification effect with respect to water-soluble impurities. “Crude Bosentan” means a Bosentan base or salt having insufficient purity and includes reaction mixtures obtained after the chemical synthesis of Bosentan as well as Bosentan having near pharmaceutical grade purity. From a practical standpoint  the crude Bosentan is typically a Bosentan base in amorphous form. Likewise  the produced “Bosentan base ” which has an enhanced purity or quality relative to the crude Bosentan  is also amorphous. The above-recited process steps are not exhaustive; additional steps can also be included. For example  the acid addition salt of Bosentan can itself be purified  such as by (re)crystallization as described above  before being converted to Bosentan base.
The first solvent is generally a polar organic solvent as described above in the context of making the Bosentan acid addition salts. Thus  examples of suitable first solvents include C3-C10 aliphatic ketones (e.g.  acetone  methyl ter.butyl ketone  etc.)  C1-C6 chlorinated hydrocarbons (e.g.  dichloromethane)  C1-C6 aliphatic alcohols (e.g.  methanol  ethanol  isopropanol)  C3-C10 aliphatic esters (e.g.  ethyl acetate)  C2-C5 aliphatic nitrites (e.g.  acetonitrile)  and ethers including cyclic ethers (e.g.  di-isopropyl ether  tetrahydrofuran)  as well as mixtures thereof.
The Bosentan acid addition salt  which can be formed before or during precipitation thereof  is conveniently isolated as a solid from the first solvent by known techniques such as filtration  etc. The precipitation of the solid state acid addition salt of Bosentan can be carried out by the techniques as described above.
The isolated solid Bosentan acid addition salt can be converted into Bosentan base by any suitable or convenient technique. Generally  the solid salt is dissolved in the second solvent and converted to base  preferably via the use of a base. Advantageously the second solvent is an polar solvent in which Bosentan base is soluble. Such solvents include water-immiscible solvents and combinations thereof. The base used to convert the salt of Bosentan to Bosentan base may be an organic or inorganic base and is preferably a base that binds the acid present in the second solvent to form a salt that is soluble in the second solvent. Suitable bases include sodium and potassium hydroxide  TEA. Upon addition of the base to the salt-containing second solvent  Bosentan generally gets extracted in the organic solvent and directly converted to amorphous polymorph upon concentration and drying.
In a preferred embodiment  the above purification process results in Bosentan base having less than 0.5% impurities.
The present invention provides a method for the preparation of compound of Formula-1 according to the known processes in the prior art.
The invention is further illustrated by the following examples  which should not be construed to limit the scope of the invention in anyway.
Characterization
Bosentan intermediate of the present invention (Formula - 2)  (Formula - 3)  (Formula - 4)  (Formula - 5)  (Formula - 6) is characterized by X-Ray powder Diffraction (XRD)  DSC analysis  and FTIR spectroscopy.
XRD: XRD Diffractograms were collected on Bruker AXS D-8 advance X- Ray powder diffract meter  Scintillation detector. Scanning Parameters : ScanType - Locked Coupled  Scan Mode -Continuous  Range (2 theta) - 3.0°- 60.0°  Rate - 3.6°/min
FTIR Spectroscopy
FTIR Spectrum was recorded on Perkin-Elmer spectrum-1spectrometer  Diffuse Reflectance Technique. The sample was finely ground with Potassium Bromide  and the spectrum was recorded using Potassium Bromide background in a Diffused reflectance accessory.
Thermal analysis
Differential Scanning Calorimetry was performed on Perkin Elmer Diamond. The Crucible was Crimped and punched prior to analysis. Experimental conditions: sample Weight: 2.0 – 3.0 mg  Heating Rate: 10°C/min.
The present disclosure is further elaborated with the help of following examples and associated figures. However  these examples should not be construed to limit the scope of the present disclosure.

EXAMPLES
Example 1: Preparation of 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl diol (Formula-2)
To a mixture of methanol (60mL) and sodium methoxide (3.8g 0.07 mol) under inert atmosphere pyrimidine -2-carboxyamidine hydrochloride (3.3g 0.02 mol) was added followed by 2-(2-methoxy phenoxy) malonic acid diethyl ester (5g  0.02 mol) at the ambient temperature and stirred for 3h. Water was added to the concentrated reaction mass and the pH was adjusted to 2 using 1N hydrochloric acid and stirred for 1h at the ambient temperature and stirred for 2h at 5-10°C. The obtained solid was filtered and washed with water and dried under vacuum for 10 hours yielding compound - 2 (4. 0g) as a pale yellow crystalline solid (99%) having the X-ray diffraction pattern with peaks at 11.062  11.516  12.523  14.886  16.081  16.368  17.12  18.04  18.286  18.994  19.697  20.74  21.359  22.592  23.232  24.075  25.099  25.767  26.054  26.645  27.343  28.063  29.074  30.323  31.449  33.016  34.653  36.016  36.708  37.136  38.393  41.271  42.419  44.641  46.637  49.058  49.468  50.041  ± 0.2 degrees two theta values.
