Browse Prior Art Database

PROCESS FOR THE SYNTHESIS OF (S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO-[5,4-B]FURAN-8-YL)ETHYL]PROPIONAMIDE AND ITS INTERMEDIATES

IP.com Disclosure Number: IPCOM000193577D
Publication Date: 2010-Mar-03
Document File: 5 page(s) / 22K

Publishing Venue

The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 47% of the total text.

Page 1 of 5

PROCESS FOR THE SYNTHESIS OF
(S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO-[5,4-B]FURAN-8- YL)ETHYL]PROPIONAMIDE
AND ITS INTERMEDIATES

(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide 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 (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-
b]furan-8-yl)ethyl]propionamide is C16H21NO2, and its molecular weight is 259.34. (S)-N-[2- (1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide is freely soluble in methanol, ethanol, DMSO, and 1-octanol, and slightly soluble in water and aqueous buffer. (S)- N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide has the following chemical structure:

O

This publication discloses the following process for preparation of (S)-N-[2-(1,6,7,8-tetrahydro- 2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide;

O N

H

I

Page 2 of 5

N

O

O

O

O

O

NH2

NH2

V IV III

BF3 DEE complex NaBH4/THF

O

TEA/THF

O

O

N

H

Cl

NH2

O

Ramelteon

2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)acetonitrile, compound of formula (V), can be obtained, for example, according to any of procedures described in U.S. Patent No. 60342329, in Japan Patent Publication No. 11140073, or in PCT Application No. WO 2006/030739, incorporated herein by reference.

The compound of formula (IV), N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8- ylidene)acetamide is obtained by oxidation of compound of formula (V), in presence of base.

The obtained compound IV can be found in two different isomeric structures, 2-(1,6,7,8- tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)acetamide (I'), and 2-(1,6-dihydro-2H-indeno[5,4- b]furan-8-yl)acetamide (I")

O

II

O

O

O

NH

NH

I' I"

Compound IV of the present application is preferably, composed of from about 90% to about 99% wt/wt of the I' isomer, and about 10% to about 1% of the I'' isomer. More preferably, compound I is composed from about 94% to about 98% of I' and the remainder I''

Page 3 of 5

Base is selected from alkali metal carbonate, alkaline earth metal carbonates, alkali metal bicarbonate and alkaline earth bicarbonates, like sodium carbonate, Potassium carbonate, Cesium carbonate, sodium bicarbonate, Potassium bicarbonate .

Solvent for the hydrolysis of compound of formula (V), is selected from polar aprotic solvent, for example dimethyl formamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran and alike.

The above reaction is conducted at a temperature of between about 0°C and about 50°C.

N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)acetamide has obtained by above process, having purity more than 98% and yield is more than 80%

This invention also relates to futher conversion of compound of formula (IV) to compound of formula (III), 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]acetamide by asymmetric reduction of double bond using catalyst under hydrogen pressure .

For above mentioned a...