Process for preparing an enantiomerically enriched, deuterated secondary alcohol from a corresponding ketone without reducing deuterium incorporation

1. A process for the preparation of a compound of Formula I-A

comprising the step of reacting a compound of Formula II-A:

or a salt thereof, with a hydride source or a deuteride source in the presence of a ketoreductase or carbonyl reductase to form a compound of Formula I-A with an enantiomeric excess of at least 80%, wherein:

the ketoreductase or carbonyl reductase is selected from CRED A161, CRED A291, CRED A311, CRED A601 KRED-NADP-118, KRED-NADH-110, ES-KRED-120, ES-KRED-126, and ES-KRED-131;

each of R 4 , R 6 and R 7 is independently selected from —CH 3 and —CD 3 ;

each R 5 is hydrogen or deuterium or a combination thereof;

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

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

each Z 4 is the same and is hydrogen or deuterium;

each Z 5 is the same and is hydrogen or deuterium; and

Y is H when a compound of Formula II-A is reacted with a hydride source; or

Y is D when a compound of Formula II-A is reacted with a deuteride source, wherein either R 7 is —CD 3 or at least one of Z 2 , Z 3 , Z 4 and Z 5 is deuterium, and wherein the amount of deuterium incorporation at each deuterium in R 7 , Z 2 , Z 3 , Z 4 and Z 5 in the compound of Formula I-A is substantially equal to the amount of deuterium incorporation at corresponding deuterium atoms in R 7 , Z 2 , Z 3 , Z 4 and Z 5 in the compound of Formula II-A.

2. The process of claim 1 , wherein each R 7 is —CD 3 .

3. The process of claim 1 , wherein each Z 2 is deuterium.

4. The process of claim 1 , wherein each Z 2 is hydrogen.

5. The process of claim 1 , wherein each R 5 is deuterium.

6. The process of claim 1 , wherein each R 5 is hydrogen.

7. The process of claim 1 , wherein each Z 3 , Z 4 and Z 5 is hydrogen.

8. The process of claim 7 , wherein R 6 is —CH 3 and R 7 is —CD 3 .

9. The process of claim 8 , wherein R 4 is —CH 3 .

10. The process of claim 7 , wherein R 6 is —CD 3 and R 7 is —CD 3 .

11. The process of claim 1 , wherein each Z 3 , Z 4 and Z 5 is deuterium.

12. The process of claim 11 , wherein each R 6 and each R 4 is —CD 3 .

13. The process of claim 1 , wherein:

a. the compound of Formula II-A is selected from any one of the following:

and

b. the compound of Formula I-A is selected from any one of the following

14. The process of claim 1 , wherein:

the compound of Formula II-A is (Compound 407); and

the compound of Formula I-A is (Compound 437(R)).

15. The process of claim 13 , wherein the compound of Formula I-A is Compound 421(R), and further comprising the step of converting Compound 421(R) to Compound 121(R):

16. The process of claim 1 , wherein the hydride source or deuteride source is (i) a cofactor selected from NAD, NADH, NADP and NADPH, (ii) a reducing sugar and (iii) a dehydrogenase that dehydrogenates the reducing sugar.

17. The process of claim 16 , wherein Y is H; and the hydride source is (i) a cofactor selected from NAD, NADH, NADP and NADPH, (ii) glucose and (iii) glucose dehydrogenase.

18. The process of claim 16 , wherein Y is D; and the deuteride source is (i) a cofactor selected from NAD and NADP, (ii) deuterated glucose, and (iii) glucose dehydrogenase.

19. The process of claim 18 , wherein the deuterated glucose is generated from (i) D-glucono-δ-lactone and (ii) a metal deuteride or a mixed metal deuteride.

20. The process of claim 19 , wherein the metal deuteride or mixed metal deuteride is NaBD 4 .

21. The process of claim 1 , wherein the step of reacting a compound of Formula II-A or a salt thereof with a hydride source or a deuteride source is performed at a pH between 6.0 and 7.5.

22. The process of claim 21 , wherein the pH is between 6.90 and 7.05.

23. The process of claim 1 , wherein the ketoreductase or carbonyl reductase is CRED A311.