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Unsaturated Impurities Formed in a Process for Preparing (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide

IP.com Disclosure Number: IPCOM000191447D
Publication Date: 2010-Jan-05
Document File: 6 page(s) / 88K

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Unsaturated Impurities Formed in a Process for Preparing
(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide

(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, of the following formula:

O

is the first in a new class of sleep agents that selectively binds to the melatonin receptors in the suprachiasmatic nucleus (SCN), versus binding to GABA receptors, such as with other commercial drugs.

Provided are novel impurities formed in a process for preparing (S)-N-[2-(1,6,7,8- tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide:
6, 7-dihydro-8H-indeno [5, 4-b] furan-8-one (compounds VIII (FA)), 5, 6-dihydro-7H- indeno [5, 6-b] furan-7-one (compound VIII (FL)), ethyl (2E)-7, 8-dihydro-6H-indeno [5, 4-b] furan-8-ylideneacetate (compound X (FA)), 2-(7, 8-dihydro-6H-indeno [5, 4-b] furan-8-yl) acetic acid (compound XI (FA)), 2-(7, 8-dihydro-6H-indeno [5, 4-b] furan-8- yl) acetamide (compound XIII (FA)), 2-(7, 8-dihydro-6H-indeno [5, 4-b] furan-8-yl) ethanamine hydrochloride (compound XIV (FA)), and N-[2-(7, 8-dihydro-6H-indeno [5,

O N

H

I

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4-b] furan-8-yl) ethyl] propanamide (compound I (FA)), of the following formulas:

O

O

O

O

O O

O

VIII(FA) X(FA)

VIII(FL)

O

O

OH

NH2

NH2 .HCl

O

O

O

XI(FA)

XIII(FA)

XIV(FA)

N

O

O

I(FA)

Procedure 1

Process for Compound VIII (FA) and VIII (FL):
a)
Preparation of 1,1-diethoxy-2-(4-bromo phenoxy)ethane:

Condensing the 4-bromophenol with 2-Bromo-1,1-diethoxy ethane in presence of base and an organic solvent.

b) Preparation of 5-bromo benzofuran:

Cyclisation of 1, 1-diethoxy-2-(4-bromophenoxy) ethane with polyphoshoric acid. The pure 5-bromo benzofuran can be obtained by column chromatography.

c) Preparation of (E)-ethyl-3-(benzofuran-5- yl)acrylate:

Coupling of 5-bromobenzofuran with ethyl acrylate, catalyzed by a palladium(0) complex in presence of base.

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The (E)-ethyl-3-(benzofuran-5- yl)acrylate was isolated and purified by column chromatography (100-200 silica; 10% ethyl acetate in hexane).

d) Preparation of ethyl-3-(benzofuran-5-yl)propanoate:

Hydrogenating (E)-ethyl-3-(benzofuran-5- yl)acrylate with suitable catalyst under hydrogen pressure in polar protic solvent or protic solvent and mixture with water thereof.

e) Preparation of 3-(benzofuran-5-yl)propanoic acid:

Hydrolysis of ethyl-3-(benzofuran-5-yl)propanoate in polar solvent or mixture with water thereof.

f) Preparation of 6,7-dihydro-8H-indeno[5,4-b]furan-8-one

Chlorinating 3-(benzofuran-5-yl)propanoic acid with suitable chlorinating agent in aliphatic alkanes or halogenated aliphatic alkanes followed by cyclisation in presence of aluminium chloride.

The product was isolated and the two compound 6,7-dihydro-8H-indeno[5,4-b]furan-8- one and 5,6-dihydro-7H-indeno[5,6-b]furan-7-one are separated by column chromatography.
6, 7-dihydro-8H-indeno [5, 4-b] furan-8-one (Compound-VIII (FA))

1H NMR: (400 MHz, CDCl3) δ 2.77-2.80 (2H, t), 3.23-3.2...