Processes for producing modulators of cystic fibrosis transmembrane conductance regulator
The present invention relates to the process for producing modulators of cystic fibrosis transmembrane conductance regulator (CFTR).
1. A method of producing the compounds of Formula I:
or pharmaceutically acceptable salts thereof, wherein R 1 is —C F 3 , R 2 is —CF 3 , R 3 is H, and ring A is selected from
comprising
contacting the compound of Formula II with a CYP-102 enzyme, BM3-M11, to produce a mixture of compounds of Formula I, wherein the compound of Formula II has the structure
in which R 1 is —CF 3 , R 2 is —CF 3 , R 3 is H, and ring A is
2. The method of claim 1 , wherein the process is optionally conducted in the presence of an organic solvent.
3. The method of claim 2 , wherein the solvent is acetonitrile, methanol, acetone, dimethylsulfoxide, and dimethylformamide or mixtures thereof.
4. The method of claim 3 , wherein the process is conducted in the presence of methanol.
5. The method of claim 2 , wherein the organic solvent is present in an amount of less than about 30% (v/v).
6. The method of claim 5 , wherein the organic solvent is present in an amount of less than about 25% (v/v).
7. The method of claim 5 , wherein the organic solvent is present in an amount of less than or equal to about 20% (v/v).
8. The method of claim 2 , wherein the organic solvent is present in an amount of between about 5% to about 25% (v/v).
9. The method of claim 8 , wherein the organic solvent is present in an amount of between about 10% to about 20% (v/v).
10. The method of claim 1 , further comprising separating the mixture of compounds of Formula I.
11. The method of claim 10 , wherein the Exo and Endo isomers and each of their enantiomeric pairs of present in the mixture of compounds of Formula I are separated by chiral LC-MS/MS.
12. The method of claim 11 , wherein ring A of the separated isomer of Formula I is
13. The method of claim 11 , wherein ring A of the separated isomer of Formula I is
14. The method of claim 11 , wherein ring A of the separated isomer of Formula I is
15. The method of claim 11 , wherein ring A of the separated isomer of Formula I is