Process for preparing aficamten
Provided herein is a process for the preparation of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, intermediates thereof, and salts of the foregoing.
1. A method of preparing a compound of Formula (1):
or a salt thereof, comprising:
(i) converting a compound of Formula (7)
to a compound of Formula (6)
(ii) converting the compound of Formula (6) to a compound of Formula (5)
and
(iii) converting the compound of Formula (5) to the compound of Formula (1) or salt thereof.
2. The method of claim 1 , wherein converting the compound of Formula (7) to the compound of Formula (6) comprises reacting the compound of Formula (7) with (R)-tert-butanesulfinamide.
3. The method of claim 2 , wherein reacting the compound of Formula (7) with (R)-tert-butanesulfinamide is performed in the presence of a Lewis acid.
4. The method of claim 2 , wherein reacting the compound of Formula (7) with (R)-tert-butanesulfinamide is performed in the presence of a water scavenger.
5. The method of claim 2 , wherein reacting the compound of Formula (7) with (R)-tert-butanesulfinamide is performed in the presence of titanium ethoxide.
6. The method of claim 2 , wherein reacting the compound of Formula (7) with (R)-tert-butanesulfinamide is performed in the presence of toluene at a temperature of between about 75° C. and about 85° C.
7. The method of claim 1 , wherein converting the compound of Formula (6) to the compound of Formula (5) comprises reacting the compound of Formula (6) with a reducing agent.
8. The method of claim 7 , wherein reacting the compound of Formula (6) with a reducing agent is performed in the presence of tetrahydrofuran at a temperature of between about −15° C. and about −5° C.
9. The method of claim 7 , wherein the reducing agent is sodium borohydride.
10. The method of claim 1 , wherein the compound of Formula (6) is used without work-up or purification.
11. The method of claim 1 , wherein converting the compound of Formula (5) to the compound of Formula (1) or salt thereof comprises converting the compound of Formula (5) to a compound of Formula (4)
or a salt thereof.
12. The method of claim 11 , wherein converting the compound of Formula (5) to the compound of Formula (4) or salt thereof comprises hydrolyzing the sulfinamide of the compound of Formula (5).
13. The method of claim 12 , wherein hydrolyzing the sulfinamide of the compound of Formula (5) is performed in the presence of an aqueous acid.
14. The method of claim 11 , wherein the compound of Formula (4) is prepared as a hydrochloride salt.
15. The method of claim 11 , wherein the compound of Formula (4) is prepared as a 4-methylbenzenesulfonate salt.
16. The method of claim 11 , further comprising obtaining the compound of Formula (4) by reacting the salt of the compound of Formula (4) with a base.
17. The method of claim 11 , wherein converting the compound of Formula (5) to the compound of Formula (1) or salt thereof further comprises converting the compound of Formula (4) or salt thereof to a compound of Formula (3)
or a salt thereof.
18. The method of claim 17 , wherein converting the compound of Formula (4) or salt thereof to the compound of Formula (3) or salt thereof comprises:
(i) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with a carboxylic acid activating agent to form an activated 1-methyl-1H-pyrazole-4-carboxylic acid, and
(ii) reacting the activated 1-methyl-1H-pyrazole-4-carboxylic acid with the compound of Formula (4) or salt thereof, to form the compound of Formula (3) or salt thereof.
19. The method of claim 18 , wherein the carboxylic acid activating agent is oxalyl chloride.
20. The method of claim 18 , wherein the carboxylic acid activating agent comprises a carbodiimide reagent.
21. The method of claim 18 , wherein the carboxylic acid activating agent comprises a carbodiimide reagent and hydroxybenzotriazole.
22. The method of claim 17 , wherein converting the compound of Formula (5) to the compound of Formula (1) or salt thereof further comprises converting the compound of Formula (3) or salt thereof to a compound of Formula (2)
or a salt thereof.
23. The method of claim 22 , wherein converting the compound of Formula (3) or salt thereof to the compound of Formula (2) or salt thereof comprises reacting hydroxylamine with the compound of Formula (3) or salt thereof.
24. The method of claim 23 , wherein reacting the compound of Formula (3) or salt thereof with hydroxylamine is performed at a temperature of 25° C. or lower.
25. The method of claim 23 , wherein reacting the compound of Formula (3) or salt thereof with hydroxylamine is performed in the presence of N-methylpyrrolidone.
26. The method of claim 22 , wherein converting the compound of Formula (5) to the compound of Formula (1) or salt thereof further comprises converting the compound of Formula (2) or salt thereof to the compound of Formula (1) or salt thereof.
27. The method of claim 26 , wherein converting the compound of Formula (2) or salt thereof to the compound of Formula (1) or salt thereof comprises:
(i) reacting propionic acid with a second carboxylic acid activating agent to form an activated propionic acid, and
(ii) reacting the activated propionic acid with the compound of Formula (2) or salt thereof.
28. The method of claim 27 , wherein the second carboxylic acid activating agent is carbonyldiimidazole.
29. A method of preparing a compound of Formula (4)
or a salt thereof, comprising converting a compound of Formula (5):
to the compound of Formula (4) or salt thereof.
30. The method of claim 29 , further comprising obtaining the compound of Formula (5) by reacting a reducing agent with a compound of Formula (6):
to form the compound of Formula (5).
31. The method of claim 30 , wherein the reducing agent is a borohydride reducing agent.
32. The method of claim 30 , further comprising obtaining the compound of Formula (6) by reacting (R)-tert-butanesulfinamide with a compound of Formula (7):
to form the compound of Formula (6).