Claims:1. An improved process for preparing Macitentan, N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide comprising;
a. Reacting 5-(4-bromophenyl)-4,6-dichloropyrimidine with N-propylsulfamide and sodium tert- pentoxide in DMSO at a temperature in the range of 10-50°C; isolating the product N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide at acidic pH and recrystallizing the product using IPA;

b. Converting N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propyl sulfamide to N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide using ethylene glycol dissolved in toluene and excess of sodium tert-pentoxide at a temperature in the range of 95-100°C and purifying the product using IPA;

c. Reacting N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of sodium tert-pentoxide and solvent mixture of toluene and THF to obtain crude Macitentan; and

d. Slurrying crude Macitentan in mixture of solvents and recrystallizing the product using methanol to obtain pure Macitentan.

2. The process as claimed in claim 1, wherein the pH in step (a) is in the range of 3.0-3.5.

3. The process as claimed in claim 1, wherein 3-4 equivalence of the base sodium tert-pentoxide is used in step (b).

4. The process as claimed in claim 1, wherein the recrystallization of the products in step (a) and step (b) is performed at a temperature in the range of 50-80?C.

5. The process as claimed in claim 1, wherein the solvents used in step (d) selected from polar protic or aprotic solvents such as C1 to C5 alcohols, esters, ethers either alone or mixtures thereof.
, Description:FIELD OF INVENTION:
The present invention relates to an improved and industrially feasible process for synthesis of Macitentan and its intermediates thereof in good yield and purity.

BACKGROUND OF THE INVENTION:
Macitentan which is chemically known as N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]-N'-propylsulfamide is an endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension.

Macitentan has been first disclosed in WO02/053557. According to the synthetic procedure disclosed in WO02/053557 as ‘Possibility B’ the compound of Formula-1 is reacted with a compound of Formula -2 as shown below to obtain Macitentan.

The preparation of Macitentan according to ‘Possibility B’ of WO’557 has been further described in article by Bolli et.al in J. Med. Chem, 2012, 55(17) pp7849-7861. The process is shown in Scheme -1 below:

According to Scheme-1, dichloropyrimidine compound (1) is reacted with a sulfamide potassium salt in DMSO at room temperature for 24-48 hr to give monochloro-pyrimidine intermediate (2). The ethylene glycol side chain is introduced by adding compound (2) to a mixture of potassium tert-butylate (3equiv) and ethylene glycol (40equiv) in dimethoxymethane and heating the mixture to a temperature in the range of 90-100°C for 24-70 hours to yield the corresponding compound (3). The last step comprises adding compound (3) to a suspension of sodium hydride in THF, stirring the mixture and diluting with DMF before addition of 5-bromo-2-chloropyrimidine. The mixture is heated to 60°C and the work up involves extraction and crystallization steps to yield Macitentan.

US2016/0052891disclsoes preparation of intermediate compound of Formula I-3 by reacting compound of Formula I-1, wherein the variable G1represents halogen, with 2-(tert-butoxy) ethanol in presence of a base at 25-140°C to obtain compound of Formula I-2 which is deprotected using TiCl4 in aprotic solvent or mixture of aprotic solvent to obtain compound of Formula I-3. The compound of Formula I-3 is further treated with 5-bromo-2-chloropyrimidine to obtain Macitentan. The process is given below in Scheme -2. The process for preparation of compound of Formula I-3 involves additional step of protection and deprotection using Lewis acid to remove the tert-butyl group.

Scheme-2
The present inventors observed that the reactivity of the compounds described by Bolli et.al can further be fine-tuned to the desired reaction by choosing appropriate metal alcoholate and counter ion having high proton affinity. The choice of suitable strong organic base is the objective of the invention which results in optimizing the reaction conditions and improving the yield and purity of the desired product.

SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides an improved, industrially feasible process for preparation of Macitentan comprising the following steps:
a. Reacting 5-(4-bromophenyl)-4,6-dichloropyrimidine with N-propylsulfamide and sodium tert-pentoxide in polar organic solvent at a temperature in the range of 10-50°C; isolating the product N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide at acidic pH and recrystallizing from solvent;
b. Converting N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide to N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide using ethylene glycol dissolved in non- polar solvent and sodium tert-pentoxide as a base at a temperature in the range of 95-100°C and purifying the product;
c. Reacting N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of sodium tert-pentoxide as base and a solvent to obtain crude Macitentan; and
d. slurrying crude Macitentan in mixture of solvents followed by recrystallization using lower alcohols to obtain pure Macitentan.

DESCRIPTION OF THE FIGURES:
Fig 1 depict the PXRD data of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide i.e. Macitentan.

DETAILED DESCRIPTION OF THE INVENTION:
The various embodiments of the present invention which follow herein relate to an improved and industrially feasible process for synthesis of Macitentan, wherein, the process alleviates the shortcomings of the prior art processes in terms of cost, yield and purity.

The objectives are met in the present invention by using a strong organic base sodium tert-pentoxide and counter ion having high proton affinity. Sodium tert–pentoxide has low hydroxyl content and is soluble in hexane, toluene, cyclohexane, diglyme and tetrahydrofuran. The solubility of sodium tert–pentoxide in non-polar solvent is a distinct advantage of this alkoxide base. The deprotonation reaction can be performed in non-polar solvents such as toluene without changing the solvent thus making the process economical and industrially feasible.

