FIELD OF THE INVENTION
The present invention relates to novel and improved process for the preparation of Macitentan and its intermediates.
The present invention further relates to an improved process for the preparation of Macitentan which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Macitentan is an endothelin receptor antagonist. The chemical name of Macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl sulfamide. Macitentan is achiral and has the following structural formula:
i
The empirical formula is Ci9H2oBr2Ne04S and a molecular weight of 588.27. Macitentan is a crystalline powder that is insoluble in water. In the solid state Macitentan is very stable, is not hygroscopic, and is not light sensitive.
Macitentan is first disclosed in US 7,094,781 B2 and the process for the preparation is specifically disclosed in J. Med. Chem., 2012, 55(17), pp 7849-7861. According to this paper crystalline form of Macitentan free base melts at the range of 135°C-136°C. The process is shown in the scheme given below:


The processes reported in the prior art involves use of multi-step synthesis wherein
intermediates are isolated by means of either filtration or centrifugation and subsequent
drying of the obtained intermediates before using the same in the next step. The isolation and
drying is a very critical step in the production which exposes the production executives to
. different solvent vapours and also to the isolated solids while handling.
Hence, there remains a need for providing efficient, industrially feasible and economically viable process for the manufacture of Macitentan to substantially eliminate the problems associated with the prior art, and that will be suitable for large-scale preparation such that the process will be safe to handle, simple and easy to carry out with high yield and purity of the product.
OBJECT OF THE INVENTION
The main object of the invention is to provide novel process for the preparation of Macitentan and its intermediates using simple and cost effective novel intermediates.

The fuither object of the invetitiori is to provide a simple, cost effective, imprbved.ind robust-process for the .preparation of Macitentpi; of formula I yielding at a high yield with • high purity without formation of undesired iihpu-ities.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel process for tli3 preparation of Maciientan of Formula I

or its sails, which comprises
a) -Reactkig compound of Formula VII

'with an alkyl formate in a solvent optionally in the presence of a base to give compound of Formula VI


b) Chlorinating compound of Formula VI in the presence of a chlorinating agent to give
compound of Formula V

c) Reacting compound of Formula V with compound of Formula IV

or its salts to give compound of Formula III

d) Reacting compound of Formula III with ethylene glycol optionally in the presence of a
phase transfer catalyst to give compound of Formula II

e) Reacting compound of Formula II with compound of Formula Ha


wherein X] is a leaving group to give Macitentan of Formula I.
In a preferred aspect, the present invention provides novel process for the preparation of Macitentan of Formula-I

.or its salts, which comprises
a) Cyclizing compound of Formula VII

by reacting with an alkyl formate in a solvent optionally in the presence of a base to give compound of Formula VI

b) Converting compound of Formula VI to Macitentan.
In another preferred aspect, the present invention provides novel process for the preparation of Macitentan of Formula-I


or its salts, which comprises
a) Cyclizing compound of Formula VII

by reacting with an alkyl formate in a solvent optionally in the presence of a base to give compound of Formula VI

b) Chlorinating compound of Formula VI in the presence of a chlorinating agent to give
compound of Formula V

. c) Converting compound of Formula V to Macitentan or its salts.
In yet another preferred aspect, the present invention provides novel process for the ^preparation-oi Macitentan ei Koitnuia-i


or its salts, which comprises
a) Cyclizing compound of Formula VII

by reacting with an alky] formate in a solvent optionally in the presence of a base to give compound of Formula VI

b) Chlorinating compound of Formula VI in the presence of a chlorinating agent to give compound of Formula V
c) Reacting compound of Formula V with compound of Formula IV


or its salts to give compound of Formula III

d) Converting compound of Formula III to Macitentan or its salts.
In yet another preferred aspect, the present invention provides novel process for the preparation of compound of Formula VI which comprises cyclizing compound of Formula VII

by reacting with an alkyl formate in a solvent optionally in the presence of a base to give compound of Formula VI

In yet another preferred aspect, the present invention provides process for the preparation of compound of Formula II

which involves reacting compound of Formula III


with ethylene glycol in the presence of a phase transfer catalyst to give compound of Formula II.
In yet another preferred aspect, the present invention provides crystalline Form-S of compound of Formula VII

characterized by its Powder X-ray diffractogram having one or more peaks at about 17.46, 19.35, 22.00, 23.50, 26.94, 28.89 ±0.2° 29.
In yet-another preferred aspect, the present invention provides use of crystalline Form-S of compound of Formula VII

characterized by its Powder X-ray diffractogram having one or more peaks at about 17.46, 19.35, 22.00, 23.50, 26.94, 28.89 ±0.2° 29 in the preparation of Macitentan.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1: Illustrates the characteristic powder X-ray diffraction (XRD) pattern of crystalline Form-S of compound of Formula VII.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides novel process for the preparation of Macitentan of Formula I


