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Enantiomerically pure atomoxetine and tomoxetine mandelate

A technology of atomoxetine hydrochloride and atomoxetine is applied in the field of enantiomerically pure atomoxetine and atomoxetine mandelate, which can solve the problem of contamination, difficulty in implementation, time-consuming, etc. question

Inactive Publication Date: 2007-04-11
TEVA PHARMA FINE CHEMI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is disadvantageous from a commercial point of view and the desired enantiomer is contaminated with the undesired (S)-(+)-tomoxetine enantiomer
In order to obtain the desired isomer, the final product requires time-consuming and tedious purification methods such as column chromatography, HPLC or other techniques, thus making this idea commercially difficult

Method used

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  • Enantiomerically pure atomoxetine and tomoxetine mandelate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] To an anhydrous organic solution of crude racemic atomoxetine in toluene (TMX content: 85.37 g / HPLC analysis) was added 8.5 ml (0.1 ml / g racemic atomoxetine) under stirring at 20 °C Cetin) methanol and 30.53g (S)-(+)-mandelic acid. Heat to about 65°C to dissolve all solids, then allow the crude mandelate to crystallize on cooling: the temperature is lowered from 65°C to 45°C in about 1 hour. Crystallization starts spontaneously around 45°C. If necessary, the reaction mixture was inoculated with (R)-atomoxetine (S)-(+)-mandelate. Then, the suspension was cooled from 45°C to 0°C in about 2 hours. The resulting slurry was stirred at 0°C for 1-2 hours, then the solid was isolated by filtration and washed with 2 x 45 mL toluene. Yield: 43%

[0042] (R)-Atomoxetine (S)-(+)-Mandelate (R-TMX-SMA) / (S)-Atomoxetine (S)-(+)-Mandelate (S-TMX -SMA): about 95 / 5% HPLC area.

[0043] Preparation of enantiomerically pure atomoxetine (S)-(+)-mandelate

Embodiment 2

[0045] 20g of crude wet atomoxetine (S)-(+)-mandelate (0.049mol, R / S=94.3:5.56; containing 6.8g toluene), 31.7ml toluene and 8.27ml methanol (1ml / g Torr Moxetine base) was mixed under stirring at about 20°C. The suspension was heated to 65°C in about 30 min to obtain a solution. (R)-(-)-tomoxetine (S)-(+)-mandelate salt crystallized on cooling: the temperature dropped from 65°C to 20°C within 3 hours. The slurry was stirred at 20°C for 1 hour, then the solid was isolated by filtration and washed twice with 10 ml of toluene. The solid was dried under vacuum to give: R-TMX-SMA / (S-TMX-SMA): 99.91 / 0.09% HPLC area.

Embodiment 3

[0047] 20 g of crude wet atomoxetine (S)-(+)-mandelate (0.049 mol, containing 6.8 g of toluene) and 31.7 ml of toluene were mixed under stirring at about 20°C. The suspension was heated to 65°C and 4.4 ml of methanol were added dropwise until a solution was obtained. The temperature was then lowered from 65°C to 20°C over 3 hours and crystallization occurred immediately. The slurry was stirred at 20°C for 1 hour, then the solid was isolated by filtration and washed twice with 10 ml of toluene. The solid was dried under vacuum at 50°C for 18 hours to give: R-TMX-SMA / S-TMX-SMA: 99.93 / 0.07% HPLC area.

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Abstract

The present invention provides enantiomerically pure (R)-(-)-tomoxetine (S)-(+)-mandelate and atomoxetine HCI. The present invention further provides enantiomerically pure (R)-(-)-tomoxetine (S)-(+)-mandelate prepared from racemic 5 tomoxetine. The present invention also provides enantiomerically pure atomoxetine HCI prepared from (R)-(-)-tomoxetine (S)-(+)-mandelate.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the following U.S. Provisional Patent Applications: No. 60 / 583,641, filed June 28, 2004; No. 60 / 609,716, filed September 14, 2004; No. 60 / 622,065; October 25, 2004 No. 60 / 652,330, filed February 11, 2005; No. 60 / 583,644, filed June 28, 2004; No. 60 / 652,332, filed February 11, 2005; No. 60 / 583,643 , filed June 28, 2004; No. 60 / 652,331, filed February 11, 2005; No. 60 / 666,666, filed March 30, 2005; No. 60 / 675,369, filed April 26, 2005 ; Application No. not yet available (Attorney's Abstract No. 12670 / 46803), filed June 9, 2005; and Application No. not yet available (Attorney's Abstract No. 12670 / 47001), filed June 14, 2005; all of these applications The contents are listed as references in this paper. technical field [0003] The present invention relates to enantiomerically pure atomoxetine and tomoxetine mandelate obtained after optical resolution of racemic atomoxetine. Backgro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/48C07C213/10
Inventor E·卡斯特里P·达维里奥S·曼托瓦尼
Owner TEVA PHARMA FINE CHEMI
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