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. A process for preparing Compound 106
or a pharmaceutically acceptable salt thereof, comprising reacting Compound 12
with Compound 6
wherein any atom not designated as deuterium is present at its natural isotopic abundance, 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 process 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 process 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 process of claim 1 , wherein Compound 12 is produced by converting Compound 10
into Compound 12
5. The process of claim 4 , wherein Compound 10 is converted to Compound 12 with a reducing agent.
6. The process of claim 5 , wherein the reducing agent is an acid.
7. The process of claim 6 , wherein the acid is HCl.
8. The process of claim 1 , wherein Compound 9
is converted into Compound 10
9. The process of claim 8 , wherein Compound 9 is converted to Compound 10 in the presence of a reducing agent and metal catalyst.
10. The process of claim 9 , wherein the reducing agent is ammonium formate and the metal catalyst is palladium on carbon.
11. The process of claim 1 , wherein Compound 9 is produced by converting Compound 8
into Compound 9
12. The process of claim 11 , wherein Compound 8 is reacted with HNO 3 /H 2 SO 4 to form a nitrated product.
13. The process of claim 12 , wherein the nitration product is subjected to potassium hydroxide in methanol to form Compound 9.
14. The process of claim 1 , wherein Compound 8 is produced by converting Compound 7
into Compound 8
15. The process of claim 14 , wherein the conversion of Compound 7 into Compound 8 is performed in the presence of an acyloxycarbonylating agent and base.
16. The process of claim 15 , wherein the acyloxycarbonylating agent is methyl chloroformate and the base is triethylamine.
17. The process of claim 14 , wherein the conversion of Compound 7 into Compound 8 is performed in the presence of 4-dimethylaminopyridine.
18. The process of claim 1 , wherein the process further comprises converting tert-butyl phenol
into Compound 7
19. The process of claim 18 , wherein the conversion of tert-butyl phenol into Compound 7 is performed in the presence of a source of X—C(CD 3 ) 3 and an acid.
20. The process 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 .