PROCESS FOR PREPARING RISPERIDONE

The present invention concerns an improved process of preparing risperidone (I).

Risperidone (I) may be prepared by a variety of processes. EP-0, 196, 132 discloses the preparation of risperidone (I) byN-alkylation of a piperidine intermediate of formula (II) with an alkylating agent of formula (III).

A higher yielding process was developed thereafter which is disclosed in ES-2006888. Herein, risperidone (I) is prepared by an intramolecular aromatic substitution reaction of a compound of formula (IV) in the presence of a base in a solvent mixture of toluene and water.

Using this process, occasionally batches have been produced that had to be destroyed because they contained decomposition products which appeared after intermediate (IV) had been converted into risperidone (I). Screening experiments showed that the decomposition was markedly enhanced in the presence of stainless steel shavings. In particular a fluorescent product formed which was isolated by column chromatography and identified by mass spectrometry and nuclear magnetic resonance to be compound (V). Rl 16889

(V)

This strained aminal compound (V) was hard to purify and isolate as a solid. Presumably the compound (V) hydrolysed to an aldehyde (VI) which could decompose into a variety of other contaminants.

Compounds (V), (VI) and further degradation products therefrom, are potentially toxic and render the risperidone (I) batches in which they occur unsuitable for conversion into drug products, in particular the risperidone long acting injection sold under the trademark Risperdal® Consta®.

Possibly a radical mechanism catalyzed by Fe 2+ cations may explain the formation of compound (V). In the scheme below R represents a radical of formula (VII)

(vπ)

Subsequent investigations have shown that whilst stainless steel catalyzes the formation of compound (V), it is probably not the root cause. Decomposition rates vary highly amongst different batches and may be in the range of from 5 to 15 % after 24 h reflux. No apparent correlation could be found between residual iron levels and extent of decomposition. Nor does a change from stainless steel equipment to enamel equipment improve the outcome of the process.

It has now unexpectedly been found that decomposition of risperidone (I) can be prevented by reacting an intermediate of Formula (IV) under an atmosphere comprising oxygen. Under an oxygen- free atmosphere, risperidone (I) when prepared from (IV) always decomposes to at least some extent.

The invention is therefore concerned with a process for preparing risperidone of formula (I)

-A-

comprising the steps of reacting an intermediate of formula (IV)

in the presence of a base and a solvent mixture comprising toluene and water, and isolating the risperidone of formula (I) formed during the reaction, characterized in that the reaction is conducted under an atmosphere comprising from 0.1 to 8 % of oxygen.

The reaction can conveniently be conducted in stainless steel or enamel or glass- lined equipment provided that the oxygen concentration is constantly maintained above 0.1 %. The remainder of the atmosphere may be either argon or nitrogen or any mixture thereof. The oxygen concentration is preferably from 1 % to 8 %.

The conversion reaction of compound (IV) is preferably conducted at a temperature above 80 ⁰ C for 4 to 5 hours. Suitable bases in the reaction are alkali metal hydroxides, preferably potassium hydroxide (KOH).

Relative to the amount of the intermediate of formula (IV), the amount of KOH ranges from 4.0 to 4.6 mol/mol; water ranges from 0.25 to 0.35 L/mol; and toluene ranges from 1.3 to 1.5 L/mol.

In particular, the process comprises the steps of a) charging a reaction vessel with toluene and KOH; b) adding water to the suspension obtained in a) while keeping the temperature between 30 and 40 °C; c) adjusting the concentration of oxygen in the atmosphere of the reaction vessel to between 1 and 8 %; d) adding an intermediate of formula (IV) while keeping the temperature above 30 ⁰ C; e) heating the reaction mixture to a temperature above 80 ⁰ C for 4 to 5 hours; f) diluting the reaction mixture with water at a temperature of 80 ⁰ C; g) separating the water phase; h) extracting the organic layer three times with water at a temperature of 80 ⁰ C; i) cooling the organic layer to a temperature between 0 and 10 ⁰ C while stirring for at least 2 hours; j) collecting the precipitated risperidone (I); k) washing the precipitated risperidone (I) with acetone; and

1) drying the risperidone (I) at a temperature between 50 and 60 ⁰ C for 16 to 20 hours.

Risperidone (I) prepared according to the above process does not contain the contaminant product (V) and thus is useful for the preparation of drug product such as risperi- done long acting injection.