Title of Invention	IMPROVED PROCESS FOR THE SYNTHESIS OF ZALEPLON
Abstract	IMPROVED PROCESS FOR THE SYNTHESIS OF ZALEPLON

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "IMPROVED PROCESS FOR THE SYNTHESIS OF ZALEPLON" (a) CIPLA LTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India (c) Indian Companylhcorporated under the Companies Act 1956 The following specification describes the nature of the invention and the manner in which it is to be performed: TECHNICAL FIELD The present invention provides an improved process for producing N-[3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide known as zaleplon. It possesses anxiolytic, antiepileptic, sedative & hypnotic properties. It is also used in the treament of insomnia. BACKGROUND AND PRIOR ART Various prior art patents report the synthesis of zaleplon. US 4,626,538 discloses novel N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7-yl)phenyl]-N-ethyl acetamide compounds and a process for synthesis of the same. The patent discloses the final step cyclisation of 3-amino 4-cyano pyrazole with N-ethyl-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide in acetic acid to give zaleplon. N-ethyl-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide is prepared by N-alkylation of 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide with ethyl iodide in presence of sodium hydride. Alternatively 3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-acetamide is alkylated with ethyl iodide in presence of sodium hydride, alkoxides and like to give zaleplon. This process leads to formation of impurities and gives a very low yield of zaleplon. The final product requires further purification. In our invention we have claimed the use of sodium hydroxide, potassium hydroxide sodium methoxide, sodium tert-butoxide and potassium tert-butoxide for the N-alkylation of N-[3-[3-(dimethyl amino)-l-oxo-2-propenyl]phenyl]alkanamide with ethyl iodide. This process avoids use of hazardous sodium hydride, which is difficult and unsafe to handle on production scale. Using metal alkoxides or hydroxides is much safer and easy to handle, it makes the process inexpensive and eco-friendly. Using this process we get high yields and with high purity (99% HPLC purity). In the second embodiment of US 462658, N[3-[3-(dimethyl amino )-l-oxo-2-propenyl]phenyl]alkanamide is reacted with 3-amino pyrazole to give intermediate 3-(3- 2. cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-alkanamide which are reacted with a base such as sodium hydride, sodium alkoxide and the like with alkyl halide to give 3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-alkyl alkanamide. The second embodiment or alternate process mentioned in US 462658 is different from the process of our invention. Further it described the condensation of N [3-[3-(diemthylamino)-l-oxo-2-propenyl]phenyl]ethyl acetamide with 3-amino pyrazole by refluxing in acetic acid. This reaction results in Zaleplon having low purity with high content of the regioisomer. The resulting Zaleplon can not be used as such for pharmaceutical use, it requires further purification which leads to yield loss. In the present invention condensation is carried out in three different catalysts such as water miscible acid, water immiscible acid and cation exchange resin, all these reactions give to a good yields of Zaleplon having high level of purity 99.9% (HPLC purity) and having regioisomer content less than 0.1%. This process provides high purity which requires no further purification and making it ideally suitable for pharmaceutical use. EP0776898 Al describes an improved process for large-scale production of zaleplon. It describes a reaction between 3-dimethylamino-l-(3-N-ethyl-N-acetylaminophenyl)-2-propen-1-one and 3-amino-4-cyano pyrazole or a suitable salt thereof in a mixture comprising water and acetic acid. Improved yields, decrease in reaction time and purity is achieved by adding water to the acetic acid. The method described also works utilizing salts of either or both starting materials. WO02/12244 A2 discloses novel crystalline polymorphic forms of zaleplon namely Forms I, II and III. and methods for the preparation thereof. Form I is an anhydrous crystal form, while forms II and III are crystalline forms which can be anhydrous or hydrates. 