Field of the Invention:
The present invention relates to improved and novel processes for the preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N-(methylsulfonyl) acetamide of formula-1, which is represented by the following structural formula:

S^

Formula-1

Background of the Invention:
2-{4-[(5>6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide is known as Selexipag. It is developed by Nippon Shinyaku under the brand name 10 Uptravi®, for the treatment of pulmonary arterial hypertension.
2-{4-[(5,6-diphenylpyrazin-2-yl)(isoprppyl)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.
2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) 15 acetamide obtained according to US'302 having less yield and with less purity.
US8791122 patent describes crystalline form-I, II and III of 2-{4-[(5,6-diphenylpyrazm-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 20 polymorphic forms of existing drug molecules. The novel crystalline form of 2-{4-[(5,6-cliphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide described herein help meet this and other needs.
The present inventors designed a modified synthesis for the preparation of the compound of formula-1 over the existing processes. 25 Brief Description:
The first aspect of the present invention is to provide an improved process for the preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide the compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of the compound of formula-1.
The third aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-4.
5 The fourth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
The fifth aspect of the present invention is to provide novel process for the preparation of the compound of formula-6.
The sixth aspect of the present invention is to provide novel process for the preparation of 10 the compound of formula-1.
The seventh aspect of the present invention is to provide novel process for the preparation of the compound of formula-1.
The eighth aspect of the present invention is to provide novel compound of formula-12.
The ninth aspect of the present invention is to provide the process for the preparation of 15 the compound of general formula-5.
The tenth aspect of the present invention is to provide novel crystalline form of the compound of formula-1, herein after designated as crystalline form-M.
Brief description of the drawings: 20 Figure 1: Illustrates the PXRD pattern of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1 obtained according to example-10.
Detailed Description:
25 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
30 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),
3

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.
As used herein the present invention the term "suitable base" refers to inorganic or organic base. Inorganic base refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organo silicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The term "acid" used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid etc.; Lewis acids and like.
The term "coupling agent" used in the present invention is selected form N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 0-(7-aza-benzotriazole-l-yl)-N,N,N\N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl
4

chloro formates such as ethyl chloro formate, ben zylchloro formate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like; optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxy benzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP).

Formula-1
The first aspect of the present invention provides an improved process for the preparation of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula-1,
comprising of: a) Reacting the compound of formula-2

Formula-2
with the compound of general formula-3
H
Formula-3 Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy; in presence of the suitable base in the suitable solvent provides the compound of formula-4
5


r^N

Formula-4,
b) reacting the compound of formula-4 with the compound of general formula-5
X. /\ /\ ^\ .OH
U)
E o

Formula-5 Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy; in presence of the suitable base in a suitable solvent provides the compound of formula-6
N. .N. ^\ ^\.^\ .OH
O
^^
Formula-6, 10 c) reacting the compound of formula-6 with methane sulfonamide in presence of the suitable coupling reagent in presence or absence of base in the suitable solvent provides the compound of formula-1, d) optionally purifying the obtained compound in step-c) using the suitable solvent to get pure compound of formula-1. 15 Wherein, in step-a) to d) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof; in step-a) to c) the suitable base is selected from organic or inorganic base; in step-c) the suitable coupling agent is selected form DCC, CDI, DIC, EDC.HC1, HATU and the 20 like; optionally in combination with HOAt, HOBt, HOCt, TBTU, DMAP optionally in presence of a base.
The second aspect of the present invention provides an improved process for the preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) 25 acetamide compound of formula-1, comprising of: a) Reacting the compound of formula-8

! ■
3
PAtbNit Q FF1 C E C HEKM A,l!

13" %■ / ft 7 / 7. & % k ! t

^<^

Formula-8

with the compound of general formula-9
X-YNH2
O Formula-9
Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy;
in presence of the suitable base in the suitable solvent provides the compound of formula-10
.NH?
^^
Formula-10, 10 b) reacting the compound of Jbrmula-10 with methane sulfonyl chloride in the suitable solvent * optionally in presence of a base provides the compound of formula-1, c) optionally purifying the obtained compound in step-b) using the suitable solvent to get pure
compound of formula-1. Wherein, in step-a) to c) the suitable solvent is selected from hydrocarbon solvents, ketone 15 solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof; in step-a) and b) the suitable base is selected from organic or inorganic base.

