WO2022232949A1

WO2022232949A1 - Processes for the preparation of the enantiomers of 3,4-methylenedioxymethamphetamine (mdma) and n-methyl-1,3-benzodioxolylbutanamine (mbdb)

Info

Publication number: WO2022232949A1
Application number: PCT/CA2022/050720
Authority: WO
Inventors: Tao Xin
Original assignee: Pharmala Biotech Inc.
Priority date: 2021-05-06
Filing date: 2022-05-06
Publication date: 2022-11-10

Abstract

The present application includes a process for preparing the (R)- or (S)- enantiomers of 3,4-methylenedioxymethamphetamine ((R)-MDMA or (S)-MDMA) and (R)- or (S)-N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB or (S)-MBDB) using (R)- tert-butanesulfinamide or (S)-tert-butanesulfinamideas a chiral auxiliary. (I) The present application also includes novel intermediate compounds useful in the preparation of (R/S)-MDMA and (R/S)-MBDB.

Description

TITLE: PROCESSES FOR THE PREPARATION OF THE ENANTIOMERS OF 3,4- METHYLENEDIOXYMETHAMPHETAMINE (MDMA) AND N-METHYL-1,3- BENZODIOXOLYLBUTANAMINE (MBDB)

RELATED APPLICATIONS

[0001] The present application claims the benefit of priority of co-pending United

States provisional patent application no. 63/201 ,610 filed on May 6, 2021 , co-pending United States provisional patent application no. 63/203,101 filed on July 8, 2021 and co pending United States provisional patent application no. 63/298,799 filed on January 12, 2022, the contents of each of which are incorporated herein by reference in their entirety.

FIELD

[0002] The present application is related to processes for preparing (R)- or (S)-

3, 4-methylenedioxymethamphetamine ((R)-MDMA/(S)-MDMA) and (R)- or (S)-N-methyl- 1 ,3-benzodioxolylbutanamine ((R)-MBDB/(S)-MBDB). In particular, the process uses (R)- tert-butanesulfinamide or (S)-tert-butanesulfinamide as a chiral auxiliary. The present application also relates to compounds useful in the preparation of the enantiomers of MDMA and MBDB.

BACKGROUND

[0003] 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (E) or molly, is a psychoactive drug first developed in 1912 by Merck. MDMA is often used recreationally today. However, an initial use of MDMA was as an adjunct to psychotherapy. More recently, MDMA has been studied in various clinical trials, for example, investigating MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD), anxiety related to advanced-stage illness, and social anxiety in autistic adults. MDMA has now been grated Breakthrough Therapy Designation to MDMA for the treatment of PTSD by the United States Food and Drug Administration (FDA).

[0004] MDMA is generally available and consumed as a racemate. However, each enantiomer has been shown to provide different pharmacological and pharmacokinetic profiles. In fact, evidence suggests that R (-)-MDMA may provide an improved therapeutic index maintaining the therapeutic effects of (±)-MDMA with a reduced side effect profile (Pitts et al. Psychopharmacology 235, 377-392, 2018).

[0005] There are many methods available to synthesize MDMA including several methods to synthesize enantiopure MDMA using, for example, chiral salts, chiral synthesis, or using chiral auxiliaries [e.g. Dunlap et al (2018), ACS Chem Neurosci; 9(10): 2408-2427; Llabres et al (2014), European J. of Med. Chem. 81 (2014) 35-46; Huot et al (2011), J Neurosci. (2011) May 11 ; 31(19): 7190-7198] Llabres et al. discloses a synthesis of both enantiomers of MDMA using t-butylsulfinamide [Llabres et al (2014), European Journal of Medicinal Chemistry 81 (2014) 35-46] [0006] N-methyl-1 ,3-benzodioxolylbutanamine (MBDB) commonly known as

Eden or Methyl-J, is an analogue of MDMA which has an ethyl group instead of a methyl group attached to the alpha carbon next to the amine. Like MDMA, MBDB is also classified as an entactogen.

SUMMARY [0007] The present application includes processes for preparing the (R)- or (S)- enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and (N-methyl-1 ,3- benzodioxolylbutanamine (MBDB) using (R)-tert-butanesulfinamide or (S)-tert- butanesulfinamide as a chiral auxiliary. In some embodiments, the application includes a process for preparing the enantiomers of MDMA and MBDB through the reduction of an imide intermediate derived from using tert-butanesulfinamide.

