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A process for the resolution of nefopam

A technology of nefopam and resolution agent, which is applied in the field of preparing single enantiomers of nefopam, can solve problems such as different biological activities, and achieve the effect of easy recovery

Inactive Publication Date: 2007-01-10
ARAKIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although Nefopam is marketed as a racemic mixture, the enantiomers of the drug have been shown to exhibit different biological activities

Method used

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  • A process for the resolution of nefopam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1 Nefopam free base

[0016] Racemic Nefopam hydrochloride (5.0 Kg, 17.2 mol) was suspended in water (12.5 L) and 2M sodium hydroxide solution (18.5 Kg), and solid sodium hydroxide (50 g) was added. Ethyl acetate (11.16 Kg) was added and the mixture was stirred for 10 minutes until complete dissolution was achieved. Stirring was stopped and the two layers separated. The ethyl acetate layer was removed and stored. The aqueous layer was further extracted with ethyl acetate (11.16 Kg) and the combined ethyl acetate extracts were dried over magnesium sulfate (500 g), filtered and evaporated to give the product as a colorless semi-solid. The above procedure was repeated to obtain the product in quantitative yield (9.31 Kg, 106%, with residual ethyl acetate).

Embodiment 2

[0017] Example 2 (+)-bis-nefopam O, O-dibenzoyl-l-tartrate

[0018] The isolated product of Example 1 (7.86 Kg, 31.0 mol) was dissolved in ethanol (14.7 Kg) and stirred at room temperature. A solution of O,O-dibenzoyl-L-tartaric acid (2.75 Kg, 0.25 molar equivalents) in ethanol (16.0 Kg) was added over a period of 20 minutes. The resulting solution was allowed to stir overnight at room temperature, during which time crystallization occurred. Crystals were collected by filtration, washed with ethanol (2 x 2 L) and dried at 45°C under reduced pressure to constant weight. The product was obtained as a colorless solid, 4.27 Kg, 32%. Chiral HPLC showed 83% (+)-Nefopam enantiomeric excess.

[0019] The solid was recrystallized in two batches from ethanol (2 x 12.16 Kg) and washed with ethyl acetate (2 x 2 L). The combined solids were dried under reduced pressure at 45°C to constant weight to obtain the product as a colorless solid, 2.90 Kg, 68%. Chiral HPLC analysis showed 99% ...

Embodiment 3

[0021] Embodiment 3 (+)-Nefopam

[0022] Sodium hydroxide (335g, 8.38mol, 2.5eq) was dissolved in water (11.9Kg) and the solution was added to the isolated product of Example 2 (2.89Kg, 3.34mol). The mixture was stirred for 10 minutes and extracted with ethyl acetate (3 x 4.38 Kg). The ethyl acetate extract was dried over magnesium sulfate (500 g), filtered and evaporated to constant weight under reduced pressure. The product was isolated as a colorless oil, 1.53 Kg, 90%.

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Abstract

A process for increasing the optical purity of a mixture of enantiomers of nefopam uses a substantially single enantiomer of a O,O-diaroyltartaric acid as a resolving agent, via a bisnefopam salt of the acid. This salt is new.

Description

field of invention [0001] The invention relates to a resolution method for preparing single enantiomers of Nefopam. Background of the invention [0002] Nefopam is a chiral drug that was developed for the treatment of moderate to severe pain. Although Nefopam is marketed as a racemic mixture, the enantiomers of the drug have been shown to exhibit different biological activities. In vitro and in vivo studies have shown that (+)-Nefopam has stronger analgesic properties and dopamine, norepinephrine and serotonin uptake inhibitory properties than (-)-Nefopam. WO03 / 105832 discloses that Nefopam has utility in the treatment of emesis and related conditions, with (+)-Nefopam being the preferred enantiomer. [0003] An efficient and reliable method of preparing the individual enantiomers of Nefopam and Nefopam analogs would be desirable. Since racemic Nefopam is readily available, classical resolution methods involving separation of asymmetric isomeric salts by selective crystal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D267/00C07D267/22
CPCC07D267/22A61P25/02A61P29/00
Inventor M·J·哈里斯S·布朗
Owner ARAKIS
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