KR20070018809A - A process for the resolution of nefopam - Google Patents

Abstract

A method for increasing the optical purity of a mixture of enantiomers of nepofamm, using a substantially single enantiomer of O, O-dialoyltartaric acid as a splitting agent, and via the bisnepofamlate of the acid . This salt is novel.

Split, enantiomer, nepofam

Description

A process for the resolution of nefopam}

The present invention relates to a resolution method for the preparation of a single enantiomer of nefopam.

Nepofarm is a chiral drug that has been developed for the treatment of severe pain. Nepofam is marketed as a racemic mixture, but the enantiomers of the drug are shown to exhibit different biological activities. In vitro and in vivo studies have shown that (+)-nepofam have more effective analgesics, dopamine, norepinephrine and serotonin-uptake inhibitory properties than (-)-nepofam. WO 03/105832 discloses that nepofarms have an effect on the treatment of emesis and related conditions, with the (+)-nepofam enantiomers taking precedence.

There is a need for an effective and reliable method for the preparation of each enantiomer of nepofam and its analogs. As racemic nepofam is readily available, typical methods of cleavage involving the separation of diastereoisomeric salts by selective crystallization may be appropriate.

Blaschke et al, Arch. Pharm. (Weinheim) 320: 341-347 (1987) discloses cleavage of nepofam using 1 molar equivalent of O, O-dibenzoyl-L-tartaric acid. The division proceeds via the formation of monotartarate.

Summary of the Invention

The present invention relates to a novel nefopam hemitartrate salt using O, O-aroyltartaric acid in which racemic or non-racemic nepofarm is involved as a substantially single enantiomer or splitting agent of O, O-dibenzoyltartaric acid. It is based on a surprising discovery that can be partitioned more effectively via formation.

An advantage of the process of the invention is that the splitting agent can be easily recovered in a state of high purity so that it can be reused in one or more successive splitting methods. In addition, if desired, less than 1.0 molar equivalent of splitting agent may be used in the process.

The method of the present invention can be carried out under methods known generally to those skilled in the art in typical optical splitting methods.

In a typical experiment, nepopalm is dissolved in ethanol and then treated with a solution of O, O-dibenzoyl-L-tartaric acid monohydrate (1.0 molar equivalent). The resulting solution is left to stand until precipitation occurs. Collection of solids and recrystallization produced (+)-bis-nepopam O, O-dibenzoyl-L-tartarate in 22% yield, greater than 99% enantiomers.

Since both enantiomers of O, O-dibenzoyltartaric acid are readily available in large amounts, both can be effectively used for cleavage, depending on which enantiomer of nepofarm is required. Thus, (-)-bis-nepofam O, O-dibenzoyl-D-tartarate can be prepared with similar yield and optical purity using O, O-di- p -toluoyl-D-tartaric acid as a splitting agent. Can be.

This splitting agent can also be used to increase the optical purity of the enantiomerically enriched nepofarm. Thus, when both enantiomers of nepofam are required, the method described above can be summarized as one enantiomer is recovered as a split and the opposite enantiomer is extracted from the mother liquor of the split. Indeed, once the (+)-bis-nepofam O, O-dibenzoyl-L-tartarate is recovered as described above, the remaining mother liquor proceeds to the separation of the nepofamm free base enriched with the (-)-isomer. Which is then purified by treatment with O, O-dibenzoyl-D-tartaric acid and crystallization of the resulting salt.

The yield of the partitioning process can be improved by a reverse resolution method. Thus, when treating racemic nepofamm with O, O-di- p -toluoyl-D-tartaric acid, (-)-bis-nepopam O, O-dibenzoyl-D-tartarate is isolated. The mother liquor is now rich in (+)-nepofam and is partitioned by conventional methods, yielding (+)-bis-nepofam O, O-dibenzoyl in good yields using O, O-dibenzoyl-L-tartaric acid. It is possible to obtain a -L-tartaric acid salt. The same reverse splitting method can also be applied with good yield separation of (-)-bis-nepofam O, O-dibenzoyl-L-tartarate.

The substantially single enantiomer used or produced in the process of the invention is at least 80% e.e., preferably at least 90% e.e., more preferably at least 95% e.e., most preferably at least 98% e.e.

The invention is embodied by the following examples.