The inventors of the present invention have developed a novel approach a well as the improved process for the preparation of Maeifentan intermediates which invoives-the use of simple, commercially available and cost effective raw materials.
The novel and improved process according to the present invention does not yield any impurities more than prescribed levels. Further, the process involves less number of solvent extractions and work up procedures which gives good yield and quality of the product.
By adopting the both novel and improved routes, the inventors of the present invention have successfully developed the compound of Formula I with good yield and high purity.
According to this invention leaving group is selected from halo such as chloro, bromo, fluoro, Iodo, alkoxy, aryloxy, lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group and etc.
According to the present invention the process for the preparation of Macite.ntan can be shown in the scheme given below:
Schcme-2


The compounds of formulae (II), (Ila), (III), (IV), (V), (VI), (VII), and (VIII) or their salts used in the present invention may be isolated or not. Any of the above reactions may be earned out in-situ reactions to obtain Macitentan or its sails. The above compounds may isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions. Further, the above compound may isolated as crystalline Forms or isolated as an amorphous form or optionally recrystallized and used for further reactions. The compounds may exist in different polymorphic forms including crystalline or amorphous forms, further the above compounds may contain water to form their hydrates or they can exist in anhydrous forms.
The term base used in the present invention is selected from organic base or inorganic base. Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to NaHC03, LiOH, NaOH, KOH, KHC03, UHCO3, Na2C03, K2C03, Li2C03, CaC03, MgC03, sodium hydride, potassium tert butoxide, sodium tert butoxide, magnesium riydro'xTde^.M'gH^, MgtfOj^S^

and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
The term solvent as used in the present invention is selected from water or acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or benzene, toluene, xylene, heptane, hexane and cyclohexane or acetone, ethyl methyl ketone, diethyl ketone, methyl tcrt-butyl ketone, isopropyl ketone or methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-bulyl acetate, or. acetonitrile, propionitrile, butyronitrile and isobutyronitrile or di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or formamide, DMF, DMSO, DMAC, N-methyl-2-pyrroIidone, N-methylformamide, N-methyl morpholinc, 2-pyrrolidone. 1-etheny 1-2-pyrrolidone and/or mixtures thereof.
The term phase transfer catalyst used in the present invention is selected from the group consisting of a quaternary ammonium salt and a quaternary phosphonium salt. Preferably the phase transfer catalyst is selected from quaternary ammonium salts selected from the group consisting of benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutyl ammonium halide, tetramethyl ammonium halide, tetraethylammonium halide, tetrabutylammonium acetate and mixtures thereof.
The term pharmaceutically acceptable salts or salts as used in the present invention is selected from sodium, potassium, calcium, magnesium and ammonium salts.
In a preferred embodiment, the present invention provides novel and improved process for the preparation of Macitentan of Formula I


or.its salts, which comprises,
a) Cyclizing compound of Formula VII

by reacting with ethyl formate in ethanol in the presence of sodium ethoxide to give compound of Formula VI

b) Chlorinating compound of Formula VI with POCI3 in acetonitrile solvent in the presence
of triethylamine to give compound of Formula V

c) Reacting compound of Formula V with compound of Formula IVA


in DMSO or DMF to give compound of Formula III

d) Reacting compound of Formula III with ethylene glycol in DMSO in the presence of
tetra-n-butylammonium bromide and potassium carbonate to give compound of Formula
II

e) reacting compound of Formula II with compound of Formula lib

to give Macitentan of Formula I.
In another preferred embodiment, the present invention provides novel process for the preparation of compound of Formula V

or its salts, which comprises
a) Cyclizing compound of Formula VII


by reacting with ethyl formate in" ethanol in the presence of sodium ethoxide to give compound of Formula VI

b) Chlorinating compound of Formula VI with POCI3 in acetonitrile solvent in the presence of triethylamine to give compound of Formula V
In yet another preferred embodiment, the present invention provides novel process for the preparation of compound of Formula VI which comprises cyclizmg- compound of Formula VII
CONH2
|j^V^CONH2
Formula VII by reacting with ethyl formate in ethanol in the presence of sodium ethoxide to give compound of Formula VI

