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Process for the optical resolution and recycling of tomoxetine

A atomoxetine, pharmaceutical technology, applied in the field of optical resolution and reuse of atomoxetine, can solve problems such as dangerous solvents

Inactive Publication Date: 2007-04-18
TEVA PHARMA FINE CHEMI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires hazardous solvents and bases unsuitable for large-scale commercial synthesis

Method used

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  • Process for the optical resolution and recycling of tomoxetine
  • Process for the optical resolution and recycling of tomoxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] (R,S)-N-Methyl-3-(2-methylphenoxy)-3-phenylpropylamine (tomoxetine synthesis)

[0065] 1100g (14.1mol) dimethyl sulfoxide, 200g (1.21mol) N-methyl-3-hydroxy-3-phenylpropylamine, 221g (3.63mol) KOH (batch industrial grade, 92.1% detection) at 110°C Heat and stir, then concentrate the mixture by vacuum distillation until about 130 g of solvent is removed. After the mixture had cooled to 80°C, 400 g (3.63 mol) of 2-fluorotoluene were added. The mixture was heated to reflux (145°C-147°C) for one hour and then allowed to cool to 90°C. 1000ml of water and 1000ml of toluene were added. The mixture was stirred for several minutes, at which point the phases separated. The aqueous phase was extracted with 2 x 200 ml toluene. The organic phase was collected and washed with 3 x 200ml water. Final organic phase weight: 1700 g. Atomoxetine content: 16.83% (weight ratio) (HPLC detection).

[0066] Yield: 92.7%.

Embodiment 2

[0068] (R)-(-)-tomoxetine (S)-(+)-mandelate (atomoxetine optical resolution)

[0069] A toluene solution of crude racemic atomoxetine prepared as described in Example 1 (376.13 g, 1.081 mL, detected by HPLC) was concentrated in vacuo to remove water. The residue was taken up in 2025 ml of toluene and 26 ml of methanol. To the resulting solution was added 94 g (0.618 mol) of (S)-(+)-mandelic acid at 25°C. Heat to 60°C-70°C to dissolve all solids, then cool the crude mandelate to crystallize. The solid was isolated by filtration at 5°C-10°C, washed with about 300 ml of toluene and dried under vacuum. Weight: 178g. Atomoxetine content: 63.2% (weight ratio) (HPLC detection). Yield: 43.15%. The ratio of (R)-(-)-atomoxetine enantiomers of the crude mandelate: R / S is about 95 / 5 (by chiral HPLC).

[0070] The crude mandelate obtained by recrystallizing 163 g from 489 ml of toluene and 49 ml of methanol is as follows: heat to 65°C-70°C to dissolve the salt, (R)-(-)-atomoxetine (S...

Embodiment 3

[0072] (R)-(-)-tomoxetine (S)-(+)-mandelate (atomoxetine optical resolution)

[0073] To a toluene solution (derived from Example 2) of 26.5 g of racemic atomoxetine crude product (0.104 mol, detected by HPLC) at 25° C., 1.6 ml of methanol and 9.6 g (0.063 mol) of (S)-(+ )-mandelic acid. Heating to 65°C-70°C dissolves all solids, and the crude mandelic acid salt crystallizes upon cooling. The salt was isolated by filtration at 5°C-10°C, washed with about 30 ml of toluene and dried in vacuo. Weight: 16.4g. Atomoxetine content: 64.35% (weight ratio) (HPLC detection). Yield: 40% (from racemic atomoxetine). The ratio of (R)-(-)-atomoxetine enantiomers of the crude mandelate: R / S is about 97 / 3 (by chiral HPLC).

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Abstract

The present invention provides a process for the optical resolution of racemic tomoxetine under reaction conditions that improve reaction yields and optical purity. The invention also provides an epimerization process for the (S)-(+) enantiomer. The invention further provides the conversion of the enantiomer obtained from the optical resolution into atomoxetine or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims protection of U.S. Provisional Patent Application 60 / 583,641 filed on June 28, 2004, 60 / 609,716 filed on September 14, 2004, 60 / 622,065 filed on Oct. 25, 2004, 60 / 652,330 filed on Feb. 11, 2005, and 60 filed on June 28, 2004 / 583,644, 60 / 652,332 of 2005.2.11 application, 60 / 583,643 of 2004.6.28 application, 60 / 652,331 of 2005.2.11 application, 60 / 666,666 of 2005.3.30 application, 60 / 675,369 of 2005.4.26 application, 2005.6. 9 application with unknown application number (attorney docket number 12670 / 46803), and 2005.6.14 application with unknown application number (attorney docket number 12670 / 47001), the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to a method for the optical resolution of racemic atomoxetine. The present invention also relates to methods for the recycling of (S)-(+)-tomoxetine. Background of the invent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C217/48C07C213/10
Inventor E·卡斯特里G·洛莫纳科S·曼托瓦尼P·达维里奥P·里瓦A·瓦拉蒂S·比安奇
Owner TEVA PHARMA FINE CHEMI
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