Example 1 : Nepo Farm  Free base

Racemic nepofam 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 thereto. Ethyl acetate (11.16 kg) was added and the mixture was stirred for 10 minutes until complete dissolution. Stopped to stir and separated into two layers. The ethyl acetate layer was removed and stored. The aqueous layer was further extracted with ethyl acetate (11.16 kg), the combined ethyl acetate extracts were dried over magnesium sulfate (500 g), filtered and evaporated to afford a colorless semi-solid product. The above procedure was repeated so that the product was fed in quantitative yield (9.31 kg, 106%, containing residues of ethyl acetate).

Example 2 : (+)- Vis - Nepo Farm  O, O- Dibenzoyl -L- Tartarate

The product (7.86 kg, 31.0 mol) isolated in Example 1 was dissolved in ethanol (14.7 kg) and stirred at room temperature. O, O-dibenzoyl-L-tartaric acid solution (2.75 kg, 0.25 mol equivalent) was added to ethanol (16.0 kg) over 20 minutes. The resulting solution was allowed to stir overnight at room temperature, during which time crystallization occurred. The crystals were collected through filtration, washed with ethanol (2X2L) and dried to a fixed weight at 45 ° C. under reduced pressure. The product was obtained as a colorless solid at 4.27 kg, 32%. Chiral high performance liquid chromatography (HPLC) showed (+)-nepofam 83% e.e.

The solid was recrystallized in two batches from ethanol (2 × 12.16 kg) and the solid was washed with ethyl acetate (2 × 2 L). The combined solids were dried to a fixed weight at 45 ° C. under reduced pressure to give a colorless solid product of 2.90 kg, 68%. HPLC analysis of chiral showed 99% e.e.

The split concentration uses 5 volumes of ethanol and yields 22% overall.

Example 3 : (+)- Nepo Farm

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

Example 4 : (+)- Nepo Farm  Hydrochloride

The product isolated in Example 3 (1.53 kg) is dissolved in isopropanol (4.81 L) and the resulting solution is heated to 50 ° C. Concentrated hydrochloric acid (498 mL) was added over 15 minutes, and then stirred at 50 ° C for 10 minutes. The solution was cooled to 30 ° C. and then cooled to 0 ° C. in an ice / salt bath (precipitation started at 35 ° C.). The mixture was then stirred at 0 ° C. for 1 hour. The precipitate was filtered off, washed with cold isopropanol (2 × 1.05 L) and the solids were dried in a vacuum oven at 35 ° C. The product is obtained as a colorless solid 1.05 kg, 96.7% e.e.

Allow to stand overnight to further precipitate the product. The precipitate was filtered off, washed with isopropanol (2 × 0.5 L) and dried in a vacuum oven at 35 ° C. The product was obtained as a colorless solid as 0.51 kg, 99% e.e.

Total yield is 1.56 kg, 89%.

Example 5

The method of Example 2 was compared with that of the conventional method Blaschke et al, supra. It is summarized in the following table.

In summary, the literature method produces monotartarate, while the new method produces bisnepohamm tartarate. The results show that the latter has a clear advantage: it is more scalable, uses less volume of solvent, does not use DMSO, only 0.25 equivalents of splitting agent, only one recrystallization is needed, Provides better optical purity of the final product.

Claims (11)

A method of increasing the optical purity of a mixture of enantiomers of nepofamm via the bisnepofam salt of the acid using a substantially single enantiomer of O, O-dialoyltartaric acid as a splitting agent. The method of claim 1, wherein the cleavage of racemic nepofamm produces a substantially single enantiomer of nepofamm. 3. The nepofam according to claim 1, comprising sequentially with racemic nepofamm or nepofamme analogs, using a single enantiomer of O, O-dibenzoyltartaric acid followed by the remaining enantiomers. To produce a substantially single enantiomer of a. 4. The process according to claim 1, for producing substantially single enantiomer (+)-nepofam, using O, O-dibenzoyl-L-tartaric acid as the dividing agent. 5. The process according to any one of claims 1 to 3, for producing a substantially single enantiomer (-)-nepofam, using O, O-dibenzoyl-D-tartaric acid as the splitting agent. The process according to any one of claims 1 to 5, wherein the process is carried out with a solvent selected from alcohols, esters, ketones and halogenated solvents. The method according to any one of claims 1 to 6, comprising the further step of converting the salt obtained by cleavage into the free base form of nepofamm or a pharmaceutically acceptable salt thereof. 8. The method of any one of claims 1 to 7, wherein the amount of the splitting agent is less than 1 equivalent. The method of claim 8, wherein the amount is 0.5 equivalents or less. Bisnepofam salt of substantially single enantiomer of O, O-dialoyltartaric acid. The salt of claim 10 wherein said acid is O, O-dibenzoyltartaric acid.