Process of making CFTR modulators

1. A method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting a compound of Formula (I):

or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof,

wherein:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro; and

X c is selected from F, Cl, Br, and I.

2. The method of claim 1 , wherein the conversion of the compound of Formula (I), or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof, comprises the steps of:

1) combining the compound of Formula (I), or a salt thereof, with at least one first base to produce a compound of Formula (II):

or a salt thereof; and

2) combining the compound of Formula (II), or a salt thereof, with compound 1:

or a salt thereof,

and at least one second base to produce Compound I, or a pharmaceutically acceptable salt thereof,

wherein in the compound of Formula (II), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R; and

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro.

3. The method of claim 1 , wherein the conversion of the compound of Formula (I), or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof, comprises combining the compound of Formula (I), or a salt thereof, with compound 1:

or a salt thereof, and at least one third base to produce Compound I, or a pharmaceutically acceptable salt thereof,

wherein in the compound of Formula (I), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro; and

X c is selected from F, Cl, Br, and I.

4. The method of claim 1 , wherein the compound of Formula (I):

or a salt thereof, is prepared by converting a compound of Formula (III):

or a salt thereof, into the compound of Formula (I), or a salt thereof,

wherein in the compound of Formula (III), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro;

X c is selected from F, Cl, Br, and I; and

wherein:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group.

5. The method of claim 4 , wherein the compound of Formula (III):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (III), or a salt thereof,

wherein:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro

X b is selected from Cl, F, —OC 6 F 5 ,

X c is selected from F, Cl, Br, and I; and

wherein:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group.

6. The method of claim 5 , wherein the compound of Formula (IV):

or a salt thereof, is prepared by converting a compound of Formula (VI):

or a salt thereof, into the compound of Formula (IV), or a salt thereof,

wherein in the compound of Formula (VI), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R; and

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro.

7. The method of claim 6 , wherein the compound of Formula (VI):

or a salt thereof, is prepared by combining compound 2:

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (VI), or a salt thereof,

wherein in the compound of Formula (VII), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro; and

X d is selected from F, Cl, Br, and I.

8. The method of claim 7 , wherein compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.

9. The method of claim 8 , wherein compound 3:

or a salt thereof, is prepared by converting compound 4:

or a salt thereof, into compound 3, or a salt thereof.

10. The method of claim 9 , wherein compound 4:

or a salt thereof, is prepared by chiral resolution of compound (±)-4:

or a salt thereof.

11. A method of preparing Compound I:

or a pharmaceutically acceptable salt thereof, comprising converting a compound of Formula (VIII):

or a salt thereof, into Compound I, or a pharmaceutically acceptable salt thereof,

wherein in the compound of Formula (VIII), or a salt thereof, X c is selected from F, Cl, Br, and I.

12. The method of claim 11 , wherein the compound of Formula (VIII):

or a salt thereof, is prepared by converting a compound of Formula (IX):

or a salt thereof, into the compound of Formula (VIII), or a salt thereof,

wherein in the compound of Formula (IX), or a salt thereof:

X c is selected from F, Cl, Br, and I; and

wherein:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group.

13. The method of claim 12 , wherein the compound of Formula (IX):

or a salt thereof, is prepared by combining a compound of Formula (X):

or a salt thereof, with a compound of Formula (V):

or a salt thereof, to produce the compound of Formula (IX), or a salt thereof,

wherein in the compound of Formula (X), or a salt thereof:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group; and

wherein in the compound of Formula (V), or a salt thereof:

X b is selected from Cl, F, —OC 6 F 5 ,

and

X c is selected from F, Cl, Br, and I.

14. The method of claim 13 , wherein the compound of Formula (X):

or a salt thereof, is prepared by combining a compound of Formula (IV):

or a salt thereof, with compound 1:

or a salt thereof, to produce the compound of Formula (X), or a salt thereof,

wherein in the compound of Formula (IV), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro; and

wherein:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group.

15. The method of claim 14 , wherein the compound of Formula (IV):

or a salt thereof, is prepared by combining a compound of Formula (XI):

or a salt thereof, with a compound of Formula (VII):

or a salt thereof, to produce the compound of Formula (IV), or a salt thereof,

wherein in the compound of Formula (XI), or a salt thereof:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group; and

wherein in the compound of Formula (VII), or a salt thereof:

X a is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro; and

X d is selected from F, Cl, Br, and I.

16. The method of claim 15 , wherein the compound of Formula (XI):

or a salt thereof, is prepared by converting a compound of Formula (XII):

or a salt thereof, into the compound of Formula (XI), or a salt thereof,

wherein in the compound of Formula (XII), or a salt thereof, R 3 is a monovalent nitrogen protecting group.

