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

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:
• R1 and R2 may be identical or different and are each independently an alkyl group or a substituted alkyl group;
• R3 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 R1 or R2 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle;
• R4 and R7 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;
• R5 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;
• R6 and R12 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, —ORa, a heteroaryl group, or a substituted heteroaryl group;
• R8 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, —ORa, —SRa, —S(═O)2Re, —S(═O)2ORe, —C(═O)ORd, —C(═O)Ra, or —C(═O)NRbRc;
• R9, R10, and R11 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, —ORa, —SRa, —S(═O)Re, —S(═O)2Re, —P(═O)2Re, —S(═O)2ORe, —P(═O)2ORe, —NRbRc, —NRbS(═O)2Re, —NRbP(═O)2Re, —S(═O)2NRbRc, —P(═O)2NRbRc, —C(═O)ORe, —C(═O)Ra, —C(═O)NRbRc, —OC(═O)Ra, —OC(═O)NRbRc, —NRbC(═O)ORe, —NRdC(═O)NRbRc, —NRdS(═O)2NRbRc, —NRdP(═O)2NRbRc, or —NRbC(═O)Ra;
• R13 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 Ra 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;
• Rb, Rc, and Rd 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 Rb and Rc are optionally taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle;
• each Re 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, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and the wavy line are defined the same as in the compound represented by formula (1), and R14 is an alkyl group or a substituted alkyl group, or R14 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle.

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:
• R1 and R2 may be identical or different and are each independently an alkyl group or a substituted alkyl group;
• R3 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 R1 or R2 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle;
• R4 and R7 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;
• R5 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;
• R6 and R12 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, —ORa, a heteroaryl group, or a substituted heteroaryl group;
• R8 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, —ORa, —SRa, —S(═O)2Re, —S(═O)2ORe, —C(═O)ORd, —C(═O)Ra, or —C(═O)NRbRc;
• R9, R10, and R11 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, —ORa, —SRa, —S(═O)Re, —S(═O)2Re, —P(═O)2Re, —S(═O)2ORe, —P(═O)2ORe, —NRbRc, —NRbS(═O)2Re, —NRbP(═O)2Re, —S(═O)2NRbRc, —P(═O)2NRbRc, —C(═O)ORe, —C(═O)Ra, —C(═O)NRbRc, —OC(═O)Ra, —OC(═O)NRbRc, —NRbC(═O)ORe, —NRdC(═O)NRbRc, —NRdS(═O)2NRbRc, —NRdP(═O)2NRbRc, or —NRbC(═O)Ra;
• R13 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 Ra 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;
• Rb, Rc, and Rd 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 Rb and Rc are optionally taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle;
• each Re 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, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and the wavy line are defined the same as in the compound represented by formula (1), and R14 is an alkyl group or a substituted alkyl group, or R14 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle.

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:
• R1 and R2 may be identical or different and are each independently an alkyl group or a substituted alkyl group;
• R3 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 R1 or R2 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle;
• R4 and R7 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;
• R5 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;
• R6 and R12 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, —ORa, a heteroaryl group, or a substituted heteroaryl group;
• R8 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, —ORa, —SRa, —S(═O)2Re, —S(═O)2ORe, —C(═O)ORd, —C(═O)Ra, or —C(═O)NRbRc;
• R9, R10, and R11 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, —ORa, —SRa, —S(═O)Re, —S(═O)2Re, —P(═O)2Re, —S(═O)2ORe, —P(═O)2ORe, —NRbRc, —NRbS(═O)2Re, —NRbP(═O)2Re, —S(═O)2NRbRc, —P(═O)2NRbRc, —C(═O)ORe, —C(═O)Ra, —C(═O)NRbRc, —OC(═O)Ra, —OC(═O)NRbRc, —NRbC(═O)ORe, —NRdC(═O)NRbRc, —NRdS(═O)2NRbRc, —NRdP(═O)2NRbRc, or —NRbC(═O)Ra;
• R13 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 Ra 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;
• Rb, Rc, and Rd 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 Rb and Rc are optionally taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle;
• each Re 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, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and the wavy line are defined the same as in the compound represented by formula (1), and R14 is an alkyl group or a substituted alkyl group, or R14 and R3 are taken together with the nitrogen atom to which they are attached to form a heterocycle or a substituted heterocycle.