DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of macitentan of formula I

formula I

BACKGROUND OF THE INVENTION
Macitentan (chemical names: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl] -N'-propylsulfamide or N-[5-(4-bromophenyl)- 6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]-N'-propylsulfuric diamide) is an endothelin receptor antagonist that has notably been approved by the US Food and Drug Administration and the European Commission for the treatment of pulmonary arterial hypertension. The last step of its two potential preparation routes described in WO 02/053557, called "Possibility A" and "Possibility B", can be summarized as shown in Scheme Al hereafter.

Scheme Al
In Scheme Al, G1 represents a reactive residue, and preferentially a chloro atom.
The preparation of macitentan according to "Possibility B" of WO 02/053557 has furthermore been described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861.
Accordingly: KOtBu was added to a solution of ethylene glycol in dimethoxyethane and the compound of formula 1-1 wherein G1 is CI (see Scheme Al above) was added thereto; after heating at 100°C for 70 h, work-up involving extraction and purification by column chromatography, the compound of formula 1-3 was obtained in a 86% yield; and the compound of formula 1-3 was added to a suspension of NaH in THF, the mixture was stirred and diluted with DMF before 5-bromo-2-chloropyrimidine was added; after heating at 60°C and work-up involving extraction and crystallisation steps, macitentan was obtained in a 88% yield.
As an alternative to the first step of the method described by Bolli et al., the compound of formula I- 1 wherein G1 is CI could be mixed with an excess of ethylene glycol (about 30-50 equivalents), an excess of tBuOK (3-4 equivalents) could be added and the resulting mixture could be heated to 100°C. After addition of water and MeOH and pH adjustment with HC1, the compound of formula 1-3 could then be filtered off and obtained, after drying under vacuum, in an about 85% yield.
The methods for manufacturing macitentan described above are however not appropriate for manufacturing macitentan in a sufficient purity unless numerous purification steps are undertaken to remove the impurities from the compound of formula 1-3 before performing the step corresponding to "Possibility B" of WO 02/053557. In this regard, it should be mentioned that ethylene glycol is actually toxic and rather difficult to remove by distillation due to a high boiling point.
However, the known synthesis routes may not be readily adapted for use on an industrial scale. Present inventors have focused on the problems associated with the prior art process and have developed improved process for the preparation of macitentan of formula I to achieve high purity.

SUMMARY OF THE INVENTION
In one aspect of the present invention encompasses an improved process for the preparation of macitentan or its pharmaceutically acceptable salts of formula I.

formula I
In another aspect of the present invention encompasses a purification process for the N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.
In another aspect of the present invention encompasses an improved process for the preparation of compound of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide free of N-[5-(4-bromophenyl)-6-hydroxypyrimidin-4-yl]-N'-propylsulfuric diamide.
In another aspect of the present invention encompasses crystalline sodium salt of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.
In another aspect of the present invention encompasses crystalline cesium salt of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.
In another aspect of the present invention is to provide a process which gives macitentan or its pharmaceutically acceptable salts with high purity.
In another aspect of the present invention is to provide a process which is operationally simple and cost effective.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: shows the X-ray powder diffraction pattern of sodium salt of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.
Figure-2: shows the X-ray powder diffraction pattern of cesium salt of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.
Figure-3: shows the DSC pattern of sodium salt of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention encompasses an improved process for the preparation of macitentan or its pharmaceutically acceptable salts of formula I.

