Preparation of pharmaceutical salts of piperazine compounds

Abstract

The present invention is generally directed to a process to directly prepare pharmaceutically acceptable salts enriched with respect to selected rotameric salts of a basic compound, by creative choice of an acid and a solvent medium. The process is particularly useful in preparing specific rotamers of pharmaceutically useful salts in desired preponderance of a rotamer.

1 . A process for directly preparing a mixture of rotamers of a salt of a substituted piperazinyl compound wherein said mixture comprises one or more rotamers of said salt in a higher molar percent than other corresponding rotamer or rotamers of said salt, said process comprising reacting said substituted piperazinyl compound with an acid in admixture with a solvent. 
     
     
         2 . The process of  claim 1 , wherein said molar percent is 45:55 of said one or more rotamers of the salt to said other corresponding rotamer or rotamers of the salt. 
     
     
         3 . The process of  claim 2 , wherein said molar percent is 25:75 of said one or more rotamers of the salt to said other corresponding rotamer or rotamers of the salt. 
     
     
         4 . The process of  claim 3 , wherein said molar percent is at least about 10:90 of said one or more rotamers of the salt to said other corresponding rotamer or rotamers of the salt. 
     
     
         5 . The process of  claim 4 , wherein said molar percent is 5:95 of said one or more rotamers of the salt to said other corresponding rotamer or rotamers of the salt. 
     
     
         6 . The process of  claim 1 , wherein one rotamer is present in an amount greater than about 55 molar percent of the total amount of salt present. 
     
     
         7 . The process of  claim 1 , wherein one rotamer is present in an amount greater than about 75 molar percent of the total amount of salt present. 
     
     
         8 . The process of  claim 1 , wherein one rotamer is present in an amount greater than about 90 molar percent of the total amount of salt present. 
     
     
         9 . The process of  claim 1 , wherein one rotamer is present in an amount greater than about 95 molar percent of the total amount of salt present. 
     
     
         10 . The process of  claim 1 , wherein said substituted piperazinyl compound is a pharmaceutical compound. 
     
     
         11 . The process of  claim 1 , wherein said acid is a pharmaceutically useful acid. 
     
     
         12 . The process of  claim 1 , wherein said acid is used in a ratio from about 1:1 to about 3:1 with respect to said substituted piperazinyl compound. 
     
     
         13 . The process of  claim 1 , wherein said solvent is used in a ratio from about 5:1 to about 20:1 with respect to said substituted piperazinyl compound. 
     
     
         14 . The process of  claim 1 , wherein said substituted piperazinyl compound has the structure of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The process of  claim 1 , wherein said higher molar percent refers to the concentration of rotamer 1 of the salt of said compound of Formula I compared to the rotamer 2 of the salt of said compound of Formula I. 
     
     
         16 . The process of  claim 1 , wherein said higher molar percent refers to the concentration of the rotamer 2 of the salt of said compound of Formula I compared to the rotamer 1 of the salt of said compound of Formula I. 
     
     
         17 . The process of  claim 1 , wherein said salt is selected from the group consisting of benzenesulfonate, nicotinate, benzoate, hydrochloride salt, glutarate, D-10-camphorsulfonate, 2-ketoglutarate. 
     
     
         18 . The process of  claim 17 , wherein said salt is benzenesulfonate. 
     
     
         19 . The process of  claim 18 , wherein said benzenesulfonate is prepared by reacting the compound of Formula I with benzenesulfonic acid in a solvent. 
     
     
         20 . The process of  claim 18 , wherein said benzenesulfonate is formed at about 0-80° C. 
     
     
         21 . The process of  claim 17 , wherein said salt is D-10-camphorsulfonate. 
     
     
         22 . The process of  claim 21 , wherein said D-10-camphorsulfonate is prepared by reacting the compound of Formula I with D-10-camphorsulfonic acid in an ester solvent. 
     
     
         23 . The process of  claim 22 , wherein said D-10-camphorsulfonate is prepared by reacting the compound of Formula I with D-10-camphorsulfonic acid in ethyl acetate. 
     
     
         24 . The process of  claim 17 , wherein said salt is glutarate. 
     
