Processes for the preparation of deuterated D-serine
Disclosed are methods for preparing deuterated analogs of D -serine and compounds useful for preparing deuterated analogs of 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; 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 95% at the position specified as deuterium.
2 . The method of claim 1 , wherein R 2 is isopropyl or t-butyl.
3 . 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.
4 . The method of claim 1 , wherein the compound of Formula E is selected from the group consisting of:
5 . The method of claim 1 , wherein the method further comprises, prior to the step of contacting the compound of Formula E with an acid, the steps of:
(i) contacting a compound of Formula B:
wherein
[R 1 ] 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; 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, wherein the compound of Formula E has a deuterium incorporation of at least 95% at each position specified as deuterium.
6 . The method of claim 4 , wherein the acid is HCl.
7 . The method of claim 5 , wherein the compound of Formula E is compound 50:
8 . The method of claim 5 , 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.
9 . 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.
10 . The compound of claim 9 , wherein
R 3 is H, D, —C(O)—X—C 1 -C 6 alkyl, —C(O)—X—C 3 -C 6 cycloalkyl, or —C(O)—X-aryl, wherein X is absent, O, NH, or S.
11 . A method for preparing 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,
the method comprising the steps of:
contacting a compound represented by the structure (B)
in which R 1 , R 2 , and R 3 are as defined for the compound of Formula (D);
with a base to form a reaction mixture; and
contacting the reaction mixture with at least 1 equivalent of a deuterium source;
under conditions such that the compound of structure (D) is formed;
wherein the compound of structure (D) has a deuterium incorporation of at least 90% at the position specified as deuterium.
12 . The method of claim 11 , wherein the base is selected from mesityllithium, 2,6-dimethoxyphenyllithium, 2,4,6-trimethoxyphenyllithium, tolyllithium, t-butyllithium, phenyllithium, lithium hexamethyldisilazide (LHMDS) and tritylsodium.
13 . The method of claim 11 , wherein the deuterium source is D 2 O.
14 . The method of claim 11 , wherein the step of contacting the reaction mixture with at least 1 equivalent of a deuterium source comprises contacting the reaction mixture with 1-10 equivalents of the deuterium source.
15 . The compound of claim 9 , wherein the compound has a deuterium incorporation of at least 95% at the position specified as deuterium.
16 . The method of claim 11 , wherein the compound of structure (D) has a deuterium incorporation of at least 95% at the position specified as deuterium.