Methods for preparation of quinazoline derivatives

A method for preparing a compound having the following structure (I):

• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
• R1 is a non-hydrogen substituent;
• R2a and R2b are each independently halo, hydroxyl, protected hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• R3a and R3b are each independently halo, hydroxyl, protected hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• or R3a joins with R4a to form a carbocyclyl or heterocyclyl ring, and R3b is halo, hydroxyl, protected hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• and
• R4a, R4b and R4c are each independently H or a non-hydrogen substituent;
• or R4a joins with R3a to form a carbocyclyl or heterocyclyl ring, and R4b and R4c are each independently H or a non-hydrogen substituent;
• wherein the method comprises preparing a mixture comprising a compound of structure (II) and a compound of structure (III), the compounds of structure (II) and (III) having the following structures, respectively:
• or a salt thereof, wherein:
• R1′ is a non-hydrogen, non-acidic substituent;
• R2a′ and R2b′ are each independently halo, protected hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• R3a′ and R3b′ are each independently halo, protected hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• or R3a′ joins with R4a′ to form a carbocyclyl or heterocyclyl ring, and R3b′ is halo, protected hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• R4a′, R4b′ and R4c′ are each independently H or a non-hydrogen substituent;
• or R4a′ joins with R3a′ to form a carbocyclyl or heterocyclyl ring, and R4b′ and R4c′ are each independently H or a non-hydrogen substituent;
• and
• X is a leaving group,
• thereby forming a carbon-carbon bond between the carbon bearing the Zn moiety on compound (II) and the carbon bearing the X moiety on compound (III).