Process for the preparation of lisdexamfetamine and related derivatives
The present invention is directed to processes for the preparation of lisdexamfetamine and related derivatives, wherein the processes comprise coupling to racemic or enantiomerically enriched amphetamine and wherein the resulting product is advantageously enantiomerically or diastereomerically enriched in the desired stereoisomer.
1. A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt thereof; comprising the steps of
reacting a compound of formula (V), wherein
PG 1 and PG 2 are each tert-butoxycarbonyl (BOC), wherein A 1 is selected from the group consisting of C 1-12 alkyl, with a compound of formula (VI); wherein the compound of formula (VI) is racemic; in the presence of an S-selective enzyme catalyst; wherein the S-selective enzyme catalyst is an immobilized S-selective protease enzyme derived from Bacillus lichenformis ; neat or in a solvent or in a mixture of solvents; to yield the corresponding compound of formula (VII); wherein the compound of formula (VII) is present in an enantiomeric excess;
de-protecting the compound of formula (VII), to yield the corresponding compound of formula (I); wherein the compound of form 6 ula (I) is present in a diastereomeric excess.
2. A process as in claim 1 , wherein A 1 is selected from the group consisting of methyl, ethyl, isopropyl and t-butyl.
3. A process as in claim 1 , wherein A 1 is methyl.
4. A process as in claim 1 , wherein the compound of formula (VI) is present in an amount in the range of from about 1 to 10 molar equivalents, relative to the moles of the compound of formula (V).
5. A process as in claim 1 , wherein the compound of formula (VI) is present in an amount in the range of from about 4 to 6 molar equivalents, relative to the moles of the compound of formula (V).
6. A process as in claim 1 , wherein the compound of formula (VI) is present in an amount of about 5 molar equivalents, relative to the moles of the compound of formula (V).
7. A process as in claim 1 , wherein the S-selective enzyme catalyst is selected from the group consisting of P6-T2-250, and P8-T2-250.
8. A process as in claim 1 , wherein the S-selective enzyme catalyst is P6-T2-250.
9. A process as in claim 1 , wherein the protease enzyme catalyst is present in an amount in the range of from about 1 wt % to about 200 wt %.
10. A process as in claim 1 , wherein the protease enzyme catalyst is present in an amount in the range of from about 50 wt % to about 200 wt %.
11. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) in a solvent; and wherein the solvent is an organic solvent.
12. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) in a solvent; wherein the solvent is an organic solvent; and wherein the organic solvent is selected from the group consisting of tert-butyl-methylether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, acetonitrile, methanol, t-butanol, dimethylformamide (DMF), dimethylsulfide (DMS), toluene, dimethoxyethane (DME) and mixtures thereof.
13. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) in a solvent; wherein the solvent is an organic solvent; and wherein the organic solvent is acetonitrile.
14. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) in a solvent; wherein the solvent is an organic solvent; wherein the organic solvent is acetonitrile and wherein the acetonitrile is present in an amount in the range of from about 1:1 vol:vol ratio relative to the amount of the compound of formula (VI) to about 20:1 vol:vol ratio.
15. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) in a solvent; wherein the solvent is an organic solvent; wherein the organic solvent is acetonitrile and wherein the acetonitrile is present in an amount in the range of from about 2:1 vol:vol ratio to about 15:1 vol:vol ratio, relative to the amount of the compound of formula (VI).
16. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) at a temperature in the range of from about 0° C. to about 120° C.
17. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) at a temperature in the range of from about 30° C. to about 70° C.
18. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound of formula (VI) at a temperature in the range of from about 30° C. to about 45° C.
19. A process as in claim 1 , wherein the ratio of the compound of formula (VI) to the compound of formula (V) is in the range of from about 3:1 to about 4:1.
20. A process as in claim 1 , further comprising reacting the compound of formula (I) with methanesulfonic acid; to yield the corresponding dimesylate salt of the compound of formula (I).
21. A process as in claim 1 , wherein the compound of formula (VII) is prepared in a diastereomeric excess of at least about 80%.
