In preferred embodiments, the intermediate compound has the structure of Formula III: ##STR12##

wherein X¹ is sulfur or sulphonyl. The intermediate compounds of Formula III may be prepared by various methods as will be understood by those skilled in the art. For example, the intermediate compounds of Formula III may be prepared according to methods described in Howard Tucker et al., Resolution of the Nonsteroidal Antiandrogen 4'-Cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-(trifluorometh yl)-propioanilide and the Determination of the Absolute Configuration of the Active Enantiomer, 31 J. Med. Chem. 885-887 (1988), the disclosure of which is incorporated herein in its entirety. As another example, the intermediate compounds of Formula III may be prepared from the compound of Formula IV: ##STR13##

wherein X¹ is sulfur or sulphonyl. Hydrolysis of the compound of Formula IV will yield the compound of Formula III. When X¹ is sulfur, the compound may further be oxidized to provide a compound where X¹ is sulphonyl.

As still another example, the intermediate compounds of Formula III may be prepared using commercially available compounds as follows: ##STR14##

wherein X² is a leaving group, preferably chloro, bromo, or iodo; NaH is sodium hydride; THF is tetrahydrofuran; and [O] is an oxidizing agent as will be understood by those skilled in the art.

As yet another example, the intermediate compound of Formula III may be prepared using commercially available materials as follows: ##STR15##

wherein mCPBA is meta-chloroperbenzoic acid, and hydrolysis is preferably performed using an aqueous acid or aqueous base solution. A racemic mixture of the intermediate compound of Formula III may be resolved according to methods of the present invention described above.

Once the more preferred substantially pure enantiomer of the intermediate compound of Formula I or III has been prepared by resolution as described above, the compound may be contacted with the aniline compound of Formula II: ##STR16##

to provide the more preferred substantially pure enantiomer of the acylanilide. R⁶ is preferably cyano, fluoro, chloro, bromo, iodo, or hydrogen. More preferably, R⁶ is cyano, fluoro, chloro, bromo, iodo, and, most preferably, R⁶ is cyano. R⁷ is preferably perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of having up to 4 carbon atoms. More preferably, R⁷ is perfluoroalkyl, and, most preferably, R⁷ is perfluoromethyl. Most preferably, R⁸ is hydrogen.

By resolving the racemic mixture of the intermediate compounds prior to synthesizing the intermediate with the more expensive aniline compound, methods according to the present invention may provide more cost effective ways of preparing substantially pure enantiomers of acylanilides such as Casodex.RTM. (bicalutamide) and/or derivatives thereof.

The present invention will now be described with reference to the following example. It should be appreciated that this example is for the purposes of illustrating aspects of the present invention, and does not limit the scope of the invention as defined by the claims.

EXAMPLE

Formation of the Salt

The salt of the (R,S)-hydroxyacid and (-)-cinchonidine was formed by mixing a solution of the hydroxyacid (one equivalent) with a solution of (-)-cinchonidine (one equivalent). Cinchonidine was generally dissolved in chloroform, but the hydroxyacid may have been dissolved in solvents such as chloroform, methylene chloride, ethyl acetate, or ethanol. The mixture was then stirred overnight at room temperature. After removal of the solvent by rotary evaporation, the residual salt was then redissolved in the desired recrystallization solvent.

Recrystallization

A typical procedure involved placing 20 mg of the salt of the (R,S)-hydroxyacid and (-)-cinchonidine in a vial. Ethyl ether (2 mL) was then added. Methylene chloride was then added dropwise (with occasional shaking) just until the salt had been solubilized. The solution was then placed at 4° C. for crystallization.

Assaying Resolution

After crystallization had occurred, the supernatant was removed. The crystals were then dissolved in deuterated chloroform (CDCl₃). The ratio of (R)- to (S)-enantiomer could then be assayed by integration of the fluorine signal(s) using ¹⁹ F NMR.

In the drawings and specification, there have been disclosed typical preferred embodiments of the invention and, although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation, the scope of the invention being set forth in the following claims.