In yet another preferred embodiment, the present invention provides process for the preparation of compound of Formula II

i.vhichUrivolves^reSctirig coBroouhtfdf Formula III ~~


with ethylene glycol in DMSO in the presence of tetra-n- butyl ammonium bromide and potassium carbonate to give compound of Foimula II.
In yet another preferred embodiment, the present invention provides crystalline Form-S of compound of Formula VII

characterized by its Powder X-ray diflfractogram having one or more peaks at about 17.46, 19.35, 22.00, 23.50, 26.94, 28.89 ±0.2° 20.
In yet another preferred embodiment, the present invention provides use of crystalline Form-S of compound of Formula VII

characterized by its Powder X-ray diffractogram having one or more peaks at about 17.46, 19.35, 22.00, 23.50, 26.94, 28.89 ±0.2° 29 in the preparation of Macitentan.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

Examples:
Examplc-1: Preparation of compound of Formula-VII

In a clean & dry round bottom flask lOOgm of compound of Formula VIII in 1000ml of ammonia were added, reaction mass were stirred for 14hrs. Absence of compound of Formula VIII was monitored by TLC. After the reaction completion reaction mass was cooled to 0-5°C, reaction mass was stirred for 2hrs. Solid was filtered and washed with 200ml of water, dried to obtain 60gms of compound of Formula VII.
ExampIe-2: Preparation of compound of Formula-VI

In a clean & dry round bottom flask lOOgm of compound of Formula VII in 1000ml of ethanol were added, 200ml of ethyl formate and 66gms of sodium ethoxide were also added at RT. Reaction mass was stirred at RT for 2hrs. Absence of compound of Formula VII was monitored by TLC. After the reaction completion 200ml of water was charged, pH was adjusted to 2-2.5 with 750ml of IN HC1 solution. Reaction mass was cooled to 10-15°C. The precipitated solid material was isolated by filtration to afford 80gm of compound of Formula VI.
ExampIe-3: Preparation of compound of Formula-V


In a clean & dry round bottom flask lOOgms of Formula VI charged. 145gms of phosphorous oxy chloride charged to the above mass. Reaction mass was cooled to 10-15°C, 90gms of triethylamine was added slowly to the above mass. Reaction mass temperature was - raised to 75-85°C. Reaction mass was stirred for 4-5hrs at same temperature. Absence of compound of Formula VII was monitored by TLC. After the reaction completion, the reaction mass was cooled to RT. Dilute HC1 was added slowly to reaction mass, reaction mass was further cooled to 10-15°C. 200mL of acetonitrile was added to the above mass. The precipitated solid material was isolated by filtration to afford 95gm of compound of Formula V.
ExampIc-4: Preparation of compound of Formula-Ill

In a clean and dried round bottom flask 950ml of DMSO charged. lOOgms of Formula
V in 25ml of DMSO was added and 144gms of compound of Formula IVa in 25ml of DMSO also added and the reaction mass was stirred for lhr at RT. Absence of compound of Formula
V and compound of Formula IVa was monitored by TLC. After the reaction completion pH of the reaction mass was adjusted to 2-3 by adding dilute HC1. Reaction mass was cooled to 2-5°C. 500ml of methanol was charged at RT, reaction mass was heated and stirred for lhr, reaction mass was cooled to RT, reaction mass was further cooled to 0-5°C. Filter the reaction mass and washed with 200ml of methanol to obtain lOOgms of compound of Formula III.
Example-5: Preparation of compound of Formula-U
O
hormuJa 11 ~~

In a clean & dry round -bottom flask 700 mL of Ethylene glycol and 3.72gms of arJiydrous potassium carbonate were charged, reaction mass was stirred. lOOgms of compound of Formula III in 300mL of DMSO were added to the above reaction mass. l.Ogm of TBAB was added the reaction mass, was stilted, and heated to 90-95°G. Reaction mass was stirred for 6-8hrs. Absence of compound of Formula III was monitored by TLC. 500mL of water was charged, pH was adjusted to 6-7 using 10% Citric acid solution. Reaction mass was cooled to 10-15°C. Filtered and dried to obtain lOOgms of Formula II.
ExampIe-6: Preparation of compound of Formula-I Macitentan

