Search

EP-4396305-B1 - SYNTHESIS OF MDMA OR ITS OPTICALLY ACTIVE (R)- OR (S)-MDMA ISOMERS

EP4396305B1EP 4396305 B1EP4396305 B1EP 4396305B1EP-4396305-B1

Inventors

  • MORRA, Nicholas
  • FAWAZ, MAJED

Dates

Publication Date
20260506
Application Date
20220901

Claims (15)

  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 is a protecting group, R 2 is a protecting group or R 1 and R 2 together with the atoms to which they are attached form a 5-membered heterocycle; ii) reacting the organometallic reagent of step i) with a compound of Formula (IIb): wherein R 3 is alkyl; and iii) converting the product of step ii) to 3,4-methylenedioxymethamphetamine.
  2. The process of claim 1, wherein the product of step ii) is: (a) a compound of: or (b) a compound of Formula (IIIc):
  3. 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:
  4. 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 is a protecting group, R 2 is a protecting group or R 1 and R 2 together with the atoms to which they are attached form a 5-membered heterocycle; 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.
  5. The process of claim 4, wherein the product of step ii) is: (a) a compound of Formula (III): or (b) a compound of Formula (IIIa):
  6. The process of any one of claims 4-5, 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:
  7. 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 is a protecting group, R 2 is a protecting group or R 1 and R 2 together with the atoms to which they are attached form a 5-membered heterocycle; 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.
  8. The process of any one of claims 1-7, wherein the compound of Formula (I) is a compound of Formula (Ia):
  9. The process of any one of claims 1-8, wherein X is bromine.
  10. The process of any one of claims 1-9, wherein R 3 is tert-butyl.
  11. The process of any one of claims 1-10, wherein step i) comprises reacting the compound of Formula (I) or Formula (Ia) with magnesium, optionally wherein the step i) further comprises adding a copper (I) salt (e.g., CuI) to the reaction mixture.
  12. The process of any one of claims 7-11, wherein the product of step ii) is: (a) a compound of Formula (IIIb): or (b) a compound of Formula (IIIb'):
  13. The process of any one of claims 7-12, 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:
  14. The process of claim 3, claim 6 or claim 13, wherein the reducing agent is lithium aluminum hydride.
  15. The process of: (a) any one of claims 1-6 or 8-11 or 14, wherein the process provides (S)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in an enantiomeric excess of a least 99.5%; or (b) any one of claims 7-14, wherein the process provides ( R )-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in an enantiomeric excess of a least 99.5%.

Description

BACKGROUND MDMA (3,4-methylenedioxymethamphetamine) is considered the prototype of a class of compounds called entactogens, which means "to touch within", their main characteristic being their ability to increase feelings of love, empathy and closeness towards others. Structurally, MDMA is a ring-substituted phenethylamine with a chiral molecular center that gives rise to two stereoisomers: S-(+)-MDMA and R-(-)-MDMA. Typically, effects of the former resemble those of psychostimulants and are primarily mediated by dopaminergic and noradrenergic pathways, including increases in motor activity and euphoria, whereas the latter induces qualitative effects similar to classical psychedelics, such as ego-dissolution and perceptive alterations, mediated by serotonergic pathways, including direct 5-HT2A receptor agonism. The molecular mechanisms for these differences are supported by preclinical evidence and point to a higher therapeutic index for the R-enantiomer. Dunlap Lee E. et. al., "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine", ACS Chemical Neuroscience, vol. 9, no. 10, XP093029160 in accordance with its abstract states "we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine". There remains a need for improved processes of making MDMA (3,4-methylenedioxymethamphetamine) and pharmaceutically acceptable salts thereof and enantiomers thereof. SUMMARY In an aspect, the present disclosure provides a process for the preparation of 3,4-methylenedioxymethamphetamine (MDMA). In some embodiments, the present disclosure provides a process for the preparation of racemic 3,4-methylenedioxymethamphetamine (MDMA). In some embodiments, the present disclosure provides a process for the preparation of enantiopure (R) or (S) 3,4-methylenedioxymethamphetamine (MDMA). In embodiments, the present disclosure provides: 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; R1 is a protecting group, R2 is a protecting group or R1 and R2 together with the atoms to which they are attached form a 5-membered heterocycle;ii) reacting the organometallic reagent of step i) with a compound of Formula (IIb): wherein R3 is alkyl; andiii) converting the product of step ii) to 3,4-methylenedioxymethamphetamine. In embodiments, the compound of Formula (IIb) is racemic. In embodiments, the present disclosure provides: 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; R1 is a protecting group, R2 is a protecting group or R1 and R2 together with the atoms to which they are attached form a 5-membered heterocycle;ii) reacting the organometallic reagent of step i) with a compound of Formula (II): wherein R3 is alkyl; andiii) converting the product of step ii) to (S)-3,4-methylenedioxymethamphetamine. In some embodiments, the present disclosure provides: 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; R1 is a protecting group, R2 is a protecting group or R1 and R2 together with the atoms to which they are attached form a 5-membered heterocycle;ii) reacting the organometallic reagent of step i) with a compound of Formula (IIa): wherein R3 is alkyl; andiii) converting the product of step ii) to (R)-3,4-methylenedioxymethamphetamine. In some embodiments, X is preferably bromine. In some embodiments, the process provides 3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in as a racemate. In some embodiments, the process provides (S)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in an enantiomeric excess of a least 99.5%. In some embodiments, the process provides (R)-3,4-methylenedioxymethamphetamine, or a pharmaceutically acceptable salt in an enantiomeric excess of a least 99.5%. DETAILED DESCRIPTION Definitions For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such