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AN IMPROVED PROCESS FOR THE PREPARATION OF (S) (+) N-METHYL-3-(1-NAPHTHALENYLOXY)-3-(2-THENYL) PROPANAMINE AND ITS INTERMEDIATE

IP.com Disclosure Number: IPCOM000175603D
Publication Date: 2008-Oct-15
Document File: 2 page(s) / 29K

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The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 51% of the total text.

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AN IMPROVED PROCESS FOR THE PREPARATION OF (S) (+) N-METHYL-3-(1-NAPHTHALENYLOXY)- 3-(2-THENYL) PROPANAMINE AND ITS INTERMEDIATE

(S) (+) N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), used as anti-depressant agent. (S) (+) N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2- thienyl)-propanamine is a key intermediate for the preparation of (S) (+) N-methyl-3-(1-naphthalenyloxy)-3-(2- thienyl) propanamine.

Provided is a process for the preparation of (S) (+) N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)- propanamine or its acid addition salts comprising reacting (S) (-) N,N Dimethyl-3-(2-thienyl)-3- hydroxyl propanamine with 1-halo naphthalene in the presence of sulfolane and alkali metal hydride . The combination of solvent and base used for the said condensation step in the provided process causes less racemisation and better chiral purity of desired product.

Examples of alkali metal hydride may be selected from the group comprising of sodium hydride, potassium hydride, lithium hydride and cesium hydride.

The condensation of (S) (-) N,N Dimethyl-3-(2-thienyl)-3- hydroxyl propanamine and 1-halo naphthalene may be carried out at a temperature range of from about ambient temperature to about reflux temperature, for a period of about 2 hours to about 20 hours.

(S) (+) N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine may be isolated in the form of base or its acid addition salt. The base compound may be isolated in the form of oil and may be further converted to its acid addition salt by contacting it with corresponding acid in suitable solvent.

(S) (+) N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine or its acid addition salts may be further converted to (S) (+) N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine or its acid addition salts such as (S) (+) N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine Hydrochloride, by any of methods known in the art.

(S) (+) N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine base or its acid addition salts obtained by the process of present invention may have the enantiomeric purity of about 98% or more.

Example 1

Preparation of (S) (+) N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine:
60% sodium hydride (2.16gm) sulfolane 30 ml were added under dry conditions and nitrogen atmosphere and the mixture was heated up to 70°C. 5.0 gm of (S) (-) N,N Dimethyl-3-(2-thienyl)-3- hydroxyl propanamine was added to the reaction mixture and the mixture was stirred for 1 hour. 7.89 gm of 1-fluoronaphthalene was then

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added to the reaction mixture in 30 to 60 minutes and the temperature was raised to 98-102°C. The reaction...