3 US2002/0072527 discloses process for preparation of novel crystalline polymorphic forms of zaleplon namely Forms I, II and III. WO 02100828 A2 describes a process for purifying zaleplon and crystalline forms of zaleplon. This invention also describes purification a process of separating zaleplon and regioisomer that tends to form as a byproduct in the synthesis of zaleplon. WO 03/011228 A2 relates to novel crystalline polymorphic forms of zaleplon and method for the preparation thereof, and their therapeutic uses. US 2003040522 describes a process for preparation of zaleplon that involves mixing N-[3-(3-(dimethyl amino)-l-oxo-2-propenyl) phenyl] -N-ethyl acetamide or a salt thereof and 3-amino-4-cyanopyrazole or a salt thereof in liquid reaction medium of water and at least one water miscible organic compound free of carboxylic acid group such as CI to C6 alcohol, nitriles, ethers, nitro compounds, amides and sulfoxide in 10 to 90 % (v/v) ratio with water; forming Zaleplon under acidic condition via an intermediates imine soluble in reaction medium at 10 to 100° C, more particularly 20 to 25° C and the slat step is recovery of Zaleplon from reaction medium. In this prior art Zaleplon obtained has low HPLC purity (in the range of 96-99 % purity) and the product is then subjected to crystallization or column purification as described in the patent to give Zaleplon which is of pharmaceutical use leading to a substantial loss in yield making the process not suitable for scale-up and industrial application. While the present invention discloses condensation reaction of N(3-(3-diemthyl amino)-l-oxo-2-propenyl)phenyl)-N-ethyl acetamide and 3-amino-4-cyano pyrazole using water immiscible acids in aqueous solvent / cation exchange resin in protic polar solvents / water miscible organic acid in non-aqueous solvent. The present invention provides Zaleplon with good yield and high purity. Further the process does not require any purification and it does not involve the use of any hazardous reagents or raw material making it ideally suitable for scale up industrial application. 4 SUMMARY OF THE INVENTION Synthesis of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide so far described uses strong base such as sodium hydride for the alkylation of 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide formed by refluxing 3-acetamidoacetophenone with Dimethyl formamide-dimethyl acetal. The present invention discloses a simple method for the N-alkylation of 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide using milder bases such as hydroxides and alkoxides of alkali metals. Cyclisation of 3-amino 4-cyano pyrazole with N-ethyl-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide in acetic acid gives zaleplon. This process leads to formation of impurities and gives a very low yield of zaleplon. The cyclisation is described in various prior art processes to proceed under acidic conditions by either use of acid solvents such as acetic acid, or use of various organic or inorganic acids in water or in a mixture of water and a water miscible solvent. The use of the corresponding salts of these intermediates has also been described. The present invention provides a simple, efficient and novel method for preparation of zaleplon by making use of water immiscible organic acids and suitable solvents for carrying out the cyclisation reaction between 3-amino 4-cyano pyrazole and N-ethyl-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide. This process leads to formation of low levels of impurities and gives a very high yield of zaleplon. The present invention describes a process for the cyclisation of 3-amino 4-cyano pyrazole and N-ethyl-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide in the presence suitable cation exchange resins in suitable solvents. 5 DETAILED DESCRIPTION In a preferred embodiment, the present invention discloses a process for the alkylation of 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide with ethyl iodide in presence of alkali metal hydroxides and alkoxides in polar aprotic solvents at ambient temperature. More preferably, the present invention discloses a process for the alkylation of 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide with ethyl iodide in the presence of sodium hydroxide or potassium hydroxide using dimethyl formamide as a solvent at temperatures ranging from 10°C to 100°C, more preferably between 20°C to 30°C. The present invention also discloses a process for the alkylation of 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide with ethyl iodide in the presence of sodium methoxide or potassium t-butoxide using dimethyl formamide as a solvent at temperatures ranging from 10°C to 100°C, more preferably between 20°C to 30°C. Condensation between N-[3-[3-(Dimethylamino)-l -oxo-2-propenyl]-phenyl]-N-ethyl acetamide (II) and 3-amino-4-cyanopyrrazole (III) requires acidic condition & it proceeds through formation of an intermediate imine product. The imine on further treatment under acidic conditions gives Zaleplon (I) as depicted in fig 1. 