In an embodiment, the process comprises conversion of 5-(4-bromophenyl)-4,6-dichloropyrimidine to N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide. Accordingly, n-propyl sulfamide which is used as starting material is dissolved in polar solvent and cooled to a temperature of 5-10°C. To the solution of n-propyl sulfamide was added sodium tert-pentoxide portion wise at the same temperature and the temperature was then raised to 30-50°C and maintained for about 30 mins with constant stirring. 5-(4-bromophenyl)-4,6-dichloropyrimidine was then added dropwise, the reaction mixture was cooled to 0°C and diluted with water. The product N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide was isolated at acidic pH, preferably in the pH range of 3-3.5 by addition of citric acid. The solid obtained was filtered and recrystallized using a polar organic solvent at reflux temperature to obtain pure N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide.

In another embodiment of the present process the conversion of N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide to N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide was carried using ethylene glycol in presence of excess sodium tert-pentoxide as base.

The base used is equal to 3-4 equivalence. Accordingly, to the solution of ethylene glycol in non-polar solvent was added sodium tert-pentoxide at room temperature followed by addition of N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide. The mixture was heated to a temperature in the range of 90-100°C with stirring for 30-40 hours. The reaction mixture was cooled to room temperature, citric acid followed by water was added and the mixture was stirred for another 10-20 minutes until precipitation of the solid. The solid was then filtered and purified using 2 to 8 volumes of organic solvent selected from C1 to C5 alcohols at a temperature in the range of 50-55°C to yield pure N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide.

The further embodiment comprises conversion of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide to N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide.

Accordingly, 5-Bromo-2-chloro pyrimidine dissolved in organic solvent was added to a solution of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide and sodium tert- pentoxide at RT, over a period of 10 min. The reaction mixture was stirred at RT for about 2 hrs. The reaction mixture was poured slowly over a dilute solution of citric acid and the product N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide was extracted in an organic solvent. The aqueous layer after separation was again extracted with the solvent and the combined organic layers were washed with water and concentrated to obtain crude N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide, i.e. Macitentan.

The crude solid obtained was further slurred in organic solvent(s) either alone or mixtures thereof at a temperature in the range of 50-60°C, allowed to cool to about 10°C, filtered, the washings with organic solvent was repeated at same temperature and the product obtained was filtered, dried to obtain the product N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide.

The product was recrystallized by heating the solution of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide in C1 to C5 alcohol at temperature in the range of 50-60°C followed by cooling to 10°C, filtering, washing and drying to obtain pure product.

The solvents used in the process steps includes, but not limited to, polar protic or aprotic solvents such as C1 to C5 alcohols, THF, ethyl acetate, isobutyl acetate, acetone, DMF, DMSO or non-polar solvents such as n-pentane, n-hexane, toluene, xylene, 1,4 dioxane or diethyl ether either alone or mixtures thereof.

The base preferably used in the present invention is sodium tert-pentoxide and is used in an amount although not limited to, equal or greater than molar equivalents relative to the starting material up to 3-4 equivalents.

The following examples, which include preferred embodiments, are intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Example 1: Preparation of N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (step 1)
N-Propylsulfamide (9.98 g) was taken in DMSO (60 mL) and cooled to 10°C. Sodium tert-pentoxide (7.96 g) was added portion wise to the above contents at 10-20°C and stirred at room temperature for 30min. 5-(4-bromophenyl)-4,6-dichloropyrimidine (10.0 g) in DMSO (20 mL) was added drop wise. The reaction mixture was further stirred at RT for 2 hr. The reaction mixture was cooled to 0°C and acidified using citric acid followed by water, pH 3.0-3.5 and obtained solid was collected by filtration. The solid was recrystallized with IPA (80 mL) to yield (11.42 g) of N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide with 85.73% yield and 99.61% purity.

Example 2: Preparation of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (step 2)
Sodium tert-pentoxide (4.42 g) was added to Ethylene glycol (24 mL) in Toluene (9.6 mL). N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N'-propylsulfamide (4.8 g) was added and stirred at 95-100°C for 36h. The reaction mixture was brought to RT, citric acid (4.8 g) followed by water (48 mL) were added and stirred for 15min. Solid was collected by filtration. The solid was purified using IPA (19.2 mL) at 50-55°C to yield N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide with 85% yield and 98.57% purity.

Example 3: Preparation of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (step 3)
5-Bromo-2-chloro pyrimidine (7.17 g) in THF (20 mL) was added to a solution of Sodium tert-pentoxide (9.7g) and N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N'-propylsulfamide (10g) in THF (100 mL) at RT over a period of 10 min. The reaction mixture was stirred at RT for 2h. The reaction mixture was poured slowly over a dilute solution of citric acid. N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N'-propylsulfamide was extracted twice with Toluene (20mL). Combined organic layers were washed with water (50 mL) and concentrated.

The crude solid (11.8 g) was taken in Methanol (118 mL), heated to 55-60°C and stirred for 1h, allowed to cool to RT, further cooled to 10°C, filtered, washed with Methanol (10 mL) to yield 10.8 g of product.

Recrystallization using Methanol
5g of crude material was dissolved in 100mL of Methanol at 60-65°C and stirred for 2h.The obtained solution was allowed to cool to 25- 30°C and the crystals formed was filtered and dried. The isolated product was with >99.8% purity. The crystalline Macitentan free base shows PXRD pattern (Fig 1) matching with the PXRD of Macitentan (Form I) of WO2014/173805.

The entire scope of this invention is not limited by the specific examples described herein, but is more readily understood with reference to appended claims.