Field Of Invention:
The present invention provides an improved process for the preparation of N-[3-(3-cyanopyrazolo[l,5-a] pyrimidin-7-yl) phenyl]-N-ethyl acetamide (Zaieplon), which is useful as anxiolytic, antiepileptic, sedative hypnotic agent and skeletal muscle relaxant. Zaieplon may be represented as the Formula (1):

The invention, more particularly, provides an improved process for the large-scale production of Zaieplon. Background of Invention
USP 4,626,538 teaches a method of making the desired compound N-[3-0-cyanopyrazolo[l,5-a] pyrimidin-7-yl) phenyl]-N-ethyl acetamide (Zaieplon) of Formula (1), by reaction of 3-dimethylamino-l-(3-N-ethyl-N-acetylamino phenyl)-2-propene-l-one with 3-amino pyrazole-4-carbonitrile in acetic acid. The patent also describes the preparation of derivatives of Zaieplon and their method of use along with composition.

EP 0776898 Al describes a method for synthesis of desired compound N-[3-(3-cyanopyrazolo[l,5-a] pyrimidin-7-yl) phenyl]-N-ethyl acetamide (Zaleplon), by the reaction of 3-dimethylamino-l- (3-N-ethyl-N-acetylamino phenyl)-2-propene-l-one or suitable salt with 3-amino pyrazole-4-carbonitrile or suitable salt in a mixture comprising of water and acetic acid, where the percentage of water in acetic acid varies from 11% to 75%, preferably water and acetic acid ratio is 1: 2 (v / v).
It is noteworthy to mention that the procedure disclosed in EP 0776898 involves, usage of the expensive acetic acid, hence the process renders a high cost process. Zaleplon obtained with the process described in the patent is having an excess percentage of isomeric impurity.
As Zaleplon is useful as anxiolytic, antiepileptic, sedative hypnotic agent and skeletal muscle relaxant, it is important to have a cost effective and commercially viable process for preparing the compound of Formula (1).
The present invention provides an improved and more efficient method for preparation of
Zaleplon, which involves commercially cheaper Formic acid with water. The process is more
convenient for commercial production.
The product is obtained with a yield of 90.0% in a single lot having a purity of >99.5% and an
isomeric impurity <0.1% in the present invention.
The main objective of the present invention is to develop a process for preparing the
compound of Formula (1), which is cost effective and commercially viable.
Summary of the Invention:
The present invention provides an improved and more efficient process for the preparation of Zaleplon of Formula (1), which comprises the condensation of 3-dimethylamino-l- (3-N-ethyl-N-acetylamino phenyl)-2-propene-l-one or suitable salt with 3-amino pyrazole-4-carbonitrile or suitable salt in an aqueous mixture of Formic acid or Propionic acid. The

process is more cost effective, commercially viable; the product is obtained with 90.0% yield
in a single lot with a higher purity (i.e.. Purity: >99.5%. Isomeric impurity: <0.1%) than the
prior art references.
Detailed Description of the Invention:
Accordingly, the present invention provides an improved process for the preparation of N-[3-
(3-cyanopyrazolo[l,5-a] pyrimidin-7-yl) phenyl]-N-ethyl acetamide (Zalepion). which
comprises: -
i. reaction of 3-dimethyl amino-l-(3-N-ethyl-N-acetyl amino phenyl)-2-
propene-l-oneofFormu(a-(2)ora suitable salt thereof with 3-amino pyrazole-4-carbonitrile of Formula-(3) or a suitable salt thereof in a mixture comprising water and an organic acid such as fonnic acid or propionic acid, preferably formic acid in a ratio such that Fonnic acid : Water is 1: 0.5 to 4, preferably 1:1 in volumetric ratios; ii. stirring of the mass of step-(i) at a temperature of 25 -100 " C, preferably at
a temperature of 25-40u C till the reaction substantially completes; iii. cooling the reaction mixture of step-(ii) to a temperature of 0 - 25 "C.
preferably 0-10°C;
iv. stirring of the reaction mixture of step-(iii) for 1-4 hours, preferably 1 hour:
v. isolation of separated solid obtained from step-(iv) by conventional
methods, accompanied by water washings; vi. drying the desired product at 50-80"C.

