WO2005099712A2

WO2005099712A2 - Process for preparation of n-[3-(3-cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-n-ethylacetamide

Info

Publication number: WO2005099712A2
Application number: PCT/IN2005/000119
Authority: WO
Inventors: Rajaram Sankara Subramanian; Natarajan Sathyanarayanan; Nagaraja Rao Janardhana Prasad; Balasubramaniam Sivaraman; Munusamy Jayamani; R. Bapat Uday
Original assignee: Sanmar Speciality Chemicals Limited
Priority date: 2004-04-19
Filing date: 2005-04-19
Publication date: 2005-10-27
Also published as: WO2005099712A3

Abstract

An improved process for preparing N-[3-(3-Cyanopyrazolo [1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, (zaleplon), comprising the steps of reacting N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide with 3-amino-4-cyanopyrazole in a reaction medium comprising (i) water and water-immiscible organic solvents in presence of either organic sulphonic acids or Lewis acids; (ii) aromatic hydrocarbons as solvent in presence of either organic sulphonic acids or Lewis acids; or (iii) water and organic sulphonic acid or Lewis acids.

Description

PROCESS FOR THE PREPARATION OF N-f3-r3-Cvanopyrazolo fl,5-al pyrimidin-7-yl)phenyll-N-ethylacetamide.

Field of the invention:

The present invention relates to an improved process for the preparation of N-[3-(3- Cyanopyrazolo [1 ,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, (Zaleplon).

Background of the invention:

Zaleplon, having the chemical name of N-[3-(3-Cyanopyrazolo[l,5-a]pyrimidin~7- yl)phenyl]-N-ethylacetamide and possessing anxiolytic, antiepileptic, sedative, hypnotic and muscular relaxant properties was approved by US FDA for the short term treatment of Insomnia. Zaleplon is available by prescription! under the brand name of sonata ®.

The structure of zaleplon is well established and represented as

Zaleplon and a process for preparing the same are disclosed in US patent 4,626,538 (hereinafter "538" patent). The '538' patent provides a general methodology for preparing zaleplon, its structurally related compounds and various intermediates involved in the process. The process disclosed in '538'patent, involves the condensation of N-(3-acetyl phenyl) ethylacetamide of the formula (1) with dimethylformamide-dimethylacetal to form N-[3-[3-(dimethylamino)-l-oxo-2- ρropenyl]phenyl]-N-acetamide of the formula (2). The primary amide of the formula (2) is alkylated using ethyl iodide and sodium hydride to form N-[3-[3- (dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide of the formula (3). Zaleplon of the formula (5) was prepared by condensing the ethyl acetamide of the formula (3) with 3-amino-4-cyano pyrazole of the formula (4) using acetic acid under refluxing conditions. The typical process is represented in scheme- 1

Scheme-1:

a: Dimethylformamide-dimethylacetal, b: Ethyl iodide/sodium hydride/DMF c: Acetic acid/reflux

An improved process for producing Zaleplon has been disclosed in US patent 5,714,607 (hereinafter "607" patent). According to the '607' patent, zaleplon is obtained in an improved yield and purity using water and acetic acid in the reaction medium rather than acetic acid alone. The '607' patent also reports that the reaction is faster in presence of water and these improved conditions reduce the reaction time from 3.0-3.5 hours to 1.0-1.5hours. According to Table-1 of the '607' patent zaleplon was obtained in yields ranging from 81.7-90.0% and in HPLC purity ranging from 98.77-99.40%.

The US patent application publication no. 2003/040522 Al reports a more advantageous process for the production of zaleplon starting from ethylacetamide of the formula (3) and 3-amino-4-cyanopyrazole of the formula (4) under acidic conditions. Thus according to the US publication no. 2003/040522, zaleplon is prepared by condensing ethylacetamide of the formula (3) or a salt thereof with 3- amino-4-cyanopyrazole of the formula (4) or a salt thereof under acidic condition in a reaction medium comprising a mixtutre of water and water miscible organic compounds at any temperatures between 10-90°C. Thus according to this process zaleplon has been obtained in yields varying between 79-96% and purity ranging between 98.50-99.50% (as determined by HPLC). Various water miscible organic solvents and organic/inorganic compounds as acids are reported in this patent publication. This publication also reports the use of acid in 1 molar ratio with respect to either of ethylacetamide or 3-amino-4-cyanopyrazole and the concentrations of the organic co-solvent and water varying between 10-90%. The publication also reports the formation and isolation of the regioisomer of zaleplon as one of the reaction by product and also as reference marker for zaleplon in determining the purity by HPLC. The mechanistic scheme for the formation of the zaleplon via an inline intermediate is also elucidated in this publication. The publication also claims the method for determining the purity of zaleplon by HPLC and an assay for zaleplon by HPLC method of analysis.