[0008] Accordingly, the present application includes a process for preparing an acid salt of a compound of Formula (R)-l or (S)-l:

wherein R¹ is selected from CH₃ and CH₂CH₃; the process comprising: reacting a compound of Formula B:

wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butylS(0)NH₂ or (S)- )-t-butylS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is selected from CH₃ and CH₂CH₃; or homologating piperonal, _{<°t °} , to provide a compound of Formula B':

reacting the compound of Formula B' with (S)-t-butylS(0)NH₂ or (R)-t- butylS(0)NH₂ to provide a compound of Formula (S)-C^im or(R)-C^im respectively:

reacting the compound of Formula (S)-C^im or (R)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (R),(S)-C" or (S),(R)-C", respectively:

wherein R¹ is CH₃or CH₂CH₃; methylating the compound of Formula (R),(R)-C or (S),(S)-C to provide a compound of Formula (R),(R)-D or a compound of Formula (S),(S)-D, respectively:

methylating the compound of Formula (R),(S)-C" or (S),(R)-C" to provide a compound of Formula (R),(S)-D' or a compound of Formula (S),(R)-D', respectively:

wherein R¹ is CH₃or CH₂CH₃; and reacting the compound of Formula (R),(R)-D or the compound of Formula (S),(S)- D with an acid to provide the acid salt of the compound of Formula (R)-l, or reacting the compound of Formula (R),(S)-D' or the compound of Formula (S),(R)-D' with an acid to provide the acid salt of the compound of Formula (S)-l. [0009] The present application also includes a compound of Formula (R)-C:

wherein R¹ is CH_30rCH₂CH₃.

[0010] The present application also includes a compound of Formula (S)-C':

wherein R¹ is CH_30rCH₂CH₃.

[0011] The present application also includes a compound of Formula (R),(R)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃.

[0012] The present application also includes a compound of Formula (S),(S)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃

[0013] The present application includes a compound of Formula (S)-C^im:

[0014] The present application also includes a compound of Formula (R)-C^im:

[0015] The present application includes a compound of Formula (R),(S)-C":

wherein R¹ is Chl3or CH2CH3.

[0016] The present application also includes a compound of Formula (S),(R)-C":

wherein R¹ is selected from CH3 and CH₂CH3.

[0017] The present application also includes a compound of Formula (R),(R)-D:

wherein R¹ is CH₃or CH₂CH₃.

[0018] The present application also includes a compound of Formula (S),(S)-D:

wherein R¹ is CH₃or CH₂CH₃. [0019] The present application also includes a compound of Formula (R),(S)-D':

wherein R¹ is CH₃or CH₂CH₃.

[0020] The present application also includes a compound of Formula (S),(R)-D':

wherein R¹ is CH₃or CFhCFh. [0021] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole.

DETAILED DESCRIPTION I. Definitions

[0022] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0023] The term “process of the application” and the like as used herein refers to a process of preparing (R)- or (S)-MDMA or (R)- or (S)-MBDB, or an acid salts thereof, as described herein. [0024] The term “and/or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of or “one or more” of the listed items is used or present. The term “and/or” with respect to pharmaceutically acceptable salts and/or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a solvate of a salt of a compound of the application.

[0025] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a solvent” should be understood to present certain aspects with one solvent, or two or more additional solvents. [0026] In embodiments comprising an “additional” or “second” component, such as an additional or second solvent, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0027] As used in this application and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0028] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and/or steps.

[0029] The term “consisting essentially of, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and/or steps.

[0030] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions to provide the product shown. A person skilled in the art would understand that, unless otherwise indicated, all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0031] The terms "about", “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word. [0032] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0033] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term Ci_₆alkyl means an alkyl group having 1 , 2, 3, 4, 5 or 6 carbon atoms.

