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 N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of Sodium tert-butoxide as base and 1,2-Dimethoxy ethane as a solvent to obtain crude Macitentan; and
b) recrystallizing the crude Macitentan in mixture of Isopropyl acetate and Methanol; and
c) further recrystallizing in Methanol to obtain pure Macitentan.

2. The process as claimed in claim 1, wherein the reaction of step a) is conducted at 0° C to room temperature.
3. The process as claimed in claim 1, wherein the ratio of Sodium tert-butoxide and N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide is 1:1by weight.
4. The process as claimed in claim 1, wherein the recrystallization of the Macitentan in step (b) is performed at a temperature in the range of 65 to 70°C.
5. The process as claimed in claim 1, wherein the recrystallization of the Macitentan in step (c) is performed at a temperature in the range of 60 to 70°C.
6. The process as claimed in claim 1, wherein the Isopropyl acetate and Methanol is used in a ratio of 1:1
, Description:FIELD OF INVENTION:
The present invention relates to an improved and industrially feasible process for synthesis of Macitentan 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.

US2016/0052891discloses 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 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 according to the scheme 1 comprises adding the 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. It is difficult to handle sodium hydride in large quantities on industrial scale as it involves risk of fire and hence the process disclosed by Bolli et.al is not feasible for the industrial production. Moreover, when sodium hydride is used; the present inventors have observed incomplete reaction.

6404/CHE/2015 discloses process for the preparation of Macitentan, wherein, the reaction of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of a base selected from the group consisting of alkali metal amides, alkali metal oxide bases, and mixtures thereof. Use of Sodamide as a base for industrial production of Macitentan also involves risk of fire and hence difficult to employ for industrial production.

IN368066 granted to the current applicant discloses reaction of 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 a solvent mixture of toluene and THF to obtain Macitentan.

642/MUM/2015 discloses reaction of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of Sodium tert-butoxide and THF to obtain Macitentan. 3266/MUM/2015 discloses reaction of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of Sodium tert-butoxide and 2-methyl THF to obtain Macitentan. However, both these processes results in low yield and necessitates multiple extractions to isolate the crude product and further requires additional purification steps, as the solvents, viz., THF and 2-methyl THF do not give clean reaction.

On analysing the above patents/patent applications and while scouting for suitable reaction conditions for the production of Macitentan in high purity and yield the present inventors have found that a judicial selection of an organic solvent along with metal alcoholate with a counter ion having high proton affinity can effectively give clean reaction.

Accordingly, it is an objective of the present invention to provide a judicial combination of suitable organic solvent and a strong organic base for the synthesis of Macitentan, to facilitate easy separation of Macitentan in high yield and purity.
SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides an improved, industrially feasible process for preparation of Macitentan comprising;
a) Reacting N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of Sodium tert-butoxide as base and 1,2-Dimethoxy ethane as a solvent to obtain crude Macitentan;
b) recrystallizing the crude Macitentan in mixture of Isopropyl acetate and Methanol; and
c) further recrystallizing in Methanol 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, obtained by example 1.

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-butoxide and counter ion having high proton affinity. Sodium tert–butoxide has low hydroxyl content and is soluble in in non-polar solvent, viz., 1,2-Dimethoxy ethane. The solubility of Sodium tert–butoxide in 1,2-Dimethoxy ethane is a distinct advantage of this alkoxide base. The deprotonation reaction can be performed without changing the solvent thus making the process economical and industrially feasible. Additionally, the process results in crude Macitentan with high yield.

In line with the above, the present invention provides an improved, industrially feasible process for preparation of Macitentan comprising;
a) Reacting N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propyl sulfamide with 5-Bromo-2-chloro pyrimidine in presence of Sodium tert-butoxide as base and 1,2-Dimethoxy ethane as a solvent to obtain crude Macitentan;
b) recrystallizing the crude Macitentan in mixture of Isopropyl acetate and Methanol; and
c) further recrystallizing in Methanol to obtain pure Macitentan.
In an embodiment, the invention provides a process for synthesis of Macitentan which process comprises reaction of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide with 5-Bromo-2-chloro pyrimidine in presence of Sodium ter-butoxide in 1, 2 dimethoxy ethane, as a non-polar solvent to obtain N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N′-propylsulfamide.

