Granted Patent B2

US 12,325,707 · App. 17/428,850 · Granted Jun 10, 2025

Inventors: Robert S. Lewis (Lexington, MA); Mahender Reddy Karla (Lexington, MA); Kathryn E. Kavouris (Cambridge, MA); Yong Dong (Chestnut Hill, MA); Adam J. Morgan (Ashland, MA); Cameron J. Cowden (Lexington, MA)

Assignee: SUN PHARMACEUTICAL INDUSTRIES, INC.

C07D487/04C07B59/002C07C309/65C07D403/04

Abstract

Claims (53)

1. A process for preparing a compound of Formula I:

or a salt thereof,

the process comprising reacting a compound of

Formula II′:

or a salt thereof, in the presence of an acid such that a compound of Formula I is formed;

wherein in Formula I and Formula II′,

Y 1 is hydrogen or deuterium;

each Y 2 is the same and is hydrogen or deuterium;

each Y 3 is the same and is hydrogen or deuterium;

and in Formula II′,

each R 1′ is C 1 -C 10 alkyl, or C 2 -C 10 alkenyl, or the two R 1′ s, taken together with the oxygen atoms to which they are attached, form a 5-7-membered heterocyclic ring which may optionally be substituted; and

each R 6 is independently selected from H and a protecting group.

2. The process of claim 1 , wherein the acid is selected from trifluoroacetic acid (TFA), phosphoric acid, hydrochloric acid, or a combination thereof.

3. A process for preparing a compound of Formula II′:

or a salt thereof;

the process comprising reacting a compound of Formula III′:

or a salt thereof;

with hydrogen gas in the presence of a hydrogenation catalyst;

wherein:

Y 1 is hydrogen or deuterium;

each Y 2 is the same and is hydrogen or deuterium;

each Y 3 is the same and is hydrogen or deuterium;

each R 1′ is C 1 -C 10 alkyl, or C 2 -C 10 alkenyl, or the two R 1′ s, taken together with the oxygen atoms to which they are attached, form a 5-7-membered heterocyclic ring which may optionally be substituted; and

each R 6 is independently selected from H and a protecting group.

4. The process of claim 3 , wherein the hydrogenation catalyst comprises rhodium and a chiral phosphine ligand (L) according to Formula IV:

wherein each of R 2a , R 2b , R 3a , R 3b , and R 4 is independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; and R 5 is secondary alkyl, tertiary alkyl, or cycloalkyl.

5. The process of claim 4 , wherein each of R 2a , R 2b , R 3a , R 3b , and R 4 is hydrogen, and R 5 is norbornyl or cyclohexyl.

6. The process according to claim 4 , wherein the hydrogenation catalyst is present in an amount of 1 mol % or less, and wherein the compound of Formula II′ has an enantiomeric excess of the (R)-enantiomer of at least 95%.

7. The process according to claim 3 , wherein the step of reacting is performed in a solvent, and the solvent is selected from dichloromethane (DCM), trifluorotoluene (TFT), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl-THF), methanol (MeOH), ethanol (EtOH), trifluoroethanol (TFE), isopropanol (iPrOH), hexafluoroisopropanol (HFIP), ethyl acetate (EtOAc), isopropyl acetate (iPrOAc), acetic acid (AcOH), and mixtures thereof.

8. The process according to claim 7 , wherein the solvent is trifluoroethanol (TFE).

9. The process according to claim 6 , wherein the compound of Formula II′ has an enantiomeric excess of the (R)-enantiomer of at least 98%.

10. The process according to claim 3 , further comprising the step of treating the compound of Formula II′ with an acid to form a salt of the compound of Formula II′, wherein the acid is selected from D-dibenzoyl tartaric acid, orotic acid, 4-nitrobenzoic acid, 1-hydroxy-2-naphthoic acid, salicylic acid, and 4-bromobenzoic acid.

11. A process for preparing a compound of Formula III′:

or a salt thereof;

the process comprising reacting a compound of Formula VIII′:

or a salt thereof;

with a compound of Formula VII:

or a salt thereof;

in the presence of a base, such that a compound of Formula III′, or a salt thereof, is formed;

wherein:

Y 1 is hydrogen or deuterium;

each Y 2 is the same and is hydrogen or deuterium;

each Y 3 is the same and is hydrogen or deuterium;

each R 1′ is C 1 -C 10 alkyl, or C 2 -C 10 alkenyl, or the two R 1′ s, taken together with the oxygen atoms to which they are attached, form a 5-7-membered heterocyclic ring which may optionally be substituted; and

each R 6 is independently selected from H and a protecting group.

12. The process of claim 11 , wherein the base is selected from tripotassium phosphate, hydrated tripotassium phosphate and potassium carbonate.

13. The process according to claim 1 , wherein the protecting group is selected from t-butoxycarbonyl, triflyl, trifluoroacetyl, and trityl.

14. The process according to claim 1 , wherein both R 6 are H.

15. The process according to claim 1 , wherein both R 1 are methyl, and wherein Y 1 is hydrogen and each of Y 2 and Y 3 is deuterium.

16. The process according to claim 1 , wherein each of Y 1 , Y 2 , and Y 3 is hydrogen.

17. The process according to claim 1 , wherein the deuterium incorporation at each position designated as deuterium is at least 90%.

18. The process according to claim 1 , wherein the deuterium incorporation at each position designated as deuterium is at least 95%.

19. The process according to claim 1 , wherein the deuterium incorporation at each position designated as deuterium is at least 97%.

Assignments (3)

Continuity (3)

References Cited (14)