FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A Process for the Preparation of Selexipag
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian
Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.

FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of substantially pure Selexipag represented by structure of Formula (I)

BACKGROUND OF THE INVENTION:
Selexipag is chemically defined as 2-[4-[(5,6-Diphenyl-2-pyrazinyl)(l-methylethyl) amino]butoxy]-N-(methylsulfonyl)acetamide and is represented by structure of formula I.

Selexipag is used for the treatment of pulmonary arterial hypertension (PAH). It was first disclosed in US7205302 in which 2-chloro-5,6-diphenylpyrazine of formula (II) is reacted with 4-(isopropylamino)-l-butanol of formula (III) to yield 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-l-butanol of formula (IV), then the product is reacted with tertiary butyl bromoacetate of formula (V) to form 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-Nisopropylamino] butyloxy} acetic acid tertiary butyl ester of

formula (VI). The tertiary butyl ester is hydrolyzed to yield 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-Nisopropylamino] butyloxy} acetic acid of formula (VII), then the acid is reacted with methane sulfonamide in presence of CDI and DBU to form Selexipag of formula (I). Selexipag was isolated from a mixture of diethyl ether and THF as residue and is purified by silica gel column chromatography. The Selexipag preparative method described in US '302 is schematically represented below in Scheme I

The process disclosed in US '302 involves the chromatographic purification of the compound of formula I which in turn render the process more costly and less eco-friendly and therefore, such processes are not viable for industrial manufacturing.

US Patent No. 8,791,122 B2 also describes a synthetic scheme for preparation of selexipag, in which 2-chloro-5,6-diphenylpyrazine of formula (II) is reacted with sodium iodide to form 2-iodo-5,6-diphenylpyrazine of formula (VIII), then the iodopyrazine is reacted with 4-(isopropylamino)-l-butanol of formula (III) to yield 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-l-butanol of formula (IV), and the product is reacted with 2-chloro-N-(methylsulfonyl)acetamide of formula (IX) to form Selexipag of formula (I). Selexipag synthetic scheme described in US '122 is schematically represented below


The process disclosed in US '122 involves numerous steps and is lengthy which renders the process industrially not viable.
The processes described in prior art suffers from drawbacks like use column chromatography for purification of Selexipag and use of reagents like iodine which makes the process less feasible on industrial scale. The inventors of the present invention, have designed an improved industrially feasible, , economic and environment friendly process for the preparation of substantially pure Selexipag.
OBJECT OF PRESENT INVENTION
1. An object of the invention is to provide a process for the preparation of substantially pure Selexipag of formula (I)
2. Another object of the present invention to provide simple, economic and industrially scalable process for the preparation of Selexipag of formula (I)
SUMMARY OF THE INVENTION
According to an aspect of present invention, there is provided a process for preparation of Selexipag represented by structure of Formula (I);

comprising,

a) reacting the compound of Formula (II) with the compound of Formula (III) at temperature ranging from 25 °C to 2.00°C to obtain the compound of formula (IV),

b) purifying the crude compound of formula (IV) by treating with a saturated hydrocarbon to obtain the pure compound of formula (IV),
c) reacting the compound of formula (IV) with the compound of formula (V) in the presence of the catalyst and the base to obtain the compound of formula (VI),

d) in-situ hydrolyzing the compound of formula (VI) using a base to afford the compound of formula (VII)

e) reacting compound of formula (VII) with methane sulfonamide in presence of a coupling reagent and a base to get the compound of formula I


f) crystallizing the compound of formula I of step (i) using organic solvent selected from an alcohol, ether, ketone or mixture thereof, to obtain the substantially pure compound of formula I.
The route of synthesis of Selexipag of structural formula (I) according to present invention can be illustrated as below in Scheme III

