Processes for the preparation of isoindole compounds and isotopologues thereof

1. A process for the preparation of an enantiomerically enriched or enantiomerically pure compound of Formula (I):

or a salt, stereoisomer, or isotopologue thereof, wherein:

R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof;

R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof;

R is (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or an isotopologue thereof;

Z is C═O, methylene, or an isotopologue thereof; and

Y 1 , Y 2 , and Y 3 are independently hydrogen or deuterium;

Comprising the step of

(a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas or deuterium gas, in a solvent, and in the presence of (1) a metal catalyst and a chiral ligand or (2) a chiral metal catalyst/ligand complex to form an enantiomerically enriched or enantiomerically pure aminosulfone of Formula (III):

or a salt or isotopologue thereof; wherein deuterium gas or a solvent containing exchangeable deuterium for proton-deuterium exchange or both is used.

2. The process of claim 1 for the preparation of an enantiomerically enriched or enantiomerically pure compound of Formula (I-a):

or a salt, stereoisomer, or isotopologue thereof, wherein:

R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof;

R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof;

R is (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or an isotopologue thereof; and

Y 1 , Y 2 , and Y 3 are independently hydrogen or deuterium;

comprising the steps of

(a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas or deuterium gas, in a solvent, and in the presence of (1) a metal catalyst and a chiral ligand or (2) a chiral metal catalyst/ligand complex to form an enantiomerically enriched or enantiomerically pure aminosulfone of Formula (III):

or a salt or isotopologue thereof; wherein deuterium gas or a solvent containing exchangeable deuterium for proton-deuterium exchange or both is used; and

(b) reacting the enantiomerically enriched or enantiomerically pure aminosulfone of Formula (III), or a salt or isotopologue thereof, with a compound of Formula (V):

or a salt or isotopologue thereof, to form the enantiomerically enriched or enantiomerically pure compound of Formula (I-a), or a salt or isotopologue thereof.

3. The process of claim 1 for the preparation of an enantiomerically enriched or enantiomerically pure compound of Formula (I-b):

or a salt, stereoisomer, or isotopologue thereof, wherein:

R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof;

R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof;

R is (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or an isotopologue thereof; and

Y 1 , Y 2 , and Y 3 are independently hydrogen or deuterium;

comprising the steps of

(a) reducing an enamine of Formula (II):

or a salt or isotopologue thereof, via hydrogenation with hydrogen gas or deuterium gas, in a solvent, and in the presence of (1) a metal catalyst and a chiral ligand or (2) a chiral metal catalyst/ligand complex to form an enantiomerically enriched or enantiomerically pure aminosulfone of Formula (III):

or a salt or isotopologue thereof; wherein deuterium gas or a solvent containing exchangeable deuterium for proton-deuterium exchange or both is used;

(b) reacting the enantiomerically enriched or enantiomerically pure aminosulfone of Formula (III), or a salt or isotopologue thereof, with a compound of Formula (VI):

or a salt or isotopologue thereof, wherein R 4 is (C 1 -C 3 )alkyl, and X is halogen, to form an enantiomerically enriched or enantiomerically pure compound of Formula (VII):

or a salt or isotopologue thereof;

(c) reducing the enantiomerically enriched or enantiomerically pure compound of Formula (VII), or a salt or isotopologue thereof, to form an enantiomerically enriched or enantiomerically pure compound of Formula (VIII):

or a salt or isotopologue thereof; and

(d) reacting the enantiomerically enriched or enantiomerically pure compound of Formula (VIII), or a salt or isotopologue thereof, with an acid chloride RCOCl, or an isotopologue thereof, to form the enantiomerically enriched or enantiomerically pure compound of Formula (I-b), or a salt or isotopologue thereof.

4. The process of claim 1 , wherein Y 1 is hydrogen or deuterium; and Y 2 and Y 3 are both hydrogen or both deuterium.

5. The process of claim 4 , wherein Y 1 is hydrogen or deuterium; and Y 2 and Y 3 are both hydrogen or both deuterium, wherein not all of Y 1 , Y 2 , and Y 3 are hydrogen.

6. The process of claim 1 , wherein the enamine of Formula (II), or a salt or isotopologue thereof, is synthesized by reacting a nitrile of Formula (IV):

or an isotopologue thereof, with LiCH 2 SO 2 R 3 , or an isotopologue thereof.

7. The process of claim 1 , wherein R 1 and R 2 are substituted or unsubstituted (C 1 -C 6 )alkoxy, or an isotopologue thereof.

8. The process of claim 7 , wherein R 1 is OMe enriched with 0, 1, 2, or 3 deuterium, and R 2 is OEt enriched with 0, 1, 2, 3, 4, or 5 deuterium.

9. The process of claim 8 , wherein R 1 is OCD 3 , and R 2 is OEt.

10. The process of claim 8 , wherein R 1 is OCD 3 , and R 2 is OCD 2 CD 3 .

11. The process of claim 1 , wherein R 3 is Me enriched with 0, 1, 2, or 3 deuterium.

12. The process of claim 1 , wherein the enamine of Formula (II), or a salt or isotopologue thereof, is an enamine of Formula (II-a):

or a salt or isotopologue thereof, wherein the enamine of Formula (II-a), or a salt or isotopologue thereof, is synthesized by reacting a nitrile of Formula (IV):

or an isotopologue thereof, with CH 3 SO 2 CH 3 and n-BuLi.

13. The process of claim 1 , wherein the enamine of Formula (II), or a salt or isotopologue thereof, is an enamine of Formula (II-b):

or a salt or isotopologue thereof, wherein the enamine of Formula (II-b), or a salt or isotopologue thereof, is synthesized by reacting a nitrile of Formula (IV):

or an isotopologue thereof, with CD 3 SO 2 CD 3 and n-BuLi.

14. The process of claim 1 , wherein R is methyl enriched with 0, 1, 2, or 3 deuterium or cyclopropyl enriched with 0, 1, 2, 3, 4, or 5 deuterium.

15. The process of claim 1 , wherein the hydrogenation in step (a) occurs with hydrogen gas.

16. The process of claim 1 , wherein the hydrogenation in step (a) occurs with deuterium gas.

17. The process of claim 1 , wherein the hydrogenation in step (a) occurs in a solvent containing exchangeable proton for proton-deuterium exchange.

18. The process of claim 17 , wherein the solvent containing exchangeable proton for proton-deuterium exchange is 2,2,2-trifluoroethanol.

19. The process of claim 1 , wherein the hydrogenation in step (a) occurs in a solvent containing exchangeable deuterium for proton-deuterium exchange.

20. The process of claim 19 , wherein the solvent containing exchangeable deuterium for proton-deuterium exchange is 2,2,2-trifluoroethanol-d 1 .

21. The process of claim 1 , wherein the hydrogenation in step (a) occurs in a solvent containing neither exchangeable proton nor exchangeable deuterium for proton-deuterium exchange.

22. The process of claim 1 , wherein the metal catalyst is Rh(cod) 2 OTf.

23. The process of claim 1 , wherein the chiral ligand is (S,R)-t-Bu Josiphos.

24. The process of claim 1 , wherein the compound of Formula (I) is

or a salt, stereoisomer, or isotopologue thereof.

25. The process of claim 1 , wherein the compound of Formula (I) is

or a salt, stereoisomer, or isotopologue thereof.