Formula-7
The third aspect of the present invention is to provide an improved process for the 20 preparation of the compound of formula-4, comprising of: a) Reacting the compound of general formula-7


Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy;
with isopropyl amine in presence or absence of a base in a suitable solvent provides the
compound of formula-4, b) optionally purifying the obtained compound in step-a) using a suitable solvent provides the
pure compound of formula-4. Wherein, in step-a) and b) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof; in step-a) a base is selected from organic or inorganic base.

10
The fourth aspect of the present invention is to provide an improved process for the preparation of the compound of formula-1, comprising of:
a) Reacting the compound of general formula-7 with isopropyl amine in presence or absence of a base in the suitable solvent provides the compound of formula-4, 15 b) optionally purifying the obtained compound in step-a) using the suitable solvent provides the pure compound of formula-4. c) reacting the compound of formula-4 obtained in step-a) or step-b) with the compound of general formula-5
o
20 Formula-5
Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy;
in presence of the suitable base in the suitable solvent provides the compound of formula-6
,OH O
Formula-6, 25 d) reacting the compound of formula-6 with methane sulfonamide in presence of the suitable coupling reagent in presence or absence of base in a suitable solvent provides the compound of formula-1,
8

10

e) optionally purifying the obtained compound in step-c) using the suitable solvent to get pure
compound of formula-1. Wherein, in step-a) to e) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof;
in step-a), c) and d) the suitable base is selected from organic or inorganic base; in step-d) the suitable coupling agent is selected form DCC, CDI, DIC, EDC.HCl, HATU and the like; optionally in combination with HOAt, HOBt, HOCt, TBTU, DMAP optionally in presence of a base.
The fifth aspect of the present invention provides a novel process for the preparation of the compound of formula-6, comprising of:
a) Reacting the compound of general formula-8


^^
Formula-8

15

with the compound of general formulal 1

,N
X'
20
Formula-11 Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy; in presence or absence of a base in the suitable solvent provides the compound of formula-12
CD U) CO Q_
CD
CN
E o
.N
^^
o
CO CN
o
to
o
CN CO
o 10
CN
%n
Formula-12, b) hydrolysis the compound of formula-12 in presence of the suitable reagent in the suitable solvent provides the compound of formula-6.
iJ- b t t.f 7~^~TWT~^—l~in™"r~t
o
CN
p- A, fe-~EW! iTFFIT"E_XrHrE"Kr^r^:r
lO
o

Wherein, in step-a) to b) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof; in step-a) the suitable base is selected from organic or inorganic base; 5 in step-b) the suitable reagent is acid or base.
The sixth aspect of the present invention provides novel process for the preparation of the compound of formula-1, comprising of:
a) Reacting the compound of general formula-8 with the compound of general formula-11 in
10 presence or absence of a base in the suitable solvent provides the compound of formula-12,
b) hydrolysis the compound of formula-12 in presence of the suitable reagent in the suitable solvent provides the compound of fmorula-6,
c) reacting the compound of formula-6 with methane sulfonamide in presence of the suitable coupling reagent in presence or absence of, base in the suitable solvent provides the
15 compound of formula-1,
d) optionally purifying the obtained compound in step-c) to get pure compound of formula-1.
Wherein, in step-a) to d) the suitable solvent is selected from hydrocarbon solvents, ketone
solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents
and polar solvent like water or their mixture thereof;
20 in step-a) and c) the suitable base is selected from organic or inorganic base; in step-b) the suitable reagent is acid or base.
in step-c) the suitable coupling agent is selected form DCC, CDI, DIC, EDC.HC1, HATU and the
like; optionally in combination with HOAt, HOBt, HOCt, TBTU, DMAP optionally in presence
^ of a base.
U)
«> 25
.« The seventh aspect of the present invention provides novel process for the preparation of
CN
E o
the compound of formula-1, comprising of:
a) Reacting the compound of general formula-8 with the compound of general formula-11 in
o> presence or absence of a base in the suitable solvent provides the compound of formula-12,
o
f5 30 b) hydrolysis the compound of formula-12 in presence of the suitable reagent in the suitable
o
5 solvent provides the compound of formula-10,
o
CO
o
10
lO
o
CN
lO
o

