Intermediates and processes for the synthesis of Ramelteon US 20080242877

ROZEREM® (Ramelteon) is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. The empirical formula for Ramelteon is C₁₆H₂₁NO₂, and its molecular weight is 259.34. Ramelteon is freely soluble in methanol, ethanol, dimethylsulfoxide (DMSO), 1-octanol and is highly soluble in water and aq. buffer. Ramelteon has the following chemical structure:

Ramelteon is the active ingredient and sold under the brand name of ROZEREM®. Ramelteon is approved by the United States Food and Drug Administration for the treatment of insomnia characterized by difficulty with sleep onset.

Different processes for preparing (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide i.e. Ramelteon are disclosed in U.S. Pat. No. 6,034,239, JP 11080106, JP 11140073 and WO 2006/030739.

U.S. Pat. No. 6,034,239 discloses the following processes for the preparation of Ramelteon:

Japan Patent Publication No. 11080106 discloses the following processes for the preparation of Ramelteon:

Japan Patent Publication No. 11140073 discloses the following processes for the preparation of an intermediate of Ramelteon:

PCT Publication No. 2006/030739 discloses the following processes for the preparation of an intermediate of Ramelteon:

The present invention provides additional processes for preparation Ramelteon and intermediates thereof.

Synthesis of Ramelteon (I) 
Example 10

The hydrochloride salt of compound of formula XIII (100.0 gm, 418 mmol) is suspended in the THF at 4000 ml, triethyl amine (116.0 ml, 836 mmol) is added and the reaction is cooled to 10° C. or less. Propionyl chloride (74 ml, 836 mmol) is added dropwise followed by agitation at 25-35° C. for 2-3 hrs. Then 1000 ml, of water is added and the THF is distilled off under reduced pressure. It dissolved in ethyl acetate and wash twice with 10% brine solution. Dry the organic layer with sodium sulfate, distill off under vacuum and product is isolated. Dry the product under vacuum.

Intermediates and processes for the synthesis of Ramelteon
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