Methods and compositions for preparing lisdexamfetamine and salts thereof

1. A method of preparing a lysine-amphetamine compound, comprising admixing an amphetamine compound of Formula I with a lysine compound of Formula II to provide a lysine-amphetamine compound of Formula III, wherein Formula I is represented by:

or a salt thereof;

Formula II is represented by:

wherein Z is

 and R 3 is hydrogen; and

Formula III is represented by:

and crystallizing said lysine-amphetamine compound of Formula III from a mixture comprising (i) at least one of a C 1 -C 4 aliphatic alcohol, C 1 -C 4 aliphatic carboxylic acid, aliphatic tertiary amine, or water, and (ii) (C 1 -C 4 alkyl)—CO 2 —(C 1 -C 4 alkyl), to provide a purified lysine-amphetamine compound of Formula III.

2. The method of claim 1 , wherein Formula I is

having a purity of at least 90% (w/w), Formula II is

and Formula III is

3. The method of claim 1 , wherein Formula I has a purity of at least 97% (w/w).

4. The method of claim 1 , comprising crystallizing said lysine-amphetamine compound of Formula III from a mixture comprising (i) at least 20% (v/v) methanol, and (ii) at least 20% (v/v) isopropyl acetate, to provide a purified lysine-amphetamine compound of Formula III.

5. The method of claim 1 , comprising re-crystallizing said purified lysine-amphetamine compound of Formula III from a mixture comprising at least one of a C 1 -C 4 aliphatic alcohol, C 1 -C 4 aliphatic carboxylic acid, aliphatic tertiary amine, or water, to provide a high-purity lysine-amphetamine compound of Formula III.

6. The method of claim 1 , wherein the purified lysine-amphetamine compound of Formula III has a purity of at least 99% (w/w).

7. The method of claim 5 , wherein the high-purity lysine-amphetamine compound of Formula III has a purity of at least 99.9% (w/w).

8. The method of claim 1 , further comprising admixing said lysine-amphetamine compound of Formula II, a hydrogenation catalyst, and a hydrogen source to provide a lysine-amphetamine compound of Formula IV, wherein the compound of Formula IV is represented by:

9. The method of claim 8 , wherein the hydrogenation catalyst comprises palladium on carbon, and the hydrogen source is hydrogen gas or ammonium formate.

10. The method of claim 8 , further comprising admixing said lysine-amphetamine compound of Formula IV and an acid to provide an acid salt of said lysine-amphetamine compound of Formula IV.

11. The method of claim 10 , wherein the acid is methanesulfonic acid.

12. The method of claim 10 , further comprising admixing a lysine compound of Formula V with a carboxylic acid-activating agent to provide a lysine compound of Formula II; wherein the lysine compound of Formula V is represented by:

13. The method of claim 1 , wherein the purified lysine-amphetamine compound of Formula III contains less than 0.6% (w/w) N-hydroxysuccinimide.

14. The method of claim 1 wherein the admixing of the amphetamine compound of Formula I with the lysine compound of Formula II to provide the lysine-amphetamine compound of Formula III is done with no additional base.

15. The method of claim 14 wherein the admixing of the amphetamine compound of Formula I with the lysine compound of Formula II to provide the lysine-amphetamine compound of Formula III is done with no diisopropylethylamine.