Synthesis of indazoles
The present invention relates to a novel method of preparing a 2-substituted indazole of formula (I) to novel intermediate compounds, and to the use of intermediate compounds for the preparation of said 2-substituted indazole.
1. A method of preparing a compound of formula (I):
comprising step (A):
reacting a compound of formula (IIa):
with a compound of formula (VI):
thereby providing said compound of formula (I).
2. The method according to claim 1 , wherein the compound of formula (IIa) is reacted with the compound of formula (VI) in an aromatic hydrocarbon solvent.
3. The method according to claim 1 , wherein the compound of formula (IIa) is reacted with the compound of formula (VI) in the presence of an organic base.
4. The method according to claim 1 , further comprising preparing the compound of formula (IIa):
by step (B):
reacting a compound of formula (VIIa):
with a reductive methylating agent,
thereby providing said compound of formula (IIa).
5. The method according to claim 4 , further comprising preparing the compound of formula (VIIa):
by step (C):
comprising reacting a compound of formula (XII):
with a compound of formula (XI):
thereby providing said compound of formula (VIIa).
6. The method according to claim 4 ,
wherein the compound of formula (IIa) and the compound of formula (VI) are reacted in an aromatic hydrocarbon solvent in step (A), and
wherein the reductive methylating agent in step (B) is methylmagnesium chloride.
7. The method according to claim 6 , the compound of formula (IIa) and the compound of formula (VI) are reacted in the presence of an organic base in an aromatic hydrocarbon solvent in step (A), wherein the organic base is N,N-diisopropylethylamine and the aromatic hydrocarbon solvent is toluene; and
wherein the compound of formula (VIIa) is reacted with the reductive methylating agent in the presence of an alkali metal halide in step (B), wherein the reductive methylating agent is methylmagnesium chloride and the alkali metal halide is lithium chloride.
8. The method according to claim 1 , wherein said compound of formula (I) is purified by crystallization from a first solvent or a mixture of solvents.
9. The method according to claim 8 , wherein said compound of formula (I) is in the form of crystalline needles (A).
10. The method according to claim 1 , comprising reacting the compound of formula (IIa) with the compound of formula (VI) in an aromatic hydrocarbon solvent, wherein the aromatic hydrocarbon solvent is selected from the group consisting of toluene, xylene and mesitylene.
11. The method according to claim 1 , comprising reacting the compound of formula (IIa) with the compound of formula (VI) in the presence of an organic base, wherein the organic base is a weak organic base.
12. The method according to claim 11 , wherein the weak organic base is a tertiary amine.
13. The method according to claim 4 , wherein the reductive methylating agent is a methylmetallic agent.
14. The method according to claim 13 , wherein the methylmetallic agent is a methylmagnesium halide.
15. The method according to claim 14 , wherein the methylmagnesium halide is methylmagnesium chloride.
16. The method according to claim 4 , comprising reacting the compound of formula (VIIa) with the reductive methylating agent in the presence of an alkali metal halide, wherein the alkali metal halide is lithium chloride.
17. The method according to claim 5 , comprising reacting the compound of formula (XII) with the compound of formula (XI) in the presence of an organic base, wherein the organic base is a weak organic base.
18. The method according to claim 17 , wherein the weak organic base is a tertiary amine.
19. The method according to claim 18 , wherein the tertiary amine is N,N-diisopropylethylamine.
20. The method according to claim 5 , comprising reacting the compound of formula (XII) with the compound of formula (XI) in the presence of a coupling agent, wherein the coupling agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P).
21. The method of claim 2 , wherein the aromatic hydrocarbon solvent is toluene.
22. The method according to claim 3 , wherein the organic base is N,N-diisopropylethylamine.
23. The method according to claim 4 , wherein the compound of formula (VIIa) is reacted with the reductive methylating agent in the presence of an alkali metal halide.
24. The method according to claim 5 , wherein the compound of formula (XII) is reacted with the compound of formula (XI) in the presence of an organic base.
25. The method according to claim 5 , wherein the compound of formula (XII) is reacted with the compound of formula (XI) in the presence of a coupling agent.
26. The method according to claim 8 , wherein said compound of formula (I) is purified by crystallization from a mixture of acetone and toluene.
27. The method according to claim 8 , wherein said compound of formula (I) is purified by crystallization in the presence of activated charcoal.
28. The method according to claim 9 , wherein said compound of formula (I) is purified by crystallization from a first solvent or a mixture of solvents followed by a further cyrstallization from a second solvent.