FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: "Process for preparation of N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-
ethyl acetamide"
2. APPLICANT (S)
(a) NAME: Centaur Chemicals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Centaur Chemicals Pvt Ltd.
Centaur House, shanti Nagar,VakoIa, Santacruz (e) Mumbai 400055. Tel No. 91-22-66499144 Fax No. 91-22-66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Process for preparation of N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide
Field of Invention
The present invention relates to an improvement in process for producing N-[3-(3-cyanopyrazolo [1, 5-a] pyrimidin-7-yl) phenyl] N- ethyl acetamide (Zaleplon) with better yield, high purity and in shorter reaction time.
Back ground of invention.
Zaleplon, whose IUPAC name is N-[3-(3-cyanopyrazolo[l,5-a] pyrimidin-7-yl)phenyl]N-ethylacetamide, processes anxiolytic, antiepileptic, sedative and hypnotic properties. U.S. Food and drug Administration for short- term treatment of Insomnia have approved this.
Zaleplon and a process for preparing the same is disclosed in U.S. Patent No. 4626,538 which is reproduced in Scheme I here- below:


The process involves reacting N-(3- acetylphenyl)ethanamide with dimethyl formamide dimethylacetal to form N-[ 3-(3-(dimethylamino) -l-oxo-2-propenyl)]acetamide (1) which is then alkylated with ethyl iodide in presence of sodium hydride to give N-[3-(3-dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide (2)
In the last step N-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]N-ethylacetamide is condensed with 3- amino-4-cyno pyrazole in refluxing glacial acetic acid for 8 hours produce the Zaleplon.
US patent 5714607 provide for an improvement over the process disclosed in the US patent 4626538. According to the US patent No. 5714607, Zaleplon may be obtained in improved yield and purity, in case the final step of the of the US Patent 4626538 is modified by adding water to the acetic acid solvent in about 10% to 85% V/V .

It is further revealed that the reaction takes place in the process is faster in the event of adding of water. The improvement envisaged reduces time required for reaction from 3 to 3.5 hours to about 1 to 3.5 hours. The preferred is a temperature of reaction is about 40°C to about 60° C, more preferred temperature is a temperature of about 50° C and the most preferred time is about 1.5 hours. The Zaleplon is obtained in yields range from 81.7% to 90% and HPLC purity range from 98.77% to 99.4%.
The patent WO 02/100828A2 and U.S. 2003/0130291 Al reveals further improvement in Zaleplon process by reacting two intermediates such as, N[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide or salt thereof and 3- amino-4-cyanopyrazole or salt thereof under acidic condition in a reaction medium comprising a mixture of water and a water miscible organic solvent. The reaction is carried out at room temperature and gives better purity of Zaleplon.
The patent WO 03/095456 Al also reveals improvement in Zaleplon process by reacting with two intermediates, such as, N[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide with 3- amino-4-cyno pyrazole in the range of 20 to 80 % (w/w) with preferred concentration at 35-45 % (w/w). The temperature rang is between 20° C- 60°C preferable at 35-45% and time required at this temperature rang is about 2.5 hours. The Zaleplon obtained is of high purity with very little impurity of isomer in crude Zaleplon.
The patent WO 03/068775 Al reveals process for producing Zaleplon by condensing 3- (N-acetyl-N-ethylamino) B-oxo-phenyl propanal sodium salt with 3-amino-4- cyano pyrazole. The sodium salt was produced by first treating 3- acetylamino

acetophenone with an alkali metal hydroxide, in particular with powdered potassium hydroxide and then with an ethylating reagent, in particular ethyl bromide and the N-(3-acetylphenyl)-N-ethyl-acetamide that is obtained is reacted with a formic acid alkylester in the presence of an alkali metal alkanoate, in particular in presence of sodium ethanolate.
Nevertheless, development of more advantages process for production of high purity of Zaleplon with shorter reaction time & lower reaction temperature is still desirable.
SUMMARY OF THE INVENTION
The present invention relates to a process for producing Zaleplon. The process envisaged according to the invention comprises of reacting N [3-[3-(arylamino)-1 -oxo-2-propenyl]phenyl]-N-ethy!acetamide with 3- amino-4- cyano pyrazole hydrochloride in aqueous acetic acid containing hydrochloric acid which produces Zaleplon in high purity, improved yield, shorter reaction time and lower reaction temperature.
DETAILED DESCRIPTION OF THE INVENTION
The improvement in the process for producing Zaleplon envisaged according to the present invention is given in Scheme II


In accordance with Scheme II above, N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyI]-N-ethyl acetamide is reacted with 3- amino-4- cyano pyrazole hydrochloride in aqueous acetic acid containing hydrochloric acid. The percentage of water in acetic acid can be in the range of 10 % to 90% preferably between 30 to 60 %. The reaction is carried out by stirring the reaction mixture at temperature rang of 0°C -50°C preferably at 25°C- 35°C.
Suitable acid for use in the method of present invention include inorganic acid such as hydrochloric acid, hydrobromic acid, Sulfuric Acid, perchloric acid, phosphoric acid, formic acid, propionic acid.

