DESC:FIELD OF INVENTION
The present invention provides an improved process for preparation of Selexipag (I) or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION
Selexipag is chemically known as “2-{4-[N-(5,6-diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n-(methylsulfonyl)acetamide” (CAS number: 475086-01-2) and represented by formula (I). It has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a broncho dilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect.

Selexipag is useful as a preventive or therapeutic agent for transient ischemic attack (TIA); diabetic neuropathy, diabetic gangrene, peripheral vascular, disease (for example, arteriosclerosis obliterans, intermittent claudication, peripheral arterial embolism, vibration disease and Raynaud's disease), systemic lupus erythematosus, reocclusion or restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (for example, acute cerebral thrombosis), diabetic nephropathy, hypertension, pulmonary hypertension, ischemic diseases (for example, cerebral infarction and myocardial infarction), angina pectoris (for example, stable angina and unstable angina), glomerulonephritis, diabetic nephropathy, allergy, bronchial asthma, ulcer, bedsore (decubitus), restenosis after intervention of coronary artery such as atherectomy and indwelling of stent, and thrombocytopia caused by dialysis.
The method for the preparation of selexipag (I) reported in the PCT publication WO 2002/088084 A1 is as shown in scheme 1 below:

The process involves reaction of 4-amino-1-butanol (II) with acetone followed by reduction with PtO2 in ethanol to obtain 4-(isopropylamino)-1-butanol (III). The platinum catalysts are very expensive and results in increasing the cost of the synthesis.
Condensation of 4-(isopropylamino)-1-butanol (III) with 2-chloro-5,6-diphenylpyrazine (IV), wherein reaction is carried out at high temperature such as 190 °C without base and solvent to obtain 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V). This reaction use temperature 190 °C which is not preferred on plant level due to safety issues.
Conversion of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) to its t-butyl ester (VI) is carried with tert-butyl bromoacetate, aq. KOH and tetra-n-butylammonium hydrogen sulfate as phase transfer catalyst in benzene as solvent to obtain 72 % yield of t-butyl ester (VI) indicating substantially incomplete reaction. The process is not feasible on plant level due to benzene solvent which is carcinogenic and low yield of t-butyl ester (VI).
In view of the above, it is therefore, desirable to provide an improved process for the preparation of selexipag of formula (I) with high yield and safe on large scale.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of selexipag (I) or its pharmaceutically acceptable salts comprising reacting 4-amino-1-butanol (II) with acetone in presence of Pd/C to obtain 4-(isopropylamino)-1-butanol (III) and the conversion of 4-(isopropylamino)-1-butanol (III) thus obtained to Selexipag (I) or its pharmaceutically acceptable salts.
The present invention further provides an improved process for the preparation of selexipag (I) or its pharmaceutically acceptable salts comprising condensing 4-(isopropylamino)-1-butanol (III) with 2-chloro-5,6-diphenylpyrazine (IV) in presence of base and organic solvent at temperature 140-160 °C to obtain 4-[N (5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) and the conversion of 4-[N (5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) thus obtained to Selexipag (I) or its pharmaceutically acceptable salts.

The present invention further provides an improved process for the preparation of selexipag (I) or its pharmaceutically acceptable salts in high yield comprising esterification of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) with tert-butyl bromoacetate in presence of base, organic solvent and tetra-N-butylammonium chloride to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetic acid tert-butyl ester (VI) and the conversion of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetic acid tert-butyl ester (VI) thus obtained to Selexipag (I) or its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention provides an improved process for the preparation of selexipag (I) or its pharmaceutically acceptable salts

comprising
reacting 4-amino-1-butanol (II)

with acetone in presence of Pd/C to obtain 4-(isopropylamino)-1-butanol (III),

and converting 4-(isopropylamino)-1-butanol (III) thus obtained to Selexipag (I) or its pharmaceutically acceptable salts.

Another embodiment of the present invention provides an improved process for the preparation of selexipag (I) or its pharmaceutically acceptable salts

comprising
condensing 4-(isopropylamino)-1-butanol (III)

with 2-chloro-5,6-diphenylpyrazine (IV)

in presence of base and organic solvent at temperature 140-160 °C to obtain 4-[N (5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V),

and converting 4-[N (5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) thus obtained to Selexipag (I) or its pharmaceutically acceptable salts.