10

c) reacting the compound of formula-10 with methane sulfonyl chloride in the suitable solvent optionally in presence of a base provides the compound of formula-1,
d) optionally purifying the obtained compound in step-c) using the suitable solvent to get pure compound of formula-1.
Wherein, in step-a) to d) the suitable solvent is selected from hydrocarbon solvents, ketone
solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents
and polar solvent like water or their mixture thereof;
in step-a) and c) the suitable base is selected from organic or inorganic base;
in step-b) the suitable reagent is acid or base.
The eighth aspect of the present invention provides a novel compound of formula-12.
.N

Formula-12 Further aspect of the present invention provides the process for the preparation of the 15 compound of formula-12.
N The compound of formula-12 obtained according to the present invention is useful in the preparation of the compound of formula-1.
The ninth aspect of the present invention provides the process for the preparation of the compound of general formula-5, comprising of reacting the compound of general formula-13 20 with the compound of general formula-14
Q_ Formula-13 Formula-14
CN
E
~ Wherein X is a leaving group such as halogen, mesyloxy, or tosyloxy;
in presence or absence of a base in the suitable solvent provides the compound of general
i? 25 formula-5.

^-
o
CN The tenth aspect of the present invention provides a crystalline form-M of the compound
2 of formula-1. The crystalline form-M of the present invention is characterized by its powder X-
CNJ Ray diffraction pattern having peaks at about 3.3, 13.6, 18.1, 20.3 & 21.4± 0.2 degrees of 2-theta
to
o
11
'■ i\. I F hi T fl F- F I f. F f. H F U U A.. T i?t £, / (■* 7 /■ 7 ft t £. I t
lO
^-
o
CN
CN CO
lO
o

and further it is depicted in figure-1.
The process of the present invention can be represented schematically as follows:




r^^
^V*H2
+ X-
Base
r^N
OH
Formula-4
Base
+ H2N-
Formula-6
v1'
Formula-7 7a: X=CI
X'
Formula-13 .OH
Formula-:)
X
°-V;s,
o
Formula-14
6 o'xb

Formula-3
Isopropyl amine
.NH,
Or
o
Formula-9


Formula-10
Wherein X is a leaving group such as halogen, mesyloxy or tosyloxy

12

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.
5 Examples:
Example-1 Preparation of 4-((5,6-dipheny!pyrazin-2-yl)(isopropyl)amino)butan-l-oI compound of formula-8
A mixture of 5-chloro-2,3-diphenylpyrazine (25 gm) compound of formula-7a and 4-(isopropyl amino)butan-l-ol (108 gm) was heated to 190-195°C and stirred the reaction mixture for 10-12
10 hours at same temperature. Cooled the reaction mixture to 25-35°C. To this reaction mixture n-heptane followed by water were added slowly at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filter the precipitated solid, washed with water and dried to get the title compound. Yield: 30 gm.
15 Example-2: Preparation of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetate
Potassium hydroxide solution (96.6 gm of potassium hydroxide dissolved in 175 ml of water) was added to the mixture of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (25lgm) and toluene (175 ml) at 25-30°C and stirred the reaction mixture for 30 minutes at the
20 same temperature. Cooled the reaction mixture to 0-5°C. Tert-butyl bromoacetate (94 gm) was slowly added to the reaction mixture at 0-5°C and stirred the reaction for 60 minutes at same temperature. Raised the temperature of the reaction mixture to 25-30°C and maintained for 60 minutes. Both the aqueous and organic layers were separated. The aqueous layer was extracted with toluene and combined the organic layers. Organic layer was washed with hydrochloric acid
25 solution followed by with aqueous sodium bicarbonate solution. Organic layer was dried with sodium sulphate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 29 gm. Example-3: Preparation of 2-(4-((5,6-diphenyIpyrazin-2-yl)(isopropyl)amino)butoxy)acetic
30 acid compound of formula-6
Aqueous sodium hydroxide solution (7.5 gm of sodium hydroxide was dissolved in 80 ml of
13