formula I
In another embodiment of the present invention encompasses an improved process for the preparation of macitentan or its pharmaceutically acceptable salts of formula I comprising the steps of;
a. condensing 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula II with N-propylsulfuric diamide or a salt in the presence of suitable base and suitable solvent to obtain N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III;
b. condensing N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III with ethylene glycol in the presence of suitable base and suitable solvent or optionally without solvent to obtain compound of formula IV;
c. treating the compound of formula IV with suitable acid and suitable solvent to obtain N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide;
d. condensing N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide with 5-bromo-2-chloropyrimidine in the presence of suitable base and suitable solvent to obtain macitentan.
In another embodiment of the present invention encompasses an improved process for the preparation of macitentan or its pharmaceutically acceptable salts of formula I comprising the steps of;
a. condensing 5-(4-bromophenyl)-4,6-dichloropyrimidine of formula II with N-propylsulfuric diamide or a salt in the presence of potassium carbonate and DMSO to obtain N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III;
b. condensing N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III with ethylene glycol in the presence of sodium tert-butoxide and DMSO or optionally without solvent to obtain compound of formula IV;
c. treating the compound of formula IV with citric acid and suitable solvent to obtain N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide;
d. condensing N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide with 5-bromo-2-chloropyrimidine in the presence of sodium tert-butoxide and THF to obtain macitentan.
In another embodiment of the present invention encompasses purification of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide comprising the steps of;
a. condensing N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III with ethylene glycol in the presence of base and solvent or optionally without solvent to obtain compound of formula IV;
b. purification of compound of formula IV optionally by recrystallisation;
c. Isolating compound of formula IV in the form of salt or free base.
In another embodiment of the present invention encompasses purification of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide comprising the steps of;
a. condensing N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III with ethylene glycol in the presence of sodium tert-butoxide and DMSO or optionally without solvent to obtain compound of formula IV;
b. purification of compound of formula IV optionally by recrystallisation;
c. Isolating compound of formula IV in the form of salt or free base.
In another embodiment of the present invention encompasses an improved process for the preparation of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide free of N-[5-(4-bromophenyl)-6-hydroxypyrimidin-4-yl]-N'-propylsulfuric diamide.
In another embodiment of the present invention encompasses novel intermediate of compound of formula IV and its use in the preparation of macitentan. Wherein X is alkali metal comprising lithium, cesium, sodium, ammonium and potassium.

formula IV
In another embodiment of the present invention encompasses crystalline sodium salt of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide characterized by X-ray powder diffraction pattern as shown in Figure-1.
In another embodiment of the present invention encompasses crystalline cesium salt of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide characterized by X-ray powder diffraction pattern as shown in Figure-2.
In another embodiment of the present invention encompasses crystalline sodium salt of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide characterized by DSC pattern as shown in Figure-3.
In another embodiment of the present invention is to provide a process which gives macitentan with high purity.

The present invention is depicted in the scheme as below:

The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alcohols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The solvent may be selected from the group consisting of water, alcohols, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alcohols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
Suitable alcohol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. A solvent may preferably be a mixture of water with alcohol, for example, a mixture of water with methanol, ethanol, or 2-propanol.
Suitable base includes but not limited to an inorganic base or organic base selected from the group comprising of carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals and the like, phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; n-butyllithium, n-hexyllithium, sodium hydride and , HMDS, lithium diisopropylamide. These inorganic bases may be used singly, or in combination of two or more kinds thereof. The organic base is selected from the group comprising of lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metal alcoholates such as sodium methoxide and sodium ethoxide. Other bases are known to the person skilled in the art.
Suitable acids includes but not limited to hydrochloric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, formic acid, lactic acid, oxalic acid, tartaric acid, methanesulfonic acid and other acids that are known to the person skilled in the art.
In the following section, embodiments are described by way of examples to illustrate the process of invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Examples
Example-1
Preparation of N-[5-(4-bromophenyl)-6-chloropyrimidin-4-yl]-N'-propylsulfuric diamide
A mixture of 5-(4-bromophenyl)-4, 6-dichloropyrimidine(100 gm, 0.3289 mole), N,N-Dimethylformamide(300 ml), potassium carbonate(113.66 gm, 0.8224 mole) and N-propylsulfuric diamide(54.55 gm, 0.3947 mole) was heated at 105-110 °C. The reaction mixture was cooled at 25-30°C; water (1500 ml) was added and pH was adjusted to acidic with solution of Citric acid (150 gm) into process water (240 ml) at 25-30°C. Solid was separated, filtered, washed with water(200 ml) and was purified using ethyl acetate(600 ml) to obtain N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide(80gm,60-70%).

