Process for preparing indolinone derivatives

A process for preparing an indolinone of the general formula (VI)

• wherein
• R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″;
• each R5 is independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″;
• R6 is is selected from —NR8(CH2)mR9 and —NR10R11, provided that optionally one to two of the CH2 groups may be substituted by —OH or halogen;
• R8 is hydrogen or C1-12 alkyl;
• R9 is selected from the group consisting of —NR10R11, —OH, —C(O)R12, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, —N+(O−)R10, and —NHC(O)R13;
• R10 and R11 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O;
• or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R′
• R12 is selected from the group consisting of hydrogen, —OH, C1-12 alkoxy and C6-12 aryloxy;
• R13 is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, and C6-12 aralkyl;
• R′ and R″ are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group —NR′R″, R′ and R″ may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R′ and R″ are bound;
• Halo is a substituent selected from the group consisting of F, Cl, Br, and I
• J is selected from the group consisting of O, S, and NH;
• one of K, L and M is C and the group —C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NR5, O and S;
• n is 0, 1 or 2;
• m is 1, 2, 3, or 4;
• and
• p is 0, 1 or 2;
• comprising the steps of
• (i) reacting a compound of general formula (I)
• wherein R5, J, K, L, M and p are as defined above,
• Q is selected from the group consisting of
• with a compound of general formula (II)
• X2—R (II)
• wherein:
• (a) one of X1 and X2 is chlorine, or bromine, and the other is selected from the group consisting of hydroxy, —O—C1-4 alkyl and —O-phenyl, and R is selected from the group consisting of C(O)—C1-4 alkyl, —C(O)—O—(C1-4)alkyl, —C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —C(O)—O—CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, or
• (b) X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
• or
• (c) X1 is hydroxy, —O—C1-4 alkyl and —O-phenyl,
• X2 is
• and R is
• to form a compound of the general formula (III)
• wherein R* is —O—R in case (a) of step (i) and —R in cases (b) and (c) of step (i);
• (ii) reacting the compound of general formula (III) with a compound of general formula (IV)
• wherein R1, R2, R3, and R4 are as defined above,
• and an amine of general formula (V)
• HR6 (V)
• wherein R6 is as defined above, to form the indolinone of the general formula (VI).