DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF PYRAZINE DERIVATIVE AND INTERMEDIATE THEREOF”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particular describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I and intermediate thereof. The compounds of formula I are used in wide variety of applications.

Formula I
wherein R1 is hydrogen, alkyl, halogenated alkyl.

BACKGROUND OF THE INVENTION
The compound of formula I is used as intermediate in the preparation of variety of compounds important in pharmaceutical and agriculture industry.
US Publication No. 4,293,552 provides a process for preparation of 2-amino-5-trifluoromethylpyrazine by reacting 4,5-diamino-6-hydroxypyrimidine sulfate with 3,3-dibromo-1,1,1-trifluoropropanone in the presence of a base.
PCT Publication Nos. WO2005014571 and WO2004101546 provides a process for preparation of 2-chloro-5-(trifluoromethyl)pyrazine by heating 5-trifluoromethylpyrazin-2-one with phosphoryl chloride in presence of concentrated sulfuric acid.
The use of phosphoryl chloride fails to provide the required selectivity for preparation of 2-chloro-5-(trifluoromethyl)pyrazine. Therefore, there is a need in the art to develop a selective, efficient and commercially viable process for preparation of the compound of formula I and intermediate thereof.

OBJECT OF THE INVENTION
The main object of present invention is to provide a selective and an efficient process for preparation of a compounds of formula I and intermediates thereof.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of compound of formula I,

Formula I
wherein R1 is hydrogen, alkyl, halogenated alkyl,
comprising a step of chlorinating a compound of formula II,

Formula II
wherein R1 is hydrogen, alkyl, halogenated alkyl,
using chlorinating agent.
In second aspect, the present invention provides a process for preparation of compound of formula II,

