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

“PREPARATION OF (Z)-2,2,2-TRIFLUORO-N-(PIPERAZIN-2-YLIDENE)ACETOHYDRAZIDE”

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 the preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide.

BACKGROUND OF THE INVENTION
(Z)-2,2,2-Trifluoro-N-(piperazin-2-ylidene)acetohydrazide is an important intermediate of sitagliptin, an oral drug for the treatment of type II diabetes.
The following processes are known for the preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide.
U.S. Pat. No. 8,969,558 provides a process for preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide from 5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole by reacting it with ethylene diamine in methanol to form (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide in 46.8% yield. This process involves formation of multiple impurities and is not feasible at a commercial scale.
Therefore, there is a need in the art to provide an efficient and industrially applicable process for the preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide to meet its high demand as a raw material for sitagliptin.
The inventors of the present invention provides a simple, cost effective and industrially viable process for preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide.

OBJECT OF THE INVENTION
The object of the present invention is to provide an economical, safe, and commercially applicable process for the preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide. The process provides high yield of highly purified product with substantial absence of impurities.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide, comprising the steps;
a) cyclizing 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide using phosphorus oxychloride to form a reaction mixture;
b) reacting the reaction mixture obtained in step a) with ethylene diamine in a solvent to obtain (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide of purity greater than 90%.

DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, cyclization of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide is carried out in a solvent selected from hydrocarbons such as hexane, heptane, xylene, toluene, chlorohydrocarbon and dichloromethane.
In a preferred embodiment, cyclization of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide is carried out in toluene.
In an embodiment, toluene is introduced in the 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide at a reaction temperature of 15-20°C.
In another embodiment, cyclization of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide is carried out using phosphorus oxychloride, wherein phosphorus oxychloride is introduced into the reaction mixture in dropwise manner at a reaction temperature of 15-20°C and in a period of 60 to 90 minutes.
In an embodiment, cyclization of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide with phosphorus oxychloride is carried out at a temperature in the range from 80-85°C.
In another embodiment, the reaction of step b) with ethylene diamine is carried out in an alcohol at a reaction temperature of -20 to -30°C, more preferably -20°C and in a period of 2 to 3 hours, more preferably in a period of 2 hours.
In another embodiment, the reaction of step b) with ethylene diamine may be carried out in a polar organic solvent selected from a group consisting of methanol, ethanol, isopropanol, tertiary butanol, pentanol, acetonitrile, and tetrahydrofuran or a mixture thereof.
In another embodiment, 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide is prepared by comprising the steps of:
a) reacting ethyl trifluoroacetate and hydrazine hydrate to form a reaction mixture-1 in an organic solvent;
b) adding chloroacetyl chloride and an aqueous base to the reaction mixture-2 to obtain 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide.
In an embodiment, the (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide, obtained in the present process have purity in the range of 85 to 99%.
In an embodiment, the yield of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide obtained in the present process is in the range of 65 to 95%.
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.