6 In another preferred embodiment, the present invention discloses a process for condensation and cyclisation of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-ethyl acetamide and 3-amino-4-cyanopyrrazole using water immiscible acids in aqueous solvents or water miscible organic acids in non-aqueous solvents. The present invention more particularly provides a novel method for the production of Zaleplon using water immiscible organic acids or cation exchange resins in suitable solvents at ambient to reflux temperatures. The acids that can be used for the reaction can be selected from edetic acid, fumaric acid, benzoic acid, salicylic acid. The condensation and cyclisation can also be performed using strong cation exchange resins, preferably containing sulphonic acid groups in protic polar solvents 7- The reaction is generally completed from 20 min to 48 hrs depending on the acid used. The following examples describe the process of the invention and are in no way limiting the scope of the invention. EXAMPLES Example 1 Preparation of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-ethyl acetamide 36.2 gm Powdered potassium hydroxide was added portion wise to a clear solution of a mixture of 100 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl] acetamide and 70 ml ethyl iodide in 1000 ml of dimethyl formamide at 39°-42°C over 60 min. the reaction mixture was stirred for 6 hrs. after completion, the reaction mixture was quenched in water and extracted in dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulphate and concentrated to get oil, which upon trituration in hexane gave a solid product which was filtered and dried at 40°C under vacuum to give 100 gm of the title compound (89% yield, HPLC purity 99.5%). Example 2 Preparation of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-ethyl acetamide 4.25 gm of Potassium tert-butoxide was added portion wise to a clear solution of 5 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl] acetamide in 50 ml dimethyl formamide. A solution of 5.25 gm Ethyl iodide in 20 ml dimethyl formamide was added drop wise over 3 hrs. at 35°C- 40°C. The reaction mass was stirred for 6 hrs and then quenched in 300 ml of water and extracted in dichloromethane. The organic layer was washed with water, dried over sodium sulphate and concentrated under vacuum to get oil, which was dissolved in 5 ml dichloromethane and 50 Hexane was added to precipitate the product. The solids obtained was filtered and washed with hexane and dried in vacuum 8 tray dryer at 35°C for 6 hrs to get 4.6 gms. of the title compound. (82% yield, HPLC purity 99.5%). Example 3 Preparation of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide 17.5 gm Sodium methoxide was added portion wise to a clear solution of 50 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl] acetamide and 85 gms ethyl iodide in 500 ml dimethyl formamide. After 6 hrs of stirring at room temperature, the reaction mass was quenched in 5 liters of water and extracted in dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulphate and concentrated under vacuum to get oil, which upon trituration in Hexane gave 51 gms of the title product as a solid (90% yield, HPLC purity 99%). Example 4 Preparation of N-[3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 2.0 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide was added to a slurry of 40 ml water containing 0.83 gm of 3-amino-4-cyanopyrazole and 6.0 gm Edetic acid. The reaction mass was heated to 60°C for 3 hrs. After cooling the reaction mixture to 20°C, 15 % aqueous sodium hydroxide solution was added and the pH of the reaction mixture was adjusted to between 9 -10. The reaction mass was stirred for 1 hr. and filtered to give 1.9 gms of the title compound (80% yield, HPLC purity 99^8%). ^ Example 5 Preparation of N-[3-(3 -cyanopyrazolo- [ 1,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 0.83 gm 3-amino-4-cyanopyrazole was added to the solution of 40 ml water containing 2 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide at room temp. 6 gm Fumaric acid was charged and reaction mass was heated to 60°C for 3 hrs. 9 After cooling to 20°C, 15 % aqueous sodium hydroxide solution was added and pH of the reaction mixture adjusted to between 9-10. The reaction mass was stirred for 1 hr. and filtered to give 2.1 gms of the title compound (84% yield, HPLC purity 99.7 %). Example 6 Preparation of N-[3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 10 gm of