Another embodiment of the present invention provides an improved process for the preparation of selexipag of formula (I) or its pharmaceutically acceptable salts

comprising
a) reacting 4-amino-1-butanol (II)

with acetone in presence of Pd/C to obtain 4-(isopropylamino)-1-butanol (III),

b) condensing 4-(isopropylamino)-1-butanol (III) with 2-chloro-5,6-diphenylpyrazine (IV)

in presence of base and organic solvent at temperature 140-160 °C to obtain 4-[N (5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V),

c) esterifying 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) with tert-butyl bromoacetate in presence of base, organic solvent and tetra-N-butylammonium chloride to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetic acid tert-butyl ester (VI),

d) hydrolysing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid tert-butyl ester (VI) to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (VII),

e) reacting 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (VII) with methanesulfonamide in presence of condensing agent, base and organic solvent.

Reacting 4-amino-1-butanol (II) with acetone according to the process of the present invention uses Pd/C catalyst. The Pd/C catalyst is far cheaper than PtO2; moreover it is easy to handle than PtO2 thus making the process economical and industrially feasible. The Pd/C catalyst can be reactivated and can be reused for an extended number of times without any substantial reduction in activity. Reaction is carried out in solvent selected from alcohol selected from methanol, ethanol, isopropanol and mixtures thereof; preferably ethanol.
The intermediate 4-(isopropylamino)-1-butanol (III) is condensed with 2-chloro-5,6-diphenylpyrazine (IV) in presence of base and organic solvent at temperature 140-160°C. The use of base and organic solvent allowed the reaction to be conveniently carried out on commercial scale at temperature 140-160°C. The base used is selected from potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and mixtures thereof; preferably potassium carbonate. The organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, xylene and mixtures thereof; preferably N-methyl-2-pyrrolidone.
The intermediate 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) is esterified with tert-butyl bromoacetate in presence of base, organic solvent and a phase transfer catalyst tetra-N-butylammonium chloride. Use of tetra-N-butylammonium chloride resulted in more than 80% yield of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid tert-butyl ester (VI). The base used is selected from potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and mixtures thereof; preferably sodium hydroxide. The organic solvent is selected from toluene, xylene, cyclohexane, heptane, dichloromethane, chloroform, chlorobenzene, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and mixtures thereof; preferably toluene.
The intermediate 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid tert-butyl ester (VI) is hydrolysed in a proper solvent in the presence of an acid or a base by a known method (for example as disclosed in WO 2002/088084 A1, which is herein incorporated as reference) to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (VII). The acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and mixtures thereof; preferably hydrochloric acid. The base is selected from potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and mixtures thereof; preferably sodium hydroxide. The solvent is selected from methanol, ethanol, tetrahydrofuran, dioxane, water and mixtures thereof; preferably methanol.
The intermediate 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (VI) is reacted with methanesulfonamide in presence of condensing agents and in the presence or absence of a base in organic solvent. The condensing agent is selected from 1,1'-carbonyl diimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexyl carbodiimide, diethyl cyanophophonate, and diphenylphophoryl azide; preferably 1,1'-carbonyl diimidazole. The base is selected from triethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; preferably 1,8-diazabicyclo[5.4.0]undec-7-ene. The organic solvent used is selected from tetrahydrofuran, diethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, propionitrile, toluene, chloroform, dichloromethane and mixtures thereof; preferably tetrahydrofuran.
The 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n-(methylsulfonyl) acetamide (I) can be converted to its pharmaceutically acceptable salts by a known method. Examples of “salt” include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid and camphor sulfonic acid; salts of alkali metal salts such as sodium salt and potassium salt; and salts of alkali earth metal salts such as calcium salt and magnesium salt.
The intermediates and selexipag (I) or its pharmaceutically acceptable salts obtained by the process of the present invention can be separated and optionally purified from the reaction mixture by a conventional separation and purification means, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography, or thin layer chromatography.
The process of the present invention is as shown in Scheme 2:

