DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will now be described with respect to preferred embodiments described herein. It should be appreciated however that these embodiments are for the purpose of illustrating the invention, and are not to be construed as limiting the scope of the invention as defined by the claims. As the substituents R¹ -R⁸ and X¹ have been defined above, they will not be further defined herein other than to describe preferred substituents for the preferred embodiments. Unless otherwise noted, all percentages used herein are percent by weight. As used herein, the term "substantially enantiomerically pure" refers to a substance that has preferably between about 95% and 100% of one form (either R or S) and between about 5% and 0% of the other form, more preferably between about 99% and 100% of one form (either R or S) and between about 1% and 0% of the other form, and, most preferably, between about 99.9% and 100% of one form (either R or S) and about 0.1% and 0% of the other form.

Embodiments of the present invention provide methods of preparing a substantially pure enantiomer of an acylanilide. Particularly preferred methods according to the present invention resolve a racemic mixture of intermediate compounds to provide Casodex.RTM. (bicalutamide) and/or its derivatives in a more cost effective manner than conventional methods that resolve the racemic mixture of Casodex.RTM. (bicalutamide) and/or its derivatives.

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: ##STR10##

The resolved intermediate compound of Formula I is then treated under conditions sufficient to provide a substantially pure enantiomer of the acylanilide. Preferably, R¹ is lower alkyl having up to 4 carbons, and R² is lower alkyl having up to 6 carbons. More preferably, R¹ is methyl and R² is methylene. R³ is preferably a direct link (i.e., one or more bonds between X¹ and R⁴). R⁴ is preferably 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. More preferably, R⁴ is phenyl which bears one, two or three substituents independently selected from hydrogen and halogen. Most preferably, R⁴ is 4-fluorophenyl. Preferably, X¹ is sulfur, sulphinyl, sulphonyl or imino. X¹ is more preferably sulfur, sulphinyl, or sulphonyl and is most preferably sulfur. The intermediate compounds according to the present invention may be prepared by various methods as will be understood by those skilled in the art. Exemplary methods of preparing particularly preferred intermediate compounds are described hereinbelow.

According to preferred embodiments of the present invention, a racemic mixture of the intermediate compound of Formula I is crystallizationally resolved. The intermediate compound of Formula I is contacted with a chiral base to obtain a diastereomeric mixture of chiral salts. The chiral salts of the diastereomeric mixture are then selectively crystallized to resolve the chiral salts into (R)- and (S)-salt enantiomers. The more preferred salt enantiomer is then treated to recover the more preferred hydroxyacid.

The chiral base is preferably (-)-cinchonidine. More preferably, the chiral base is (-)-cinchonidine (96%), which is commercially available from Aldrich of Milwaukee, Wis. While the chiral base is preferably (-)-cinchonidine, other chiral bases may be employed including, but not limited to, brucine.

In particularly preferred embodiments, the substantially pure enantiomer of the more preferred (R)-hydroxyacid is resolved as follows: ##STR11##

The selective crystallization is preferably performed by contacting the diastereomeric mixture of the (R,-)-salt and the (S,-)-salt with a solvent system. The solvent system preferably includes methylene chloride and diethyl ether. The methylene chloride/diethyl ether solvent system preferably includes between about 1 and 40 percent by volume methylene chloride and between about 60 and 99 percent by volume diethyl ether, more preferably includes between about 5 and 30 percent by volume methylene chloride and between about 70 and 95 percent by volume diethyl ether, and most preferably includes between about 10 and 20 percent by volume methylene chloride and between about 80 and about 90 percent by volume diethyl ether. A particularly preferred solvent system consists essentially of between about 10 and 20 percent by volume methylene chloride and between about 80 and 90 percent by volume diethyl ether.

Progress of the resolution may be monitored by ¹⁹ F NMR analysis, as illustrated in FIGS. 1 through 3. FIG. 1 shows a ¹⁹ F NMR spectrum of the pure salt of the (R)-hydroxyacid and (-)-cinchonidine. This (R)-hydroxyacid was made by asymmetric synthesis as described in the co-pending and co-assigned application entitled "Methods of Asymmetrically Synthesizing Enantiomers of Casodex, Its Derivatives and Intermediates Thereof" to Nnochiri N. Ekwuribe. This spectrum was used as a standard for comparison in determining the resolution of the racemic mixture. FIG. 2 shows a ¹⁹ F NMR spectrum of the salt of the racemic (R,S)-hydroxyacid and (-)-cinchonidine prior to resolution. The left portion of the signal is from the (S)-hydroxyacid and the right portion of the signal is from the (R)-hydroxyacid. FIG. 3 shows a ¹⁹ F NMR spectrum of the salt of the racemic (R,S)-hydroxyacid and (-)-cinchonidine after one round of crystallization. This spectrum illustrates that approximately 78% of the crystals formed were the cinchonidine salt of the (S)-hydroxyacid. Thus, the solution was becoming enriched with the salt of the more preferred (R)-hydroxyacid.

While those skilled in the art will understand how to recover the intermediate compound from the salt, the (R)-intermediate compound (e.g., (R)-hydroxyacid) is preferably recovered from the salt by acidification with aqueous 1M HCl followed by extraction with an organic solvent, such as methylene chloride or ethyl acetate.

According to another aspect of the present invention, the intermediate compound of Formula I may be separated by various means for physico-chemical separation known in the art, such as chromatographic resolution. Exemplary methods may be found in G. Subramanian, A Practical Approach to Chiral Separations by Liquid Chromatography, John Wiley & Sons, 1994; Thomas E. Beesley, Raymond P. W. Scoff, Chiral Chromatography, John Wiley & Son Ltd., 1999; and Satinder Ahuja, Chiral Separations: Applications and Technology, American Chemical Society, 1996. In a preferred method, the intermediates are separated using high pressure liquid chromatography (HPLC) by methods such as those described in Krstulovic, A. M., ed. Chiral Separations by HPLC: Applications to Pharmacological Compounds, Halsted Press, 1989. One skilled in the art will understand how to chromatographically resolve the intermediate compounds described herein..