Method of preparing a DON prodrug from L-glutamic acid
The present disclosure provides methods of preparing a compound of Formula (I): wherein R 1 , R 2 , and R 3 are as defined as set forth in the application. In one embodiment, a compound of Formula (I) is prepared in >95% chemical purity and >95% enantiomeric excess.
1. A method of preparing a compound of Formula I:
the method comprising:
(a) reacting a compound of Formula II:
with diazomethane in a solvent at a temperature of about −78° C. to about 0° C., wherein:
X 1 is selected from the group consisting of halogen, benzotriazole,
R 1 is C 1 -C 4 alkyl;
R 2 is C 1 -C 4 alkyl;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, (aryl)alkyl, and (heteroaryl)alkyl;
R 4a is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl; and
R 4b is selected from the group consisting of C 1 -C 8 alkyl and —CF 3 .
2. The method of claim 1 , wherein:
X 1 is:
3. The method of claim 2 , wherein R 4a is ethyl.
4. The method of claim 1 , wherein the compound of Formula II is prepared in situ and reacted with diazomethane without isolation or purification.
5. The method of claim 1 , wherein the compound of Formula II:
wherein:
X 1 is:
and
R 4a is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl;
is obtained by reacting a compound of Formula III:
wherein:
R 1 is C 1 -C 4 alkyl;
R 2 is C 1 -C 4 alkyl; and
R 3 is selected from the group consisting of C 1 -C 6 alkyl, (aryl)alkyl, and
(heteroaryl)alkyl;
with a compound having Formula IV:
wherein:
R 4a is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl,
in a solvent in the presence of a base at a temperature of about −45° C. to about 20° C.
6. The method of claim 5 , wherein the compound of Formula III is obtained by reacting a compound of Formula V:
wherein:
R 1 is C 1 -C 4 alkyl;
R 2 is C 1 -C 4 alkyl;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, (aryl)alkyl, and
(heteroaryl)alkyl; and
PG 1 is a protecting group,
with a deprotecting agent in a solvent at a temperature of about 0° C. to about 60° C.
7. The method of claim 6 , wherein PG 1 is aralkyl, and the deprotecting agent is hydrogen in the presence of a catalyst.
8. The method of claim 6 , wherein the compound of Formula V is obtained by reacting a compound of Formula VI:
wherein:
R 1 is C 1 -C 4 alkyl; and
PG 1 is a protecting group,
with a compound of Formula VII:
wherein:
R 2 is C 1 -C 4 alkyl; and
R 3 is selected from the group consisting of C 1 -C 6 alkyl, (aryl)alkyl, and
(heteroaryl)alkyl;
in a solvent in the presence of a coupling agent at a temperature of about 0° C. to about 60° C.
9. The method of claim 8 , wherein the coupling agent comprises dicyclohexylcarbodiimide, diisopropylcarbodiimide, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-HCl.
10. The method of claim 9 , wherein the coupling agent further comprises ethyl cyano(hydroximino)acetate.
11. The method of claim 8 , wherein the compound of Formula VI is obtained by reacting a compound of Formula VIII:
wherein:
R 1 is C 1 -C 4 alkyl;
PG 1 is a protecting group; and
PG is a protecting group,
with an amine deprotecting agent in a solvent at a temperature of about 0° C. to about 60° C.,
wherein the amine deprotecting agent selectively removes PG in the presence of PG 1 .
12. The method of claim 11 , wherein PG is selected from the group consisting of fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl, and carboxybenzyl.
13. The method of claim 11 further comprising reacting the
with an acid in a solvent to form a salt that precipitates from solution.
14. The method of claim 11 wherein the compound of Formula VIII is obtained by reacting a compound of Formula IX:
with R 1 —X 2 , wherein:
R 1 is C 1 -C 4 alkyl; and
X 2 is selected from the group consisting of —OH and —Br,
in solvent.
15. The method of claim 1 , wherein R 1 is isopropyl.
16. The method of claim 1 , wherein R 2 is methyl.
17. The method of claim 1 , wherein R 3 is:
18. The method of claim 1 , wherein isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate is obtained in about 10-90% yield starting from a compound of Formula IX.
19. The method of claim 1 , wherein isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate is obtained in about 98% chemical purity or more starting from a compound of Formula IX.
20. The method of claim 1 , wherein isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate is obtained in about 98% ee or more starting from a compound of Formula IX.