Title of Invention

A PROCESS FOR INCREASING THE OPTICAL PURITY OF A MIXTURE OF ENANTIOMERS OF NEFOPAM

Abstract A process for increasing the optical purity of a mixture of enantiomers of nefopam uses a substantially single enantiomer of a O,O-a'iaroyltartaric acta as a resolving agent, via a bisnefopam salt of the acid. This salt is new.
Full Text A PROCESS FOR THE RESOLUTION OF NEFOPAM Field of the Invention
The present invention relates to a resolution process, for the manufacture of the single enantiomers of nefopam. Background to the Invention
Nefopam is a chiral drug that has been 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 more potent analgesic and dopamine, norepinephrine and serotonin-uptake inhibitory properties than (-)-nefopam. W003/105832 discloses that nefopam has utility in the treatment of emesis and related conditions, with (+)-nefopam being the preferred enantiomer.
An efficient and reliable method for the preparation of the individual enantiomers of nefopam and nefopam analogues is desirable. As racemic nefopam is readily available, a classical resolution process, involving separation of diastereoisomeric salts by selective crystallisation may be suitable.
Biaschke et al, Arch. Pharm. (Weinheim) 320:341-347 (1987), discloses resolution of nefopam, using 1 molar equivalent of 0,0-dibenzoyl-L-tartaric acid. The resolution proceeds via formation of the monotartrate salt. Summary of the Invention
This invention is based on the surprising discovery that racemic or non-racemic nefopam can be resolved more efficiently, using a substantially single enantiomer of 0,0-dibenzoyltartaric acid or a related 0,0-aroyltartaric acid as a resolving agent, via formation of a novel bisnefopam tartrate (nefopam hemitartrate) salt.
An advantage of the process of the present invention is that the resolving agent can be easily recovered in a state of high purity, such that it can be re-used in one or more subsequent resolution processes. Further, if desired, less than 1.0 molar equivalent of resolving agent may be used in the process. Description of the Invention
The process of this invention may be carried out under conditions that are generally known to those skilled in the art of classical optical resolution methods.

In a typical experiment, nefopam was dissolved in ethanol then treated with a solution of 0,0-dibenzoyl-L-tartaric acid monohydrate (1.0 mol equivalent). The resulting solution was allowed to stand until precipitation occurred. Collection of the solid and recrystallisation produced the (+)-bis-nefopam 0,0-dibenzoyl-L-tartaric salt in 22% yield and 99% enantiomeric excess.
Since both enantiomers of, say, 0,0-dibenzoyltartaric are readily available in quantity, either can be used to effect the resolution, depending on which enantiomer of nefopam is required. Thus, (-)-bis-nefopam 0,0-dibenzoyl-D-tartaric salt may be prepared in a similar yield and optical purity, utilizing 0,0-di-p-toluoyl-D-tartaric acid as the resolving agent.
The resolving agent may also be used to increase the optical purity of enantiomerically-enriched nefopam. Thus, when both enantiomers of nefopam are required, the processes described above can be compressed, one enantiomer being recovered by the resolution and the opposite enantiomer being extracted from the mother liquors of the resolution. In practice, when (+)-bis-nefopam 0,0-dibenzoyl-L-tartaric salt is recovered as described above, the mother liquors remaining are processed to isolate nefopam free base enriched in the (-)-isomer, which is then purified by treatment with 0,0-dibenzoyl-D-tartaric and crystallization of the resultant salt.
The yield of the resolution procedure can be improved by a reverse resolution process. Thus, when racemic nefopam is treated with 0,0-di-p-toluoyl-D-tartaric acid, (-)-bis-nefopam 0,0-dibenzoyl-D-tartaric salt is isolated. The mother liquors, now enriched with (+)-nefopam, can be resolved in the normal way, using 0,0-dibenzoyl-L-tartaric acid, to give (+)-bis-nefopam 0,0-dibenzoyl-L-tartaric salt, in good yield. The same reverse resolution process can be applied to the isolation of (-)-bis-nefopam 0,0-dibenzoyl-L-tartaric salt, in good yield.
A substantially single enantiomer that is used in or produced by the process of the invention may be in at least 80% e.e., preferably at least 90% e.e., more preferably at least 95% e.e., and most preferably at least 98% e.e.
The present invention is illustrated by the following Examples.

