Field of the Invention:
The present invention relates to novel crystalline form of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide compound of formula-1, which is represented by the following structural formula:
The present invention also relates to improved processes for the preparation of amorphous form and crystalline form-I of the compound of formula-1.
Background of the Invention:
2-{4-[(5,6-diphenylpyrazm-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide is known as Selexipag. It is developed by Nippon Shinyaku under the brand name Uptravi®, for the treatment of pulmonary arterial hypertension.
2-{4-[(5,6-diphenylpyrazm-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide was firstly described in US7205302B2 herein after referred as US'302. The said patent also describes its process for the preparation.
US8791122 (herein after referred as US'122) patent describes crystalline form-I, II and III of 2-{4-[(5}6^iphenylpyrazm-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide. Because of drug compounds having, for example, improved stability, solubility, shelf life and in vivo pharmacology, are consistently sought, there is an ongoing need for new or pure salts, hydrates, solvates and polymorphic forms of existing drug molecules. The novel crystalline form of 2- {4-[(5,6-diphenyIpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide described herein help meet this and other needs.
US* 122 patent describes amorphous form of the compound of formula-1. This patent does not disclose any detailed process for amorphous form and PXRD pattern of amorphous compound of formula-1.

The present invention provides an improved process for the preparation of amorphous form of the compound of formula-1.
Brief Description:
The first aspect of the present invention is to provide novel crystalline form of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino] butoxy} -N-(methylsulfonyl) acetamide compound of formula-1, herein after designated as crystalline form-D.
The second aspect of the present invention is to provide process for the preparation of crystalline form-D of 2- {4-[(5}6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methyl sulfonyl) acetamide compound of formula-1.
The third aspect of the present invention is to provide an improved process for the preparation of amorphous form of 2-{4-[(5)6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
The fourth aspect of the present invention is to provide an improved process for the preparation of crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-
yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Figure 2: Illustrates the IR spectrum crystalline form-D of 2-{4-[(5J6-diphenylpyrazin-2-
yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Figure 3: Illustrates the PXRD pattern of amorphous form of 2-{4-[(5,6-diphenylpyrazin-2-
yl)(isopropyl) amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula-1.
Figure 4: Illustrates the IR spectrum of amorphous form of 2-{4-[(5,6-diphenylpyrazin-2-
yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Figure 5: Illustrates the DSC thermogram of crystalline form-D of 2-{4-[(5,6-diphenyIpyrazin-
2-yI) (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Detailed Description:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane,

cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1; 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The first aspect of the present invention provides novel crystalline form-D of 2-{4-[(5,6-diphenyIpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula-1. The crystalline form-D of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 4.1, 6.3, 11.7, 12.2, 16.0, 17.8, 19.9, 20.8, 21.7, 23.2 & 24.4± 0.2° 20 and further it is depicted in figure-1. The crystalline form-D of the present invention is characterized by its IR spectrum and is further depicted in figure-2.
The second aspect of the present invention provides a process for the preparation of the crystalline form-D of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at a suitable temperature optionally under reduced pressure,
b) adding the obtained compound in step-a) to pre-cooled solvent system,
c) stirring the reaction mixture at a suitable temperature,
d) filtering the obtained solid in step-c) provides the crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound

of formula-1. Wherein in step-a) the suitable temperature is 100 to 150°C, preferably 130-145°C; in step b) the solvent system may be a single solvent or mixture of solvents and is selected from hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents; preferably hydrocarbon solvents; most preferably n-heptane; in step c) the suitable temperature is below 30°C.
Preferred embodiment of the present invention provides a process for the preparation of the crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at 13 5-145°C under reduced pressure,
b) adding the obtained compound in step-a) to pre-cooled n-heptane,
c) stirring the reaction mixture at 0-5°C,
d) filtering the obtained solid in step-c) provides the crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound offormula-1.
Further embodiment of the present invention provides a process for the preparation of the crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at 150-170°C,
b) adding the compound obtained in step-a) to pre-cooled n-heptane,
c) stirring the reaction mixture for 1 hour at 0-5°C,
d) filtering the obtained solid in step-c) provides the crystalline form-D of 2-{4-[(5,6-diphenyl pyrazin-2-yl) (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Further aspect of the present invention crystalline form-D of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1 according to the present invention having particle size of D(0.9) < 200 urn, preferably D(0.9) < 150 urn.
The third aspect of the. present invention provides an improved process for the

