Methods and compositions for preparation of amphetamine conjugates and salts thereof
View Patent ↗The invention provides methods and compositions for preparing amphetamine conjugates, such as lisdexamfetamine, homoarginine-D-amphetamine, and salts thereof. In one embodiment, the invention provides methods of preparing an amphetamine conjugate from a chloramphetamine intermediate.
1. A method of preparing an acyl-amphetamine compound of Formula III, comprising:
(a) admixing an acyl-halamphetamine compound of Formula I, a hydrogenation catalyst, and hydrogen gas to provide an acyl-amphetamine compound of Formula II; which acyl-amphetamine compound of Formula II is admixed with a deprotecting agent to provide an acyl-amphetamine compound of Formula III; or
(b) admixing an acyl-halamphetamine compound of Formula I and a deprotecting agent to provide an acyl-halamphetamine compound of Formula IIa; which acyl-halamphetamine compound of Formula IIa is admixed with a hydrogenation catalyst and hydrogen gas to provide an acyl-amphetamine compound of Formula III;
wherein the acyl-halamphetamine compound of Formula I is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 3 represents independently for each occurrence C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or aryl; and
X is Cl, Br, or I;
wherein the acyl-amphetamine compound of Formula II is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl; and
R 3 represents independently for each occurrence C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or aryl;
wherein the acyl-halamphetamine compound of Formula IIa is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl; and
X is Cl, Br, or I; and
the acyl-amphetamine compound of Formula III is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl.
2. The method of claim 1 , wherein R 1 is hydrogen.
3. The method of claim 1 , wherein R 2 is hydrogen.
4. The method of claim 3 , wherein R 3 is C 1 -C 6 haloalkyl.
5. The method of claim 3 , wherein R 3 is trifluoromethyl.
6. The method of claim 1 , wherein the hydrogenation catalyst comprises palladium.
7. The method of claim 1 , wherein the hydrogenation catalyst comprises palladium on carbon.
8. The method of claim 7 , wherein the step requiring admixing a hydrogenation catalyst and hydrogen gas further comprises admixing acetic acid.
9. The method of claim 8 , further comprising isolating the acyl-amphetamine compound of Formula II as a solid comprising from about 15% (w/w) to about 40% (w/w) water.
10. The method of claim 8 , further comprising crystallizing the acyl-amphetamine compound of Formula II from a mixture comprising acetic acid and water.
11. The method of claim 1 , wherein after the acyl-amphetamine compound of Formula II is admixed with a deprotecting agent to provide an acyl-amphetamine compound of Formula III, the method further comprises admixing an alkyl tetrahydrofuran and isolating the acyl-amphetamine compound of Formula III.
12. The method of claim 1 , wherein the deprotecting agent comprises a base and a compound R 4 —OH, wherein R 4 is hydrogen, C 1 -C 6 alkyl, or aryl.
13. The method of claim 12 , wherein the base is an alkali metal hydroxide.
14. The method of claim 1 , wherein the deprotecting agent is a mixture of sodium hydroxide and water.
15. The method of claim 1 , wherein the method comprises admixing an acyl-halamphetamine compound of Formula I, a hydrogenation catalyst, and hydrogen gas to provide an acyl-amphetamine compound of Formula II; which acyl-amphetamine compound of Formula II is admixed with a deprotecting agent to provide an acyl-amphetamine compound of Formula III.
16. The method of claim 1 , wherein the acyl-halamphetamine compound of Formula I is represented by:
the acyl-amphetamine compound of Formula II is represented by:
and
the acyl-amphetamine compound of Formula III is represented by:
17. A method of preparing an acyl-amphetamine compound, comprising admixing an acyl-halamphetamine compound of Formula Ia, a hydrogenation catalyst, and a hydrogen source to provide an acyl-amphetamine compound of Formula III, wherein the acyl-halamphetamine compound of Formula Ia is represented by:
wherein:
A is
Pg is a protecting group that undergoes deprotection under hydrogenation conditions;
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 3 is, independently for each occurrence, absent, hydrogen, or Pg, in accordance with the rules of valence and provided that one occurrence of R 3 is hydrogen, another occurrence of R 3 is absent, and the remaining occurrence of R 3 is Pg; and
X is Cl, Br, or I; and
wherein the acyl-amphetamine compound of Formula III is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
A is —N(H)R 2 or
18. The method of claim 1 , further comprising admixing a halamphetamine compound of Formula IV and a protected lysine compound of Formula V to provide a compound of Formula I; wherein the halamphetamine compound of Formula IV is represented by:
or a salt thereof, wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl; and
X is Cl, Br, or I; and
wherein the protected lysine compound of Formula V is represented by:
wherein:
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl; and
R 3 represents independently for each occurrence C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or aryl; and
Z is a leaving group.
19. The method of claim 18 , wherein the compound of Formula I is represented by:
the acyl-amphetamine compound of Formula II is represented by:
the acyl-halamphetamine compound of Formula IIa is represented by:
the acyl-amphetamine compound of Formula III is represented by:
the halamphetamine compound of Formula IV is represented by:
or a hydrochloride salt thereof; and
the protected lysine compound of Formula V is represented by:
20. The method of claim 18 , wherein Z is chloro, bromo, fluoro, iodo, or
wherein R 5 is hydrogen or C 1 -C 6 alkyl.
21. The method of claim 18 , further comprising admixing water and alkali metal bicarbonate.
22. The method of claim 18 , further comprising admixing a norephedrine compound of Formula VI and a halogenating agent to provide a halamphetamine compound of Formula IV; wherein the norephedrine compound of Formula VI is represented by:
or a salt thereof, wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl.
23. The method of claim 1 , further comprising admixing an acyl-amphetamine compound of Formula III and an acid to provide an acid salt of said acyl-amphetamine compound of Formula III.
24. A compound of Formula I, Ia, or II, wherein Formula I is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 3 represents independently for each occurrence C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or aryl; and
X is Cl, Br, or I;
wherein Formula Ia is represented by:
wherein:
A is
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 3 is, independently for each occurrence, absent, hydrogen, or
in accordance with the rules of valence and provided that one occurrence of R 3 is hydrogen, another occurrence of R 3 is absent, and the remaining occurrence of R 3 is
and
R 4 represents independently for each occurrence hydrogen, C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;
X is Cl, Br, or I; and
wherein Formula II is represented by:
wherein:
R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
R 2 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl; and
R 3 represents independently for each occurrence C 1 -C 6 haloalkyl.