Method for preparing cyclopropane derivatives
The present invention relates to the preparation of cyclopropane derivatives, in particular 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-4,8-dihydro-1H-purin-6-one, especially via the [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octan-1-yl]methanol intermediate.
1. A compound of the formula (5):
or a tautomer, racemate or stereoisomer thereof,
wherein n is an integer from 0 to 5, X is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, hydroxyl, C 1-6 alkoxy or amino; and R 11 is hydroxyl or amino.
2. The compound according to claim 1 , which is an compound of formula (5′):
3. A method for the preparation of a compound of formula (5) or a tautomer, racemate or stereoisomer thereof, according to claim 1 :
wherein n, X and R 11 have the same meaning as that defined in claim 1 ,
comprising the step of transforming the —COR 12 moiety of a compound of formula (4) thereby obtaining the compound of formula (5);
wherein R 12 is —OR 3 or amino and R 3 is selected from C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-6 haloalkyl or C 6-10 haloarylC 1-6 alkylene.
4. The method according to claim 3 , wherein the preparation of said compound of formula (4) comprises reacting a compound of formula (2) with a compound of formula (3):
thereby obtaining a compound (4a)
wherein R 19 is OR 23 and R 23 is selected from C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-6 haloalkyl or C 6-10 haloarylC 1-6 alkylene, and R 4 and R 5 are each independently selected from C 1-6 alkyl, C 6-10 arylC 1-6 alkylene or C 6-10 aryl.
5. The method according to claim 4 , further comprising the step of transforming the ester moiety of compound (4a) into an amide moiety, thereby obtaining a compound of formula (4b),
6. 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 —NR 1 R 2 ; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C 1-6 alkyl, aminoC 1-6 alkyl, nitro, formamido, —NHR 18 or OR 7 ; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R 7 is selected from C 1-4 alkyl, C 6-10 arylC 1-6 alkylene or C 6-10 aryl, R 18 is selected from C 6-10 arylC 1-6 alkylene, C 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C 6-10 arylC 1-6 alkyloxycarbonyl; and
R 1 is selected from hydrogen, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 haloarylC 1-6 alkylene;
R 2 is selected from C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 haloarylC 1-6 alkylene;
comprising the step of hydrolyzing or reducing a compound of formula (8);
wherein n is an integer from 0 to 5 and X is C 1-6 alkyl, C 1-6 haloalkyl C 2-6 alkenyl, C 2-6 alkynyl, halogen, hydroxyl, C 1-6 alkoxy or amino; and
wherein B′ is B or selected from the group consisting of purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR 1 R 2 ; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C 1-6 alkyl, aminoC 1-6 alkyl, nitro, formamido, —NHR 18 , —NR 24 R 25 or OR 7 ; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R 7 is selected from C 1-4 alkyl, C 6-10 arylC 1-6 alkylene or C 6-10 aryl, R 18 is selected from C 6-10 arylC 1-6 alkylene, C 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C 6-10 arylC 1-6 alkyloxycarbonyl, R 24 and R 25 are independently hydrogen or C 1-6 alkyl; and
R 1 is selected from hydrogen, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 1-4 alkyl, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 haloarylC 1-6 alkylene;
R 2 is selected from C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 1-4 alkyl, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 halo arylC 1-6 alkylene.
7. The method according to claim 6 , wherein said compound of formula (8) is prepared by coupling a compound of formula (5a) with a compound of formula B′—H,
wherein n is an integer from 0 to 5, X is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, hydroxyl, C 1-6 alkoxy or amino; and R 11 is hydroxyl or amino;
B′ has the same meaning as that defined in claim 6 ; and
H is hydrogen.
8. The method according to claim 7 , wherein prior to coupling compound of formula (5a) with compound B′—H, the hydroxyl moiety of the compound of formula (5) is transformed to obtain a compound of formula (6):
wherein LG represents a leaving group selected from halo, mesylate, tosylate, azide, nosylate, triflate, cyano or imidazolyl.
