Composition and methods for modulating a kinase cascade
The invention relates to compounds and methods for modulating one or more components of a kinase cascade. The invention also relates to substantially pure compound 1 and substantially pure compound 1 salt (e.g., compound 1 hydrochloride salt and compound 1 benzenesulfonate salt). The invention further relates to methods of preparing substantially pure compound 1 and compound 1 salts.
1. A process of preparing compound 1:
or a pharmaceutically acceptable salt or solvate thereof, comprising Step 3:
converting compound 12 to compound 1:
2. The process of claim 1 , further comprising Step 2:
converting compound 11 to compound 12:
3. The process of claim 2 , wherein Step 2 comprises reacting compound 11 with trimethylsilylchloride in a polar protic solvent.
4. The process of claim 3 , wherein the polar protic solvent is selected from methanol, ethanol, and isopropanol.
5. The process of claim 2 , wherein the reaction is carried out at a temperature from about 40° C. to about 60° C.
6. The process of claim 2 , further comprising Step 1:
converting compound 10 to compound 11:
7. The process of claim 6 , wherein in Step 1 compound 10 is reacted with a base and acetonitrile in a polar aprotic solvent to form compound 11.
8. The process of claim 7 , wherein the polar aprotic solvent is selected from tetrahydrofuran, ethyl acetate, acetone, and dimethylsulfoxide.
9. The process of claim 7 , wherein the base is potassium bis(trimethylsilyl)amide.
10. The process of claim 6 , wherein the reaction is carried out at a temperature less than about 10° C.
11. The process of claim 1 , wherein in Step 3 compound 12 is reacted with reagent A in an ether solvent to form compound 1.
12. The process of claim 11 , wherein the ether solvent is selected from anisole and diethyl ether.
13. The process of claim 1 , wherein the reaction is carried at a temperature from about 120° C. to about 160° C.
14. The process of claim 1 , further comprising reacting compound 1 with benzenesulfonic acid in the presence of a polar aprotic solvent and an ether solvent.
15. A process of preparing the benzenesulfonate salt of compound 1:
comprising
converting compound 12 to compound 1:
wherein compound 12 is formed by reacting compound 11:
with trimethylsilylchloride in a polar protic solvent, and
reacting compound 1 with benzenesulfonic acid in the presence of a polar aprotic solvent and an ether solvent.
16. The process of claim 15 , wherein the polar aprotic solvent is selected from acetonitrile, ethyl acetate, and tetrahydrofuran.
17. The process of claim 15 , wherein the ether solvent is selected from anisole and diethyl ether, preferably wherein the ether solvent is anisole.