Processes for the preparation of deuterated D-serine

1. A method for preparing D-serine-2-d,

the method comprising:

contacting a compound of Formula E;

 wherein

R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl; and

R 3 is H, D, or a protecting group,

with acid under conditions suitable for opening of the oxazolidine ring;

and optionally removing the R 3 protecting group in the same or in a separate step as the contacting step,

such that D-serine-2-d is formed;

wherein the D-serine-2-d has a deuterium incorporation of at least 90% at the position specified as deuterium.

2. The method of claim 1 , wherein in the compound of Formula E, R 2 is C 1 -C 6 alkyl.

3. The method of claim 1 or claim 2 , wherein R 2 is isopropyl or t-butyl.

4. The method of claim 1 , wherein R 3 is a protecting group.

5. The method of claim 1 , wherein R 3 is a protecting group selected from —C(O)H, —C(O)—X—C 1 -C 6 alkyl, —C(O)—X—C 3 -C 6 cycloalkyl, —C(O)—X—CH 2 -aryl, —C(O)—X-aryl, and —CH 2 -aryl, wherein X is absent, O, NH, or S.

6. The method of claim 1 , wherein the compound of Formula E is selected from the group consisting of:

and wherein the contacting step comprises removing the protecting group in the same step as the opening of the oxazolidine ring.

7. The method of claim 1 , wherein the method further comprises, prior to the step of contacting the compound of Formula E to conditions suitable for removal of the amine-protecting group R 3 and opening of the oxazolidine ring, the steps of:

(i) contacting a compound of Formula B:

wherein

R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 -aryl, or aryl;

R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl; and

R 3 is H, D, or a protecting group,

 with a base to form a first reaction mixture;

(ii) contacting the first reaction mixture with a deuterium source to form a second reaction mixture under conditions such that the compound of structure (D) is formed:

wherein R 1 , R 2 and R 3 are as defined for the compound of Formula (B); and

(iii) contacting the second reaction mixture with a base to form the compound of Formula E.

8. The method of claim 6 , wherein the acid is HCl.

9. The method of claim 7 , wherein the compound of Formula E is compound 50:

10. The method of claim 7 , wherein the step of contacting the second reaction mixture with a base comprises contacting the second reaction mixture with 1-10 equivalents of lithium deuteroxide.

11. A compound represented by the structure (D):

wherein

R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 -aryl, or aryl;

R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl; and

R 3 is H, D, or a protecting group;

wherein the compound has a deuterium incorporation of at least 90% at the position specified as deuterium.

12. The compound of claim 11 , wherein R 3 is H.

13. The compound of claim 11 , wherein R 3 is a protecting group selected from the group consisting of —C(O)H, —C(O)—X—C 1 -C 6 alkyl, —C(O)—X—C 3 -C 6 cycloalkyl, —C(O)—X—CH 2 -aryl, —C(O)—X-aryl, —CH 2 -aryl, —S(O) 2 C 1 -C 6 alkyl, and S(O) 2 -aryl, wherein X is absent, O or NR 4 , wherein R 4 is H or C 1 -C 6 alkyl.

14. The compound of claim 13 , wherein R 3 is a protecting group selected from the group consisting of —C(O)H, —C(O)—X—C 1 -C 6 alkyl, —C(O)—X—C 3 -C 6 cycloalkyl, —C(O)—X—CH 2 -aryl, —C(O)—X-aryl, —S(O) 2 C 1 -C 6 alkyl, and S(O) 2 -aryl, wherein X is absent, O or NR 4 , wherein R 4 is C 1 -C 6 alkyl.

15. A method for preparing a compound represented by the structure (E):

wherein

R 2 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl; and

R 3 is H, D, —C(O)H, —C(O)—X—C 1 -C 6 alkyl, —C(O)—X—C 3 -C 6 cycloalkyl, —C(O)—X—CH 2 -aryl, —C(O)—X-aryl, or —CH 2 -aryl, wherein X is absent, O, NH, or S;

wherein the compound has a deuterium incorporation of at least 90% at the position specified as deuterium,

the method comprising the steps of:

(i) contacting a compound represented by structure (B)

in which R 1 is H or C 1 -C 6 alkyl,

R 2 and R 3 are as defined for the compound of Formula (E)

with a base to form a reaction mixture;

(ii) contacting the reaction mixture with a deuterium source;

under conditions such that the compound represented by structure (D) is formed:

in which R 1 is H or C 1 -C 6 alkyl,

R 2 and R 3 are as defined for the compound of Formula (E)

and

(iii) reacting the compound of structure (D) with a base to form the compound of structure (E).

16. The method of claim 15 , wherein the base of step (i) is selected from mesityllithium, 2,6-dimethoxyphenyllithium, 2,4,6-trimethoxyphenyllithium, tolyllithium, t-butyllithium, phenyllithium, lithium hexamethyldisilazide (LHMDS), trityllithium, phenyl sodium and tritylsodium.

17. The method of claim 15 , wherein the deuterium source is D 2 O.

18. The method of claim 15 , wherein the step of contacting the reaction mixture with a deuterium source comprises contacting the reaction mixture with 1-10 equivalents of the deuterium source.

19. The method of claim 15 , wherein,

the compound represented by the structure (E) is compound 50:

the compound represented by structure (B) is compound 30a:

 and

the base of step (i) is selected from mesityllithium, 2,6-dimethoxyphenyllithium and 2,4,6-trimethoxyphenyllithium.

20. The method of claim 15 , wherein,

the compound represented by the structure (E) is compound 50c:

the compound represented by structure (B) is compound 30e:

 and

the base of step (i) is selected from mesityllithium, 2,6-dimethoxyphenyllithium and 2,4,6-trimethoxyphenyllithium.

21. The method of claim 15 , wherein,

the compound represented by the structure (E) is compound 50d:

the compound represented by structure (B) is compound 30d:

 and

the base of step (i) is selected from mesityllithium, 2,6-dimethoxyphenyllithium and 2,4,6-trimethoxyphenyllithium.