preparation of amorphous form of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula-1; comprising of melting the compound of formula-1 by heating to a temperature 100 to 150°C, preferably 130 to 145°C optionally under reduced pressure and cooled the obtained residue to a temperature below 30°C, preferably 0-5°C to provide pure amorphous form of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Preferred embodiment of the present invention provides an improved process for the preparation of amorphous form of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1; comprising of melting the compound of formula-1 by heating at 135-145°C under reduced pressure and cooled the obtained residue to 0-5°C to provide pure amorphous form of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino] butoxy} -N-(methylsulfonyl) acetamide compound of formula-1.
Further embodiment of the present invention provides an improved process for the preparation of amorphous of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy} -N-(methyl sulfonyl) acetamide compound of formula-1; comprising of:
a) Heating the compound of formula-1 at 150-170°C ,
b) cooling the obtained residue to below 0-5°C ,
c) drying the obtained solid to provide an amorphous form of 2-{4-[(5,6-diphenyl pyrazin-2-yl) (isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1 and its PXRD pattern is shown in figure-3 and its IR spectrum is shown in figure-4.
The fourth aspect of the present invention provides an improved process for the preparation of the crystalline form-I of 2-{4-[(5,6-diphenyIpyrazin-2-yl)(isopropyl)amino] butoxy} -N-(methylsulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at a suitable temperature optionally under reduced pressure,
b) cooling the obtained compound to a suitable temperature,
c) adding a suitable solvent to the obtained compound in step-b),
d) stirring the reaction mixture,
e) cooling the reaction mixture to a suitable temperature and stirring the reaction mixture,

f) further cooling the reaction mixture to a suitable temperature and stirring the reaction mixture,
g) filtering the precipitated solid in step-f) provides the crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Wherein in step-a) the suitable temperature is 120 to 150°C, preferably 130-145°C;
in step-b) the suitable temperature is below 120°C;
in step-c) the suitable solvent may be a single solvent or mixture of solvents and is selected from
hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents; preferably hydrocarbon
solvents; most preferably n-heptane;
in step e) the suitable temperature is 20-40°C; preferably 25-35°C;
in step-f) the suitable temperature is below 20°C; preferably 0-5°C.
Preferred embodiment of the present invention provides an improved process for the preparation of the crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino] butoxy}-N-(methylsulfonyl) acetamide compound of.formula-1; comprising of:
a) Melting the compound of formula-1 at 135-145°C underreduced pressure,
b) cooling the obtained compound to 110-120°C,
c) adding n-heptane to the obtained compound in step-b),
d) stirring the reaction mixture,
e) cooling the reaction mixture to 25-35°C and stirring the reaction mixture,
f) further cooling the reaction mixture to 0-5°C and stirring the reaction mixture,
g) filtering the precipitated solid in step-f) provides the crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
Further embodiment of the present invention provides an improved process for the preparation of the crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyI)amino] butoxy}-N-(methylsulfonyl) acetamide compound of formula-1; comprising of:
a) Melting the compound of formula-1 at 150-170°C ,
b) cooling the obtained compound to 110-120°C,
c) adding n-heptane to the compound obtained in step-b),

