Method for preparing cyclopropane derivatives

A method for the production of a compound of formula (A):

• or a tautomer, a racemate, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, or solvate thereof,
• wherein B is selected from the group comprising purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2;
• each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18 or OR7;
• and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl;
• and
• R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
• R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
• comprising the step of hydrolyzing or reducing a compound of formula (8);
• wherein n is an integer from 0 to 5 and X is C1-6alkyl, C1-6haloalkyl C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino;
• and
• wherein B′ is B or selected from the group consisting of purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2;
• each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18, —NR24R25 or OR7;
• and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl, R24 and R25 are independently hydrogen or C1-6alkyl;
• and
• R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
• R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10halo arylC1-6alkylene.

A method for the preparation of a compound of formula (A)

• or a tautomer, a racemate, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, or solvate thereof,
• wherein B is selected from the group comprising purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2;
• each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18 or OR7;
• and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl;
• and
• R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
• R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
• comprising the step of coupling a compound of formula (10) or (12),
• with a with a compound of formula B′—H under Mitsunobu conditions,
• wherein H is hydrogen,
• wherein B′ is B or selected from the group consisting of purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2;
• each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6 alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18, —NR24R25 or OR7;
• and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl, R24 and R25 are independently hydrogen or C1-6alkyl;
• and
• R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
• R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10halo arylC1-6 alkylene;
• R13 is selected from the group consisting of hydrogen, C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl, C6-10haloarylC1-6alkylene, C6-10aminoaryl, C1-6aminoalkyl, C6-10aminoarylC1-6alkylene and C1-6alkoxy, and R14 is a group selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl C1-6haloalkyl, C6-10haloarylC1-6alkylene, C6-10aminoaryl, C1-6aminoalkyl, C6-10aminoarylC1-6alkylene and C1-6alkoxy, each group being optionally substituted with one or more substituents each independently selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino.