Process for the preparation and purification of eplerenone

The present invention describes a new process for the preparation and purification of Eplerenone.

Eplerenone, (7α,11α,17α)-9,11-epoxy-17-hydroxy-3-oxo-pregn-4-ene-7,21-dicarboxylic acid, γ-lactone, 7-methyl ester, is a mineralocorticoid receptor antagonist useful in the treatment of high blood pressure and congestive heart failure. It is marketed under the name of INSPRA™.

Most of the patents and literature information dealing with the preparation of Eplerenone are based on the use of the known trienone I as a starting material. In turn, the trienone I is obtained from the natural product Canrenone by 11-bio-hydroxylation followed by mesylation and elimination. The trienone I is then treated with diethylaluminum cyanide to form the 7-cyano derivative II that, after a reduction/oxidation sequence, yields intermediate III.

Crude intermediate III is reacted with diazomethane to provide the methyl ester intermediate IV which is then epoxidized using hydrogen peroxide in the presence of an initiator to yield Eplerenone.

The original patent, U.S. Pat. No. 4,559,332, for the preparation of Eplerenone describes the epoxidation reaction of IV using hydrogen peroxide in the presence of trichloroacetonitrile as initiator. This patent does not disclose any information with respect to the purity of the material obtained, its purification, or the removal of impurities.

When the present inventors repeated the preparation taught in U.S. Pat. No. 4,559,332, it was observed that the purity of the resulting Eplerenone was low (70%) and attempts to purify the resulting product to a level meeting the requisite specifications for use as a pharmaceutical active were unsuccessful [typically, known impurities cannot be >0.2% (w/w)]. In particular, dihydroxylated compounds V and VI, which were isolated and identified, were very difficult to remove. Noteworthy is that similar compounds were mentioned elsewhere in the literature (U.S. Pat. No. 6,887,991), although methods for their removal were not disclosed.

Other patent literature on processes for the synthesis of Eplerenone, for instance WO2001/042272, discloses examples for the purification of Eplerenone by recrystallization; however, the main objective of these patents was the preparation of various polymorphic and solvated forms. Again, even after numerous attempts to remove the dihydroxylated impurities V and VI from crude Eplerenone by recrystallization using these solvents and solvent mixtures, we were unable to obtain satisfactory purities of finished pharmaceutical active.

Therefore, an industrially acceptable method to prepare and purify Eplerenone was required.

Surprisingly, we have discovered a novel process for the preparation of Eplerenone which is based on the reaction of trienone IV with hydrogen peroxide in the presence of an initiator followed by the purification of the crude material by converting the compounds V and VI into their corresponding protected alcohols (VII and VIII wherein R=C(O)R′ or S(O) 2 R″, more preferably R=C(O)CH 3 or S(O) 2 CH 3 ) and precipitation of Eplerenone from the reaction mixture. It could optionally be further purified by subsequent recrystallization.

This new method of purification by derivatization was extensively studied using various reagents, bases and solvents. The most preferred results were obtained by treatment of the reaction mixture with acetic anhydride and triethylamine, followed by recrystallization. This novel method of derivatization of the impurities present in crude Eplerenone allowed removal of the corresponding acetylated derivatives VII and VIII (wherein R=C(O)CH 3 ) by recrystallization in a single solvent.

According to one embodiment of the present invention there is provided a new and improved three step, one-pot process for the preparation and purification of Eplerenone. This process is robust and amenable to scale-up to industrial levels.

Other advantages of the present invention include the improved cost efficiency and simplicity of the process. As well, the Eplerenone produced meets purity specifications of >99% with all known impurities being <0.2% (w/w).

Further and other advantages of this invention will be appreciated by those skilled in the art.

This method of purification has not been reported previously for the preparation of Eplerenone, to our understanding.

The hydrogen peroxide-mediated epoxidation of IV to crude Eplerenone was achieved by dissolution in an organic solvent, most preferably a C1-C3 chlorinated organic solvent, for instance dichloromethane followed by the addition of an initiator and a base. Examples of the initiator include trichloroacetonitrile and examples of the base include potassium hydrogenphosphate dibasic. Aqueous hydrogen peroxide is then added and the reaction is performed between 10 and 40° C. and further processed using standard aqueous extractive techniques.

The reaction mixture is then derivatized using a derivatizing agent in combination with an organic amine base such as triethylamine. Examples of the derivatizing agent include anhydrides of formula [R′OC(O)] 2 or [R′OC(O)] 2 and activated carboxylates of formula R′C(O)X wherein X is a leaving group such as a halogen, most preferably X is chlorine. R′ can be C1 to C6 alkyl, aryl or aralkyl, most preferably, R′ is methyl. In another embodiment, the derivatizing agent can be sulfonate-ester forming agents of formula R″S(O) 2 X wherein R″ is C1 to C6 alkyl or aryl, most preferably R″ is methyl and X is as defined above.

The most preferred derivatizing agents for this invention are acetylating and sulfonating agents, such as acetic anhydride and acetyl chloride or sulfonates such as methanesulfonyl chloride. This reaction is preferably carried out at about 5° C. to about 50° C., most preferably at reflux temperature. The amount of organic base and derivatizing reagent should be sufficient to effect conversion of V and VI to their respective acetates or sulfonates, for instance about 0.1 to about 1.0 equivalents based on the original amount of III. Eplerenone is then optionally further purified by recrystallization from suitable organic solvents, for instance C3-C6 ketones, most preferably methyl ethyl ketone.

The following examples are representative of embodiments of the present invention and are not intended to be limiting.