Selexipag (I) or its pharmaceutically acceptable salts of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, excipients, or diluents.
To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLES:
Example 1: Preparation of 2-chloro-5,6-diphenylpyrazine (IV)
A solution of 95 gm methanol is 500 ml water was added slowly at 0-5 °C to a solution of 52.5 gm glycinamide hydrochloride in 600 ml methanol and then stirred at same temperature for 45 minutes. To the reaction mixture was then added 100 gm benzil and maintained under stirring for 4-5 hrs and then neutralized with 185 ml conc. hydrochloric acid to obtain solid. The solid obtained was washed with 400 ml water and dried to obtain 97.6 gm 2-hydroxy-5,6-diphenylpyrazine. Yield: 82.70 %.
50 gm of 2-hydroxy-5,6-diphenylpyrazine obtained was treated with 250 ml of POCl3 and then heated the reaction mixture at 100-110 °C with stirring for 5-6 hrs. the reaction mixture was cooled to room temperature and poured in 1000 ml of ice water at 0-5 °C and maintained with stirring for 60 minutes. The solid obtained was filtered, washed with water and dried to obtain 41.3 gm of desired compound. Yield: 77.00 %.
Example 2: Preparation of 4-(isopropylamino)-1-butanol (III).
200 gm of 4-amino-1-butanol (II) was dissolved in a mixed solvent of 400 ml of acetone and 1000 ml of ethanol and, after adding 20 gm of 10% Pd/C, hydrogenation was carried out under the pressure of 10 kg for 4-5 hours. The reaction solution was filtered to remove the catalyst and the filtrate obtained was concentrated to obtain desired compound in quantitative yield, as a colorless oily substance.
Example 3: Preparation of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V).
5 gm of 2-chloro-5,6-diphenylpyrazine (IV) in 25 ml N-Methyl-2-pyrrolidone (NMP) and 5.18 gm of K2CO3 were mixed with 9.92 gm of 4-(isopropylamino)-1-butanol (III), the reaction mixture was then heated with stirring at 150-155 °C for 20-21 hrs. The reaction solution was air-cooled, poured into 25 ml water, extracted with 20 ml ethyl acetate. Aqueous layer washed with 10 ml ethyl acetate. Ethyl acetate layers are combined and washed with 15 ml of water, dried over anhydrous magnesium sulfate and then concentrated to obtain 6.3 gm of residue. 6 gm of the residue was purified by silica gel column chromatography by eluting with 2000 ml hexane and 550 ml ethyl acetate to obtain solid 3.2 gm of the desired compound. Yield: 49.41 %.
Example 4: 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester (VI):
3.0 gm of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) was dissolved in 39 ml of toluene and 0.76 gm of tetra-n-butylammonium chloride was added with stirring. 40 ml of an aqueous 35% sodium hydroxide solution was then added at 0-5 °C. 1.62 gm of tert-butyl bromoacetate was added dropwise so as to control the temperature within a range from 5 to 10°C. After stirring for 60 minutes, an ice bath was removed and the mixture was stirred at room temperature for one hour. Layers are separated and aqueous layer was washed with 10 ml of toluene. The toluene layers are combined and washed with 15 ml water, dried over anhydrous magnesium sulfate and then concentrated to obtain 3.19 gm of the desired compound, as an oily substance. Yield: 80.00 %.
Example 5: Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (VII):
6.0 gm of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester was dissolved in 60 ml of methanol and 30 ml of 1N sodium hydroxide solution was added. After the mixture was heated at reflux for 1.5 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in 60 ml water. After washing with 30 ml diethyl ether, the pH of aqueous layer was adjusted to 4.1 with 3.0 ml of conc hydrochloric acid and then extracted with 30 ml ethyl acetate. Layers are separated and aqueous layer was washed with 30 ml of ethyl acetate. The ethyl acetate layers were combined and washed with 30 ml water, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was treated with 30 ml heptane to obtain solid, which was then filtered and washed with 6 ml hexane and dried to obtain 3.8 gm of the desired compound. Yield: 71.83 %.
Example 6: Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (I):
A solution of 3 gm of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid in 48 ml of tetrahydrofuran, 1.28 gm of 1,1'-carbonyl diimidazole was added and, after stirring the reaction mixture at 65-70°C for 2 hrs, the reaction mixture cooled to room temperature, 0.695 gm of methanesulfonamide was added. After stirring for 30 minutes, 1.11 gm of 1,8-diazabicyclo[5.4.0.]-7-undecene was added dropwise with stirring for 40 minutes. To the mixture, 30 ml of 1N hydrochloric acid was added and extracted with 30 ml of ethyl acetate followed by layer separation. Aqueous layer washed with 15 ml ethyl acetate and then ethyl acetate layers combined and washed with 30 ml water and then with 30 ml of 5% brine solution. The ethyl acetate layer then concentrated under reduced pressure, and then 36 ml of heptane added to obtain solid which was then filtered and washed with 3 ml heptane and dried to obtain 3.0 gm of the desired compound. Yield: 84.51 %.
,CLAIMS:1. An improved process for the preparation Selexipag (I) or its pharmaceutically acceptable salts