Example 2: Preparation of 4 6- dichloro 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl compound (formula-3)
5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl diol (Formula-2) 4g (0.0128mol) was taken in acetonitrile (20mL) and Collidine(3.88g 0.032mol). Phosphorous oxy chloride was added (19.64g  0.128mol) slowly and refluxed for 5 to six hours  the reaction mass were quenched in water and the product was extracted in ethyl acetate. Organic layer was washed with water  sodium bicarbonate and saturated brine and dried over anhydrous sodium sulphate and concentrated. The concentrated reaction mass was isolated using n-heptane and the obtained solid was dried under vacuum yielding 3.4g of slightly brown solid 4 6- dichloro 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl compound (formula-3) (99%) having the X-ray diffraction pattern with peaks at 8.547  9.867  11.068  11.97  13.851  14.726  15.539  17.213  18.428  20.463  22.232  22.704  23.536  23.937  24.827  26.291  26.545  27.294  27.815  28.223  29.278  30.022  30.5  31.447  31.996  32.454  33.43  33.644  34.251  34.89  35.662  36.393  37.402  38.523  39.022  40.238  40.724  41.35  41.93  43.732  44.289  45.24  47.267  47.978  49.123  49.438  50.22  ± 0.2 degrees two theta values.
Example 3: Preparation of 4-tert-Butyl-N-[6-chloro5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl-4-yl]-benzene sulfonamide compound of formula-4.
p-t-butyl benzene sulphonamide (2.2g 0.0104mol) was taken in Dimethyl Sulphoxide and potassium carbonate was added (2.75g 0.0198mol) under inter atmosphere and stirred for 0.5h. 3.4g of 4 6- dichloro 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl compound (formula-3) 3.44g  0.009mol was added and heated to 120°C and maintained at the same temperature for 2h. The reaction mass was quenched in 1N hydrochloric acid and stirred for 2h. Product precipitates out and was filtered and washed with water and dried under vacuum yielding 4.3g(96%) of pale yellow crystalline solid 4 6- dichloro 5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl compound of formula-3 having the X-ray diffraction pattern with peaks at 8.547  9.867  11.068  11.97  13.851  14.726  15.539  17.213  18.428  20.463  22.232  22.704  23.536  23.937  24.827  26.291  26.545  27.294  27.815  28.223  29.278  30.022  30.5  31.447  31.996  32.454  33.43  33.644  34.251  34.89  35.662  36.393  37.402  38.523  39.022  40.238  40.724  41.35  41.93  43.732  44.289  45.24  47.267  47.978  49.123  49.438  50.22  ± 0.2 degrees two theta values.
This was optionally purified using acetonitrile under the reflux condition to give pure pale yellow to off white crystalline product for formula-4 having the XRD.
Example 4: Preparation of Bosentan.
Mono sodium ethylene glycolate was dissolved in ethylene glycol 26.72g  0.430mol and 4-tert-Butyl-N-[6-chloro5-(2-methoxyphenoxy) [2 2]-bipyrimidinyl-4-yl]-benzene sulfonamide 3.7g (0.007mol) was added and heated to 110 to 115°C for 5h. The reaction mass was quenched with 141ml water and then acidified to pH 2 using 1N hydrochloric acid and the product was extracted in Dichloro methane. Organic layer was dried over anhydrous sodium sulphate and concentrated to get 3.5g of crude amorphous Bosentan.
Example 5: Preparation of Bosentan citrate.
Bosentan 1.0g  0.0018mol and citric acid 0.35g  0.0018mol were taken in mixture of acetonitrile 4mL and stirred at an ambient temperature for 8h and 8ml of diisopropyl ethyer was added. The reaction mixture was stirred for 30 min and the solid was filtered and washed with di isopropyl ether 2.0 mL to get 99.0% pure material and was further purified using ethylacetate acetonitrile and Diisopropyl ether mixture. Bosentan citrate having the X-ray diffraction pattern with peaks at 3.357  6.726  8.330  8.735  9.219  10.313  13.560  15.248  15.504  15.990  16.434  16.769  17.550  17.788  18.337  18.647  19.407  20.231  20.716  21.373  21.746  22.577  22.969  23.771  24.253  24.561  25.120  25.731  26.249  26.574  27.138  27.891  28.933  31.748  32.366  33.626  36.043  37.369  37.756 ± 0.2 degrees two theta values.