water) was added to the solution of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl) amino)butoxy)acetate (30 gm) in methanol (290 ml) at 30-35°C. Heated the reaction mixture to reflux temperature and stirred for 3 hours at the same temperature. Distilled off solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 5 25-30°C. Water was added to the obtained compound and acidified the reaction mixture using diluted hydrochloric acid at the same temperature. Extracted the reaction mixture with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and dried with sodium sulphate. Distilled off the solvent from the organic layer under reduced pressure. Diisopropyl ether (60 ml) was added to the obtained compound at 25-30°C and stirred for 60
10 minutes at the same temperature. Filtered the precipitated solid; washed with diisopropyl ether and dried to get the title compound. Yield: 19 gm.
Example-4: Preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amiiio]butoxy}-N-(methylsulfonyl) acetamide compound of formula-!
15 Triethylamine (9.6 gm) was added to the mixture of 2-(4-((5,6-diphenyIpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (10 gm), dichloromethane (100 ml), N,N-dicyclohexylcarbodiimide (4.9 gm), hydroxybenzotriazole (3.5 gm) and methane sulfonamide (3.39 gm) at 25-30°C and stirred the reaction mixture for 12 hours at the same temperature. Filtered the unwanted compounds from the reaction mixture and washed with dichloromethane.
20 The organic layer was washed with water, followed by with aqueous citric acid solution and then washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (20 ml) and carbon (1 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was
25 slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 4.5 gm.
Example-5: Preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide compound of formula-1
30 Sodium t-butoxide (96.6 gm) was added to the mixture of n-methy pyrrolidinone (125 ml) and 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (25 gm) compound of formula-8 at 0-
14

5°C and stirred the reaction for 20 minutes at the same temperature. 2-chloro-N-(methylsulfonyl)acetamide (23.7 gm) was slowly added to the reaction mixture at 0-5°C and raise the temperature of the reaction mixture to 25-30°C. Stirred the reaction mixture for 10-12 hours at 25-30°C and water was added to it at the same temperature. The reaction mixture was 5 extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (50 ml) and carbon (2.5 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-^
10 heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washec with n-heptane and dried to get the title compound. Yield: 14 gm.
Example-6: Preparation of 2-chIoro-N-(methyIsuIfonyl)acetamide A mixture of methane sulfonamide (100 gm) and chloroacetyl chloride (356.4 gm) was heated to
15 reflux temperature and stirred it for 10 hours at the same temperature. Cooled the reaction mixture to -10 to -5°C and stirred it for 2 hours at the same temperature. Filtered the precipitated solid, washed with toluene followed by n-heptane and dried to get the title compound. Yield: 175 gm. Example-7: Purification of the compound of formula-1
20 Methanol (20 ml) was added to the compound of formula-1 (2 gm) at 25-30°C and heated to reflux temperature. Dichloromethane (3 ml) was added to the reaction mixture at reflux temperature and stirred for 15 minutes at the same temperature. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 2 gm
25 Example-8: Purification of the compound of formula-1
Mesitylene (10 ml) was added to the compound of formula-1 (2 gm) at 25-30°C and heated to 100-105°C. Stirred the reaction mixture for 15 minutes at 100-105°C. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with mesitylene and dried to get the title compound.
30 Yield: 2 gm
Example-9: Purification of the compound of formula-1
15

Ethyl acetate (30 ml) was added to the compound of formula-1 (3 gm) at 25-30°C and heated to reflux temperature. Stirred the reaction mixture for 20 minutes at the same temperature and filtered the reaction mixture. The filtrate was slowly added to the mixture of n-heptane (3 ml) and water (300 ml) at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the 5 precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 2 gm
Example-10: Preparation of crystalline form-M of compound of formula-1 Ethyl acetate (10 ml) and water (2 ml) was added to the compound of formula-1 (2 gm) at 25-30°C and heated to reflux temperature. Stirred the reaction mixture for 20 minutes at the same
10 temperature and filtered the reaction mixture. Distilled off the filtrate under reduced pressure and cooled to 25-30°C. 10 ml of n-heptane was added to the obtained compound at 25-30°C and stirred it for 45 minutes at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 2 gm; PXRD of the obtained compound is illustrated in figure-1.
15
20
U) CO
ft- 25
CD
30
P^TE::,