Accordingly, N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide was taken in 1, 2 dimethoxy ethane and cooled to ~0° C. Sodium tertiary butoxide was added followed by 5-Bromo-2-chloro pyrimidine dissolved in 1,2-Dimethoxy ethane under stirring at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, citric acid was added into reaction mixture to precipitate the product. The 1,2 dimethoxy ethane solvent was distilled under reduced pressure and then the reaction mixture was diluted with water and obtained crude solid was collected by filtration.
The ratio of Sodium tert-butoxide and N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide may be taken preferably in 1:1 by weight.
The recrystallization of the Macitentan in mixture of Isopropyl acetate and Methanol is performed at a temperature in the range of 65 to 70°C.

The recrystallization of the Macitentan in Methanol is performed at a temperature in the range of 60 to 70°C.

The Isopropyl acetate and Methanol can be used in a ratio of 1: 3; preferably in a ratio of 1: 2. More preferably, Isopropyl acetate and Methanol was used in a ratio of 1: 1.

The inventive step of the reaction lies in the use of judicial combination of organic base and non-polar solvent, i.e., Sodium tertiary butoxide and 1, 2 dimethoxy ethane (DME). Use of DME solvent facilitates maximum conversion of starting material, i.e. N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide with the remaining starting material in the range of below 0.5 to 1%. Additional advantage is that the reaction is very fast and completes within 30 min to 1Hr.

In reported literature, it is observed that multiple purifications using Ethyl acetate are carried out to reach API grade material when 2-Methyl THF as solvent was used for the reaction.

The present inventors have also observed considerable amount of unreacted starting material when the reaction was carried out in in different solvents for longer time at room temperature. However, an instantons reaction observed when 1,2-dimethoxy ethane was used as solvent. As the most of the starting material consumed during reaction, multiple purification are not need to reach API grade purity. Details of these reactions are given in the table below.

Sr. No. Solvent Base Reaction temperature Reaction time Isolated yield Purity
1 2-Methy THF Sod. Tert. butoxide Room temperature 2-3Hrs 56% 98.34%
2 THF Sod. Tert. butoxide Room temperature Overnight Lot of unreacted SM seen on TLC. Not isolated
3 DMF Sod. Tert. butoxide Room temperature 6-7Hrs Lot of unreacted SM seen on TLC. Not isolated
4 1,4-dioxane Sod. Tert. butoxide Room temperature 6-7Hrs Lot of unreacted SM seen on TLC. Not isolated
5 Cyclopentyl methyl ether Sod. Tert. butoxide Room temperature 4-5Hrs No reaction observed.
6 1,2-dimethoxy Ethane Sod. Tert. butoxide Room temperature 30 min 52% 99.62%
7 1,2-dimethoxy Ethane Sod. Tert. butoxide 0 degree 30 min 78% 99.87%

Also use of reported solvents for recrystallization of Macitentan required multiple purifications either with Methanol or with some other solvents to get API grade material. However, the combination of Isopropyl acetate and Methanol results in API grade Macitentan without going for multiple re-crystallizations, as demonstrated in examples 1 and 2. However, recrystallization with Methanol is required to remove residual solvents in the API.

The use of combination of Sodium tertiary butoxide and 1, 2 dimethoxy ethane(DME) reduces the dependency of solvent extraction of the crude Macitentan obtained by the condensation of N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide and 5-Bromo-2-chloro pyrimidine. The crude Macitentan can be directly precipitated by the addition of Citric acid, as demonstrated in example 1 and 2. The use of this combination of Sodium tertiary butoxide and 1, 2 dimethoxy ethane not only reduces the additional cost involved in the use of solvents for the extraction of the product but also additional labour and time involved in the production of Macitentan.

Since the DME facilitates maximum conversion of starting material, i.e. N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide in 30 mins to 1 hr; the API grade product can be achieved very easily by simple crystallizations as demonstrated in examples 1 and 2.

In another process variant, the crude Macitentan was precipitated by the addition of citric acid can also extracted into a solvent for example, Ethyl acetate; evaporated the solvent and recrystallised the crude using a mixture of Isopropyl acetate and Methanol; followed by recrystallization from Methanol.

The synthetic process for the preparation of Macitentan is shown in below scheme.