DETAILED DESCRIPTION OF INVENTION:
Accordingly, the present invention relates to a process for the preparation of substantially pure Selexipag represented by structure of Formula (I). Accordingly, the present invention to provide simple, economic and industrially scalable process for the preparation of Selexipag of formula (I).
According to the present invention, a process for preparation of Selexipag represented by structure of Formula (I);

comprising,
a) reacting the compound of Formula (II) with the compound of Formula (III) at temperature ranging from 25°C to 200°C to obtain the compound of formula (IV),

b) purifying the crude compound of formula (IV) by treating with a saturated hydrocarbon to obtain the pure compound of formula (IV),
c) reacting the compound of formula (IV) with the compound of formula (V) in the presence of a catalyst and a base to obtain a reaction mixture comprising the compound of formula (VI),

d) in-situ hydrolyzing the compound of formula (VI) using a base to afford the compound of formula (VII),

e) reacting compound of formula (VII) with methane sulfonamide in presence of the coupling reagent and the base to obtain the crude compound of formula I,

f) crystallizing the crude compound of formula I using organic solvent selected from an alcohol, ether, ketone or mixture thereof, to obtain the substantially pure compound of formula I.
In an embodiment of the present invention, wherein in the step (a), involves the reaction of the compound of Formula (II) with the compound of Formula (III) at temperature ranging from 25°C to 200°C to obtain a reaction mixture comprising the compound of formula (IV)


In accordance with an embodiment of the present invention, wherein the step (a), after completion of the reaction, the reaction mass cooled to room temperature, the compound of formula IV extracted with organic solvent and the organic solvent distilled out to obtain an oily residue.
In specific embodiment of the present invention; the organic solvent selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s).
In accordance with an embodiment of the present invention, wherein the step (a), the crude compound of formula (IV) can be isolated from the oily residue by addition of mixture of water and alcohol.
In specific embodiment of the present invention; the alcohol solvents selected from group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
In another embodiment of the present invention, wherein the step (b), the crude compound of formula (IV) obtain in step (a) purified by treating with a saturated hydrocarbon to obtain pure compound of formula (IV).
In accordance with another embodiment of the present invention; saturated hydrocarbon used in the step (b) is selected from group consisting of methane, hexane and cyclohexane.

In another embodiment of the present invention, wherein the step (c), the compound of formula (IV) reacted with the compound of formula (V) in the presence of a catalyst and a base to obtain a reaction mixture comprising the compound of formula (VI)

In accordance with another embodiment of the present invention the catalysts used in the step (c) are selected from group consisting of Tetra-alkyl-ammonium or phosphonium salts , Tetra-n-butyl ammonium bromide or Methyl- triethyl ammonium chloride.
In accordance with another embodiment of the present invention; the base used in the step (c) is organic base selected from group consisting of triethylamine, diisoproylethylamine, pyridine and methyl amine.
In accordance with another embodiment of the present invention; the base used in the step (c) is inorganic base selected from group consisting of potassium carbonate and sodium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide.
In another embodiment of the present invention, wherein the step (d), the compound of formula (VI) hydrolyzed in-situ using base to obtain the compound of formula (VII)


In accordance with another embodiment of the present invention, the base used in the step (d) is organic base selected from group consisting of triethylamine, diisoproylethylamine, pyridine and methyl amine.
In accordance with another embodiment of the present invention; the base used in the step (d) is inorganic base selected from group consisting of potassium carbonate and sodium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide.
In another embodiment of the present invention, wherein the step (e), the compound of formula (VII) reacted with methane sulfonamide in presence of a coupling reagent and base to obtain the compound of formula I.

