Synthesis of indazoles

Patent metadata

Field	Value
Publication number	US-10501417-B2
Application number	US-201716097065-A
Country	US
Kind code	B2
Filing date	Apr 25, 2017
Priority date	Apr 29, 2016
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

The present invention relates to a novel method of preparing a 2-substituted indazole of structure: (I), to intermediate compounds, and to the use of intermediate compounds for the preparation of said 2-substituted indazole.

First claim

The invention claimed is:

1. A method of preparing a compound of formula (I):

comprising
reacting a compound of formula (V):

with a vinyl sulfone compound of formula (IX′):

wherein R is methyl, to provide the compound of formula (I).

2. The method according to claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (IX′) in an aromatic hydrocarbon solvent.

3. The method according to claim 1 , further comprising
reacting a compound of formula (VI):

with a reductive methylating agent, to provide the compound of formula (V)

4. The method according to claim 3 , further comprising
reacting a compound of formula (VIII):

with a compound of formula (VII):

to provide the compound of formula (VI)

5. The method according to claim 4 ,
wherein the compound of formula (V) and the compound of formula (IX′) are reacted in an aromatic hydrocarbon solvent, and
wherein the reductive methylating agent is methylmagnesium chloride.

6. The method according to claim 5 ,
wherein the aromatic hydrocarbon solvent is toluene;
and
wherein the compound of formula (VI) is reacted with the reductive methylating agent in the presence of an alkali metal halide wherein the reductive methylating agent is methyl magnesium chloride and the alkali metal halide is lithium chloride.

7. The method according to claim 1 , wherein said compound of formula (I) is purified by crystallization.

8. The method according to claim 7 , wherein the compound of formula (I) is purified by crystallization from a solvent, and wherein said solvent is ethanol.

9. The method according to claim 7 , wherein the compound of formula (I) is purified by crystallization from a solvent, and wherein said solvent is isopropanol.

10. The method according to claim 1 , comprising reacting the compound of formula (V) with the compound of formula (IX′) in an aromatic hydrocarbon solvent at the reflux temperature of said solvent.

11. The method according to claim 3 , wherein the reductive methylating agent is a methylmetallic agent.

12. The method according to claim 11 , wherein the methylmetallic agent is a methylmagnesium halide.

13. The method according to claim 12 , wherein the methylmagnesium halide is methylmagnesium chloride.

14. The method according to claim 3 , comprising reacting the compound of formula (VI) with the reductive methylating agent in the presence of an alkali metal halide.

15. The method of claim 4 , comprising reacting the compound of formula (VIII) with the compound of formula (VII) in the presence of an organic base.

16. The method according to claim 15 , wherein the organic base is a weak organic base.

17. The method according to claim 16 , wherein the weak organic base is a tertiary amine.

18. The method according to claim 4 , comprising reacting the compound of formula (VIII) with the compound of formula (VII) in the presence of a coupling agent.

19. The method of claim 2 , wherein the aromatic hydrocarbon solvent is toluene.

20. The method of claim 14 , wherein the alkali metal halide is lithium chloride.

21. The method of claim 17 , wherein tertiary amine is N,N-diisopropylethylamine.

22. The method of claim 18 , wherein the coupling agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P).

Assignees

• Bayer Pharma AG

Inventors

• Thaler Tobias
• Platzek Johannes
• Guimond Nicolas

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title