22. A process as in claim 1 , wherein the compound of formula (I) is prepared in a diastereomeric excess of at least about 90%.
23. A process as in claim 1 , wherein the compound of formula (I) is prepared in diastereomeric ratio of (S,S) to (S,R) diastereomers of about 98:2.
24. A process as in claim 1 , wherein the dimesylate salt of the compound of formula (I) is prepared in a diastereomeric excess of at least about 80%.
25. A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt thereof; comprising the steps of
reacting a compound of formula (V), wherein PG 1 is a first nitrogen protecting group, wherein PG 2 is a second nitrogen protecting group, wherein PG 1 and PG 2 are the same, wherein PG 1 and PG 2 are each Boc, and wherein A 1 is methyl;
with a compound of formula (VI); wherein the compound of formula (VI) is racemic; and wherein the compound of formula (VI) is present in an amount of about 5 molar equivalents;
in the presence of a S-selective enzyme catalyst; wherein the S-selective enzyme catalyst is an immobilized S-selective protease enzyme catalyst derived from Bacillus lichenformis ; and wherein the S-selective enzyme catalyst is present in an amount in the range of from about 50 wt % to about 200 wt %, relative to the amount of the compound of formula (V);
in an organic solvent; wherein the organic solvent is acetonitrile; and wherein the acetonitrile is present in an amount in the range of from about 2:1 vol:vol to about 15:1 vol:vol ratio, relative to the amount of the compound of formula (VI); at a temperature in the range of from about 30° C. to about 45° C.; to yield the corresponding compound of formula (VII);
wherein the compound of formula (VII) is present in a diastereomeric excess;
de-protecting the compound of formula (VII), to yield the corresponding compound of formula (I); wherein the compound of formula (I) is present in a diastereomeric excess;
reacting the compound of formula (I) with methanesulfonic acid; to yield the corresponding dimesylate salt; wherein the dimesylate salt of the compound of formula (I) is present in a diastereomeric excess.
26. A process for the preparation of a diastereomerically enriched compound of formula (XX)
wherein
R 1 is benzyl;
R 2 methyl;
R 3 hydrogen;
R 4 is an amino acid radical, wherein the amino acid is lysine;
or a pharmaceutically acceptable salt thereof; comprising
reacting a compound of formula (XXIa), wherein
R 5 is selected from the group consisting of C 1-12 alkyl, with a compound of formula (XII); wherein the compound of formula (XII) is racemic; in the presence of an R-selective enzyme catalyst; wherein the R-selective enzyme catalyst is an immobilized R-selective protease enzyme derived from Bacillus Lichenformis ; neat or in a solvent; to yield the corresponding compound of formula (XX); wherein the compound of formula (XX) is present in an enantiomeric excess.
27. A process for the preparation of a diastereomerically enriched compound of formula (XX)
wherein
R 1 is benzyl;
R 2 is methyl;
R 3 is hydrogen;
R 4 is an amino acid radical, wherein the amino acid is lysine;
or a pharmaceutically acceptable salt thereof; comprising
reacting a compound of formula (XXIb), wherein
R 4A is a nitrogen-protected amino acid radical, wherein the amino acid is lysine and the nitrogen protecting group is tert-butoxycarbonyl (BOC), and wherein R 5 is selected from the group consisting of C 1-12 alkyl, with a compound of formula (XII); wherein the compound of formula (XII) is racemic; in the presence of a R-selective enzyme catalyst; wherein the R-selective enzyme catalyst is an immobilized R-selective protease enzyme derived from Bacillus Lichenformis ; neat or in a solvent; to yield the corresponding compound of formula (XXIII); wherein the compound of formula (XIII) is present in an enantiomeric excess;
de-protecting the compound of formula (XXIII); to yield the corresponding compound of formula (XX); wherein the compound of formula (XX) is present in an enantiomeric excess.
28. A process as in claim 1 , wherein said immobilized S-selective protease enzyme derived from Bacillus lichenformis is immobilized on a solid support.
29. A process as in claim 25 , wherein said immobilized S-selective protease enzyme derived from Bacillus lichenformis is immobilized on a solid support.