WO2006070244A2

WO2006070244A2 - A process for the preparation of zaleplon

Info

Publication number: WO2006070244A2
Application number: PCT/IB2005/003814
Authority: WO
Inventors: Bakulesh Mafatlal Khamar; Indravadan Ambalal Modi; Manish Chandrakant Shukla; Vala Vala Srinivas; Nirav Keshavlal Kagathara; Nilesh Manjibhai Jamaria; Suryabhan Prabhakar Dange; J. Venkat Raman
Original assignee: Bakulesh Mafatlal Khamar; Indravadan Ambalal Modi
Priority date: 2004-11-22
Filing date: 2005-12-19
Publication date: 2006-07-06
Also published as: WO2006070244A3

Abstract

The present invention relates to a novel and commercially feasible process for the preparation of pyrazolo[1,5-a]pyrimidine compound Zaleplon, wherein a novel intermediate 7-(3bromophenyl)-3,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile is coupled with acetamide to yield a N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide which on ethylation gives Zaleplon.

Description

A PROCESS FOR THE PREPARATION OF ZALEPLON

FIELD OF INVENTION:

[7-(3-disubstituted amino)phenyl]pyrazolo[l,5-a]pyrimidines are useful as anxiolytic and antiepileptic agents as well as sedative-hypnotic agents and skeletal muscle relaxants. Zaleplon

[formula-I], chemically named as 7V-[3-(3-cyanopyrazolo[l,5-α]pyrimidine-7-yl)phenyl]-N- ethylacetamide and having [CAS NO. 151319-34-5], is approved by the U.S. Food and Drug

Administration for the short-term treatment of insomnia and is marketed under the brand name of

Sonata®.

DESCRIPTION OF PRIOR ART:

Processes for preparing Zaleplon have been disclosed in US Patent No. 4626538 and European Patent No. 208846. ^' The process shown in scheme- 1, involves condensation of N-(3- acetylphenyl)ethanamide with diraethylformamide dimethylacetal to form N-[3-[3- (dimethylamino)-l-oxo-2-propenyl]phenyl]acetamide [II]; This compound was then subjected to Ν-alkylation with ethyliodide, forming N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N- ethylacetamide [III]. In the last step, this amido derivative [III] is condensed with 3-amino-lH- pyrazole-4-caτbonitrile in re fluxing glacial acetic acid to yield Zaleplon [I]. Scheme-1;

In the second process as shown in Scheme-2, the acetamide [II] is obtained in the same way as disclosed in scheme-1 and reacted with 3-amino-lH-pyrazole-4-carbonitrile to give the intermediate N-[3-[3-cyanopyrazolo[l,5-a]pyrimidine-7-yl]phenyl]acetamide [IV]. The formed acetamide derivative [IV] is reacted with ethyl iodide in the presence of a base such as sodium hydride, sodium alkoxide, to give Zaleplon.

Scheme-2:

sodium hydride

DMF Ethyl iodide

US Patent No. 5714607, discloses an improvement upon the process as described in Scheme- 1 of US Patent No. 4626538, wherein Zaleplon is obtained in improved yield and purity if final step is earned out using aqueous acetic acid as solvent. This procedure resulted in a yield of 81.7- 90% with a HPLC purity of 98.77 to 99.4%.

PCT Publication No. WO02/100828 discloses a process for preparing Zaleplon wherein, _V-[3-[3- (dimethylamino)- 1 -oxo-2-propenyl]phenyl]-N-ethylacetamide and 3-amino- 1 H-pyrazole-4- carbonitrile are reacted in the reaction medium of water and a water-miscible organic compound under acidic conditions. The reaction proceeds through an imine inteπnediate (prone to precipitate from water), which remains dissolved in the reaction medium of this process. The process proceeds at ambient temperature to produce Zaleplon in high yields and FIPLC purity of at least 98.5%.

None of the above prior processes mention how to reduce the formation of regioisomer N-[3-(3- cyanopyrazolo[l,5-a]pyrimidine-5-yl)phenyl]-N-ethylacetamide [V] as byproduct.

Because of the I high degree of structural and ^[V c^]hemical similarity between Zaleplon and its isomer, these compounds are very difficult to separate by standard crystallization methods. The presence of impurity such as [V] necessitates additional crystallization from less polar solvents. Multiple crystallization causes substantial loss of the desired active ingredient. Despite this, the final product does not meet the required purity.