Example 1 Nefopam free base
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 stirred for 10 minutes until complete dissolution was achieved. Stirring was stopped and two layers separated out. 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 with magnesium sulphate (500 g), filtered and evaporated to furnish the product as a colourless semi-solid. The above process was repeated, to furnish the product in quantitative yield (9.31 Kg, 106%, contained residual ethyl acetate). Example 2 (+)-Bis-nefopam 0,0-dibenzoyl-l-tartaric acid salt
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 0,O-dibenzoyl-L-tartaric acid (2.75 Kg, 0.25 mol equiv.) in ethanol (16.0 Kg) was added over a period of 20 minutes. The resulting solution was allowed to stir at room temperature overnight during which time crystallisation occurred. The crystals were collected by filtration, washed with ethanol (2 x 2 L) and dried to constant weight at 45 °C under reduced pressure. The product was obtained as a colourless solid, 4.27 Kg, 32%. Chiral HPLC indicated 83% e.e. for (+)-nefopam.
The solid was recrystallised in two batches from ethanol (2 x 12.16 Kg) and the solid washed with ethyl acetate (2x2 L). The combined solids were dried to constant weight at 45°C under reduced pressure to furnish the product as a colourless solid, 2,90 Kg, 68%. Chiral HPLC analysis indicated 99% e.e,
Resolution concentration uses 5 volumes of ethanol with an overall 22% yield. Example 3 (+)-Nefopam
Sodium hydroxide (335 g, 8.38 mol, 2.5 equiv.) was dissolved in water (11.9 Kg) and the solution added to the isolated product of Example 2 (2.89 Kg, 3.34 mol). The mixture was stirred for 10 minutes and extracted with ethyl acetate (3 x 4.38 Kg). The ethyl acetate extracts were dried with magnesium sulphate (500g),

filtered and evaporated under reduced pressure to constant weight. The product was isolated as colourless oil, 1.53 Kg, 90%, Example 4 (+)-Nefoparn hydrochloride salt
The isolated product of Example 3 (1.53 Kg) was dissolved in isopropanol (4.81 L) and the resulting solution heated to 50° C. Concentrated hydrochloric acid (498 ml) was added over 15 minutes, followed by stirring at 50°C for 10 minutes. The solution was allowed to cool to 30°C followed by cooling in an ice/salt bath to 0°C (precipitation begins at 35DC). The mixture was stirred for a further 1 hour at 0°C. The precipitate was filtered and washed with cold isopropanol (2 x 1.05 L) and the solid dried in a vacuum oven at 35°C. The product was obtained as a colourless solid, 1.05 Kg, 96.7% e.e.
On standing overnight, further product precipitated. The precipitate was filtered and washed with isopropanol (2 x 0.5 L) and dried in the vacuum oven at 35°C. The product was obtained as a colourless solid, 0.51 Kg, 99% e.e. Total yield 1.56 Kg, 89%. Example 5
The process of Example 2 was compared with the prior art process of Blaschke et a/, supra. They may be summarised in the following Table.
(Table Removed)
In summary, the literature method prepares the monotartrate salt whereas the novel method prepares the bisnefopam tartrate salt (hemitartrate). Results show that the latter has clear advantages: it is more scaleable, uses lower volumes of solvent, does not use DMSO, requires only 0.25 equivalents of resolving agent, requires only one recrystallisation, and gives a better e.e. of the final product.