In accordance with another embodiment of the present invention; the coupling reagents used in the step (e) selected from group consisting of 1,1-carbonyl diimidazole and TBTU.
In accordance with another embodiment of the present invention; the base used in the step (e) is organic base selected from group consisting of triethylamine,

diisoproylethylamine, pyridine, l,8-Diazabicyclo(5.4.0)undec-7-ene[DBU] and methyl amine.
In accordance with another embodiment of the present invention; in the step (e), the compound of formula I is isolated by addition of water to the reaction mass, adjusting the pH to 4 to 6 using 16%HC1, extracting the crude compound of formula I with organic solvent, distilling out solvent to obtain oil and precipitating out the crude compound of formula I by addition of second solvent and antisolvent.
In accordance with another embodiment of the present invention; the organic solvent used in the step (e) selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s).
In another embodiment of the present invention; wherein the step (f); the crude compound of formula I crystallizing out using organic solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, DIPE, MTBE, butanone, methyl isobutyl ketone, acetophenone, methyl isopropyl ketone or mixture(s) thereof to obtain substantially pure Selexipag.
In the following example, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way
Examples:
Example 1: Preparation of Selexipag
Stage-A: Preparation of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-
ol (Formula IV).

A reaction mixture of 5-chloro-2, 3-diphenylpyrazine (100 g, 0.375 moles) and 4-(isopropylamino) butan-1-ol (250 g, 1.905 moles) were heated at 180-190°C for 24 hr. After completion of reaction, the reaction mass was cooled to room temperature. To the reaction mixture; water (1000 ml) was added and reaction mixture was extracted with ethyl acetate (1500 ml) and the organic layer was concentrated to obtain oily residue. To the obtained residue ~37-40% aq. methanol was added and obtained solid was filtered washed with water to obtain wet cake. The obtained wet cake is suspended in cyclohexane (400) at 50- 60 C, cooled, filtered and dried to give 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (formula IV). (Wt- 100 g; 77%, purity-95.2%).
Stage-B: Preparation of 2-(4-((5,6-diphenylpyrazin-2-
yi)(isopropyi)amino)butoxy)acetic acid (formula VII).
To a solution of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (formula IV) (80 g, 0.221 moles) in toluene (1200 ml) were added tetrabutylammonium bromide (25 g, 0.077 moles) and aqueous 60% sodium hydroxide solution (170 ml). The tert-butyl bromoacetate (202 ml, 1.368 moles) was added drop wise at room temperature under constant stirring. The reaction is stirred at 70 C for 12-14 hrs. After completion of the reaction, biphasic layers were separated and aqueous layer was re-extracted with toluene (200 ml). Organic layers were combined and concentrated toluene layer completely to obtain the tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetate as oily mass (Wt-100 g) (formula VI).
The above oily mass (100 g) was dissolved in methanol (1500 ml) and 30% sodium hydroxide solution (350 ml) was added at room temperature, and then reaction mass was heated to 70°C for 12 hrs. After completion of the reaction, water was added, pH was adjusted around 2.5 of the aqueous layer using 16% hydrochloric acid solution to precipitate the product, which was filtered and washed with water (300 ml). The

obtained crude product was dissolved in ethyl acetate (300 ml) at 50-60 C, cooled to room temperature and was added MTBE (1000 ml) to obtain product precipitation. Then the precipitation of the product is filtered and dried to obtain 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (formula VII) (Wt: 60 g, 65%. Purity: 99%)
Stage-C: Preparation of Selexipag
To the reaction mixtures of 2-(4-((5,6-diphenylpyrazin-2-yl)
(isopropyl)amino)butoxy)acetic acid (formula VII) (50 g, 0.119 moles); anhydrous tetrahydrofuran (500 ml) and 1,1-carbonyl diimidazole (30 g, 0.185 moles) were added and reaction mixture was heated at 70 C and stirred for 30 min. The resultant reaction mixture was cooled at room temperature and to the reaction mixture; methane sulfonamide (20 g, 0.210 moles) and l,8-diazabicyclo[5.4.0]-7-undecane (25 ml) were charged and reaction mass was stirred at 70°C for 6-8 hrs, after completion of the reaction, tetrahydrofuran was distilled completely under reduced pressure to obtain syrupy mass, which was diluted with water, and washed with MTBE (3 x 400 ml). The pH of aqueous layer was adjusted to 5 - 6 using 16% hydrochloric acid, and the product was extracted with ethyl acetate (600 ml). The ethyl acetate layer distilled completely under reduced pressure at below 50°C to obtain thick mass. The obtained thick mass was dissolved in methanol (100 ml) at 60-70 C, cooled to room temperature and to the reaction mass diisopropylether (1000 ml) was added and reaction mass stirred for 4-6 hrs to obtain solid. The obtained solid was filtered and washed with diisopropylether (50 ml) to give the crude compound of formula I; Selexipag. (Wt: 65 g; purity: 98%).
Stage-D: Purification of compound of formula I (Selexipag)
The wet solid of crude Selexipag (65 g) was suspended in methanol (100 ml) and heated at 50-60°C for 15 min. The resuting reaction mass was cooled to room