d) stirring the reaction mixture,.
e) cooling the reaction mixture to 25-35°C and stirring the reaction mixture,
f) further cooling the reaction mixture to 0-5°C and stirring the reaction mixture,
g) filtering the precipitated solid in step-f) provides the crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
The term "melting" refers to "heating the compound up to completely melted the compound" at a suitable temperature optionally under reduced pressure.
2-{4-[(5,6-diphenylpyrazm-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide was carried out using BRUKER-AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°; step time : 0.22 sec and step size: 0.03°C.
Differential scanning calorimetric (DSC) analysis was performed on Q10 V9.9 Build 303 calorimeter (or) Q2000 V24.11 Build 124 calorimeter with aluminium pans, heating the samples from 40 to 200°C under closed conditions at a rate of 10.00°C/min.
IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
2- {4-[(5.6-diphenylpyrazm-2-yl)(isopropyl)amino]butpxy} -N-(methylsulfonyl) acetamide compound of formula-1 used in the present invention is synthesized by the prior known processes or according to US7205302B2.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of crystalline form-D of compound of formula-1
Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15
minutes. The above obtained residue was added to 100 ml of pre-cooled n-heptane (cooled at 0-
5°C). Stirred the reaction mixture for 60 minutes at 0-5°C. Filtered the precipitated solid, washed
with n-heptane and dried to get the title compound.
Yield: 9 gm; PXRD of the obtained compound is depicted in figure-1 and IR is depicted in
figure-2.
Example-2: Preparation of amorphous form of compound of formula-1
Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes and the above obtained residue was cooled to 0-5°C. Unload the obtained compound and dried to get the title compound.
Yield: 9 gm; Purity by HPLC: 99.74%; PXRD of the obtained compound is depicted in figure-3 and IR is depicted in figure-4.
ExampIe-3: Preparation of crystalline form-1 of compound of formula-1
Melting the compound of formula-1 (5 gm) at 140-145°C under reduced pressure for 15 minutes. 50 ml of n-heptane was added to the above obtained residue at 115-120°C. Stirred the reaction mixture for 20 minutes at 115-120°C. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 60 minutes at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 4 gm; Purity by HPLC: 99.68%.
Example-4: Preparation of crystalline form-D of compound of formula-1.
Sodium t-butoxide (40 gm) was added to pre-cooled solution of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (25 gm) in n-methyl pyrrolidone (100 ml) at 0-5°C and stirred

the reaction mixture for 45 min at same temperature. 2-chloro-N-(methylsulfonyl)acetamide (35.5 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 5 hours. The reaction mixture was poured into pre-cooled water at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. The reaction mixture was washed with methyl tertiary butyl ether. Acidified the reaction mixture using acetic acid at 0-5°C. The temperature of the reaction mixture was raised to 25-30°C and separated both the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate and combined the organic layers. The organic layer was washed with aqueous sodium chloride solution and dried the organic layer with sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol. Methanol (1000 ml) was added to the obtained residue at 25-30°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid and washed with methanol. Dissolved the obtained compound in 1200 ml of methanol at 60-65°C and filtered the . solution through hyflow bed and washed with methanol. Cooled the filtrate to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with methanol. The obtained wet solid was dissolved in a mixture of ethyl acetate (150 ml) and ethanol (150 ml) at 80-85°C. Charcoal (10 gm) was added to the solution at 80-85°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with a mixture of ethanol and ethyl acetate. The filtrate was cooled to 25-35°C and stirred for 5 hours at same temperature. Filtered the precipitated solid and washed the mixture of ethyl acetate and ethanol. Heated the obtained compound to 160-165°C for 15 minutes. The above obtained oily residue was added to 500 ml of pre-cooled n-heptane at 0-5°C. Stirred the reaction mixture for 1 hour at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.
Yield: 49 gm. Purity by HPLC: 99.74%. PXRD of the obtained compound is depicted in figure-1, IR is depicted in figure-2 and DSC thermogram is illustrated in figure-5.
Example-5: Preparation of crystalline form-D of compound of formula-1
Melting the compound of formula-1 (10 gm) at 160-165°C under reduced pressure for 15 minutes. The above obtained residue was added to 100 ml of pre-cooled n-heptane (cooled at 0-5°C). Stirred the reaction mixture for 60 minutes at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 9 gm.
Example-6: Preparation of crystalline form-I of compound of formula-1
Melting the compound of formula-1 (5 gm) at 160-165°C for 15 minutes. 50 ml of n-heptane was added to the above obtained residue at 115-120°C. Stirred the reaction mixture for 20 minutes at 115-120°C. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 60 minutes at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 4 gm.
Example-7: Preparation of amorphous form of compound of formula-1
Melting the compound of formula-1 (10 gm) at 160-165°C under reduced pressure for 15 minutes and the above obtained oily residue was cooled to 0-5°C. Unload the obtained compound and dried to get the title compound. Yield: 9 gm.

