Purification method for 5-(thiazol-4-yl)indolin-2-one derivative

Abstract

The present invention addresses the problem of providing a purification method for a 5-(thiazol-4-yl)indolin-2-one derivative that is useful as a medication. The present invention provides a purification method for a compound represented by formula (1) (in the formula, each n is independently 2, 3, 4, 5, or 6, R 1 and R 2 are identical or different and each independently represent a C 1-6 alkyl group, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 each represent a hydrogen atom, a C 1-6 alkyl group, an aryl group, or a heteroaryl group), or a geometric isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. The purification method includes a purification step performed using a solid-phase support adsorbent in the presence of a purification solvent.

1 - 20 . (canceled) 
     
     
         21 . A mixture of a compound represented by formula (1) or a geometrical isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a compound represented by formula (7) or a geometrical isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (7) is less than 0.07% in relation to the compound represented by formula (1);
 wherein formula (1) is:   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  and R 2  may be identical or different and are each independently an alkyl group or a substituted alkyl group; 
 R 3  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group, or R 1  or R 2  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle; 
 R 4  and R 7  may be identical or different and are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 R 5  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 R 6  and R 12  may be identical or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethyloxy group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, —OR a , a heteroaryl group, or a substituted heteroaryl group; 
 R 8  is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, —OR a , —SR a , —S(═O) 2 R e , —S(═O) 2 OR e , —C(═O)OR d , —C(═O)R a , or —C(═O)NR b R c ; 
 R 9 , R 10 , and R 11  may be identical or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethyloxy group, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, —OR a , —SR a , —S(═O)R e , —S(═O) 2 R e , —P(═O) 2 R e , —S(═O) 2 OR e , —P(═O) 2 OR e , —NR b R c , —NR b S(═O) 2 R e , —NR b P(═O) 2 R e , —S(═O) 2 NR b R c , —P(═O) 2 NR b R c , —C(═O)OR e , —C(═O)R a , —C(═O)NR b R c , —OC(═O)R a , —OC(═O)NR b R c , —NR b C(═O)OR e , —NR d C(═O)NR b R c , —NR d S(═O) 2 NR b R c , —NR d P(═O) 2 NR b R c , or —NR b C(═O)R a ; 
 R 13  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 n is an integer selected from 2, 3, 4, 5, and 6; 
 each R a  is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group; 
 R b , R c , and R d  may be identical or different and are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group, or said R b  and R c  are optionally taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle; 
 each R e  is independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group; and 
 the wavy line represents either cis or trans; 
 
         
         and formula (7) is: 
       
       
         
           
           
               
               
           
         
         
           wherein
 n, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and the wavy line are defined the same as in the compound represented by formula (1), and R 14  is an alkyl group or a substituted alkyl group, or R 14  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle. 
 
         
       
     
     
         22 . A pharmaceutical composition comprising a compound represented by formula (1) or a geometrical isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein a compound represented by formula (7) or a geometrical isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof is comprised at less than 0.07% in relation to the compound represented by formula (1);
 wherein formula (1) is:   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  and R 2  may be identical or different and are each independently an alkyl group or a substituted alkyl group; 
 R 3  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group, or R 1  or R 2  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle; 
 R 4  and R 7  may be identical or different and are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 R 5  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 R 6  and R 12  may be identical or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethyloxy group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, —OR a , a heteroaryl group, or a substituted heteroaryl group; 
 R 8  is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, —OR a , —SR a , —S(═O) 2 R e , —S(═O) 2 OR e , —C(═O)OR d , —C(═O)R a , or —C(═O)NR b R c ; 
 R 9 , R 10 , and R 11  may be identical or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethyloxy group, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, —OR a , —SR a , —S(═O)R e , —S(═O) 2 R e , —P(═O) 2 R e , —S(═O) 2 OR e , —P(═O) 2 OR e , —NR b R c , —NR b S(═O) 2 R e , —NR b P(═O) 2 R e , —S(═O) 2 NR b R c , —P(═O) 2 NR b R c , —C(═O)OR e , —C(═O)R a , —C(═O)NR b R c , —OC(═O)R a , —OC(═O)NR b R c , —NR b C(═O)OR e , —NR d C(═O)NR b R c , —NR d S(═O) 2 NR b R c , —NR d P(═O) 2 NR b R c , or —NR b C(═O)R a ; 
 R 13  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 n is an integer selected from 2, 3, 4, 5, and 6: 
 each R a  is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group; 
 R b , R c , and R d  may be identical or different and are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group, or said R b  and R c  are optionally taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle; 
 each R e  is independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group; and 
 the wavy line represents either cis or trans; 
 
         
         and formula (7) is: 
       
       
         
           
           
               
               
           
         
         
           wherein
 n, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and the wavy line are defined the same as in the compound represented by formula (1), and R 14  is an alkyl group or a substituted alkyl group, or R 14  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle. 
 