PCT Publication No. WO03/068775, discloses a method for producing Zaleplon as shown in Scheme-3 by condensing 3 -(N- acetyl ~7V-ethylamino)-β-oxo-phenylpropanal sodium salt [VIII] with 3-amino-lH-pyrazole-4-carbonitrile [IX], wherein the said sodium salt can be produced by first treating 3-ac^'etylamino acetophenone [VI] with an alkali metal hydroxide, in particular with powdered potassium hydroxide and then with an ethylating reagent, in particular ethyl bromide and the 7V-(3-acetylphenyl)-N-ethylacetamide [VII] thus obtained is reacted with a foπnic acid alkyl ester in the presence of an alkali metal alkanolate, in particular in the presence of sodium ethanolate.

Scheme-3:

[VI]

PCT Publication No. WO03/095456 discloses a process for the preparation of Zaleplon, wherein the reaction , involves condensation of N-[3-[3-(dimethylamino)-l~oxo-2- propenyl]phenyl]acetamide ([II] of Scheme-2), with 3-amino-lH-pyrazole-4-carbonitrile in a reaction medium comprising of aqueous solution of formic acid at concentration in range of 20 to 80%w/w. The regioisomer is formed though in low amount and necessitates the crystallization step to achieve the desired purity at the cost of low yield.

PCT Publication No. WO2004/035585, discloses a process for the preparation of Zaleplon, wherein iV-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-iV-ethylacetamide is reacted with 3- amino-lH-pyrazole-4-carbonitrile in an aqueous formic acid reaction medium at a temperature ranging from 40⁰C to 70⁰C. SUMMARY:

The object of the invention is to prepare Zaleplon avoiding the formation of the regioisomer N-

[3-(3-cyanopyrazolo[l,5-a]pyrimidine-5-yl)phenyl]-N-ethylacetamide [V] as byproduct. The process involves preparation of sodium salt of l-(3-bromophenyl)-3-hydro^yprop-2-en-l-one [XI] from l-(3-bromophenyl)ethanone [X] and ethylformate and subsequent reaction of the said sodium salt with 3-amino-lH-pyrazole-4-carbonitrile to provide a novel intermediate 7-(3- bromophenyl)-3,7-dihydropyrazolo[l,5-Ω]pyrimidine-3-carbonitrile[XII] as product. This novel intermediate on carbon-nitrogen coupling with acetamide provides intermediate [XIII], which on Ν-ethylation gives Zaleplon.

DETAILED DESCRIPTION OF THE INVENTION:

The process of the present invention as per scheme-4 comprises of the following steps:

1. Reaction of l-(3-bromophenyl)ethanone [X] and ethylformate in presence of sodium ethoxide to give sodium salt of l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one[XI]

2. Condensation of sodium salt of l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one [XI] with 3-amino-4rcyanopyrazole to yield 7-(3-bromophenyl)pyrazolo[l,5-α]pyrimidine-3- carbonitrile [XII]

3. Reaction of 7-(3-bromophenyl)pyrazolo[l,5-α]pyrimidine-3-carbonitrile[XII] and acetamide to yield N-[3-(3-cyanopyrazolo[l,5-α]pyrimidin-7-yl)phenyl]acetamide[XIII]

4. N-ethylation of N-[3-(3-cyanopyrazolo[l,5-α]pyrimidin-7-yl)phenyl]acetamide [XIII] to yield zaleplon.

Sodium alkoxide used in present process can be selected from sodium methoxide, sodium methoxide. N-ethylation in the last step can be carried out using ethylating agents like ethyliodide, ethylbromide, diethylsulphate in presence of base such as sodium hydride, sodium hydroxide potassium hydroxide. Condensation of sodium salt of l-(3-bromophenyl)-3- hydroxyprop-2-en-l-one with 3-amino-4-cyanopyrazole is carried out in presence of acid such as HCl, H₃PO₄, H₂SO₄, CH₃COOH, HNO₃, HCOOH or mixtures thereof at about 50⁰C to reflux temperature Of the solvent and more preferably at about 10O⁰C to about 105⁰C. The reaction of 7-(3-bromophenyl)pyrazolo[l,5-α]pyrimidine-3-carbonitrile and acetamide is earned out in presence of bases such as K₂CO₃, Cs₂CO₃, K₃PO₄, copper salts such as CuSCN, Cu₂O, CuSO₄, CuO, Cu(OAc)₂ and copper halides such as CuI, CuBr, CuCl₂ and ethyl enediamines such as N₅N '-dimemethyl ethyl enediamine, N-methylethylenediamine, 1,2- cyclohexanediamine in solvents such as tetrahydrofuran , dioxane, dimethylformamide.