The compound Zaleplon of Formula (1) was obtained in good yield with high purity (i.e., >99.5%, Isomeric impurity: <0.1%) with the ratio of Formic acid : Water in step (i) is 1:1 in volumetric ratios.
Water may suitably added to formic acid at the beginning of the process. Alternatively it may be added to the reaction mixture during the process, in portions or in gradually increasing the volume of water portions. One aspect of the invention involves the addition of first portion of water at the beginning of the reaction and followed by the addition of second portion of water after completion of the reaction has given the product in a good yield and purity. The reaction was generally completed in 12-16 hours at a temperature of 25-40 C according to the above procedure as mentioned in step (ii).
Accordingly, the above process has produced Zaleplon in extremely high purity (i.e., >99.5%. Isomeric impurity: <0.1%) and in high yield (-90.0%) by using an aqueous mixture of formic acid at about 25% to 50% (v/v). In addition, the isomeric impurity is very less and the reaction temperature decreases from 50-55 ° C (as mentioned in the prior art) to a temperature of 25-40 ° C. In contrast, the known prior art methods use acetic acid and water mixture results a product consisting of isomeric impurity at higher levels. The present process produced the compound with less isomeric impurity and good yield; hence the present process renders more cost effective than prior art methods.
The following synthetic scheme illustrates an improved process of the present invention, which comprises the reaction of 3-dimethylamino-l- <3-N-ethy]-N-acetylaminophenyl)-2-propen-1-one of Formula (2) with3-aminopyrazoie-4-carbonitrile of Formula (3) to afford N-[3-(3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl-N-ethyl acetamide (Zaleplon) of Formula (1).


The present invention will be explained in more detail with reference to the following
examples, which are provided by way of illustration only and should not be construed to limit
the scope of the invention.
Examples:
Example-1:
A mixture of 3-dimethyl amino-l-(3-N-ethyl-N-acetyl amino phenyl)-2-propene-l-one (25
grams. 0.0% Moles) and 3-amino pyrazole-4-carbonitrile (11.0 grams. 0.101 Moles ) were
added to formic acid (125 ml) and water (125 ml). The reaction mixture was heated to 25-

40llC and stirred for 12-14 hours, further the reaction mixture was cooled lo 0-10(1C and allowed io crystalline the product under stirring. The separated crystalline solid was filtered, washed with water. Further the compound was dried at 60-70°C to afford the desired product Zaleplon.
(Yield: 26.7 grams. 91.0%, Purity: 99.59%, Isomeric impurity: 0.07%). The following examples shows the results of various experiments, which are conducted to check the effect on yield and purity of the desired compound by varying the factors such as mole ratio of the reactants, conditions of the reaction and reaction time. Example-2:
3-dimetbyl amino-1- (3-N-ethyl-N-acetyl amino phenyl)-2-propene-l -one (10.0 grams, 0.038 Moles) and 3-amino pyrazole-4-carbonitrile (4.4 grams, 0.040 Moles) was added to the mixture of formic acid (25ml) and water (50 ml). The reaction mixture was heated to 40-50"C and stirred for 1.0 to 1.5 hours. Further the reaction mixture was cooled to 0-10°C and allowed to crystallize the product under stirring. The desired crystallized product was filtered, washed with water and further dried at 60-70°C to afford the desired product Zaleplon. (Yield: 10.5 grams, 89.6%, Purity: 99.4%, Isomeric impurity: 0.2%). Example-3:
A mixture of 3-dimethyl amino-l-(3-N-ethyl-N-acetyl amino phenyl)-2-propene-1 -one (10.0 grams, 0.038 Moles) and 3-amino pyrazole-4-carbonitrile(4.4 grams, 0.040 Moles) were added to formic acid (25 ml) and water (50 ml). The reaction mixture was heated to 50-55T and stirred for 1.0-1.5 hours. Further the reaction mixture was cooled to 0-10"C and allowed to crystallize the product under stirring, the desired crystallized product was filtered, washed with water and further dried at 60-70"C to afford the product Zaleplon. (Yield: 10.5 grams, 89.5%, Purity: 99.34%, Isomeric impurity: 0.23%).