In another embodiment, the crude Macitentan thus obtained was recrystallised by dissolving in a mixture of Isopropyl acetate and Methanol at a temperature of 60 to 70°C, allowed to cool to about 10°C, filtered and washed with Methanol.

The Isopropyl acetate and Methanol was used in a ratio of 1: 3; preferably in a ratio of 1: 2. More preferably, Isopropyl acetate and Methanol was used in a ratio of 1: 1.

In yet another embodiment, the Macitentan thus obtained was again recrystallised by dissolving only in Methanol, at a temperature of 60-65°C followed by cooling to 10°C, filtering, washing and drying to obtain crystalline solid of Macitentan with a purity of more than 99.5%. The PXRD of the Macitentan thus obtained exhibits peaks that matches with polymorphic Form I, as shown in figure 1.

The base, Sodium tert-butoxide is used in an amount although not limited to, equal or greater than molar equivalents relative to N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide and upto 3 to 4 equivalents. More preferably, sodium tert-butoxide and N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide are preferably used in a ratio of 1:1 by weight.

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-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N′-propylsulfamide
Without solvent extraction:
1,2-Dimethoxy ethane (200ml) and N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide (20g) were cooled to ~0° C. Sodium tertiary butoxide (20gm) was added followed by 22.4gm of 5-Bromo-2-chloro pyrimidine dissolved in 1,2-Dimethoxy ethane (100ml) under stirring at room temperature for 30 mins. The progress of the reaction was monitored by TLC (starting material is --absent) and after completion of the reaction, Citric acid (20g) was charged in to reaction mixture and the solvent distilled off. The reaction mixture was diluted with water (200ml) and crude solid (~30gm) obtained was collected by filtration.

A) Recrystallisation from Isopropyl acetate and Methanol:

The crude (~30mg) thus obtained, was dissolved in solvent mixture of Isopropyl acetate (60ml) and Methanol (60ml) followed by heating to a temperature of 65-70°C till complete dissolution is achieved. The solution was cooled to RT, further cooled to 10°C, filtered and washed with Methanol to obtain Macitentan 23gm.
Purity: by HPLC = 99.76%

B) Recrystallisation from Methanol :
The Macitenten (23gm) was taken in Methanol (360 mL), heated to 55-60°C and stirred for 1h, allowed to cool to RT, further cooled to 10°C, filtered, to yield 21.2g of crystalline Macitenten.
Overall yield = 21.2g (78%)
Purity = more than 99.87% by HPLC.

The crystalline solid thus obtained was subjected to PXRD and found from the XRD pattern that the crystal form of the material obtained according to the process matches with Form I disclosed in WO2014/173805.

Example 2:
Preparation of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]-N′-propylsulfamide
With solvent extraction:
1,2-Dimethoxy ethane (50ml) and N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-N′-propylsulfamide (5g) were cooled to ~0° C. Sodium tertiary butoxide (5gm) was added followed by 22.4gm of 5-Bromo-2-chloro pyrimidine dissolved in 1,2-Dimethoxy ethane (25ml) under stirring at room temperature for -30 mins. Progress of the reaction monitored by TLC (starting material absent) and after completion of the reaction, Citric acid (5g) solution was charged into reaction mixture and the solvent was distilled off. The reaction mixture was diluted with water (50ml) and extracted into Ethyl acetate (15mlx3) and distilled the Ethyl acetate solvent, to obtain crude Mecitentan.

A) Recrystallisation from Isopropyl acetate and Methanol:

The crude thus obtained, was dissolved in solvent mixture of Isopropyl acetate (15ml) and Methanol (15ml) followed by heating to a temperature of 65-70°C till complete dissolution is achieved. The solution was cooled to RT, further cooled to 10°C, filtered and washed with Methanol to obtain Macitentan 5gm.

Purity: 99.86% by HPLC

B) Recrystallisation from Methanol:

The Macitentan (5gm) was taken in Methanol (90 mL), heated to 60-65°C and stirred for 1h, allowed to cool to RT, further cooled to 10°C, filtered, washed with Methanol to yield 4.6 g of crystalline Macitentan. The methanol purification eliminate residual solvents, if any and bring them within applicable limits.

Overall yield = 68%
Purity = more than 99.86% by HPLC.
The crystalline solid thus obtained was subjected to PXRD and found from the XRD pattern that the crystal form of the material obtained according to the process matches with Form I disclosed in 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.