Deuterated CFTR potentiators
This invention relates to compounds of Formula I: and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a CFTR potentiator.
1. Compound 106
or a pharmaceutically acceptable salt thereof, obtained by a process comprising reacting compound 12
with compound 6
to form a compound of Formula 106, wherein any atom not designated as deuterium is present at its natural isotopic abundance, and wherein the percentage of isotopic enrichment for each designated deuterium is at least 90%, and
optionally treating compound 106 with a base to produce a pharmaceutically acceptable salt of Compound 106.
2. The compound of claim 1 , wherein the reaction of compound 12 with compound 6 is performed in the presence of a coupling agent and base.
3. The compound of claim 2 , wherein the coupling agent is (N,N,N′,N′)-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate and the base is N,N′-diisopropylethylamine.
4. The compound of claim 1 , wherein compound 12 is produced by converting compound 10
into compound 12
5. The compound of claim 4 , wherein compound 10 is converted to compound 12 with a reducing agent.
6. The compound of claim 5 , wherein the reducing agent is an acid.
7. The compound of claim 6 , wherein the acid is selected from HX, wherein HX is HCl.
8. The compound of claim 1 , wherein compound 10 is produced by converting compound 9
into compound 10
9. The compound of claim 8 , wherein compound 9 is converted to compound 10 in the presence of a reducing agent and metal catalyst.
10. The compound of claim 9 , wherein the reducing agent is ammonium formate and the metal catalyst is palladium on carbon.
11. The compound of claim 1 , wherein compound 9 is produced by converting compound 8
into compound 9
12. The compound of claim 11 , wherein compound 8 is reacted with HNO 3 /H 2 SO 4 to form a nitrated product.
13. The compound of claim 12 , wherein the nitration product is subjected to potassium hydroxide in methanol to form compound 9.
14. The compound of claim 1 , wherein compound 8 is produced by converting compound 7
into compound 8
15. The compound of claim 14 , wherein the reaction of compound 7 to form compound 8 is performed in the presence of an acyloxycarbonylating agent and base.
16. The compound of claim 15 , wherein the acyloxycarbonylating agent is methyl chloroformate and the base is triethylamine.
17. The compound of claim 14 , wherein the reaction is performed in the presence of 4-dimethylaminopyridine.
18. The compound of claim 1 , wherein the process further comprises converting tert-butyl phenol
into compound 7
19. The compound of claim 18 , wherein the conversion of tert-butyl phenol to form the compound of Formula 7 is performed in the presence of a source of X—C(CD 3 ) 3 and an acid.
20. The compound of claim 19 , wherein the source of X—C(CD 3 ) 3 is tert-butanol-d 10 and the acid is D 2 SO 4 .