WO 03/095456 Al reports the formation of zaleplon in aqueous solutions of formic acid, concentrations in the range of 20-80% (w/w). Crude zaleplon is obtained in Example-1 of this publication as white to off-white crystals in the yield of 87.5% with purity 99.69% (as determined by HPLC) which upon purification using methanol gives the product with purity of 99.98% (as determined by HPLC). This publication also reports the purification of zaleplon on a large scale. (5Kg level).

Thus the subject matter of US 4,626,538, US 5,714,607, US 2003/040522A1 and WO 03/095456 Al are incorporated herein as references.

When the experiments are performed as per the various methods reported in the above mentioned prior arts, the regio isomer of the formula (6) is also formed atleast in the range of 0.5-3.0% as determined by HPLC . Thus the final product will always be contaminated with its regioisomer and further purification is the utmost necessity in all the reported methods.

Also the various methods reported in the prior arts for producing zaleplon uses either acetic acid, acetic acid-water mixture, water and water miscible co solvents like alcohols, ethers, nitriles, Tetrahydrofuran, DMF, DMSO, etc and water miscible acids like hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, formic acid, propionic acid, oxalic acid, malonic acid, tartaric acid etc. The various embodiments of the priors arts when performed on various levels does not take into considerations the factors like corrosiveness of acid, distillation of acids during work up procedures, recovery of organic solvents used and recycling the same.

Summary of the Invention:

The object of the present invention is to provide a process for preparing zaleplon without the formation of its regio-isomer (6) or a process wherein the regio-isomer formed is less than or equal to 0.5%.

Another object of the present invention is to prepare zaleplon by an industrially and environment friendly process using milder, cheaper and versatile acids in the form of organic sulphonic acids and Lewis acids.

Yet another object of the present invention is to produce zaleplon in a cost effective manner. It would be appreciated by those skilled in the art that after isolation of the product, water-immiscible organic solvents can be separated from water and the solvent can be distilled and recycled. The present invention provides an improved process for producing N-[3-(3- Cyanopyrazolo [l,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (zaleplon) by reacting N-[3-[3-(dimemylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide with 3-amino-4-cyanopyrazole under acidic conditions in a reaction medium consisting of

(i) water and water-immiscible organic solvents in the presence of either organic sulphonic acids or Lewis acids; (ii) aromatic hydrocarbons as solvent in the presence of either organic sulphonic acids or Lewis acids; or (iii) water in the presence of organic sulphonic acids or Lewis acids.

In another embodiment the present invention relates to pure zaleplon having a purity of atleast 99.0% (as determined by HPLC)

In yet another embodiment of the present invention, zaleplon produced by this process can be purified either by treating with a mixture of methylenedichloride, silica gel, ethyl acetate or with solvents like dimethyl sulphoxide, N-methyl pyrrolidone.

In yet another aspect, the present invention relates to pure zaleplon having a purity of atleast 99.9% (as determined by HPLC)

In still a further aspect, the present invention relates to the cost-effective method for producing zaleplon.

Detailed Description of the invention:

The present invention provides an improved process for the preparation of zaleplon by reacting N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide of the formula (3) with 3-amino-4-cyanopyrazole of the formula (4) in a reaction medium selected from (i) water and water-immiscible organic solvents in the presence of either organic sulphonic acids or Lewis acids; (ii) aromatic hydrocarbons as solvent in the presence of either organic sulphonic acids or Lewis acids; and (iii) water in the presence of organic sulphonic acid or Lewis acids. The process of the present invention is depicted in scheme - 2. Scheme-2

d: Water and water-immiscible organic solvents in the presence of either organic sulphonic acids or Lewis acids., e: aromatic hydrocarbons as solvent in the presence of either organic sulphonic acids or Lewis acids; f: water in the presence of organic sulphonic acids or Lewis acids.

As one of the embodiments of the present invention the reaction medium for preparing zaleplon from compounds of the formula 3 and 4 comprises water- immiscible organic solvents like chloroform, methylenedichloride, ethylacetate, toluene, xylenes, halogenated aromatic hydrocarbons and other organic solvents in which compounds of the formula 3 and 4 are soluble. Also in the present embodiment the solvents are chosen in such a way that they are inert to both the reactants and /or products. The ratio of the organic solvent and water in the reaction medium is preferably from 10% to 90% (v/v) of organic solvent and water and more preferably from 35% to 60% (v/v) of organic solvent and water and most preferably 35% (v/v) of organic solvent and water.

In another embodiment of the present invention the aromatic hydrocarbons used as solvent for the preparation of zaleplon are from the group comprising of toluene, xylenes, halogenated aromatic hydrocarbons that are inert to both the reactants and /or products.

Zaleplon, being an active pharmaceutical ingredient regulated by ICH guidelines in terms of residual solvents and impurity profiles use of water-immiscible solvents and aromatic hydrocarbons like Benzene, carbon tetrachloride, ethylene dichloride etc are avoided.