Preferred acid is hydrochloric acid in the amount 0.5 to 5 molar equivalent preferable 2.0 molar equivalent with respect to compound.
The reaction can also be carried out by adding water miscible solvent to above reaction mixture. The suitable water miscible solvents include methanol, ethanol. Isopropanol, Tetrahydrofuran, dioxane, Acetonitrile, hexamethyl phosphoramide (HMPA), hexamethyl phosphorous triamide (HMPT), dimethyl formamide, dimethyl sulfoxide, Any of the above solvents can be used in any combination.The improved conditions shorten the reaction time to about 1 minute to 2 hours.
Anilines used in the process may be unsubstituted or substituted.R1and R2 are selected from the groups consisting of hydrogen, alkyl, alkoxy, halogen. The most preferred is halogen, preferable p-chloroaniline. N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethylacetamide can be prepared starting from N [3-[3-(dimethy!amino)-l-oxo-2-propenyl] phenyl] acetamide in one step by alleviation with ethyl bromide in dimethylformamide using powdered sodium hydroxide as the base followed by reaction with substituted aniline and hydrochloric acid. Use of powdered potassium hydroxide instead of sodium hydroxide also gives similar results.
Alternatively the intermediate N- ethyl derivative can be isolated and treated with substituted aniline-hydrochloric acid in methanol to get N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethylacetamide.

N-[3-[3-(P-Chlorophenylamino) - 1- oxo -2-propenyll phenyll-N-ethylacetamide.
A solution of N [3-[3-(dimethyl amino)-1-oxo-2-propenyl] phenyl]-N-ethylacetamide (100 gm, 0.431 mol) in dimethyl formamide (40 ml) was stirred at 0-5°C and powdered sodium hydroxide(30 gm.0.75 moles) was then added followed by Tetrabutylammonium bromide (1.0 gm). The reaction mixture was stirred at 0-5°C for 15min and then ethyl bromide (72.8 gm, 0.668 moles) was added in 1 hr. The reaction mixture was stirred at room temperature for 2 hrs. p-chloro aniline (66 gms,0.517moles) was then added to reaction mixture followed by addition of concentrated hydrochloric acid (100 ml) at temp 20°C-25°C to obtain pH of reaction mixture in the rang of 3-4. The solution was stirred for 3 to 4 hrs, chilled to 5°-10°C and the crystalline product formed was filtered, washed with water, dried at about 50°C-60°C to yield desired product (130 gm 88.1 %) mp 138°Cto 140°C.
Example 2
N-[3-(3-Cyano pvrazoIo[l,5-alyrimidin-7-vl)phenyI]-N-ethvl acetamide.(Zaleplon)
To a stirred mixture of 3-amino-4-cyano pyrazole hydrochloride (50.6 gms, 0.35 mole) and N-[3-[3-(p-Chlorophenylamino)-l- oxo -2-propenyl] phenyl]-N-ethylacetamide (100 gms, 0.29 moles) in acetic acid (250 ml)and water (125 ml) at room temperature was added hydrochloric acid (60 ml). The solution was stirred for 15 min and then diluted with water (375 ml). The mixture was cooled to 15-20 ↑8 C and stirred for 30 min, and filtered. The solid was washed with water and dried at about at 60 ↑8 C to yield desired product (82 gms, 92 %)

We claim:
1) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide having general formula:

Wherein:
R & R are selected from group consisting of hydrogen, alkyl, alkoxy or halogen.
comprising the steps of:
a) reacting N [3-[3-(dimethyl amino)-l-oxo-2-propenyl] phenyl]-N-ethylacetamide with ethyl bromide in dimethyl formamide at ambient temperature in presence of base and phase transfer catalyst for 2 hours to obtain N-[3-(3-dimethylamino)-1 -oxo-2-propenyl] phenyl] -N-ethylacetamide;
b) condensing N-[3-(3- dimethylamino)-l-oxo-2-propenyl]phenyI]-N~ethylacetamide with substituted aniline in inorganic acid at temperature 20°C to25 °C at pH 1 to 10 for 3 to 4 hours to obtain N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide;
2) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide according to claim 1 wherein, base is used for preparation of N [3-[3-

(aryIamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide is inorganic base such as potassium hydroxide, sodium hydroxide, ammonium hydroxide and potassium carbonate.
3) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyI
acetamide according to claim 1 wherein, preferred inorganic base is sodium hydroxide.
4) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl
acetamide according to claim 1 wherein, phase transfer catalysts are benzytrimethyl
ammonium chloride, hexadecyltributyl phosponium bromide and tributyl ammonium
bromide.
5) A process for preparing N [3-[3-(arylamino)-l-Oxo-2-propenyl] phenyl]-N-ethyl
acetamide according to claim 1 wherein, preferred phase transfer catalyst is tributyl
ammonium bromide.
6) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl
acetamide according to claim 1 wherein, substituted amine having a general formula;

Wherein, R1 & R2 are selected from group consisting of hydrogen, alkyl, alkoxy or halogen.

7) A process for preparing N [3-[3-(aryIamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide according to claim 1 wherein, preferred substituted amine is P-chloroaniline.
8) A process for preparing N [3-[3-(ary]amino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide according to claim 1 wherein, condensation carried out in inorganic acids such as hydrochloric acid, sulphuric acid, ortho-phosporic acid.
9) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl acetamide according to claim 1 wherein, condensation preferably carried out in hydrochloric acid.
10) A process for preparing N [3-[3-(arylamino)-l-oxo-2-propenyl] phenyl]-N-ethyl
acetamide according to claim 1 wherein, condensation preferably carried out at pH 3 to 4.