comprising
a) reacting 4-amino-1-butanol (II)

with acetone in presence of Pd/C to obtain 4-(isopropylamino)-1-butanol (III),

b) condensing 4-(isopropylamino)-1-butanol (III) with 2-chloro-5,6-diphenylpyrazine (IV)

in presence of base and organic solvent at temperature 140-160 °C to obtain 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V),

c) esterifying 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) with tert-butyl bromoacetate in presence of base, organic solvent and tetra-N-butylammonium chloride to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetic acid tert-butyl ester (VI),

d) hydrolysing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid tert-butyl ester (VI) to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (VII),

e) reacting 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy} acetic acid (VII) with methanesulfonamide in presence of condensing agent, base and organic solvent.
2. An improved process for the preparation Selexipag (I) or its pharmaceutically acceptable salts

comprising
a) reacting 4-amino-1-butanol (II)

with acetone in presence of Pd/C to obtain 4-(isopropylamino)-1-butanol (III),

and
b) converting 4-(isopropylamino)-1-butanol (III) to selexipag (I) or its pharmaceutically acceptable salts.
3. An improved process for the preparation Selexipag (I) or its pharmaceutically acceptable salts

comprising
a) condensing 4-(isopropylamino)-1-butanol (III)

with 2-chloro-5,6-diphenylpyrazine (IV)

in presence of base and organic solvent at temperature 140-160 °C to obtain 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V),

and
b) converting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V) to selexipag (I) or its pharmaceutically acceptable salts.
4. An improved process for the preparation Selexipag (I) or its pharmaceutically acceptable salts

comprising
a) esterifying 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (V)

with tert-butyl bromoacetate in presence of base, organic solvent and tetra-N-butylammonium chloride to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}acetic acid tert-butyl ester (VI),

and

b) converting 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy} acetic acid tert-butyl ester (VI) to selexipag (I) or its pharmaceutically acceptable salts.
5. The process according to claim 1 a) and claim 2 a), wherein the reaction is carried in solvent selected from methanol, ethanol, isopropanol and mixtures thereof.
6. The process according to claim 1 b), claim 1 c), claim 3 a) and claim 4 a), wherein the base is selected from potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and mixtures thereof.
7. The process according to claim 6, wherein the base used in claim 1 b) and claim 3 a) is potassium carbonate.
8. The process according to claim 6, wherein the base used in claim 1 c) and claim 4 a) is sodium hydroxide.
9. The process according to claim 1 b) and claim 3 a), wherein the organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, xylene and mixtures thereof.
10. The process according to claim 1 c) and claim 4 a), wherein the organic solvent is selected from toluene, xylene, cyclohexane, heptane, dichloromethane, chloroform, chlorobenzene, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and mixtures thereof.
11. The process according to claim 1 e), wherein the condensing agent is selected from 1,1'-carbonyl diimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexyl carbodiimide, diethyl cyanophophonate, and diphenylphophoryl azide.
12. The process according to claim 1 e), wherein the base is selected from triethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.
13. The process according to claim 1 e), wherein the organic solvent is selected from tetrahydrofuran, diethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, propionitrile, toluene, chloroform, dichloromethane and mixtures thereof.