One of the embodiments of the present invention includes the use of either organic sulphonic acid or the Lewis acids for the reaction in combination with any of the solvents mentioned above.

Organic sulphonic acids can be either aliphatic or aromatic. Also organic sulphonic acids can be used either in hydrate or anhydrous forms. Thus organic sulphonic acids are selected from the group comprising para toluene sulphonic acid, pyridine para toluene sulphonic acid, benzene sulphonic acid, methane sulphonic acid, hexane sulphonic acid, heptane sulphonic acid, octane sulphonic acid etc., However the use of methane sulphonic acid as one of the embodiments of the present invention leads to the formation of the regioisomer in higher amounts.

Another embodiment of the present invention is the use of Lewis acids in the reaction medium. Lewis acids are selected from the group comprising Boron trifluoride etherate, tin halides, zinc chloride, Titanium tetrachloride, Trimethyl silylhalides etc.

In the present invention the reactions are conducted at temperatures ranging from 0°C to the boiling point of the reaction mixture depending upon the solvent used. However the more preferable temperature for performing the reaction is 25-100°C and the most preferable range is 40-60°C. The time taken for completion of the reaction is about 1-48 hours necessarily depending upon the choice of solvent, choice of acid and the choice of reaction temperature.

By following Hie preferred embodiments of the present invention, the product precipitates out from the reaction medium at the time of completion of reaction in most of the cases. Pure zaleplon may be collected by filtration. The yield of the product may be increased by cooling the reaction mixture.

Zaleplon, obtained by the preferred embodiments described above is further purified to obtain in a pharmaceutically acceptable form of very high quality. The purification method involves either precipitation or crystallization of zaleplon using the solution comprising either mixture of solvents like methylene dichloride/ethylacetate/silica gel or dimethl sulphoxide, N-methyl-2- pyrrolidone.

The scope of the preferred embodiments of the present invention is further illustrated by the following non-limiting examples.

Example-1

A mixture of lg (0.004 moles) of N-[3-[3-(dimethylamino)-l-oxo-2- propenyl]phenyl]-N-ethylacetamide (3) and 0.42 g (0.004 moles) of 3-amino-4- cyanopyrazole (4) in mixture of toluene and water is warmed to 55°C to 60°C followed by the addition of . Paratoluene sulphonic acid monohydrate(PTSA) 0.73g (0.004 moles). After about 1 hour, the reaction mixture is cooled to a temperature of about 35 to 40° C. The crystalline product obtained is filtered off, washed with water and dried .The product is obtained in 70% yield and the purity by HPLC is 99.96 %. [H ¹ NMR data, 400 MHz, CDCI3 : 8.83,d,lH (H-5)., 8.45,s,lH (H-2)., 8.00,m,2H (H-11,H-13), 7.698,m,lH (H-10)., 7.48, m,lH (H-9)., 7.23,d,lH (H-6)., 3.85,q,2H (H-15),1.95,s,3H (H-18)., 1.18,t,3H (H-16)] Example-2

A mixture of lg (0.004 moles) of N-[3-[3-(dimethylamino)-l-oxo-2- propenyl]phenyl]-N-ethylacetamide (3) and 0.42 g (0.004 moles) of 3-amino-4- cyanopyrazole (4) in mixture of xylene and water is warmed to 55°C to 60°C followed by the addition of 0.73g (0.004 moles) of para toluene sulphonic acid monohydrate (PTSA). After about 1 hour, the reaction mixture is cooled to a temperature of about 35 to 40°. Crystalline product obtained is filtered off, washed with Water and dried .The purity of the product obtained is 99.96 % (as determined by HPLC).

Example-13

Purification of N- r3-(3-Cvanopyrazolo fl,5-al Pyrimindin-7-vπ Phenyll-N-ethvI acetamide:

METHOD-1

Zaleplon, as obtained either in examples 1 & 2 with 99.96% purity as determined by HPLC, is further purified by dissolving zaleplon (70.0g, 0.223mol) in 1.3L of methylene dichloride followed by refluxing with activated carbon (17.5g) for 2 hours. Resulting reaction mixture is filtered through hyflo, and stirred with silica gel (70g, 60-120mesh) for 2 hours. Reaction mixture is filtered, followed by washing the bed with methylene dichloride (150mL). Filterates are combined and mixed with 300mL of ethyl acetate. Mixture of methylene dichloride and ethyl acetate is distilled under vacuum at 70-80°C. To the residual mass another 300mL of ethyl acetate is added and distillation is continued. This process is repeated once again and to the final residue obtained 200mL of ethyl acetate is added. Off-white product obtained is filtered and air-dried at 80-100°C. 55-60g of product is obtained as a white to off-white solid in 80% yield and with very high purity of 99.96%. METHOD-2