EXAMPLE
Example 1: Preparation of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide:
Methyl tert-butyl ether (700 ml) and hydrazine hydrate (123 gm) were added to a reactor at 25-30°C. The reaction mass was cooled to 5-10°C and a solution of ethyl trifluoroacetate (350 gm in 350 ml of methyl tert-butyl ether) was added dropwise to the reaction mass in 1-2 hours at 5-15°C. After addition, temperature was raised gradually to 20-22°C and stirred for an hour. After completion of the reaction, the reaction mass was cooled to 0-5°C. Chloroacetyl chloride (306 gm) and 50% sodium hydroxide solution (221 gm) were added simultaneously into the reaction mass at 0-10°C in 2-3 hours. After addition, temperature was raised gradually to 20-22°C and reaction mass was stirred for an hour. Water (70 gm) was added into the reaction mass and stirred for 30 minutes. The layers were separated. Toluene (700*2 ml) was added in the organic layer and distilled half volume at 20-30°C under reduce pressure (300-50 mbar) for achieving the water content <0.5% of slurry. Then, slurry was filtered and washed the wet cake with toluene to obtain 1-(chloroacetyl)-2-(trifluoroacetyl) hydrazine.
Purity (GC): 98%;
Yield: 92%.
Example-2: Preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide:
1-(Chloroacetyl)-2-(trifluoroacetyl)hydrazide (178.4 gm) and toluene (464 gm) were charged in a reactor. The reaction mass was cooled to 15-20°C and then phosphorus oxychloride (267 gm) was added dropwise to the reaction mass at the same temperature in a duration of 60-90 minutes. After complete addition, the reaction temperature was raised to 85°C and stirred for 10-15 hours. Thereafter, reaction mass was treated with ethylene diamine (196 gm) and methanol (802 gm) at a temperature of -25°C in a duration of 2 hours. After reaction completion, reaction was raised to -5 to 0°C and maintained for 1 hour. The reaction mass was filtered under reduced pressure and washed with 25% of aqueous methanol at 30°C to obtain the titled compound. Purity: 95-98%;
Example-3: Preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide:
1-(Chloroacetyl)-2-(trifluoroacetyl)hydrazide (178.4 gm) and toluene (464 gm) were charged in a reactor. The reaction mass was cooled to 15-20°C and then phosphorus oxychloride (267 gm) was added dropwise to the reaction mass at the same temperature in a duration of 60-90 minutes. After complete addition, the reaction temperature was raised to 85°C and stirred for 10-15 hours. Thereafter, reaction mass was treated with ethylene diamine (196 gm) and ethanol (800 gm) at a temperature of -25°C in a duration of 2 hours. After reaction completion, reaction was raised to -5 to 0°C and maintained for 1 hour. The reaction mass was filtered under reduced pressure and washed with 25% of aqueous methanol at 30°C to obtain the titled compound. Purity: 88-95 %
Example-4: Preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide:
1-(Chloroacetyl)-2-(trifluoroacetyl)hydrazide (178.4 gm) and heptane (464 gm) were charged in a reactor. The reaction mass was cooled to 15-20°C and then phosphorus oxychloride (267 gm) was added dropwise to the reaction mass at the same temperature in a duration of 60-90 minutes. After complete addition, the reaction temperature was raised to 85°C and stirred for 10-15 hours. Thereafter, reaction mass was treated with ethylene diamine (196 gm) and methanol (802 gm) at a temperature of -25°C in a duration of 2 hours. After reaction completion, reaction was raised to -5 to 0°C and maintained for 1 hour. The reaction mass was filtered under reduced pressure and washed with 25% of aqueous methanol at 30°C to obtain the titled compound. Purity: 95-98 %
Example-5: Preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide:
1-(Chloroacetyl)-2-(trifluoroacetyl)hydrazide (178.4 gm) and toluene (464 gm) were charged in a reactor. The reaction mass was cooled to 15-20°C and then phosphorus oxychloride (267 gm) was added dropwise to the reaction mass at the same temperature in a duration of 60-90 minutes. After complete addition, the reaction temperature was raised to 85°C and stirred for 10-15 hours. Thereafter, reaction mass was treated with ethylene diamine (196 gm) and isopropanol (800 gm) at a temperature of -25°C in a duration of 2 hours. After reaction completion, reaction was raised to -5 to 0°C and maintained for 1 hour. The reaction mass was filtered under reduced pressure and washed with 25% of aqueous methanol at 30°C to obtain the titled compound. Purity: 95-97 %
Example-6: Preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide:
1-(Chloroacetyl)-2-(trifluoroacetyl)hydrazide (178.4 gm) and toluene (464 gm) were charged in a reactor. The reaction mass was cooled to 15-20°C and then phosphorus oxychloride (267 gm) was added dropwise to the reaction mass at the same temperature in a duration of 60-90 minutes. After complete addition, the reaction temperature was raised to 85°C and stirred for 10-15 hours. Thereafter, reaction mass was treated with ethylene diamine (196 gm) and propanol (802 gm) at a temperature of -25°C in a duration of 2 hours. After reaction completion, reaction was raised to -5 to 0°C and maintained for 1 hour.
The reaction mass was filtered under reduced pressure and washed with 25% of aqueous methanol at 30°C to obtain the titled compound. Purity: 94-96 %.
,CLAIMS:WE CLAIM
1. A process for preparation of (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide, comprising the steps;
a) cyclizing 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide using phosphorus oxychloride to form a reaction mixture;
b) reacting the reaction mixture obtained in step a) with ethylene diamine in a solvent to obtain (Z)-2,2,2-trifluoro-N-(piperazin-2-ylidene)acetohydrazide.
2. The process as claimed in claim 1, wherein the cyclization of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide is carried out in a solvent selected from a group consisting of hexane, heptane, xylene, toluene, chlorohydrocarbon and dichloromethane.
3. The process as claimed in claim 1, wherein the cyclization of 1-(chloroacetyl)-2-(trifluoroacetyl)hydrazide is carried out at a temperature selected in the range from 80-85°C.
4. The process as claimed in claim 1, wherein the solvent used in step b) is selected from a group consisting of methanol, ethanol, isopropanol, tertiary butanol, pentanol, acetonitrile, and tetrahydrofuran or a mixture thereof.
5. The process as claimed in claim 1, wherein the step b) reaction is carried out at a temperature selected in the range from -20 to -30°C.
Dated this 26th day of September, 2022.