Example 6: Preparation of Bosentan tartarate.
Bosentan 1.0g  0.0018mol and tartaric acid 0.27g  0.0018mol were taken in mixture of acetonitrile 4mL and stirred at ambient temperatures for 8h and 8ml of diisopropyl ethyer was added. The reaction mixture was stirred for 30min and the solid was filtered and washed with di isopropyl ether 2.0 mL to get 99.0% pure material and further purified using ethylacetate acetonitrile and Diisopropyl ether mixture. Bosentan citrate having the X-ray diffraction pattern with peaks at 3.416  6.799  8.933  9.260  9.845  10.639  11.564  14.224  15.461  16.194  16.882  17.618  17.843  18.266  18.456  19.421  20.140  20.594  21.420  22.463  23.338  23.830  24.567  25.063  26.500  27.802  29.161  29.677  31.528  31.998  33.435  36.137  36.644  37.486  39.437  42.596  45.021  46.681  47.031  47.730  49.188  51.536  57.573  59.858 ± 0.2 degrees two theta values.
Example 7: Preparation of Bosentan Base
Bosentan citrate 1.0g  0.00134mol and methylene di chloride 8ml were taken in water 8ml and the pH was adjusted to 8 using 1% sodium bicarbonate solution. The mass was stirred at an ambient temperature for 1h and separated.

We claim :
1. Acid addition salts of Bosentan.
2. The Bosentan acid addition salt according to claim 1  wherein said acid has a pKa higher than 3.
3. The Bosentan acid addition salt according to claim 1  wherein said salts are in solid form.
4. The Bosentan acid addition salt according to claim 3  wherein said salts are in crystalline form.
5. The Bosentan acid addition salt according to claim 1  wherein said acid addition salt is selected from Bosentan citrate and Bosentan tartarate.
6. The Bosentan acid addition salt according to claim 5  wherein said salt is selected from crystalline Bosentan citrate and crystalline Bosentan tartarate.
7. A method of making an acid addition salt of Bosentan  which comprises: a) combining Bosentan base and an acid having a pKa higher than 3 in an organic solvent to form a solution; b) precipitating a Bosentan acid addition salt from said solution and c) isolating the precipitated Bosentan acid addition salt.
8. The method according to claim 7  wherein said acid is selected from the group of citric acid and tartaric acid.
9. The method according to claim 7  wherein said organic solvent is selected from the group consisting of ketones  chlorinated hydrocarbons  hydrocarbons  alcohols  esters; aliphatic nitriles; ethers and mixtures thereof.
10. The method according to claim 9  wherein said organic solvent is selected from the group consisting of acetone  methyl tert.butyl ketone  dichloromethane  methanol  ethanol  isopropanol  ethyl acetate  butyl acetate  acetonitrile  di-isopropyl ether  methyl tertiary butyl ether tetrahydrofuran  and mixtures thereof.
11. A method of purifying Bosentan  which comprises: a) preparation of an acid addition salt of Bosentan by following any method discussed in earlier claims  b) isolation of said acid addition salt of Bosentan from organic solvent c) optionally re crystallizing by using an organic solvent d) converting Bosentan acid addition salt into Bosentan base and e) isolation of Bosentan base.
12. According to claim 11  wherein Bosentan base is amorphous in nature.
13. The method according to claim 12  wherein said organic solvent is selected from the group consisting of ketones  chlorinated hydrocarbons  hydrocarbons  alcohols  esters  aliphatic nitrites  ethers and mixtures thereof.
14. According to claim 13  wherein said organic solvent is selected from the group consisting of acetone  methyl tert.butyl ketone  dichloromethane  methanol  ethanol  isopropanol  ethyl acetate  butyl acetate  acetonitrile  di-isopropyl ether  methyl tertiary butyl ether tetrahydrofuran  and mixtures thereof.
15. The method according to claim 11  wherein said converting step comprises contacting said Bosentan acid addition salt with an organic or inorganic base in organic solvent.
16. The method according to claim 11  which further comprises recrystallizing said isolated acid addition salt of Bosentan prior to said converting step.
17. A process which comprises dissolving a solid Bosentan acid addition salt according to claim 12 in an organic solvent  and precipitating said salt to obtain a purified solid Bosentan acid addition salt.
18. Bosentan citrate salt.
19. Bosentan tartarate salt.