Raceme sulpiride resolution process.

This invention relates to a process for the resolution of raceme sulpiride with high yields of both levo-sulpiride and dextro-sulpiride of pharmaceutical purity.

Sulpiride or N-ethyl-2(2-methoxy-5-sulphamido-benzamidomethyl)-pyrrolidine of formula <chemistry id="chem0001" num="0001"><img file="EP0053584A1_D0001.tif" /></chemistry>is known to be a therapeutically active compound particularly useful in the neurological and psychiatric field as an antipsychotic.

It is also known that sulpiride, which contains one asymmetric carbon atom (indicated by an asterisk in the formula), is in reality an equimolecular mixture of two optically active compounds of which the levo-sulpiride is much more effective as a psychiatric drug than the dextro-sulpiride. Many attempts have been made up to the present time to isolate the more active levo-sulpiride from the raceme mixture, all consistently with negative results.

A stereospecific synthesis was therefore devised (French Patent Application 79-03216).

This synthesis, which uses proline as its starting substance, can be used only for the production of levo-sulpiride from 1-proline, because d-proline, which would be necessary for preparing dextro-sulpiride by the same method, is a product not available commercially and very costly to prepare.

It has now been found that dextro-sulpiride, which is practically ineffective as an antipsychotic, has a quite unexpected strong therapeutic activity towards forms of behaviour decadence in senescence. This is the basis for the need to find an industrial method for its production.

A method for the resolution of raceme sulpiride has been unexpectedly found which enables both optically pure levo-sulpiride and optically pure dextro-sulpiride to be obtained with very high yields. The conversions are also high, and the unconverted raceme sulpiride can be recovered practically completely. The method is consequently industrially economical for the production of levo- and dextro-sulpiride, a further factor being that there is no consumption of costly reactants or solvents.

The new method consists essentially of salifying raceme sulpiride with an equimolecular quantity of L(-)pyroglutamic acid to give a salt of formula: <chemistry id="chem0002" num="0002"><img file="EP0053584A1_D0002.tif" /></chemistry>in 95 vol % ethanol, the solution being heated to its boiling point.

On cooling the ethanol solution containing the mixture of L(-)pyroglutamate of levo-sulpiride and L(-)pyroglutamate of dextro-sulpiride to 20⁰C_l the L(-)pyroglutamate of levo-sulpiride separates in crystalline form and is filtered off, the L(-)pyroglutamate of dextro-sulpiride being obtained by evaporating the cold residual solution.

The free levo- and dextro-sulpiride are recovered from said salts by hydrolysis with NH₄OH.

L(-)pyroglutamic acid is recovered from the alkaline mother liquors from which the levo-sulpiride and dextro-sulpiride were precipitated, and is recycled.

The raceme sulpiride present as an impurity in both the separated levo-sulpiride and dextro-sulpiride is recovered from these products by fractional crystallisation of the relative hydrochlorides.

In order to facilitate reproduction of the process according to the present invention, one example is described hereinafter, and contains all the operating details.

It is however apparent that these details can be varied without altering the inventive idea and thus leaving its scope.

EXAMPLE

<tables id="tabl0001" num="0001"><img file="EP0053584A1_D0003.tif" /></tables>The mixture of these substances is heated to boiling point until completely dissolved, the solution then being cooled to 20°C and filtered.

The crystalline precipitate when dried weighs 32.5 g. The mother liquors when evaporated to dryness leave a vitreous residue weighing 31 g.

The two solids are dissolved separately each in 100 ml of deionised water, and the solutions obtained are each treated with ammonium hydroxide at 70°C until pH 10 is attained. They are then cooled and filtered.

By hydrolysis of the crystalline product solution, 23 g of product are obtained which after drying has a <maths id="math0001" num=""><img file="EP0053584A1_D0004.tif" /></maths> of -42.5° (5% DMF).

Under the same conditions, the solution obtained from the vitreous residue gives 21.5 g of product which after drying has a <maths id="math0002" num=""><img file="EP0053584A1_D0005.tif" /></maths> of +42.5° (5% DMF).

The mother liquors from the two precipitations are combined, evaporated to low volume, taken up in deionised water and eluted through a column of a strongly acid resin, for example Amberlite IR 120, on the basis of about 1 g of product per 10 ml of activated resin.

The elution is carried out with deionised water, and various 50 ml fractions are collected.

The first three fractions contain the L(-)pyroglutamic acid, and by evaporating these to dryness 16 g of acid are recovered, which can be recycled.

The two optically active sulpirides still impure with raceme product are each dissolved under hot conditions in a stoichiometric quantity of IN HC1.

They are allowed to crystallise at 20°C and are filtered. The hydrochlorides obtained by crystallisation are combined, dissolved in 150 ml of water at 70°C, the solution adjusted to pH 10 with ammonium hydroxide, cooled, filtered and the product dried.

The product obtained (18 g) is constituted by practically raceme sulpiride, and is recycled.

The hydrochloride liquors are heated to 70°C, alkalised with ammonium hydroxide to pH 10, and cooled.

When filtered and dried, the products obtained have the following characteristics: ₂₀<ul id="ul0001" list-style="none"><li>- 12.5 g of L(-)sulpiride; <maths id="math0003" num=""><img file="EP0053584A1_D0006.tif" /></maths> - 65⁰ (5% DMF); M.P. 188-190°C</li><li>- 12.5 g of D(+)sulpiride; <maths id="math0004" num=""><img file="EP0053584A1_D0007.tif" /></maths> + 65 (5% DMF); M.P. 188-190°C</li></ul>

The following are substantially obtained from 46 g.of raceme sulpiride: <tables id="tabl0002" num="0002"><img file="EP0053584A1_D0008.tif" /></tables>

Efficiency 93% with 54% conversion.

16 g of acid for recycling are recovered from 17.5 g of L(-)pyroglutamic acid.