Process for the preparation of optically pure indeno [5,4-b] furan derivatives WO 2008062468 ..Ramelteon

The present invention relates to process for the preparation of (-)-(S)-N-[2- (l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (RAMELTEON) (I) in its pure isomeric form and free from its enantiomeric isomer.

1

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MTl and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTl or MT2 receptors, and high selectivity for human MTl and MT2 receptors compared to the

MT3 receptor.

Ramelteon is a selective melatonin receptor agonist that has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complain of some type of insomnia and 20 million Americans suffer from chronic insomnia. It is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, leading to impairment of next day functioning. Insomnia has been linked to a variety of health problems, including obesity, diabetes, hypertension, heart disease, and depression. Ramelteon is the first and only prescription sleep medication that has shown no evidence of abuse and dependence, and as a result, has not been designated as a controlled substance by the DEA. Its approval also allows physicians to prescribe ramelteon for long-term use in adults. Ramelteon provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. However, clinical comparisons with other hypnotic agents are not available and will be needed to better differentiate these products.

Our objective is to prepare either racemic Ramelteon (±)-l or it's intermediate 2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (+)-(2) and separations of desired isomers of either (1) or (2) using chiral and/or achiral stationary phases for batch process, super-critical or sub-critical chromatography and/or continuous process chromatography.

United State patent 6,034,239 reports formation of chiral intermediate (-)-(S)-N- [2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)]ethylamine (S)-2 by the catalytic asymnjetric hydrogenation of 2-(l,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- ylidene)ethylamine (3) in the presence of catalytic amount of BINAP -ruthenium complex in approximately 89% ee followed by purification by preparing acid salt and its condensation with propionyl chloride to get Ramelteon (1) in pure form.

An alternate process for preparing Ramelteon is reported in JMC, 45,

4222-4239 (2002). Herein the exo double bond of the intermediate (A) was asymetrically reduced using (S)-2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (binap)- Ru complex as the catalyst to obtain enantiomerically pure compound (B). Compound (B) is subsequently converted to (S)-(-) Ramelteon (1) through intermediate steps of Claisen condensation, ozonolysis and finally cyclization.

Thus both the above process uses expensive catalyst and involves very sophisticated reaction conditions which make them commercially less viable. Therefore, there exists a need to develop a process for obtaining Ramelteon in an enantiomerically pure form which is cost effective, uses easily available reagents, is scalable with ease and overall commercially more viable. We herein disclose such a process. The process is provided in the following Scheme 1 below:

A process for preparing enantiomerically pure Ramelteon (S)-I comprising the steps of i) reacting a compound of formula (2) either in racemic or enantiomerically pure form with propionyl chloride (4) to obtain Ramelteon (1) with retention of configuration;

Process for the preparation of optically pure indeno [5,4-b] furan derivatives
WO 2008062468 A2......http://www.google.com/patents/WO2008062468A2?cl=en

Reference
1	*	RIVARA ET AL: "Reassessing the melatonin pharmacophore-Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 14, no. 10, 15 May 2006 (2006-05-15), pages 3383-3391, XP005364989 ISSN: 0968-0896
2	*	T. YAMANO ET AL: "Approach to the stereoselective synthesis of melatonin receptor agonist Ramelteon via asymmetric hydrogenation" TETRAHEDRON ASYMMETRY, vol. 17, no. 2, 23 January 2006 (2006-01-23), pages 184-190, XP002481301 NLELSEVIER, AMSTERDAM.
3	*	UCHIKAWA O ET AL: "Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 45, 1 January 2002 (2002-01-01), pages 4222-4239, XP002990691 ISSN: 0022-2623 cited in the application