SUMMARY OF THE INVENTION

Embodiments of the present invention provide a synthetic method comprising a resolution step which takes place prior to the addition of the most expensive components of the active compound. By resolving an intermediate compound rather than resolving the completely synthesized drug as described above for conventional methods, methods according to the present invention may reduce or eliminate the need for additional post-synthesis procedures and/or reduce or eliminate the need to recycle the less-preferred enantiomer. Additionally, the use of expensive starting materials such as: ##STR7##

to produce the less-preferred enantiomer may be avoided, which may reduce the costs of producing a substantially pure form of the more-preferred enantiomer.

According to embodiments of the present invention, methods of preparing a substantially pure enantiomer of an acylanilide such as Casodex.RTM. (bicalutamide) and/or its derivatives are provided. The methods include resolving an intermediate compound having the structure of Formula I: ##STR8##

wherein

R¹ is alkyl or haloalkyl having up to 4 carbons;

R² is alkyl having up to 6 carbon atoms;

R³ is a direct link or alkyl having up to 6 carbon atoms;

R⁴ is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons; or R⁴ is phenyl which bears one, two or three substituents independently selected from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl; or R⁴ is naphthyl; or R⁴ is a 5- or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl each of up to 4 carbon atoms, or oxy or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents; and
X¹ is oxygen, sulfur, sulphinyl (--SO--), sulphonyl (--SO₂ --), imino (--NH--) or alkylimino (--NR⁵ --) where R⁵ is alkyl having up to 6 carbon atoms.

The resolved intermediate compound of Formula I is then treated under conditions sufficient to provide a substantially pure enantiomer of the acylanilide.

In some embodiments of the present invention, the step of resolving an intermediate compound of Formula I includes crystallizationally resolving the intermediate compound of Formula I. The crystallizationally resolving step includes contacting the intermediate compound of Formula I with a chiral base to provide a diastereomeric mixture of a chiral salt, crystallizationally resolving the diastereomeric mixture of the chiral salt to provide a substantially pure enantiomer of the chiral salt, and recovering a substantially pure enantiomer of the intermediate compound of Formula I. The contacting step preferably includes contacting the intermediate compound of Formula I with (-)-cinchonidine to provide a diastereomeric mixture of the chiral salt. The step of crystallizationally resolving the diastereomeric mixture of the chiral salt preferably includes contacting the diastereomeric mixture of the chiral salt with a solvent system comprising, for example, methylene chloride and diethyl ether. In other embodiments, the step of resolving an intermediate compound of Formula I may include high performance liquid chromatographically resolving the intermediate compound of Formula I.

The resolved intermediate is preferably contacted with an aniline compound having the structure of Formula II: ##STR9##
wherein

R⁶ is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;

R⁷ is cyano, carbamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of having up to 4 carbon atoms; or phenylthio, phenylsulphinyl or phenylsulphonyl; and

R⁸ is hydrogen or halogen;

under conditions sufficient to provide a substantially pure enantiomer of an acylanilide. The substantially pure enantiomer of the acylanilide is preferably the (R)-enantiomer of Casodex.RTM. (bicalutamide).

By resolving intermediates rather than resolving completely synthesized drugs, methods according to the present invention may provide more cost effective ways of synthesizing substantially pure enantiomers of acylanilides such as Casodex.RTM. (bicalutamide) and derivatives thereof than are provided by conventional resolution techniques. For example, methods according to the present invention may be more cost effective because they resolve the intermediates prior to reacting them with the expensive aniline component, avoiding unwanted costs associated with the expensive aniline component, which is typically wasted in the production of the less-preferred enantiomer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a ¹⁹ F NMR spectrum of the pure salt of the (R)-hydroxyacid and (-)-cinchonidine.

FIG. 2 shows a ¹⁹ F NMR spectrum of the salt of the racemic (R,S)-hydroxyacid and (-)-cinchonidine prior to resolution.

FIG. 3 shows a ¹⁹ F NMR spectrum of the salt of the racemic (R,S)-hydroxyacid and (-)-cinchonidine after one round of crystallization.