Synthesis of MDMA or its optically active (R)- or (S)-MDMA isomers
Provided herein is a process for the preparation of 3,4-methylenedioxymethamphetamine, (R)-3,4-methylenedioxymethamphetamine and (S)-3,4-methylenedioxymethamphetamine.
1. A process for the preparation of 3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt thereof, the process comprising:
i) preparing an organometallic reagent from a compound of Formula (I):
wherein X is a halogen; R 1 and R 2 together with the atoms to which they are attached form a 1,3-dioxolane;
ii) reacting the organometallic reagent of step i) with a compound of Formula (II):
wherein R 3 is alkyl; and
iii) converting the product of step ii) to 3,4-methylenedioxymethamphetamine.
2. The process of claim 1 , wherein X is bromine.
3. The process of claim 1 , wherein R 3 is tert-butyl.
4. The process of claim 1 , wherein step i) comprises reacting the compound of Formula (I) with magnesium.
5. The process of claim 1 , wherein step i) comprises reacting the compound of Formula (Ia) with magnesium.
6. The process of claim 1 , wherein the step i) further comprises adding a copper (I) salt to the reaction mixture.
7. The process of claim 6 , wherein the copper (I) salt is CuI.
8. The process of claim 1 , wherein the product of step ii) is a compound of Formula (IIIb):
9. The process of claim 1 , wherein the step iii) comprises reacting a group of Formula (IVb) with a reducing agent to provide a group of Formula (Vb), or a pharmaceutically acceptable salt thereof:
10. The process of claim 9 , wherein the reducing agent is lithium aluminum hydride.
11. A process for the preparation of (R)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt thereof, the process comprising:
i) preparing an organometallic reagent from a compound of Formula (I):
wherein X is a halogen; R 1 and R 2 together with the atoms to which they are attached form a 1,3-dioxolane;
ii) reacting the organometallic reagent of step i) with a compound of Formula (IIa):
wherein R 3 is alkyl; and
iii) converting the product of step ii) to (R)-3,4-methylenedioxymethamphetamine.
12. The process of claim 11 , wherein X is bromine.
13. The process of claim 11 , wherein R 3 is tert-butyl.
14. The process of claim 11 , wherein step i) comprises reacting the compound of Formula (I) with magnesium.
15. The process of claim 11 , wherein step i) comprises reacting the compound of Formula (Ia) with magnesium.
16. The process of claim 11 , wherein the step i) further comprises adding a copper (I) salt to the reaction mixture.
17. The process of claim 16 , wherein the copper (I) salt is CuI.
18. The process of claim 11 , wherein the product of step ii) is a compound of Formula (IIIb):
19. The process of claim 11 , wherein the step iii) comprises reacting a group of Formula (IVa) with a reducing agent to provide a group of Formula (Va), or a pharmaceutically acceptable salt thereof:
20. The process of claim 19 , wherein the reducing agent is lithium aluminum hydride.
21. The process of claim 11 , wherein the process provides (R)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in an enantiomeric excess of a least 99.5%.
22. A process for the preparation of (S)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt thereof, the process comprising:
i) preparing an organometallic reagent from a compound of Formula (I):
wherein X is a halogen; R 1 and R 2 together with the atoms to which they are attached form a 1,3-dioxolane;
ii) reacting the organometallic reagent of step i) with a compound of Formula (II):
wherein R 3 is alkyl; and
iii) converting the product of step ii) to (S)-3,4-methylenedioxymethamphetamine.
23. The process of claim 22 , wherein X is bromine.
24. The process of claim 22 , wherein R 3 is tert-butyl.
25. The process of claim 22 , wherein step i) comprises reacting the compound of Formula (I) with magnesium.
26. The process of claim 22 , wherein step i) comprises reacting the compound of Formula (Ia) with magnesium.
27. The process of claim 22 , wherein the step i) further comprises adding a copper (I) salt to the reaction mixture.
28. The process of claim 27 , wherein the copper (I) salt is CuI.
29. The process of claim 22 , wherein the product of step ii) is a compound of Formula (III):
30. The process of claim 22 , wherein the step iii) comprises reacting a group of Formula (IV) with a reducing agent to provide a group of Formula (V), or a pharmaceutically acceptable salt thereof:
31. The process of claim 30 , wherein the reducing agent is lithium aluminum hydride.
32. The process of claim 22 , wherein the process provides (S)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in an enantiomeric excess of a least 99.5%.