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Processes for the preparation of tomoxetine

A technology of alkali metal and hydroxide, which is applied in the preparation of organic compounds, chemical instruments and methods, preparation of amino hydroxyl compounds, etc., can solve the problem of low activity of 2-fluorotoluene

Inactive Publication Date: 2007-04-04
TEVA PHARMA FINE CHEMI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As pointed out in US6541668, aromatic nucleophilic substitution to obtain tomoxetine cannot be carried out under conditions known for other 3-aryloxy-3-phenylpropylamines, because 2-fluorotoluene is more reactive than other aromatic rings used Low

Method used

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  • Processes for the preparation of tomoxetine

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[0026] The invention provides a preparation method of tomoxetine with improved reaction yield and / or shortened total reaction time. The method includes the steps of:

[0027] (a) in the presence of an alkali metal hydroxide, N-methyl-3-hydroxyl-3-phenylpropylamine is mixed with dimethyl sulfoxide (DMSO) to form a slurry;

[0028] (b) adding 2-fluorotoluene to the slurry to obtain a reaction mixture;

[0029] (c) heating the resulting mixture to obtain tomoxetine; and

[0030] (d) Recovery of the tomoxetine formed.

[0031] DMSO is used as a reagent rather than a solvent, so it can be added in small amounts and can even be considered a catalyst. The amount of DMSO used in the reaction is about 0.1 to about 20 moles per mole of N-methyl-3-hydroxy-3-phenylpropylamine. Preferably, DMSO is added in an amount of about 3 to about 4 moles per mole of N-methyl-3-hydroxy-3-phenylpropylamine.

[0032] Suitable alkali metal hydroxides may be selected from potassium hydroxide, barium ...

Embodiment 1

[0054] Preparation of tomoxetine

[0055] 30 g (0.384 mol) of dimethyl sulfoxide, 20 g (0.121 mol) of N-methyl-3-hydroxy-3-phenylpropylamine and 22.6 g (0.363 mol) of potassium hydroxide (industrial grade in bulk, 90.1% analysis) were stirred Mix and heat at 100°C for 1 hour. The resulting slurry was cooled to 80°C, and 40.0 g (0.363 mol) of 2-fluorotoluene was added. The mixture was heated to reflux (135-137°C), held for 3 hours and then cooled to about 90°C. Then 120ml of water and 120ml of toluene were added. The mixture was stirred for a few minutes, then the phases were separated. The aqueous phase was extracted with 3 x 30 ml toluene. The organic solvent was collected and washed with 3 x 30ml water. The final weight of the organic phase was 206 g. The tomoxetine content was 14.28% by weight (HPLC analysis). Yield: 95.2%.

Embodiment 2

[0057] Preparation of tomoxetine

[0058] In the Stir to mix at 20-25 for 1 hour. Then 40.0 g (0.363 mol) of 2-fluorotoluene was added to the resulting slurry. The mixture was then heated to reflux (142-145°C) for 2 hours and cooled to about 80°C. Then 120ml of water and 120ml of toluene were added. The mixture was stirred for a few minutes, then the phases were separated. The aqueous phase was extracted with 3 x 20 ml toluene. The organic solvent was collected and washed with 4 x 30ml of water. The final weight of the organic phase was 206 g. The tomoxetine content was 13.25% by weight (HPLC analysis). Yield: 88.4%.

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Abstract

Provided are processes for preparing tomoxetine comprising reacting N-methyl-3-hydroxy-3-phenylpropylamine with dimethylsulfoxide (DMSO) and 2-fluorotoluene in the presence of an alkali base to form tomoxetine. Also provided is the conversion of said tomoxetine into atomoxetine or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application Nos. 60 / 583641 (filed June 28, 2004), 60 / 609716 (filed September 14, 2004), 60 / 622065 (filed October 25, 2004), 60 / 652330 (filed February 11, 2005), 60 / 583644 (filed June 28, 2004), 60 / 652332 (filed February 11, 2005), 60 / 583643 (filed June 28, 2004), 60 / 652331 (filed February 11, 2005), 60 / 666666 (filed March 30, 2005), 60 / 675369 (filed April 26, 2005), application with unknown application number (attorney file number 12670 / 46803) (filed June 9, 2005) and application with unknown application number (Attorney Docket No. 12670 / 47001) (filed June 14, 2005), all of which are incorporated herein by reference. field of invention [0003] The present invention relates to a novel process for the preparation of racemic tomoxetine. Background of the invention [0004] Atomoxetine, or (R)(-)-N-methyl-3-(2-met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C217/48
Inventor E·卡斯特里G·罗莫纳科S·曼托瓦尼P·达维奥P·里瓦A·瓦拉蒂S·比安奇
Owner TEVA PHARMA FINE CHEMI
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