Another method of purification involves first a process of dissolving zaleplon (70.0g, 0.223mol) in 140ml of N-methyl-2- pyrrolidone followed by treating with activated carbon (17.5g) at 100°C for 2 hours. Resulting reaction mixture is filtered through hyflo at 100°C. The filtered reaction mixture is cooled to 10°C. White product obtained was filtered, washed with chilled IPA and air-dried at 80-100°C. 48-52g of product is obtained as a white to off-white solid in 70-75% yield and with very high purity of 99.96%. METHOD-3

Another process for purification involves first dissolving zaleplon (70.0g, 0.223mol) in 140ml of DMSO followed by treating with activated carbon (17.5g) at 80°C for 2 hours. Resulting reaction mixture is filtered through hyflo at 100°C. The filtered reaction mixture is cooled to 10°C. White product obtained was filtered, washed with chilled IPA and air-dried at 80-100°C. 50-55g of product is obtained as a white to off-white solid in 75-80% yield and with very high purity of 99.96%

Claims

Claims:

1. An improved process for preparing N-[3-(3-Cyanopyrazolo [l,5-a]pyrimidin-7- yl)phenyl]-N-ethylacetamide, (zaleplon), comprising the steps of reacting N-[3- [3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide with 3-amino-4- cyanopyrazole in a reaction medium comprising

(i) Water and water-immiscible organic solvents in presence of either organic sulphonic acids or Lewis acids;

(ii) Aromatic hydrocarbons as solvent in presence of either organic sulphonic acids or Lewis acids; or

(iii) Water and organic sulphonic acid or Lewis acids.

2. The process according to claiml, wherein the water-immiscible organic solvents is selected from methylene dichloride, chloroform, ethylacetate, toluene, xylenes, halogenated aromatic hydrocarbons and other organic solvents in which the reactants are soluble.

3. The process according to claim 1, wherein the aromatic hydrocarbons are selected from a group comprising toluene, xylenes, halogenated and other aromatic hydrocarbons that are inert to the reactants and / or products.

4. The process according to claim 1, wherein the reaction medium contains 10% to 90%) (v/v) of the organic solvent and water.

5. The process according to claim 4, wherein the reaction medium contains about 35% to 60% (v/v) of organic solvent and water.

6. The process according to claim 1, wherein the reaction medium comprises only aromatic hydrocarbons as the solvent.

7. The process according to claim 1, wherein the reaction medium comprises only water as the solvent.

8. The process according to claim 1, wherein the organic sulphonic acids can be either aliphatic or aromatic.

9. The process according to claim 8, wherein the organic sulphonic acid is selected from paratoluene sulphonic acid, benzene sulphonic acid, pyridine paratouluene sulphonic acid, methane sulphonic acid, hexane sulphonic acid, heptane sulphonic acid and octane sulphonic acid.

10. The process according to claim 9, wherein the organic sulphonic acids can be either anhydrous or hydrated compounds.

11. The process according to claim 10, wherein the organic sulphonic acids can be obtained directly as acids or can be generated from their respective sodium salts.

12. The process according to claiml, wherein the Lewis acid is selected from Borontrifluoride etherate, tin halides, zinc halides, Titanium tetrachloride and Trimethylsilyl halides

13. The process according to claim 1 wherein the acids used are in the molar ratio of 0.5 to 2.0 with respect to either of ethylacetamide or 3-amino-4-cyano pyrazole.

14. The process according to claim 1, wherein the reaction is performed at temperatures ranging from 0°C to the boiling point of the reaction mixture depending upon the solvents used.

15. The process according to claim 14, wherein the reactions is carried out preferably at a temperature in the range of 25-100°C.

16. The process according to claim 15, wherein the most preferable temperature range for carrying out the reaction is 30-60°C.

17. The process according to claiml, wherein the time for completion of reaction is about 1 - 30 hours depending on the choice of solvent, acids and temperature.

18. The process according to claim 1, wherein zaleplon is prepared as per the procedure described in Example- 1.

19. The process according to claim 1, wherein zaleplon is prepared as per the procedure described in Example-2.

20. The process according to claim 1, wherein zaleplon is prepared without the formation of its regioisomer.

21. The process according to claim 1, wherein pure zaleplon is obtained directly.

22. The process according to claims 1 and 21, wherein the purity of zaleplon is 99.96% (purity as determined by HPLC).

23. The process according to claim 1, wherein zaleplon is prepared as per the examples 4 and 7.

24. The process according to claim 1, wherein zaleplon is prepared with the regioisomer of less than 0.5%.

25. The process according to claim 1, wherein the zaleplon is purified as described in method- 1, method-2 & method -3 of Example 13 using solvents like DMSO, N- methyl -2-pyrrolidone, DMF, or solvent mixtures comprising MDC, ethylacetate, silica gel.