We Claim:
1. A process for the preparation of the crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl)
(isopropyl)amino]butoxy}-N-(methyl sulfonyl) acetamide compound of formula-1
comprising of:
a) Heating the compound of formula-1 to a suitable temperature optionally under reduced pressure,
b) combining the oily residue obtained in step-a) to the solvent system at a suitable temperature,
c) stirring the reaction mixture for less than 2 hours at a suitable temperature,
d) filtering the solid obtained in step-c) provides the crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino] butoxy}-N-(methylsulfonyl) acetamide compound of formula-1.
2. The process according to claim 1, wherein in step-a) the suitable temperature is 90 to 170°C,
preferably 140-170°C;
in step b) the solvent system is a single solvent or mixture of solvents and is selected from hydrocarbon solvents, ester solvents, chloro solvents, ketone solvents; preferably hydrocarbon solvents; most preferably n-heptane; in steps-b) and c) the suitable temperature is below 40°C.
3. A process for the preparation of the crystalline form-D of compound of formula-1 and
characterized by any of the following:
i) X-ray diffractogram having peaks at about 4.1, 6.3, 11.7, 12.2, 16.0, 17.8, 19.9,20.8,21.7,
23.2&24.4±0.2°29;or ii) its powder X-Ray diffraction pattern substantially in accordance with that shown in
figure-1; or iii) its differential scanning calorimetric (DSC) thermogram shown in figure-3,
the process comprising:
a) heating the compound of formula-1 to 140-170°C under reduced pressure,
b) combining the oily residue obtained in step-a) to pre-cooled n-heptane,
c) stirring the reaction mixture for less than 2 hours at below 35°C,
d) filtering the obtained solid in step-c) to provide the crystalline form-D of compound of formula-1.

4. An improved process for the preparation of the crystalline form-I of 2-{4-[(5,6-diphenyl
pyrazin-2-yl)(isopropyl)amino] butoxy} -N-(methylsulfonyl) acetamide compound of
formula-1; comprising of:
a) Melting the compound of formula-1 at 140-170°C optionally under reduced pressure,
b) cooling the obtained compound to 110-120°C,
c) adding n-heptane to the compound obtained in step-b),
d) stirring the reaction mixture,
e) cooling the reaction mixture to 25-35°C and stirring the reaction mixture,
f) further cooling the reaction mixture to 0-5°C and stirring the reaction mixture,
g) filtering the precipitated solid in step-f) provides the crystalline form-I of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula-1.
5. Crystalline fonn-D of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino] butoxy}-N-
(methylsulfonyl) acetamide compound of formula-1 obtained according to any preceding
claims having particle size of D(0.9) < 200 urn, preferably D(0.9) < 150 um.
6. Use of crystalline form-D of 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl) amino] butoxy}-
• N-(methylsulfonyl) acetamide compound of formula-1 obtained according to any of
preceding claims in the preparation of pharmaceutical composition.
7. The pharmaceutical composition comprising 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)
amino] butoxy}-N-(methylsulfonyl) acetamide compound of formula-1 obtained according
to any of preceding claims and a pharmaceutically acceptable carrier.