Showing posts with label WO 2010055481. Show all posts
Showing posts with label WO 2010055481. Show all posts

Sunday, 18 January 2015

Process for the preparation of ramelteon WO 2010055481

Ramelteon (1) is a melatonin receptor agonist with both high affinity for melatonin MTi and MT2 receptors and selectivity over the MT3 receptor.
Figure imgf000002_0001
Ramelteon demonstrates full agonist activity in vitro in cells expressing human MTi or MT2 receptors, and high selectivity for human MTi and MT2 receptors compared to the MT3 receptor.

Ramelteon has demonstrated efficacy in the treatment of insomnia characterized by difficulty with sleep onset. Approximately one in three American adults complains of some type of insomnia, and 20 million Americans suffer from chronic insomnia, which is characterized by difficulty falling asleep, difficulty staying asleep, or poor quality sleep, often 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 has also been prescribed for long-term use in adults, provides a unique therapeutic mechanism of action for therapy of insomnia and represents a new treatment option. United States Patent No. 6,034,239 discloses the formation of chiral intermediates (S)-(- )-N-[2-(l,6,7,8,-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine (sometimes referred to as compound S-2 or intermediate compound S-2) by the catalytic asymmetric hydrogenation of 2- (l,2,6,7,-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine (compound 3 in the reaction scheme shown below) in the presence of a catalytic amount of BINAP-ruthenium complex in approximately 89% e.e. (enantiomeric excess). 

Following the catalytic reaction, the product is purified by preparing acid salts and acylated with propionyl chloride (compound 4 in the reaction scheme shown below) to obtain ramelteon (compound 1 in the reaction scheme shown below) in its pure (S) isomer form.
Figure imgf000003_0001
An alternate process for preparing ramelteon is disclosed in the Journal of Medicinal Chemistry, Vol. 45, pp. 4222-4239 (2002), wherein the exo double bond of intermediates (A) shown below was asymmetrically reduced using (S)-2, 2'-bis-(diphenylphosphino)-l, 1 '- binaphthyl (binap)-Ru complex as the catalyst to obtain the enantiomerically pure compound (B). Compound (B) is subsequently converted to ramelteon (1) through the intermediate steps of Claisen condensation, ozonolysis and cyclization.
Figure imgf000003_0002
m Both of the above processes uses expensive catalyst and give poor enantioselectivity. Additionally, these processes are expensive due to the need to perform multiple purifications steps in order to achieve an enantioselectivity of at least about 99% or greater of the desired isomer.

PCT Patent Publication No. WO 2008/062468 A2 discloses the following process for the preparation of ramelteon:
Figure imgf000004_0001

WO 2008/062468 teaches that separation of the enantiomers of intermediate (2) may be accomplished by: i) optical resolution of the racemic amine intermediate (2) by preparing acid salts with chirally pure acids; or ii) chromatographic techniques using chiral and/or achiral stationary phases for batch process, super critical or sub critical chromatography and/or continuous process chromatography. 

Although WO 2008/062468 mentions the possible use of optical resolution with chirally pure acids, there is no further teaching, discussion or disclosure of this method. WO 2008/062468 does, however, provide detailed descriptions of chromatographic methods for separating the isomers of intermediate compound (2). 

The disclosed chromatographic process suffers the following disadvantages:
• Preparative chromatography is time consuming & expensive;
• Highly sophisticated instrumentation required; • Not commercially feasible.
PCT Patent Publication No. WO 2008/106179 discloses a process for the preparation of ramelteon that involves the following reaction steps:
Figure imgf000005_0001
wherein X= O-alkyl or NH2 and chiral reduction of the compound of formula IV in the presence of Ru-BINAP complex under hydrogen atmosphere in an organic solvent.
Figure imgf000005_0002
The process disclosed in WO 2008/106179 is similar to the process disclosed in United States Patent No. 6,034,239 and the Journal of Medicinal Chemistry, Vol. 45 in that a Ru-BINAP complex is employed.
Resolution of racemic mixtures via reaction with optically active acids and the subsequent crystallization of the resulting salts is preferably employed when the chiral carbon of the racemic compound is an alpha carbon {i.e., one carbon removed) to the functional group forming the acid addition salt.

 As the distance between the chiral carbon of the racemic compound to the functional group of the racemic compound increases to beta (i.e., two carbon removed) & gamma (i.e., three carbon removed), the resolution of the diastereomeric salt becomes more difficult and not very useful.

Ramelteon has a chiral center at the gamma carbon, which makes the separation of the isomer with an optically active acid quite a daunting task. Similarly, N-[2-(l, 6, 7, 8,- tetrahydro-2H-indeno [5, 4-b]furan-8-yl)]ethylamine (compound T), an intermediate useful in the production of ramelteon has a chiral center at the gamma carbon which would lead a skilled artisan to believe that optical resolution with an optically active acid could prove difficult.

InventorsManjunath Narayan BhanuChandrasekhar SinhaBhupesh AherAmol BandalAtul ParabLess «
ApplicantWatson Pharma Private Limited

The present invention further includes a process for the synthesis of ramelteon that comprises the step of separating N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8- yl)]ethylamine (compound 2) into its isomers using an optically active acid to achieve high enantioselectivity of the desired isomer. This embodiment may further include the step of acylating the substantially pure enantiomer, (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)]ethylamine (compound (S)-2) using a suitable acylating agent, such as propionyl chloride) to provide (S)-7V-[2-(l,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propionamide (ramelteon or compound 1) substantially free of the (R)-isomer.
One embodiment of the present invention for the preparation of ramelteon is shown below in Scheme 1.
Figure imgf000007_0001

Example 2
Preparation of (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl)ethyl] propionamide (ramelteon)
Triethyl amine (15.15 g, 0.15 mol) and propionyl chloride (13.66 g, 0.15 mol) were added to a solution of S-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)]ethylamine (25 g, 0.12 mol) (compound (S)-2) (prepared in Example 1) in dichloromethane and stirred at room temperature for 2 hours. 75 mL water was added to the reaction mixture, and the layers were separated. The dichloromethane layer was concentrated under reduced pressure and purified from a mixture of acetone and hexane to give (S)-N-[2-(l, 6, 7, 8-tetrahydro-2H-indeno [5, 4-b] furan- 8-yl) ethyl] propionamide (compound 1) having a chiral purity of 99% or greater enantioselectivity.