We claim:
1. A process for increasing the optical purity of a mixture of enantiomers of nefopam by using a substantially single enantiomer of a O,O-diaroyltartaric acid as a resolving agent, characterised in that the relative amounts of the mixture of enantiomers of nefopam and the resolving agent are such that a bisnefopam salt of the acid is formed.
2. A process as claimed in claim 1, for preparing a substantially single enantiomer of nefopam by means of resolution of racemic nefopam.
3. A process as claimed in claim 1 or claim 2, for preparing a substantially single enantiomer of nefopam, which comprises reverse resolution of racemic nefopam or nefopam analogue, using sequentially a single enantiomer of a O,O-dibenzoyltartaric acid and then the other enantiomer.
4. A process as claimed in any of claims 1 to 3, for preparing substantially single enantiomer (+)-nefopam, which uses 0,0-dibenzoyl-L-tartaric acid as the resolving agent.
5. A process as claimed in any of claims 1 to 3, for preparing substantially single enantiomer (-)-nefopam, which uses 0,0-dibenzoyl-D-tartaric acid as the resolving agent.
6. A process as claimed in any preceding claim, which is conducted in a solvent selected from alcohols, esters, ketones and halogenated solvents.
7. A process as claimed in any preceding claim, which comprises the further
step of conversion of the salt obtained by the resolution to the free base
form of nefopam or a pharmaceutically acceptable salt thereof.
8. A process as claimed in any of claims 1 to 7, wherein the amount of the

resolving agent is less than 1 equivalent.
9. A process as claimed in claim 8, wherein said amount is no more than 0.5 equivalent.



Documents:

2963-DELNP-2006-Abstract-(04-03-2009).pdf

2963-DELNP-2006-Abstract-(14-09-2009).pdf

2963-delnp-2006-abstract.pdf

2963-DELNP-2006-Claims-(04-03-2009).pdf

2963-DELNP-2006-Claims-(14-09-2009).pdf

2963-DELNP-2006-Claims-(16-09-2009).pdf

2963-delnp-2006-claims.pdf

2963-DELNP-2006-Correspondence-Others-(02-09-2009).pdf

2963-DELNP-2006-Correspondence-Others-(04-03-2009).pdf

2963-DELNP-2006-Correspondence-Others-(14-09-2009).pdf

2963-DELNP-2006-Correspondence-Others-(16-09-2009).pdf

2963-delnp-2006-correspondence-others.pdf

2963-delnp-2006-description (complete).pdf

2963-DELNP-2006-Form-1-(14-09-2009).pdf

2963-delnp-2006-form-1.pdf

2963-delnp-2006-form-18..pdf

2963-DELNP-2006-Form-2-(14-09-2009).pdf

2963-delnp-2006-form-2.pdf

2963-DELNP-2006-Form-3-(04-03-2009).pdf

2963-DELNP-2006-Form-3-(14-09-2009).pdf

2963-DELNP-2006-Form-3.pdf

2963-delnp-2006-form-5.pdf

2963-delnp-2006-gpa.pdf

2963-DELNP-2006-PCT-304.pdf

2963-delnp-2006-pct-search report.pdf

2963-DELNP-2006-Petition-137-(02-09-2009).pdf


Patent Number 236366
Indian Patent Application Number 2963/DELNP/2006
PG Journal Number 44/2009
Publication Date 30-Oct-2009
Grant Date
Date of Filing 23-May-2006
Name of Patentee ARAKIS LTD.
Applicant Address CHESTERFORD RESEARCH PARK, LITTLE CHESTERFORD, SAFFRON WALDEN, ESSEX, CB10 1XL, U.K.
Inventors:
# Inventor's Name Inventor's Address
1 HARRIS, MICHAEL JOHN C/O ULTRAFINE LTD., SYNERGY HOUSE, GUILDHALL CLOSE, MANCHESTER SCIENCE PARK, MANCHESTER M15 6SY, U.K.
2 BROWN, STUART C/O ULTRAFINE LTD., SYNERHY HOUSE, GUILDHALL CLOSE, MANCHESTER SCIENCE PARK, MANCHESTER M15 6SY, U.K.
PCT International Classification Number C07D 267/00
PCT International Application Number PCT/GB2004/005198
PCT International Filing date 2004-12-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0328871.9 2003-12-12 U.K.