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Process for the preparation of optically active (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine

a technology of n-dimethyl-3-(1-naphthalenyloxy) and n-dimethyl-3-(1-naphthalenyloxy)3-(2thienyl)propanamine, which is applied in the field of process for the preparation of optically active (s)(+)n, and n-dimethyl-3-(1-naphthalenyloxy)3-(2thienyl)propanamine, which

Inactive Publication Date: 2006-11-30
TEVA PHARM USA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach enables the efficient synthesis of enantiomerically enriched DNT and its conversion to pharmaceutically acceptable salts, improving the yield and purity of duloxetine, specifically achieving high enantiomeric enrichment and racemization, thus addressing the inefficiencies in prior art processes.

Problems solved by technology

The drawback of the processes described in Scheme 2 is the lack of processes for synthesizing an enantiomerically pure DNT and a racemization process for the reprocessing of the undesirable enantiomer.

Method used

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  • Process for the preparation of optically active (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
  • Process for the preparation of optically active (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
  • Process for the preparation of optically active (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine

Examples

Experimental program
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Effect test

example 1

Preparation of (S)-DNT di-p-toluoyl-L-tartarate in toluene

[0040] A 1.24 g portion of di-p-toluoyl-L-tartaric acid was added to a solution of 2 g (R,S)-DNT in 10 ml of toluene. The resulting mixture was heated to 75° C. for 10 minutes, and then cooled to room temperature. The resulting solid was filtered, and dried in a vacuum oven to give 1.15 g of (S)-DNT di-p-toluoyl-L-tartarate.

example 2

Preparation of (S)-DNT di-p-toluoyl-L-tartarate in EtOAc / Ether

[0041] A 1.24 g portion of di-p-toluoyl-L-tartaric acid was added to a solution of 2 g (R,S)-DNT in 10 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for an hour. The addition of 6 ml of ether resulted in a precipitate. The mixture was then heated to reflux, and an additional 20 ml of ethyl acetate were added. The mixture was cooled to room temperature, filtered, washed with 10 ml of ether, and dried in a vacuum oven to give 1.41 g of (S)-DNT di-p-toluoyl-L-tartarate.

example 3

Preparation of (S)-DNT

[0042] A solution of 10 percent by weight NaOH was added to a mixture of 1 g of (S)-DNT di-p-toluoyl-L-tartarate in 30 ml of water and 30 ml of dichloromethane to provide a pH of 14, and stirred for an hour. After phase separation, the organic phase was washed with water (30 ml), dried over Na2SO4, filtered, and concentrated to dryness to give 0.4 g of brownish oil (62.17 percent ee).

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Abstract

Diasteromerically enriched salts of (S)-DNTH+ EPA− and (R)-DNTH+EPA−, methods of preparing such diasteromerically enriched salts of (S)-DNTH+ EPA− and (R)-DNTH+ EPA−, and methods of preparing enantiomerically enriched (S)-DNT and enantiomerically enriched (R)-DNT are provided.

Description

RELATED APPLICATIONS [0001] This application claims benefit of U.S. Provisional Application Nos. 60 / 726,502, filed Oct. 12, 2005, 60 / 736,746, filed Nov. 14, 2005, 60 / 661,711, filed Mar. 14, 2005, and 60 / 773,593, filed Feb. 14, 2006.FIELD OF THE INVENTION [0002] The present invention provides processes for synthesis of duloxetine intermediate. The present invention also provides processes for converting these duloxetine intermediate into pharmaceutically acceptable salts of duloxetine. BACKGROUND [0003] Duloxetine is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI), depression, and pain management. Duloxetine hydrochloride, CAS Registry No. 136434-34-9, has the chemical structure Formula I. [0004] An intermediate in the synthesis of duloxetine is (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine. The intermediate is also known as (S)-(+)-DNT, has been assigned the CAS ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D333/22
CPCA61K31/38C07D333/20C07D333/16A61P13/00A61P25/24A61P29/00
Inventor INI, SANTIAGOABRAMOV, MILILIBERMAN, ANITA
Owner TEVA PHARM USA INC