         
       
     
     
         23 . A pharmaceutical composition comprising a compound represented by formula (1) or a geometrical isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (1) is comprised at 99.95% or greater over the compound represented by formula (1) and a compound represented by formula (7) or a geometrical isomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof;
 wherein formula (1) is:   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  and R 2  may be identical or different and are each independently an alkyl group or a substituted alkyl group; 
 R 3  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group, or R 1  or R 2  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle; 
 R 4  and R 7  may be identical or different and are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 R 5  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 R 6  and R 12  may be identical or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethyloxy group, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, —OR a , a heteroaryl group, or a substituted heteroaryl group; 
 R 8  is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, —OR a , —SR a , —S(═O) 2 R e , —S(═O) 2 OR e , —C(═O)OR d , —C(═O)R a , or —C(═O)NR b R c ; 
 R 9 , R 10 , and R 11  may be identical or different and are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethyloxy group, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, —OR a , —SR a , —S(═O)R e , —S(═O) 2 R e , —P(═O) 2 R e , —S(═O) 2 OR e , —P(═O) 2 OR e , —NR b R c , —NR b S(═O) 2 R e , —NR b P(═O) 2 R e , —S(═O) 2 NR b R c , —P(═O) 2 NR b R c , —C(═O)OR e , —C(═O)R a , —C(═O)NR b R c , —OC(═O)R a , —OC(═O)NR b R c , —NR b C(═O)OR e , —NR d C(═O)NR b R c , —NR d S(═O) 2 NR b R c , —NR d P(═O) 2 NR b R c , or —NR b C(═O)R a ; 
 R 13  is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, or a substituted heteroaryl group; 
 n is an integer selected from 2, 3, 4, 5, and 6; 
 each R a  is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group; 
 R b , R c , and R d  may be identical or different and are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group, or said R b  and R c  are optionally taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle; 
 each R e  is independently an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, or a substituted aryl group; and 
 the wavy line represents either cis or trans; 
 
         
         and formula (7) is: 
       
       
         
           
           
               
               
           
         
         
           wherein
 n, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and the wavy line are defined the same as in the compound represented by formula (1), and R 14  is an alkyl group or a substituted alkyl group, or R 14  and R 3  are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle. 
 
         
       
     
     
         24 . The mixture of  claim 21 , wherein:
 R 1  and R 2  may be identical or different and are each independently a C 1-6 alkyl group, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  may be identical or different and are each independently a hydrogen atom, a C 1-6 alkyl group, a substituted C 1-6 alkyl group, a C 3-6 cycloalkyl group, a substituted C 3-6 cycloalkyl group, a C 6-10 aryl group, a substituted C 6-10 aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered substituted heteroaryl group, and R 14  is a C 1-6 alkyl group; or   R 1  or R 2  and R 3  are taken together with the nitrogen atom to which they are attached to form a 6- to 10-membered heterocycle or substituted heterocycle, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  may be identical or different and are each independently a hydrogen atom, a C 1-6 alkyl group, a substituted C 1-6 alkyl group, a C 3-6 cycloalkyl group, a substituted C 3-6 cycloalkyl group, a C 6-10 aryl group, a substituted C 6-10 aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered substituted heteroaryl group, and R 14  and R 3  are taken together with the nitrogen atom to which they are attached to form a 6- to 10-membered heterocycle or substituted heterocycle.   
     
     
         25 . The mixture according to  claim 21 , wherein R 1  and R 2  may be identical or different and are each independently a C 1-6 alkyl group, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  may be identical or different and are each independently a hydrogen atom, a C 1-6 alkyl group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group, and R 14  is a C 1-6 alkyl group. 
     
     
         26 . The mixture according to  claim 21 , wherein R 1  and R 2  may be identical or different and are each independently a C 1-3 alkyl group. 
     
     
         27 . The mixture according to  claim 26 , wherein R 1  and R 2  are both ethyl groups. 
     
     
         28 . The mixture according to  claim 21 , wherein R 13  is an aryl group. 
     
     
         29 . The mixture according to  claim 28 , wherein R 13  is a phenyl group. 
     
     
         30 . The mixture according to  claim 21 , wherein R 4  and R 6  may be identical or different and are each independently a C 1-6 alkyl group. 
     
     
         31 . The mixture according to  claim 30 , wherein R 4  and R 6  may be identical or different and are each independently a C 1-3 alkyl group. 
     
     
         32 . The mixture according to  claim 21 , wherein R 3  and R 5  are both hydrogen atoms. 
     
     
         33 . The mixture according to  claim 21 , wherein R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are all hydrogen atoms.