Example-2
Preparation of N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy) pyrimidin-4-yl]-N'-propylsulfuric diamide
A mixture of N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (100.0 gm, 0.2464 mole), monoethylene glycol (700 ml) and sodium tert-butoxide (118.44 gm, 1.2324 mole) was heated up to 105-110°C. The reaction mixture was cooled at 25-30°C; water (700 ml) was added and stirred for 2 hours at 25-30°C. Solid was separated, cooled at 10-15°C and pH was adjusted to acidic with solution of Citric acid (80 gm) into process water (200 ml) at 10-15°C. N-Butyl acetate (600 ml) was added to the reaction mass at 25-30°C. The reaction mass was heated to 60-65°C, stirred for 1 hour and cooled 25-30°C. The solid was filtered and washed with N-Butyl acetate (50 ml) to obtain N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (65.0-75.0 gm, 83.3-91.6%).

Example-3
Preparation of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl) oxy] ethoxy]-4-pyrimidinyl]-N'-propylsulfamide) (Macitentan)
N-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-N'-propylsulfuric diamide (100.0 gm, 0.2318 mole) and tetrahydrofuran (1000 ml) was added to the reaction mixture at 25-30oC. Sodium tert-butoxide (111.40gm, 1.1592 mole) and 5-bromo-2-chloropyrimidine (98.66gm, 0.5100 mole) in THF (200 ml) was added to the reaction mixture at 0-5°C. Solid was separated, cooled at 10-15°C and pH was adjusted to acidic with solution of Citric acid (80 gm) into process water (200 ml) at 5-15°C. Methanol (400 ml) was added to the reaction mass at 60-65oC and Ethyl acetate (200 ml) was added to obtain the clear solution. The reaction mixture was cooled at 25-30°C, dried to obtain N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl) oxy] ethoxy]-4-pyrimidinyl]-N'-propylsulfamide) (Macitentan) (85-95 gm, 62.5-69.8%).
,CLAIMS:Claims
1. A process for the preparation of macitentan or its pharmaceutically acceptable salts of formula I comprising the steps of;

formula I
a. condensing a compound of formula II with N-propylsulfuric diamide or a salt in the presence of potassium carbonate and DMF to obtain a compound of formula III;
b. condensing a compound of formula III with ethylene glycol in the presence of sodium tert-butoxide and DMSO or optionally without solvent to obtain compound of formula IV;
c. treating the compound of formula IV with citric acid and suitable solvent to obtain N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide;
d. condensing N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide with 5-bromo-2-chloropyrimidine in the presence of sodium tert-butoxide and THF to obtain macitentan or its pharmaceutically acceptable salts.

2. A process for the preparation of macitentan or its pharmaceutically acceptable salts comprising the steps of;
a. condensing a compound of formula II with N-propylsulfuric diamide or a salt in the presence of suitable base and suitable solvent to obtain a compound of formula III;
b. converting the compound of formula III in to macitentan or its pharmaceutically acceptable salts thereof.

3. A process for the purification of N-5-(4-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide comprising the steps of;
a. condensing N-5-(4-bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide of formula III with ethylene glycol in the presence of suitable base and suitable solvent or optionally without solvent to obtain compound of formula IV;
b. purification of compound of formula IV optionally by recrystallisation;
c. Isolating compound of formula IV in the form of salt or free base;
d. converting the compound of formula IV in to macitentan or its pharmaceutically acceptable salts thereof.

4. A compound of formula IV and its use in the preparation of macitentan or a pharmaceutically acceptable salts of formula I, wherein X is alkali metal comprising lithium, cesium, sodium, ammonium and potassium.

formula IV

5. A process for the preparation of macitentan or a pharmaceutically acceptable salts free of N-[5-(4-bromophenyl)-6-hydroxypyrimidin-4-yl]-N'-propylsulfuric diamide.

6. The process according to claim 1, 2 and 3 wherein the suitable base is selected from carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals, phosphates, acetates, formates, n-butyllithium, n-hexyllithium, sodium hydride, HMDS, lithium diisopropylamide, lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-diethylaniline, N- ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8-diazabicyclo[5.4.0]- 7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metal alcoholates.

7. The process according to claim 1, 2 and 3 wherein the suitable solvent is selected from water, esters, alcohols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, halogenated hydrocarbons or mixtures thereof.

8. The process according to claim 7, wherein the solvent is selected from methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG ,butanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, and 1,2-dichloroethane.

Dated this 16th day of Feb, 2016

Ananda Babu Thirunavakarasu