WO2004035585A1

WO2004035585A1 - Synthesis of zaleplon

Info

Publication number: WO2004035585A1
Application number: PCT/IN2002/000209
Authority: WO
Inventors: Renugadevi Gurusamy; Sankara Subramanian RAJARAM
Original assignee: Sanmar Speciality Chemicals Ltd
Current assignee: Sanmar Speciality Chemicals Ltd
Priority date: 2002-10-16
Filing date: 2002-10-16
Publication date: 2004-04-29
Anticipated expiration: 2005-04-16
Also published as: AU2002343201A1

Abstract

This invention relates to an improvement in the process of synthesizing N-[3-(3-cyanopyrazolo [1,5-a] pyrimindin-7-yl)phenyl]-N-ethyl acetamide. 3-dimethylamino-1-(3-N-ethyl-N-acetylaminophenyl)-2-propen-1-one is reacted with 3-aminopyrazole-4-carbonitrile in an aqueous formic acid reaction medium at a temperature ranging from 40 °C to 70 °C. This process results in better yields and higher purity of the final product.

Description

Synthesis of Zaleplon

Technical field:

N-[3-(3-cyanopyrazolo [1,5-a] ρyrimindin-7-yl) phenyl]-N-ethyl acetamide is an anxiolytic, antiepileptic sedative, hypnotic agent and skeletal muscle relaxant. This compound is being effectively used in curative and prophylactic pharmaceutical compositions against manifestations of the aforesaid symptoms.

Background Art:

US patent no.4,626,538 reports a process for preparing N-[3-(3- cyanopyrazolo [1,5-a] pyrimindin-7-yl) ρhenyl]-N-ethyl acetamide by reacting 3 -dimethylamino- 1 -(3-N-eth.y l-N-acety larninophenyl)-2-ρropen- 1 -one with 3 - aminopyrazole-4-carbonitrile in acetic acid medium.

EP patent no.776,898 Al and US patent no.5,714,607 report an improvement once the above referenced US patent no.4,626,538 resulting in better yield and purity of the final product. This improvement consists of adding water to acetic acid medium during the reaction.

Disclosure of the invention:

It is the object of this invention to provide a one-pot process for the preparation of N-[3-(3-cyanopyrazolo [1,5-a] ρyrimindin-7-yl) phenyι]-N-efhyl acetamide resulting in hitherto unreported yield and purity. It has now been found that the yield and purity of N-[3-(3- cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide can be enhanced by carrying out the reaction of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one with 3-amino pyrazole-4-carbonitrile in the presence of aqueous formic acid instead of aqueous acetic acid as reported in prior art literature. Formic acid is odourless, environment friendly and leads to a cost-effective process for manufacturing the title compound.

Yet another advantage of using aqueous formic acid instead of acetic acid the invented process is that the time for completion of the reaction is decreased from 3.5 hours to about 1 hr. Further, it is noticed that the reaction temperature is decreased to about 50°C as against the reflux temperature of about 90°C in the prior art. The product crystallizes out in the reaction medium itself on completion of the reaction, thus avoiding multiple process steps. The overall advantage of this improved process are better yields, high purity, reduced reaction time and cost effectiveness. Since crystallization is in situ, this improved process may also be considered as a one-pot process. In the known prior process, the reaction is carried out as the reflux temperature of acetic acid which results in the formation of contaminating side products, which is also avoided in this improved process.

Water and formic acid ratio to be used in this process may be about 20% to 80%. 2:2 v/v of water and formic acid mixture has also been found effective.

This invention relates to a process for synthesising N-[3-(3- cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide which consists of reacting 3-dimethylamino-l-(3-N-ethyl-N-acetylaminophenyl(-2- propen-1-one with 3-amino pyrazole-4-carbonitrile in an aqueous formic and reaction medium and subsequently recovering the product from the reaction mixture in a known manner. The product which crystallizes after the completion of the reaction is of 99% purity and may be filtered off and further purified by recrystallization.

The reaction scheme shown below shows the process of the present invention.

SCHEME 1

Formic acid Water

This reaction is carried out in a reaction medium consisting of 10% to 60% of water and formic acid mixture. After heating the mixture for about 1 hour upto 70°C the reaction is completed. The title compound which is crystallized on cooling of the reaction mixture is filtered. The yield of the product is calculated to be 85% as compared with 76% overall yield obtained when the procedure reported in the US patent no.4,626,538 is used.