9. The method according to claim 6 , wherein the preparation of said compound of formula (8) comprises reacting a compound of formula (5b) with a compound of formula (13),
wherein R 15 is —OR 27 or R 28 , R 16 is selected from the group consisting of amino, nitro, formamido and hydrogen, R 17 is selected from halo, C 1-6 alkoxy, C 1-6 aryloxy, C 6-10 arylC 1-6 alkyleneoxy, C 1-6 alkylsulfinyl, C 6-10 arylsulfinyl, C 6-10 arylC 1-6 alkylenesulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylsulfinyl, C 6-10 arylC 1-6 alkylenesulfonyl, C 1-6 alkylthio, C 6-10 arylthio, C 6-10 arylC 1-6 alkylenethio, C 1-6 alkylsulfonate, C 6-10 arylsulfonate, haloC 1-4 alkylsulfonate, C 1-6 alkylphosphonate and C 6-10 arylphosphonate;
R 27 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 6-10 aryl and C 1-10 arylC 1-6 alkylene,
R 28 is selected from halo, C 1-6 alkoxy, C 1-6 aryloxy, C 6-10 arylC 1-6 alkyleneoxy, C 1-6 alkylsulfinyl, C 6-10 arylsulfinyl, C 6-10 arylC 1-6 alkylenesulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylsulfinyl, C 6-10 arylC 1-6 alkylenesulfonyl, C 1-6 alkylthio, C 6-10 arylthio, C 6-10 arylC 1-6 alkylenethio, C 1-6 alkylsulfonate, C 6-10 arylsulfonate, haloC 1-4 alkylsulfonate, C 1-6 alkylphosphonate and C 6-10 arylphosphonate; and
R 26 is selected from, hydrogen, C 6-10 arylC 1-6 alkylene or COR 30 , wherein R 30 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkyloxy, 9-fluorenylmethyloxy, or C 6-10 arylC 1-6 alkyloxy.
10. The method according to claim 7 , wherein compound (5a) is prepared using a method comprising the step of transforming the —COR 12 moiety of a compound of formula (4) thereby obtaining the compound of formula (5a),
wherein R 12 is —OR 3 or amino and R 3 is selected from C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-6 haloalkyl or C 6-10 haloarylC 1-6 alkylene.
11. The method according to claim 10 , further comprising the step of crystallizing and purifying said compound of formula (5a) or (5b).
12. The method according to claim 6 , wherein the compound of formula (A) is a compound of formula (A′):
13. 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 —NR 1 R 2 ; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C 1-6 alkyl, aminoC 1-6 alkyl, nitro, formamido, —NHR 18 or OR 7 ; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R 7 is selected from C 1-4 alkyl, C 6-10 arylC 1-6 alkylene or C 6-10 aryl, R 18 is selected from C 6-10 arylC 1-6 alkylene, C 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C 6-10 arylC 1-6 alkyloxycarbonyl; and
R 1 is selected from hydrogen, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 haloarylC 1-6 alkylene;
R 2 is selected from C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 haloarylC 1-6 alkylene;
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 —NR 1 R 2 ; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C 1-6 alkyl, aminoC 1-6 alkyl, nitro, formamido, —NHR 18 , —NR 24 R 25 or OR 7 ; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R 7 is selected from C 1-4 alkyl, C 6-10 arylC 1-6 alkylene or C 6-10 aryl, R 18 is selected from C 6-10 arylC 1-6 alkylene, C 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C 6-10 arylC 1-6 alkyloxycarbonyl, R 24 and R 25 are independently hydrogen or C 1-6 alkyl; and
R 1 is selected from hydrogen, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 1-4 alkyl, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 haloarylC 1-6 alkylene;
R 2 is selected from C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 1-4 alkyl, C 6-10 haloaryl, C 1-4 haloalkyl or C 6-10 halo arylC 1-6 alkylene;
R 13 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-6 haloalkyl, C 6-10 haloarylC 1-6 alkylene, C 6-10 aminoaryl, C 1-6 aminoalkyl, C 6-10 aminoarylC 1-6 alkylene and C 1-6 alkoxy, and R 14 is a group selected from C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl C 1-6 haloalkyl, C 6-10 haloarylC 1-6 alkylene, C 6-10 aminoaryl, C 1-6 aminoalkyl, C 6-10 aminoarylC 1-6 alkylene and C 1-6 alkoxy, each group being optionally substituted with one or more substituents each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, hydroxyl, C 1-6 alkoxy or amino.
14. The method according to claim 13 , wherein said compound of formula (10) is a compound of formula (5a) or (14)
wherein n is an integer from 0 to 5, X is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, hydroxyl, C 1-6 alkoxy or amino.
15. The method according to claim 9 , wherein compound (5b) is prepared using a method comprising the step of transforming the —COR 12 moiety of a compound of formula (4) thereby obtaining the compound of formula (5b);
wherein R 12 is —OR 3 or amino and R 3 is selected from C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-6 haloalkyl or C 6-10 haloarylC 1-6 alkylene.
16. The method according to claim 9 , wherein compound (5b) is prepared using a method comprising reacting a compound of formula (2) with a compound of formula (3):
thereby obtaining a compound (4a)
wherein R 19 is OR 23 and R 23 is selected from C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-6 alkylene, C 6-10 haloaryl, C 1-6 haloalkyl or C 6-10 haloarylC 1-6 alkylene, and R 4 and R 5 are each independently selected from C 1-6 alkyl, C 6-10 arylC 1-6 alkylene or C 6-10 aryl;
followed by transforming the ester moiety of compound (4a) into an amide moiety, thereby obtaining a compound of formula (5b).