Process for the synthesis of anthranilic acid/amide compounds and intermediates thereof

A process for the preparation of a compound of formula (Z) or a salt thereof:

• wherein,
• R1 and R2 are independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl and C3-C6 cycloalkyl;
• R3 is selected from the group consisting of hydrogen, halogen, cyano, C1-C4 haloalkyl and C3-C6 cycloalkyl;
• R is selected from the group consisting of hydrogen or COR11;
• wherein, R11 is selected from the group consisting of C1-C4 alkoxy, O-benzyl and O-phenyl;
• R10 is selected from the group consisting of CX3, OR9, and NR4aR4b;
• wherein, X represents halogen;
• R9 is selected from the group consisting of hydrogen and C1-C4 alkyl;
• R4a and R4b are independently selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl;
• and NR4aR4b represent —N═S(R7R8)═(O)n;
• n represents an integer from 0-1;
• R7 and R8 are independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl-C1-C4 alkyl;
• comprising step a) and one or more of steps b) to f):
• a) reacting a substituted aniline of formula (II) with a trihaloacetonitrile of formula (IX) to obtain a compound of formula (Z), wherein R10 is CX3;
• or
• i. reacting a substituted aniline of formula (II) with acetonitrile to obtain a substituted 2-aminoacetophenone of formula (III),
• and
• ii. halogenating the compound of formula (III) using a halogenating reagent to obtain a compound of formula (Z), wherein R10 is CX3;
• b) hydrolyzing the compound of formula (Z), wherein R10 is CX3, with a base or an acid to obtain a compound of formula (Z), wherein R10 is OR9 and R9 is hydrogen;
• or
• converting the compound of formula (III) to a compound of formula (Z), wherein R10 is OR9 and R9 is hydrogen, without isolation of the compound of formula (Z) wherein R10 is CX3;
• c) converting the compound of formula (Z), wherein R10 is CX3, to a compound of formula (Z), wherein R10 is OR9 and R9 is alkyl;
• with a base or an acid and in the presence of an alcoholic solvent;
• d) reacting the compound of formula (Z), wherein R10 is CX3, with a substituted amine of formula (VIII) to obtain a compound of formula (Z), wherein R10 is NR4aR4b;
• e) reacting the compound of formula (Z), wherein R10 is OR9 and R9 is hydrogen;
• with a substituted amine of formula (VIII) and a coupling reagent or a halogenating reagents and optionally in the presence of a base to obtain a compound of formula (Z), wherein R10 is NR4aR4b;
• or
• i. reacting the compound of formula (Z), wherein R10 is OR9 and R9 is hydrogen;
• with an acid to obtain a compound of formula (IVa),
• and
• ii. reacting the compound of formula (IVa) with a substituted amine of formula (VIII) to obtain compound of formula (Z), wherein R10 is NR4aR4b;
• f) reacting the compound of formula (Z), wherein R10 is OR9 and R9 is C1-C4 alkyl;
• with a substituted amine of formula (VIII) in the presence of a base to obtain a compound of formula (Z), wherein R10 is NR4aR4b;
• wherein R, R1, R2, R3, R4a and R4b are as defined above.