WO 02/12244 A2 has reported three crystalline polymorphic forms of N-[3-(3- cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide - Form I, Form II and Form III. The present invention corresponds to Form I, as evidenced by XRD and DSC data.

The invention will now be described with reference to specific embodiments. EXAMPLES

EXAMPLE 1:

N-[3-(3-cyanopyrazolo [1,5-al pyrimindin-7-yr) phenyll-N-ethyl acetamide

A mixture of 5g of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one and 2.1g of 3-aminopyrazole-4- carbonitrile in 15 ml of formic acid and 10 ml water is warmed to 50°C. After about 1 hour the reaction mixture is cooled to a temperature of about 0 to 5°C and the crystalline product formed is filtered, washed with water and dried at 60°C. The product is obtained in 78% yield and the purity by HPLC is 99.61%.

EXAMPLE 2:

N-[3-(3-cyanopyrazolo [1,5-al pyrimindin-7-yl) phenyll-N-ethyl acetamide

A mixture of 5g of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one and 2.1g of 3-aminopyrazole-4- carbonitrile in 15 ml of formic acid and 45 ml water is warmed to 50°C. After about 1 hour the reaction mixture is cooled to a temperature of about 0 to 5°C and the crystalline product formed is filtered, washed with water and dried at 60°C. The product is obtained in 70% yield and the purity by HPLC is 99.80%. EXAMPLE 3:

N-[3-(3-cyanopyrazolo [1,5-a] pyrimindin-7-vD phenyll-N-ethyl acetamide

A mixture of 5g of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one and 2.1g of 3-aminopyrazole-4- carbonitrile in 10 ml of formic acid and 20 ml water is warmed to 50°C. After about 1 hour the reaction mixture is cooled to a temperature of about 0 to 5°C and the crystalline product formed is filtered, washed with water and dried at 60°C. The product is obtained in 85% yield and the purity by HPLC is 99.72%.

EXAMPLE 4:

N-r3-(3-cyanopyrazolo [1,5-a] pyrimindin-7-vD phenyll-N-ethyl acetamide

A mixture of 5g of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one and 2.1g of 3-aminopyrazole-4- carbonitrile in 25 ml of formic acid and 25 ml water is warmed to 50°C. After about 1 hour the reaction mixture is cooled to a temperature of about 0 to 5°C and the crystalline product formed is filtered, washed with water and dried at 60°C. The product is obtained in 70% yield and the purity by HPLC is 99.51%.

EXAMPLE 5:

N-[3-(3-cvanopyrazolo [1,5-a] pyrimindin-7-yl) phenyll-N-ethyl acetamide

A mixture of 5g of 3-dimethylamino-l-(3-N-ethyl-N- acetylaminophenyl)-2-propen-l-one and 2.1g of 3-aminopyrazole-4- carbonitrile in 5 ml of formic acid and 10 ml water is warmed to 50°C. After about 1 hour the reaction mixture is cooled to a temperature of about 0 to 5°C and the crystalline product formed is filtered, washed with water and dried at 60°C. The product is obtained in 80% yield and the purity by HPLC is 99.65%.

TABLE 1:

The following table summarizes the various reaction conditions followed in the process of formation of N-[3-(3-cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide.

Claims

CLAIMS:

1. A process for synthesizing_N-[3-(3-cyanopyrazolo [1,5-a] pyrimindin-7- yl) phenyl]-N-ethyl acetamide which consists of reacting 3- dimethylamino-l-(3-N-ethyl-N-acetylaminophenyl)-2-propen-l-one with 3-aminopyrazole-4-carbonitrile in an aqueous formic acid reaction medium and subsequently recovering the product from the reaction mixture in a known manner.

2. The process as claimed in claim 1 wherein said reaction is carried out in aqueous formic acid medium of about 20% to about 80% v/v of water and formic acid.

3. The process as claimed in claims 1 and 2 wherein the reaction mixture is heated to 40°C to 60°C for about 1 to 2 hours.

4. The process as claimed in claim 3 wherein said reaction mixture is cooled and the crystallized product filtered off.

5. The process as claimed in claim 4 wherein said product obtained after filtration is further purified.

6. A process for synthesizing N-[3-(3-cyanopyrazolo [1,5-a] pyrimindin-7- yl) phenyl]-N-ethyl acetamide substantially as herein described with reference to the examples.

7. N-[3-(3-cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide whenever prepared by a process as claimed in claims 1 to 6.