Amberlite AR 120 resin (H ) form was added to 2 gm of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-ethyl acetamide and 1.16 gm of 3-amino-4-cyanopyrazole in 20 ml water. The reaction mass was stirred at room temperature for 48 hrs, filtered and extracted in dichloromethane. The organic layer was washed with water, dried over sodium sulphate and filtered. To the clear dichloromethane solution, 120 ml hexane was added and the mixture stirred for 24 hours to give 1.7 gms of the title compound as a solid (72% yield, HPLC purity 99.7 %). Example 7 Preparation of N-[3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 2 gm of N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-ethyl acetamide and 1 gm of 3-amino-4-cyanopyrazole was dissolved in 10 ml methanol. 12 gm Amberlite AR 120 resin (H form) was added as a slurry with 10 ml water. The reaction mass was refluxed for 5 hrs. and cooled to 25 °C and filtered and the solids washed with methanol. 30 ml water is added to the clear filtrate and the mixture stirred for 30 mts. The precipitated product was filtered to give 1.5 gms of the title product (63% yield, HPLC purity 99.8 %) Example 8 Preparation of N-[3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 43.75 gm Maleic acid was added to a solution of 13 gm 3-amino-4-cyanopyrazole and 25 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide in 125 ml 10 absolute alcohol. The reaction mass was heated to 60°C for 30 min and 625 ml water was added at same temp. The reaction mixture was cooled gradually to 25 °C and stirred for 6 hrs, The precipitated product was filtered to give 24 gms of the title product (81% yield, HPLC purity 99.8 %) Example 9 Preparation of N-[3-(3-cyanopyrazolo-[l ,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 37.5 gm Maleic acid was added to a solution of 4.15gm 3-amino-4-cyanopyrazole and 25 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]-phenyl]-N-ethyl acetamide in 250 ml of methanol. The reaction mass was heated to 65°C for 8 hrs and 250 ml water was added at same temp. The reaction mixture was cooled gradually to 25°C and stirred for 6 hrs. The precipitated product was filtered and dried to give 26.0 gms of the title compound (88% yield, HPLC purity 99.75 %) Example 10 Preparation of N-[3-(3-cyanopyrazolo-[l,5-a]-pyrimidin-7-yl)-phenyl]-N-ethyl acetamide 3 gm N-[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethyl acetamide was charged to the solution of 1.24 gm of 3-amino-4-cyanopyrazole in 30 ml water. To this, 4.5 gm maleic acid dissolved in 20 ml water was added at 60°C drop wise in 10 min. the reaction mass was stirred for 2 hrs at same temperature and cooled gradually to 25°C .the precipitated product was filtered and dried to give 3.2 gms of the title compound (90% yield, HPLC purity 99.65 %). 11 We claim, 1. Improved process for the manufacture of zaleplon characterized in that the said process comprising reacting 3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide with ethyl iodide in aprotic solvent such as N,N-dimethyl formamide at temperatures ranging from 0 to 60°C for 2 to 12 hours in presence of bases selected from alkali metal hydroxides or alkoxides selected from sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium methoxide or sodium t-butoxide to give N-ethyl-[3 -[3 -(dimethylamino)-1 -oxo-2-propenyl]-phenyl]-acetamide; condensing N-ethyl- [3 - [3 -(dimethylamino)-1 -oxo-2-propenyl] -phenyl] -acetamide with 3 -amino-4-cyanopyrazole in presence of water-immiscible organic acids selected from edetic acid, fumaric acid, salicyclic acid or benzoic acid or a strong cation exchange resin in the H form in solvents selected from water, methanol, ethanol, isopropanol or mixtures thereof at temperatures ranging from 20 to 80°C; and Zaleplon is isolated from the reaction. 2. Improved process for the manufacture of zaleplon as claimed in claim 1 wherein the said N-ethyl-[3-[3-(dimethylamino)-l-oxo-2-propenyl]-phenyl]-acetamide obtained from claimed 1 is condensed with 3-amino-4-cyanopyrazole in presence of water-miscible organic acids selected from formic acid, maleic acid, tartaric acid, citric acid, oxalic acid or succinic acid in solvents selected from methanol, ethanol or isopropanol having water content from 0.1 to 9.5% at temperatures ranging from 20 to 80°C and filtering zaleplon from the reaction mixture. 3. Improved process for the manufacture of Zaleplon as substantially described herein with reference to the foregoing examples 1 to 10. Dated this the 3rd day of Sept 2003 Dr. Gopakumar G. Nair Gopakumar Nair Associates

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