Processes for the preparation of Tezacaftor and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10875846-B2
Application number	US-202016741276-A
Country	US
Kind code	B2
Filing date	Jan 13, 2020
Priority date	Jan 15, 2019
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

The present invention provides processes for the preparation of Tezacaftor, as well as intermediates useful in the preparation thereof. In particular, processes are provided for the preparation of a compound of Formula (3), and its conversion to Tezacaftor (1).

First claim

What is claimed is:

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.

Assignees

• Apotex Inc

Inventors

• Emmett Michael R
• Bodhuri Prabhudas
• Zhao Yajun
• Cammisa Eduardo Gustavo
• Green Stuart P

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07C269/04

  from amines with formation of carbamate groups · CPC title

• C07C271/28

  to a carbon atom of a non-condensed six-membered aromatic ring · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07C211/52

  the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups · CPC title