Process of isolating enantiomer component from enantiomer mixtures by particle-size-controlled crystallization

Abstract

The present invention discloses a process for isolating enantiomer components from a mixture of enantiomers through particle-size-controlled crystallization, comprising the steps of: (a) forming a solution of a mixture of enantiomers (R) and (S) in a solvent in the absence of any further additives or agents; (b) seeding the solution of step (a) simultaneously or consecutively with seed crystals of enantiomer (R) and with seed crystals of enantiomer (S), wherein the seed crystals of enantiomer (R) differ in size and/or in quantity from the seed crystals of enantiomer (S) to allow separation of the crystals composed of a mixture enriched with enantiomer (R) from the crystals composed of a mixture enriched with enantiomer (S); (c) inducing simultaneous crystallization of enantiomer (R) and enantiomer (S); and (d) isolating crystals composed of a mixture enriched with enantiomer (R) from crystals composed of a mixture enriched with enantiomer (S) through size separation of the crystals, preferably through sieving, melting or sedimentation, in particular through sieving.

1 . A process for isolating enantiomer components from a mixture of enantiomers through particle-size-controlled crystallization, comprising the steps of:
 (a) forming a solution of a mixture of enantiomers (R) and (S) in a solvent in the absence of any further additives or agents;   (b) seeding the solution of step (a) simultaneously or consecutively with seed crystals of enantiomer (R) and with seed crystals of enantiomer (S), wherein the seed crystals of enantiomer (R) differ in size and/or in quantity from the seed crystals of enantiomer (S) to allow separation of the crystals composed of a mixture enriched with enantiomer (R) from the crystals composed of a mixture enriched with enantiomer (S);   (c) inducing simultaneous crystallization of enantiomer (R) and enantiomer (S); and   (d) isolating crystals composed of a mixture enriched with enantiomer (R) from crystals composed of a mixture enriched with enantiomer (S) through size separation of the crystals, preferably through sieving, melting or sedimentation, in particular through sieving.   
     
     
         2 . The process as claimed in  claim 1 , further comprising the steps of:
 (e) dissolving the isolated crystals composed of a mixture enriched with the enantiomer (R) in a solvent in the absence of any further additives or agents and, separately therefrom, dissolving the isolated crystals composed of a mixture enriched with the enantiomer (S) in a solvent in the absence of any further additives or agents;   (f) seeding the solution of enantiomer (R) with seed crystals of enantiomer (R) and, separately therefrom, seeding the solution of enantiomer (S) with seed crystals of enantiomer (S);   (g) inducing crystallization of enantiomer (R) and, separately therefrom, inducing crystallization of enantiomer (S);   (h) isolating the crystals composed of a mixture further enriched with enantiomer (R) and, separately therefrom, isolating the crystals composed of a mixture further enriched with enantiomer (S).   
     
     
         3 . The process as claimed in  claim 1  or  2 , wherein the mixture of enantiomers (R) and (S) is a racemate of enantiomers (R) and (S), preferably forming a conglomerate. 
     
     
         4 . The process as claimed in  claim 1 , wherein the “mother liquor” solution remaining after step (d) and/or step (h) is recycled as solution in step (a) and/or the solution in step (a) is replenished prior to step (b) and the entire process is repeated. 
     
     
         5 . The process as claimed in  claim 1 , wherein the solvent in step (a) and/or step (e) is selected from the group consisting of: water, organic solvents, aliphatic or aromatic hydrocarbons, alcohols, ethanol, methanol, propanol, isopropanol, n-butanol, tert-butanol, esters, ketones, acetone or methylethylketon or mixtures thereof, and preferable is ethanol. 
     
     
         6 . The process as claimed in  claim 1 , wherein the mixture of enantiomers (R) and (S) is a mixture of ((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine (1) and ((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine (2), preferably a racemate of ((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine (1) and ((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine (2), such that: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The process as claimed in  claim 1 , wherein the mixture of enantiomers (R) and (S) is a mixture of ((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine and ((S)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine, and wherein said enantiomers are present as hydrochloride salts 
     
     
         8 . ((R)-(4-Imino-6-methyl-1,4,5,6-tetrahydro-[1,3,5]triazin-2-yl)-dimethylamine hydrochloride obtainable by the process as claimed in  claim 1 . 
     
     
         9 . The process as claimed in  claim 1 , wherein the mixture of enantiomers (R) and (S) is a mixture of (R,R)-hydrobenzoin (3) and (S,S)-hydrobenzoin (4), preferably a racemate of (3) and (4), such that: 
       
         
           
           
               
               
           
         
       
     
     
         10 . (R,R)-Hydrobenzoin obtainable by the process as claimed in  claim 9 . 
     
     
         11 . (S,S)-Hydrobenzoin obtainable by the process as claimed in  claim 9 .