ExampIe-4:
3-dimethylamino-l-{3-N-ethyl-N-acety!aminophenyl)-2-propen-l-one(!0.0 grams, 0.038 Moles) and 3-amino pyrazo!e-4-carbonitrile(4.4 grams, 0.040 Moles) was added to the mixture of formic acid (50 ml) and water (50 ml). The reaction mixture was heated to 40-50"C and stirred for 1.0-1.5 hours. Further the reaction mixture was cooled to 0-10°C and allowed to crystallize the product under stirring. The desired crystallized product was filtered, washed with water and further dried at 60-70°C to afford the Zaleplon. (Yield: 9.4 grams. 80%, Purity: 99.2%, Isomeric impurity: 0.2%). Example-5:
A mixture of 3-dimethyl amino-l-(3-N-ethyl-N-acetyl amino phenyl)-2-propene-l -one (25.0 grams, .096 Moles ) and 3-amino pyrazole-4-carbonitrile (11.0 grams, 0.100 Moles ) were stirred at 25-40"C in formic acid { 125ml) and water (125 ml) for 20-25 hours. Further the reaction mixture was cooled to 0-10"C and allowed to crystallize the product under stirring, the desired crystallized product was filtered, washed with water and further dried at 60-70"C to afford the product Zaleplon (Yield: 22.4 grams, 76.5%. Purity: 99.76%, Isomer impurity : 0.03%). Example-6:
3-diinethylamino-l-(3-N-ethyl-N-acetylaminophenyl)-2-propen-l-one (10.0 grams. 0.038 Moles) and 3-amino pyrazole-4-carbonitriie(4.4 grams, 0.040 Moles) was added to the mixture of formic acid (50 ml) and water (50 ml). The reaction mixture was heated to 95-100°C and stirred for 30-60 min. Further the reaction mixture was cooled to O-lOV and allowed to crystallize the product under stirring. The desired crystallized product was filtered, washed with water and further dried at 60-70°C to afford the Zaleplon. (Yield: 10.1 grams, 86%, Purity: 99.07%, Isomeric impurity: 0.15%).

Example-7:
3-dimethylamino-i-(3-N-ethyl-N-acetylaminophenyl)-2-propen-l-one{ 10.0 grams, 0.038 Moles) and 3-amino pyrazole-4-carbonitrile(4.4 grams, 0.040 Moles) was added to the mixture of propionic acid (50 ml) and water (50 ml). The reaction mixture was heated to 40-50"C and stirred for 6-7 hours. Further the reaction mixture was cooled to 0-10"C and allowed to crystalline product under stirring. The desired crystallized product was filtered, washed with water and further dried at 60~70"C to afford the Zaleplon. (Yield: 7.5 grams, 64%, Purity: 96.5%, Isomeric impurity: 2.83%).
We claim:
1. An improved process for the preparation of N-[3-(3-cyanopyra£olo[1.5-a] pyrimidin-
7-yl) phenyl]-N-ethyl acetamide (Zaleplon), which comprises: -i. reaction of 3-dimethy! amino-]-(3-N-ethyl-N-acetyl amino phenyl)-2-propene-l~ one of Formula-(2) or a suitable salt thereof with 3-amino pyrazo!e-4-carbonitrile of Formula-(3) or a suitable salt thereof in a mixture comprising water and an organic acid such as formic acid or propionic acid, preferably formic acid in a ratio such that Formic acid : Water is 1: 0.5 to 4, preferably 1:1 in volumetric ratios;
ii. stirring of the mass of step-(i) at a temperature of 25 -100" C, preferably at a temperature of 25-40 "C till the reaction substantially completes;
iii. cooling the reaction mixture of step-(ii) to a temperature of 0 - 25 "C. preferably 0-10"C;
iv. stirring of the reaction mixture of step-(iii) for 1-4 hours, preferably 1 hour;

v. isolation of separated solid obtained from step-(iv) by conventional methods.
accompanied by water washings; vi. drying the desired product at 50-80 ° C.
2. The process as claimed in claim-1 of step (i), wherein the organic acid is formic acid.
3. The process as claimed in claim-1 of step (i), where in the reaction is carried in a mixture comprising 25% to 50% v/v of formic acid: water.
4. The process as claimed in claim-1 of step (i), where in the reaction is carried in a mixture of formic acid: water is 1 : 1 in volumetric ratio.
5. The process as claimed in claim-1 of step (iii), wherein the reaction temperature is 25-40°C.
6. An improved process for the preparation of Zaleplon as herein described with
particular reference to examples.