Scheme-4:

[XII]

The present invention will now be illustrated by following non-limiting examples: EXAMPLES:

[1] PREPARATION OF SODIUM SALT OF l-(3-BROMOPHENYL)-3- HYDROXYPROP-2-EN-l-ONE

To a 50 L three neck round bottom flask is charged 250 gm of l-(3-bromophenyl)ethanone and

750 ml of THF at room temperature. To above flask was added 186 gm of ethylformate in 60 minutes and 870 gm 21%w/w of sodium ethoxide solution in 90 minutes. The reaction mixture was stirred for 10 hours at room temperature. To above reaction mixture was added 1000 ml of hexane and further stirred for 60 minutes. The reaction mass was filtered and cake washed twice with 500 ml of hexane. Weight of diy product was 290 gm. Yield = 92%

[2] Preparation of 7-(3-bromophenyl)pyrazolo[l, 5-a]pyrinιidine-3-carbonitrile To a 5 L of three-necked round flask were charged 1515 ml of glacial acetic acid and 133.5 gm of 3-amino-4-cyanopyrazole. Above reaction mass was stirred for 30 minutes to get clear solution. To this solution was added 190 ml of concentrated HCl slowly. To this reaction mass was charged a solution of 280 gm of sodium salt l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one in 981 ml water at 8-10⁰C and the reaction mass was stirred at same temperature for 60 minutes. The reaction mass was further stirred at room temperature for 7-8 hours. To above reaction mixture was added 500 ml of water and stirred for 1 hour at room temperature. The reaction mass was filtered and the cake washed twice with 500 ml water. The product was dried. The weight of diy product was 300 gm. Melting point: 232-233⁰C. ¹H NMR (300 MHz, CDCl₃) δ: 8.89 (d,lH), 8.84(s,lH), 8.29(t,lH), 8.06(d,lH), 7.84(d,lH), 7.61(s,lH), 7.59(d,lH)

[31 Preparation of N-[3-(3-cyanopyrazoIo[l,5-alpyrimidin-7-yI)phenvIlacetamide

To a 3.0 L three neck round bottom flask was charged 19.06 gm (0.1003mole) of copper (I) iodide, 300 gm (1.003mole) of 7-(3-bromophenyl)pyrazolo[l,5-a]pyrimidine-3-carbonitrile, 174.52 gm (3.009mole) of acetamide, 415.24 gm (3.009mole) of potassium carbonate, 26.47 gm (0.3009mole) of N,N'-dimethylethylenediamine and 1500 ml of 1,4-dioxane. The reaction mixture was refluxed for 20-23 hours and cooled to room temperature. The solid obtained was filtered, washed with 1,4-dioxane and subsequently with water dried. The product was crystallized from dimethylformamide to yield 168gm. Melting point: 262-264⁰C. ¹H NMR (300 MHz, CDCl₃) δ: 10.25(s,lH), 8.88(d,lH), 8.83(s,lH), 8.3(s,lH), 7.82(d,lH), 7.68(d,lH), 7.55(d,lH), 7.49(t,lH), 2.07(s,3H)

[41 Preparation of JV-fS-O-cvanopyrazolofl.S-fllpyrimidine^-vDphenyll-TV-ethylacetamide (Zaleplon)

To a 2.0 L four neck round bottom flask is charged tetrahydrofuran (700ml), N-[3-(3- cyanopyrazolo[l,5-a]pyrimidin-7-yl)phenyl]acetamide(75gm,0.2697mol) and powdered KOH (60.41gm,1.0788mol) and the mixture is cooled to 5 to 10⁰C. To this is added diethyl sulfate (83.14gm, 0.5395mol) and reaction mixture is stirred at 5 to 10⁰C for 2.5 hours and at room temperature for 1 hour. The reaction mixture is cooled to 10-15 C and acetic acid (48.55gm, 0.809mol) and water (150ml) are charged. The layers are separated. Aqueous layer is extracted with methylene chloride. Combined organic layers are dried with sodium sulfate. The solvent is distilled. Isopropyl acetate is added and co-distilled and cooled to 5 to 10⁰C. Reaction is filtered to get 61.45gm. Crude product is crystallized from mixture of acetonitrile and isopropyl acetate(l :3, 7 vol) to yield 49.66gm pure zaleplon of polymorphic form I. %Yield = 60%

