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A PROCESS FOR THE PREPARATION OF 6-(5-CHLOROPYRIDIN-2-YL)-5H-PYRROLO[3,4-B]PYRAZINE-5,7(6H)-DIONE AS AN INTERMEDIATE FOR ESZOPICLONE

IP.com Disclosure Number: IPCOM000177829D
Publication Date: 2009-Jan-05

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure relates to a process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I. The present disclosure further relates to a process for the preparation of eszopiclone using 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I as an intermediate.

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A PROCESS FOR THE PREPARATION OF 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione AS AN InTERMEDIATE FOR ESZOPICLONE

Abstract

The present disclosure relates to a process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I.

Formula I

The present disclosure further relates to a process for the preparation of eszopiclone using 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I as an intermediate.

Eszopiclone is a nonbenzodiazepine hypnotic agent and it is the dextrorotatory isomer of zopiclone.  Eszopiclone is chemically (+)-(5S)-6-(chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methyl- piperazine-1-carboxylate of Formula II.

Formula II

Eszopiclone is presently in the market for the treatment of insomnia.  Eszopiclone decreases sleep latency and improves sleep maintenance when administered at bed time.

U.S. Patent No. 6,444,673, PCT application Nos. WO 07/083188 and WO 07/088073, and U.S. Publication 2007/0054914, provide processes for the separation of eszopiclone from zopiclone of Formula III using optically active salts.

Formula III

U.S. Patent No. 3,862,149 provides a process for the preparation of zopiclone using 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I as an intermediate.

Formula I

The process provided in

U.S.

‘149 patent for preparing 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I involves reacting furo[3,4-b]pyrazine-5,7-dione of Formula IV,

Formula IV

with 2-amino-5-chloropyridine in the presence of acetonitrile at reflux temperature to obtain 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V,

Formula V

and cyclizing the compound of Formula V at reflux temperature using thionyl chloride.  The process involves isolation of the compound of Formula V as a solid by pH adjustment and it is further purified by washing and drying before subjecting to cyclization.

The present authors have developed an advantageous process for the preparation of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I.  The present process does not require the isolation of 3-{[(5-chloropyridin-2-yl)amino]carbonyl} pyrazine-2-carboxylic acid of Formula V and it avoids the use of corrosive reagents such as thionyl chloride. Further, the present authors have observed that the reaction of furo[3,4-b]pyrazine-5,7-dione of Formula IV with 2-amino-5-chloropyridine can be carried out at ambient temperature conditions.  The present process also improves the yield and purity of 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione of Formula I.  Thus, by employing the present process, zopiclone and eszopiclone can be prepared in an economic and environmentally preferable way.

A first asp...