In a clean & dry round bottom flask 500mL of THF and 25gms of NaH were charged, iOQOrol of compound of Formula II in THF were also charged. Reaction mass was stirred at RT, 62gms of compound of Formula Ha also charged to the reaction mass. Reaction mass heated at 60-65°C, the reaction mass was stirred for 4-6hrs. Absence of compound of Formula II was monitored by TLC. 500mL of water was charged. Reaction mass was cooled to 15-20°C, 400mL of water and 500mL of ethyl acetate were charged, reaction mass stirred. Layers were settled and separated. Wash organic layer with 200mL of HC1 and 200mL of 10% NaCl solution. lOgms of carbon was added. Reaction mass was filtered and washed with lOOmL of ethyl acetate. Solvent distilled out and the obtained compound recrystallized from methanol to obtain lOOgms of compound of Formula I.

We claim:
1. Novel process for the preparation of Macitentan of Formula I

or its salts, which comprises
a) Reacting compound of Formula VII

with an alkyi formate in a solvent optionally in the presence of a base to give compound of Formula VI

b) Chlorinating compound of Formula VI in the presence of a chlorinating agent to give
compound of Formula V

c) Reacting compound of Formula V with compound of Formula IV

Formula IV
or its salts to givecc J ~rry ,_ TTt
Formula III d) Reacting compound of Formula III with ethylene glycol optionally in the presence of a phase transfer catalvst to eive comnound of Formula II
hormula n
'. - e) Reacting compound of For ' " *'* ' ^
JL uiuiuia lid
wherein Xi is a leaving group to give Macitentan of Formula I. 2. Novel process for the preparation of Macitentan of Formula-I

Forrnula-I
or its salts, which comprises

a) Cyclizing compound of Formula VII

by reacting with an alkyl formate in.a solvent optionally in the presence of a base to give compound of Formula VI

b) Converting compound of Formula VI to Macitcntan,
3. Novel process for the preparation of Macitcntan of Formula-I

or its salts, which comprises a) Cyclizing compound of-Formula VII

by reacting with an alkyl formate in a solvent optionally" in the presence of a base to give compound of Formula VI


b) Chlorinating compound of Formula VI in the presence of a chlorinating agent to give
compound of Formula V

c) Converting compound of Formula V to Macitentan or its salts.
' 4. Novel process for the preparation of Macitentan of Formula-I

or its salts, which comprises a) Cyclizing compound of Formula VII

by reacting with an alkyl formate in a solvent optionally in the presence of a base to give compound of Formula VI


b) Chlorinating compound of Formula VI in the presence of a chlorinating agent to give
compound of Formula V

c) Reacting compound of Formula V with compound of Formula IV

or its salts to give compound of Formula III

d) Converting compound of Formula IH'to Macitentan or its salts. •
5. Novel process for the preparation cf compound of Formula VI which comprises cyclizing compound of Formula VII

by reacting with an alkyl formate in a solvent optionally in the presence of a base to give compound of Formula VI


6. Process for the preparation of compound of Formula II

which involves reacting compound of Formula III

with ethylene glycol in the presence of a phase transfer catalyst to give compound of Formula II.
7. The process as claimed in any of the proceeding claims, where solvent used in the preparation of any of the compounds is selected from water or acetic acid, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or benzene, toluene, xylene, heptane, hexane and cyclohexane or acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone or methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or acetonitrile, propionitrile, butyronitrile and isobutyronitrile or di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or formamide, DMF, DMSO, DMAC, N-methyl-2-pyrrolidone, N-methylformarnide, N-methyl morpholine, 2-pyrrolidone, l-ethenyl-2-pyrrolidone and/or mixtures thereof.

8. The process as claimed in any of the proceeding claims, where phase transfer catalyst is selected from quaternary ammonium salts selected from the group consisting of benzyltriethylammoniurn halide, hexadecyltrimethylanimoniurn halide, tetrabutylammonium halide, tetramethylammonium halide, tetraethylammonium halide, tetrabutylammonium acetate and mixtures thereof.
9. Crystalline Form-S of compound of Formula VII

characterized by its Powder X-ray dtffractogram having one or more peaks at about 17.46, 19.35, 22.00, 23.50, 26.94, 28.89 ±0.2° 20.
10. Use of crystalline Form-S of compound of Formula VII

characterized by its Powder X-ray diffractogram having one or more peaks at about 17.46, 19.35, 22.00, 23.50, 26.94, 28.89 ±0.2° 29 in the preparation of Macitentan.