Formula II
wherein R1 is hydrogen, alkyl, halogenated alkyl,
comprising a step of reacting 3,3-dibromopropanone derivative with glycinamide in presence of a metal acetate.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkyl” includes unsubstituted and substituted C1-C4 alkyl chain selected from methyl, ethyl, propyl, isopropyl and butyl or the like. “halogenated alkyl” refers to C1-C4 alkyl chain containing halogen such as trifluoromethyl, difluoromethyl, fluoromethyl, dichloromethyl, difluoroethyl, trifluoroethyl and monofluoroethyl.
As used herein, halogen includes chlorine, bromine, iodine and fluorine or the like.
As used herein, “chlorinating agent” includes thionyl chloride, sulfuryl chloride and phosphoryl chloride or the like.
As used herein, “metal acetate” includes sodium acetate and potassium acetate.
In an embodiment of the present invention, the compound of formula I is selected from a group consisting of 2-chloro-5-(trifluoromethyl)pyrazine; 2-chloro-5-(difluoromethyl)pyrazine; 2-chloro-5-(monofluoromethyl)pyrazine; 2-chloro-5-(trichloromethyl)pyrazine; 2-chloro-5-(dichloromethyl)pyrazine and 2-chloro-5-(monochloromethyl)pyrazine or the like.
In another embodiment of the present invention the compound of formula II exists in tautomerism with the corresponding pyrazin-2(1H)-one.
In another embodiment of the present invention, the compound of formula II is selected from a group consisting of 5-(trifluoromethyl)pyrazin-2(1H)-one; 5-(difluoromethyl)pyrazin-2(1H)-one; 5-(monofluoromethyl)pyrazin-2(1H)-one; 5-(trichloromethyl)pyrazin-2(1H)-one; 5-(dichloromethyl)pyrazin-2(1H)-one and 5-(monochloromethyl)pyrazin-2(1H)-one or the like.
In an embodiment of the present invention, 3,3-dibromopropanone derivative is selected from a group consisting of 3,3-dibromo-1,1,1-trifluoropropanone; 3,3-dibromo-1,1-difluoropropanone; 3,3-dibromo-1-fluoropropanone; 1,1-dibromopropanone; 3,3-dibromo-1,1,1-trichloropropanone; 3,3-dibromo-1,1,-dichloropropanone and 3,3-dibromo-1-chloropropanone or the like.
In an embodiment of the present invention, the chlorination is carried out in a solvent selected from a group consisting of acetonitrile, dichloromethane and dichloroethane or the like.
In another embodiment of the present invention, the process of chlorination is carried out in presence of a catalyst selected from a group consisting of N,N-dimethylformamide and N-pyrrolidone or the like.
In another embodiment of the present invention, the catalyst is used in molar ratio of 0.1 to 0.2 equivalents with respect to the compound of formula II.
In another embodiment of the present invention, the chlorination is carried out at a temperature range of 30-50ºC.
In another embodiment of the present invention, the reaction of 3,3-dibromopropanone derivative with glycinamide is carried out in a solvent selected from a group consisting of acetonitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidinone, methanol, ethanol, isopropanol and water or the like.
In another embodiment of the present invention, glycinamide is used as an acid salt wherein acid is selected from the group consisting of hydrochloric acid and hydrobromic acid or the like.
In another embodiment of the present invention the molar ratio of sodium acetate with respect to the 3,3-dibromopropanone derivative is in the range of 3 to 5 equivalents.
In another embodiment of the present invention, the reaction of 3,3-dibromopropanone derivative with glycinamide is carried out at a temperature range of 60-110ºC.
In another embodiment of the present invention, the compound of formula I are isolated using chlorinated solvents selected from a group consisting of dichloromethane, trichloromethane, tetrachloromethane and dichloroethane or the like.
The present invention provides a process for preparation of compound of formula I, having purity greater than 95% and preferably greater than 98%.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore, should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of 3,3-dibromo-1,1,1-trifluoropropan-2-one
Trifluoroacetone (200 g) was added to concentrated sulfuric acid (1840 g) at a temperature of 15 to 20oC. The reaction mass was cooled to a temperature of 5 to 10oC and then liquid bromine (341g) was added dropwise to reaction mass while maintaining reaction mixture at the same temperature. After completion of addition, temperature was raised gradually to 50 to 55oC and the reaction mass was stirred for 18-20 hours. The reaction was monitored by gas chromatography. After completion of reaction, layers were separated, nitrogen gas was passed through the organic layer at a temperature of 25-50oC for 5 to 6 hours to remove residual bromine and obtain 3,3-dibromo-1,1,1-trifluoropropan-2-one.
Purity 99.1%; Yield: 85%.
Example 2: Preparation of 5-(trifluoromethyl)pyrazin-2(1H)-one
Sodium acetate (89 gm) and 3,3-dibromo-1,1,1-trifluoropropan-2-one (73.2 gm) in water (300 gm) was heated at a temperature of 95 to 100°C and stirred for an hour. The reaction mixture was gradually cooled to a temperature of 60 to 65°C. Glycinamide hydrochloride solution (30 gm) in water (60 gm) was added into the reaction mass at a temperature of 60 to 65°C and stirred for 4-5 hours at a temperature of 60 to 65°C. The reaction was monitored by GC-MS. After completion of the reaction, the reaction mass was cooled to a temperature of 25 to 30°C. The reaction mass was extracted with ethyl acetate (4 x 60 gm), the organic layer was washed with 20% sodium chloride solution (30 gm) and concentrated under reduced pressure to obtain 5-(trifluoromethyl)pyrazin-2(1H)-one.
Example 3: Preparation of 2-chloro-5-trifluoropyrazine.
Thionyl chloride (4.35 gm) was added to a mixture of ethylene dichloride (9.95 gm), 5-(trifluoromethyl)pyrazin-2(1H)-one (1.5 gm) and DMF (0.134 gm) and refluxed 40°C to 50°C for an hour. Reaction was monitored by Gas Chromatography. After completion of reaction, temperature was reduced to a temperature of 20 to 30°C. The reaction mass was poured into crushed ice (50 gm) and stirred for 15 minutes and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water (25 mL) and concentrated under reduced pressure to obtain 2-chloro-5-trifluoropyrazine.
,CLAIMS:WE CLAIM
1. A process for preparation of a compound of formula I,

Formula I
wherein R1 is hydrogen, alkyl, halogenated alkyl,
comprising a step of chlorinating a compound of formula II,

Formula II
wherein R1 is hydrogen, alkyl, halogenated alkyl,
using a chlorinating agent.
2. The process as claimed in claim 1, wherein the process for preparation of compound of formula II,

Formula II
wherein R1 is hydrogen, alkyl, halogenated alkyl,
comprises a step of reacting 3,3-dibromopropanone derivative with glycinamide in presence of a metal acetate.
3. The process as claimed in claim 1, wherein the chlorinating agent is selected from a group consisting of thionyl chloride, sulfuryl chloride and phosphoryl chloride.
4. The process as claimed in claim 1, wherein the chlorination is carried out in a solvent selected from a group consisting of acetonitrile, dichloromethane and dichloroethane.
5. The process as claimed in claim 1, wherein the chlorination is carried out in presence of a catalyst selected from a group consisting of N, N-dimethylformamide and N-pyrrolidone.
6. The process as claimed in claim 1, wherein the chlorination is carried out at a temperature range of 30-50ºC.
7. The process as claimed in claim 2, wherein the formation of compound of formula II is carried out at a temperature range of 60-110ºC.
8. The process as claimed in claim 2, wherein the metal acetate is selected from sodium acetate and potassium acetate.
9. The process as claimed in claim 2, wherein the reaction is carried out in a solvent selected from a group consisting of acetonitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidinone, methanol, ethanol, isopropanol and water.
10. The process as claimed in claim 2, wherein the glycinamide is used as a salt of acid selected from a group consisting of hydrochloric acid and hydrobromic acid.

Dated this 23rd day of March, 2022.