17. The method of claim 16 , wherein the compound of Formula (XII):

or a salt thereof, is prepared by converting the compound of Formula (XV):

or a salt thereof, into the compound of Formula (XII), or a salt thereof,

wherein in the compound of Formula (XV), or a salt thereof, R 3 is a monovalent nitrogen protecting group.

18. The method of claim 17 , wherein the conversion of the compound of Formula (XV), or a salt thereof, into the compound of Formula (XII), or a salt thereof, comprises the steps of:

1) Converting the compound of Formula (XV):

or a salt thereof, into the compound of Formula (XIV):

or a salt thereof;

2) Converting the compound of Formula (XIV), or a salt thereof, into the compound of Formula (XIII):

or a salt thereof; and

3) Converting the compound of Formula (XIII), or a salt thereof, into the compound of Formula (XII), or a salt thereof,

wherein in the compounds of Formulae (XIII)-(XV), or a salt thereof, R 3 is a monovalent nitrogen protecting group; and wherein in the compound of Formula (XIV), or a salt thereof:

R 4 is —SO 2 R; and

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro.

19. The method of claim 18 , wherein the compound of Formula (XV):

or a salt thereof, is prepared by converting compound 2:

or a salt thereof, into the compound of Formula (XV), or a salt thereof.

20. The method of claim 19 , wherein compound 2:

or a salt thereof, is prepared by converting compound 3:

or a salt thereof, into compound 2, or a salt thereof.

21. The method of claim 20 , wherein compound 3:

or a salt thereof, is prepared by chiral resolution of compound (±)−3:

or a salt thereof.

22. The method of claim 21 , wherein compound (±)−3:

or a salt thereof, is prepared by converting compound (±)−4:

or a salt thereof, into compound (±)−3, or a salt thereof.

23. The method of claim 22 , wherein compound (±)−4:

or a salt thereof, is prepared by combining compound 5:

or a salt thereof, with 2-nitropropane to produce compound (±)−4, or a salt thereof.

24. The method of claim 2 , wherein compound 1:

or a salt thereof, is prepared by converting compound 6:

or a salt thereof, into compound 1, or a salt thereof.

25. The method of claim 24 , wherein compound 6:

or a salt thereof, is prepared by converting compound 7:

or a salt thereof, into compound 6, or a salt thereof.

26. The method of claim 25 , wherein compound 7:

or a salt thereof, is prepared by combining compound 8:

or a salt thereof, with compound 9:

or a salt thereof, to produce compound 7, or a salt thereof.

27. The method of claim 26 , wherein compound 8:

or a salt thereof, is prepared by converting compound 10:

or a salt thereof, into compound 8, or a salt thereof.

28. The method of claim 27 , wherein compound 10:

or a salt thereof, is prepared by converting compound 11:

or a salt thereof, into compound 10, or a salt thereof.

29. The method of claim 28 , wherein compound 11:

or a salt thereof, is prepared by converting compound 12:

or a salt thereof, into compound 11, or a salt thereof.

30. The method of claim 29 , wherein compound 12:

or a salt thereof, is prepared by converting compound 13:

or a salt thereof, into compound 12, or a salt thereof.

31. The method of claim 30 , wherein compound 13:

or a salt thereof, is prepared by converting compound 14:

or a salt thereof, into compound 13, or a salt thereof.

32. The method of claim 31 , wherein compound 14:

or a salt thereof, is prepared by converting compound 15:

or a salt thereof, into compound 14, or a salt thereof.

33. The method of claim 32 , wherein compound 15:

or a salt thereof, is prepared by converting compound 16:

or a salt thereof, into compound 15, or a salt thereof.

34. The method of claim 33 , wherein compound 16:

or a salt thereof, is prepared by converting compound 17:

or a salt thereof, into compound 16, or a salt thereof.

35. The method of claim 34 , wherein compound 17:

or a salt thereof, is prepared by converting compound 18:

or a salt thereof, into compound 17, or a salt thereof.

36. The method of claim 35 , wherein compound 18:

or a salt thereof, is prepared by converting compound 19:

or a salt thereof, into compound 18, or a salt thereof.

37. A compound selected from:

and salts thereof,

wherein:

Xa is selected from F, Cl, Br, I, and —OSO 2 R;

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro;

X b is selected from CI, F, —OC 6 F 5 ,

X c is selected from F, Cl, Br, and I;

X d is selected from F, Cl, Br, and I;

R 3 is a monovalent nitrogen protecting group;

R 4 is —SO 2 R; and

R is selected from —C 1-10 alkyl, —C 1-10 haloalkyl, and aryl optionally substituted with —C 1-10 alkyl, —C 1-10 haloalkyl, halo, or nitro; and

wherein:

R 1 is hydrogen and R 2 is a monovalent nitrogen protecting group;

R 1 and R 2 are independently selected from monovalent nitrogen protecting groups; or

R 1 and R 2 , together with the atoms to which they are attached, form a nitrogen protecting group; and

wherein the compound is not:

or a salt thereof.