temperature, and to the reaction mass MTBE (1000 ml) was added and the reaction mass was stirred for 6 hrs. the obtained solid was filtered and washed with MTBE (50 ml) and dried to give Selexipag.(Wt-50 g, Purity- 99.8%).

We claim:
1. A process for preparation of Selexipag represented by structure of Formula
(i);

comprising,

with the compound of Formula (III)

a) reacting the compound of Formula (II)
at temperature ranging from 25°C to 200°C to obtain the compound of formula (IV),


b) purifying the crude compound of formula (IV) by treating with a saturated hydrocarbon to obtain the pure compound of formula (IV),
c) reacting the compound of formula (IV) with the compound of formula (V)

in the presence of a catalyst and a base to obtain the compound of formula (VI),

d) in-situ hydrolyzing the compound of formula (VI) using a base to afford the compound of formula (VII),

e) reacting compound of formula (VII) with methane sulfonamide in presence of a coupling reagent and a base to obtain the crude compound of formula I,

f) crystallizing the crude compound of formula I using organic solvent to obtain the substantially pure the compound of formula I.

2. The process as claimed in claim 1, wherein the step (a) further involves the
isolation of the compound of formula IV from the reaction mixture comprises the
steps of:
i) extracting the compound of formula IV with organic solvent wherein the
organic solvent selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof, ii) distilling the organic solvent to obtain an oily residue, iii) isolating the crude compound of formula (IV) from oily residue by adding mixture of water and alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
3. The process as claimed in claim 1; wherein saturated hydrocarbon used in step (b) is cyclohexane.
4. The process as claimed in claim 1; wherein catalyst used in the step (c) is selected from group consisting of Tetra-alkyl-ammonium or phosphonium salts, Tetra-n-butyl ammonium bromide or Methyl- triethyl ammonium chloride.
5. The process as claimed in claim 1; wherein base used in the step (c) and step (d) is selected from group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and calcium hydroxide.
6. The process as claimed in claim 1; wherein coupling reagent used in the step (e) is selected from group consisting of 1,1 -carbonyl diimidazole and TBTU.
7. The process as claimed in claim 1; wherein base used in step (e) is organic base selected from group consisting of triethylamine, diisoproylethylamine, 1,8-Diazabicyclo(5.4.0)undec-7-ene[DBU], pyridine and methyl amine.

8. The process as claimed in claim 1, wherein the step (e) further involves the
isolation of the compound of formula I from the reaction mixture comprises the
steps of:
A. adding water to the reaction mixture and adjusting the P to 4-6 with HC1,
B. extracting the mixture with organic solvent selected from the group
consisting of methyl acetate, ethyl acetate, propyl acetate, butyl acetate,
isobutyl acetate or mixture(s) thereof,
C. distilling out organic solvent of the step (A) to obtain an oily residue,
D. precipitating the crude compound of formula I by addition of solvent
selected from. group consisting of methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol and antisolvent selected from group
consisting of tetrahydrofuran, dioxane, DIPE and MTBE.
9. The process as claimed in claim 1; wherein organic solvent used in step (f) is
selected from the group consisting of methanol, ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane,
DIPE, MTBE, butanone, methyl isobutyl ketone, acetophenone, methyl isopropyl
ketone or mixture(s) thereof.