Claims

We claim:

1. A process for the preparation of zaleplon comprising

(a) reaction of l-(3-bromophenyl)ethanone and alkylformate in presence of sodium alkoxide to give sodium salt of l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one

(b) reaction of sodium salt of l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one with 3- amino-4-cyanopyrazole in presence of acid to give 7-(3- bromophenyl)pyrazolo[ 1 ,5-a]pyrimidine-3-carbonitrile

(c) reaction of 7-(3-biOmophenyl)pyrazolo[l,5-α]pyrimidine-3-carbonitrile with acetamide in presence of base, copper salt and ethylenediamine to give 7V-[3-(3- cyanopyrazolo[ 1 ,5-«]pyrimidin-7-yl)phenyl]acetamide

(d) reaction of N-[3-(3-cyanopyrazolo[l,5-α]pyrimidin-7-yl)phenyl]acetamide with ethylating agent to yield zaleplon.

2. A process of preparation of zaleplon as claimed in claim 1, wherein sodium alkoxide is selected from sodium methoxide, sodium ethoxide and alkylformate is selected from ethylformate , methylformate.

3. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of sodium salt of l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one with 3-amino-4-cyanopyrazole is earned .^'out in presence of acids such as HCl, H₃PO₄, H₂SO₄, CH₃COOH, HNO₃, HCOOH or mixtures thereof.

4. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of sodium salt of l-(3-bromophenyl)-3-hydroxyprop-2-en-l-one with 3-amino-4-cyanopyrazole is carried out, at about 50⁰C to reflux temperature of the solvent and more preferably at about. 100⁰C to about 105⁰C.

5. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of 7-(3- bromophenyl)pyrazolo[l,5-α]pyrimidine-3-carbonitrile with acetamide is carried out in presence of bases such as K₂CO₃, Cs₂CO₃, K₃PO₄ and copper salts such as CuSCN, Cu₂O, CuSO₄, CuO, Cu(OAc)₂ and copper halides such as CuI, CuBr, CuCl₂.

6. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of 7-(3- bromophenyl)pyrazolo[l,5-β]pyrimidine-3-carbonitrile with acetamide is earned out in presence ethylenediamines such as N,N'-dimemethylethylenediamine, N- methylethylenediamine, 1,2-cyclohexanediamine and the like in solvents such as tetrahydrofuran , dioxane, dimethylformamide.

7. A process of preparation of zaleplon as claimed in claim 1, wherein the molar ratio of acetamide to 7-(3-bromophenyl)pyrazolo[l,5-a]pyrimidine-3-carbonitrile is 0.01-0.05 : 1 and more preferably 0.03 : 1, base to 7-(3-bromophenyl)pyrazolo[l,5-α]pyrimidine-3- carbonitrile is 0.1-0.4 : 1 and more preferably 0.3 : 1, copper salts to 7-(3- bromophenyl)pyrazolo[l,5-α]pyrimidine-3-carbonitrile is 0.02-0.2 : 1 and more preferably 0.1 : 10 and ethylenediamine to 7-(3-bromophenyl)pyrazolo[l,5-α]pyrimidine- 3-carbonitrile is 0.05-0.4 : 1 and more preferably 0.3 : 1.

8. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of JV-[3-(3- cyanopyrazolo[l,5-α]pyrimidin-7-yl)phenyl]acetamide with ethylating agent is carried out in presence of base such as sodium hydride, sodium hydroxide potassium hydroxide.

9. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of N-[3-(3- cyanopyrazolo[l,5-α]pyrimidin-7-yl)phenyl]acetamide with ethylating agent is earned out optionally in biphasic solvent system in presence of phase transfer catalyst wherein the organic phase is tetrahydrofuran, methylene dichloride, toluene.

10. A process of preparation of zaleplon as claimed in claim 1, wherein reaction of N-[3-(3- cyanopyrazolo[l,5-tf]pyrimidin-7-yl)phenyl]acetamide is carried out with ethylating agents such as ethyliodide, ethylbromide, diethyl sulphate and the like.