Processes for the preparation of Tezacaftor and intermediates thereof

1. A process for the preparation of Tezacaftor (1):

comprising:

(i) cyclizing, in the presence of a catalyst (C3) and a solvent (S7), a compound of Formula (3):

or a salt thereof,

wherein

R 1 is H or P 1 ;

R 2 is H or P 2 ; and

P 1 and P 2 are hydroxyl protecting groups that may be the same or different;

to provide either Tezacaftor (1) when each of R 1 and R 2 is H, or, a compound of Formula (2):

or a salt thereof,

wherein

R 1′ is H or P 1 ;

R 2′ is H or P 2 ;

R 1′ and R 2′ are not both H; and

P 1 and P 2 are hydroxyl protecting groups that may be the same or different; and

(ii) when either or both of R 1 and R 2 in the compound of Formula (3) is a hydroxyl protecting group P 1 or P 2 , deprotecting the compound of Formula (2) in the presence of a solvent (S8) to provide Tezacaftor (1).

2. The process of claim 1 , wherein the catalyst (C3) is palladium(II) chloride.

3. The process of claim 1 , wherein R 1 is P 1 ; R 2 is P 2 ; and P 1 and P 2 are CR a R b R c groups that may be the same or different, wherein R a , R b and R c are independently selected from the group consisting of H, an unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted alkyl group having 1 to 10 carbon atoms in the alkyl portion, an unsubstituted aryl group having 6 to 14 ring carbon atoms, and a substituted aryl group having 6 to 14 ring carbon atoms; wherein at least one of R a , R b and R c is a substituted or unsubstituted aryl group having 6 to 14 ring carbon atoms.

4. The process of claim 3 , wherein each of P 1 and P 2 is a benzyl group.

5. The process of claim 3 , wherein deprotecting the compound of Formula (2) comprises hydrogenation in the presence of a catalyst (C4) that is palladium on carbon.

6. The process of claim 1 , wherein the compound of Formula (3), or a salt thereof, is prepared by reacting, in the presence of a catalyst (C2), a solvent (S6) and a base (B2), a compound of Formula (5):

or a salt thereof,

wherein

X is halide or trifluoromethanesulfonate;

R 1 is H or P 1 ; and

P 1 is a hydroxyl protecting group.

with a compound of Formula (4):

wherein

R 2 is H or P 2 ; and

P 2 is a hydroxyl protecting group.

7. The process of claim 6 , wherein the catalyst (C2) is bis(benzonitrile)palladium(II) dichloride.

8. The process of claim 7 , wherein the catalyst (C2) is used in combination with a phosphine ligand (L) that is 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

9. The process of claim 6 , wherein the compound of Formula (5), or a salt thereof, is prepared by reacting, in the presence of a solvent (S5) and an activator (Ac2), a compound of Formula (7):

wherein

X is halide or trifluoromethanesulfonate;

with a compound of Formula (6):

wherein

R 1 is H or P 1 ; and

P 1 is a hydroxyl protecting group.

10. The process of claim 9 , wherein the activator (Ac2) is a Lewis acid of the Formula MY n , wherein M is a metal selected from the group consisting of aluminum, bismuth, copper, indium, scandium, ytterbium and zinc; Y is trifluoromethanesulfonate or halide; and n is the valency of metal M.

11. The process of claim 10 , wherein the activator (Ac2) is copper(II) triflate.

12. The process of claim 9 , wherein the compound of Formula (7), or a salt thereof, is prepared by a process comprising:

(i) reacting, in the presence of a solvent (S1), a compound of Formula (12):

wherein

X is halide or trifluoromethanesulfonate;

with a compound P a -LG 1 ,

wherein

P a is an amino protecting group; and

LG 1 is a leaving group;

to afford a compound of Formula (11):

(ii) reducing, in the presence of a solvent (S2) and a reductant, the compound of Formula (11) to afford a compound of Formula (10):

or a salt thereof,

wherein

X is halide or trifluoromethanesulfonate; and

P a is an amino protecting group;

(iii) reacting, in the presence of a solvent (S3), a compound of Formula (10) and a compound of Formula (9):

wherein

G is OH or LG 2 ; and

LG 2 is a leaving group,

to afford a compound of Formula (8):

wherein

X is halide or trifluoromethanesulfonate; and

P a is an amino protecting group; and

(iv) deprotecting the compound of Formula (8) to provide the compound of Formula (7).

13. The process of claim 12 , wherein X is bromide.

14. The process of claim 13 , wherein P a is a tert-butoxycarbonyl group.

15. A compound of Formula (3):

or a salt thereof,

wherein

R 1 is H or P 1 ;

R 2 is H or P 2 ; and

P 1 and P 2 are hydroxyl protecting groups that may be the same or different.

16. The compound of claim 15 , wherein R 1 is P 1 ; R 2 is P 2 ; and P 1 and P 2 are CR a R b R c groups that may be the same or different, wherein R a , R b and R c are independently selected from the group consisting of H, an unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted alkyl group having 1 to 10 carbon atoms in the alkyl portion, an unsubstituted aryl group having 6 to 14 ring carbon atoms, and a substituted aryl group having 6 to 14 ring carbon atoms; wherein at least one of R a , R b and R c is a substituted or unsubstituted aryl group having 6 to 14 ring carbon atoms.

17. The compound of claim 16 , wherein R 1 and R 2 are both benzyl.

18. A compound of Formula (10):

wherein

X is s halide or trifluoromethanesulfonate; and

P a is an amino protecting group selected from the group consisting of substituted or unsubstituted alkyloxycarbonyl groups; substituted or unsubstituted arylalkyloxycarbonyl groups; substituted or unsubstituted alkylcarbonyl groups; and substituted or unsubstituted arylalkylcarbonyl groups.

19. The compound of claim 18 , wherein X is bromide.

20. The compound of claim 19 , wherein P a is a tert-butoxycarbonyl group.