     
         25 . The process of  claim 24 , wherein said glutarate is prepared by reacting said compound of Formula I with glutaric acid in a nitrile solvent. 
     
     
         26 . The process of  claim 25 , wherein said nitrile is acetonitrile. 
     
     
         27 . The process of  claim 17 , wherein said salt is 2-ketoglutarate. 
     
     
         28 . The process of  claim 27 , wherein said 2-ketoglutarate is prepared by reacting said compound of Formula I with 2-ketoglutaric acid in a nitrile solvent. 
     
     
         29 . The process of  claim 28 , wherein said nitrile is acetonitrile. 
     
     
         30 . The process of  claim 17 , wherein said salt is a nicotinate. 
     
     
         31 . The process of  claim 30 , wherein said nicotinate is prepared by reacting said compound of Formula I with nicotinic acid in water. 
     
     
         32 . The process of  claim 17 , wherein said salt is benzoate. 
     
     
         33 . The process of  claim 32 , wherein said benzoate is prepared by reacting said compound of Formula I with benzoic acid in a mixture of water and acetone solvent. 
     
     
         34 . The process of  claim 1 , wherein said solvent is water, a ketone, ether, ester, alcohol, nitrile, hydrocarbon or mixtures thereof. 
     
     
         35 . The process of  claim 34 , wherein said ester is selected from the group consisting of ethyl acetate, isopropyl acetate and mixtures thereof. 
     
     
         36 . The process of  claim 34 , wherein said alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol and mixtures thereof, said nitrite is acetonitrile, and said ether is THF, and said hydrocarbon is toluene. 
     
     
         37 . A process for directly preparing a mixture of rotamers of the benzenesulfonate salt of a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein said mixture comprises one or more rotamers of the benzenesulfonate salt in a higher molar percent than other corresponding rotamer or rotamers of the benzenesulfonate salt, said process comprising: 
         (a) preparing a first intimate mixture of said compound of Formula I in a solvent; 
         (b) maintaining said first intimate mixture at about 0-10° C.; 
         (c) preparing a second intimate mixture of benzene sulfonic acid in the same or different solvent as stated in step (a); 
         (d) combining said first intimate mixture and said second intimate mixture at 0-10° C. to prepare a combined mixture and heating the combined mixture to induce crystallization of the benzenesulfonate salt; and 
         (e) isolating the benzenesulfonate salt. 
       
     
     
         38 . The process of  claim 37 , wherein said molar percent is 45:55 of said one rotamer of the benzenesulfonate salt to said the other corresponding rotamer of the benzenesulfonate salt. 
     
     
         39 . The process of  claim 37 , wherein said molar percent is 25:75 of said one rotamer of the benzenesulfonate salt to said other corresponding rotamer of the benzenesulfonate salt. 
     
     
         40 . The process of  claim 37 , wherein said molar percent is 10:90 of said one rotamer of the benzenesulfonate salt to said other corresponding rotamer of the benzenesulfonate salt. 
     
     
         41 . The process of  claim 37 , wherein said molar percent is 5:95 of said one rotamer of the benzenesulfonate salt to said other corresponding rotamer of the benzenesulfonate salt. 
     
     
         42 . The process of  claim 37 , wherein said solvent is water, a ketone, ether, ester, alcohol, nitrile, hydrocarbon or mixtures thereof. 
     
     
         43 . The process of  claim 42 , wherein said ester is selected from the group consisting of ethyl acetate, isopropyl acetate and mixtures thereof. 
     
     
         44 . The process of  claim 43 , wherein said ester is isopropyl acetate. 
     
     
         45 . The process of  claim 42 , wherein said ketone is acetone. 
     
     
         46 . The process of  claim 42 , wherein said ether is THF. 
     
     
         47 . The process of  claim 42 , wherein said nitrile is acetonitrile. 
     
     
         48 . The process of  claim 42 , wherein said hydrocarbon is toluene. 
     
     
         49 . The process of  claim 42 , wherein said alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol and mixtures thereof. 
     
     
         50 . The process of  claim 49 , wherein said alcohol is ethyl alcohol. 
     
     
         51 . The process of  claim 42 , wherein said solvent comprises isopropyl acetate and ethyl alcohol.