[0034] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0035] The term “MDMA” as used herein refers to a compound having the chemical name: 1-(1 ,3-benzodioxol-5-yl)-N-methylpropan-2-amine or 3,4- methylenedioxymethamphetamine, and having the chemical formula:

[0036] The term “(R)-MDMA” as used herein refers to a compound having the chemical name: (2R)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine or (R)-3,4- methylenedioxymethamphetamine, and having the chemical formula:

[0037] The term “(S)-MDMA” as used herein refers to a compound having the chemical name: (2S)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine, or (S)-3,4- methylenedioxymethamphetamine, and having the chemical formula:

[0038] The term “MBDB” as used herein refers to a compound having the chemical name: 1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine or N-methyl-1 ,3- benzodioxolylbutanamine, and having the chemical formula:

[0039] The term “(R)-MBDB” as used herein refers to a compound having the chemical name: (2R)-1-(1 ,3-benzodioxol-5-yl)-N-methylbutan-2-amine or (R)-N-methyl- 1 ,3-benzodioxolylbutanamine, and having the chemical formula:

[0040] The term “(S)-MBDB” as used herein refers to a compound having the chemical name: (2S)-1-(1 ,3-benzodioxol-5-yl)-N-methylbutan-2-amine or (S)-N-methyl- 1 ,3-benzodioxolylbutanamine, and having the chemical formula:

[0041] The term “(R)-t-butyiS(0)NH₂” or “(R)-tert-butanesulfinamide” as used herein to a compound having the chemical name (R)-(+)-2-methyl-2-propanesulfinamide, and having the chemical formula:

[0042] The term “(S)-t-butyiS(0)NH₂” or “(S)-tert-butanesulfinamide” as used herein to a compound having the chemical name (S)-(+)-2-methyl-2-propanesulfinamide, and having the chemical formula:

[0043] The term “reducing agent” as used herein means any compound or combination of compounds that reduces a desired functional group. A reducing agent results in the overall addition of electrons, or in the case of organic chemistry, hydrogen atoms to the functional group.

[0044] The term “inert solvent” as used herein means a solvent that does not interfere with or otherwise inhibit a reaction. Accordingly, the identity of the inert solvent will vary depending on the reaction being performed. The selection of inert solvent is within the skill of a person in the art. [0045] The term “solvent” includes both a single solvent and a mixture comprising two or more solvents. [0046] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3^rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0047] The term “major isomer” as used herein refers to a stereochemical isomer, including a regional isomer, that is the most abundant isomer in a mixture of isomers of the same compound. Conversely, the term “minor isomer” as used herein refers to a stereochemical isomer, including a regional isomer, that is not the most abundant isomer in a mixture of isomers of the same compound.

[0048] The term “enantiomeric excess” or “ee” is the absolute difference between the mole fraction of each enantiomer for a racemic compound.

[0049] In the processes of the application, when compounds, including starting materials and products, are referred to as single isomers, e.g. R- or S-isomers, this means that the single isomer comprises less than 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% by weight of the alternate isomer based on the total amount of R- and S-isomers.

[0050] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

II. Processes of the Application

[0051] The present application includes a process for preparing (R)- or (S)-3,4- methylenedioxymethamphetamine (R-MDMA or S-MDMA) or (R)- or (S)-N-methyM ,3- benzodioxolylbutanamine (R-MBDB or S-MBDB) using (R)-tert-butanesulfinamide or (S)- tert-butanesulfinamide as a chiral auxiliary. In particular, the application includes a process for preparing (R)- or (S)-3, 4-methylenedioxymethamphetamine (R-MDMA or S- MDMA) or (R)- or (S)-N-methyM ,3-benzodioxolylbutanamine (R-MBDB or S-MBDB) through the reduction of an imide intermediate derived from using tert-butanesulfinamide. [0052] Accordingly, the present application includes a process for preparing an acid salt of a compound of Formula (R)-l or (S)-l:

B wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butylS(0)NH₂ or (S)- )-t-butylS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is selected from CH₃ and CH₂CH₃; or homologating piperonal,

, to provide a compound of Formula B':

wherein R¹ is CH₃or CH₂CH₃; and reacting the compound of Formula (R),(R)-D or the compound of Formula (S),(S)-

D with an acid to provide the acid salt of the compound of Formula (R)-l, or reacting the compound of Formula (R),(S)-D' or the compound of Formula (S),(R)-D' with an acid to provide the acid salt of the compound of Formula (S)-l.

[0053] Therefore the present application also includes a process for preparing an acid salt of a compound of Formula (R)-l

wherein R¹ is selected from CH₃ and CH2CH3; the process comprising: reacting a compound of Formula B

B wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butylS(0)NH₂ under reductive amination conditions to provide a compound of (R),(R)-Formula C

wherein R¹ is selected from CH₃ and CH₂CH₃; or homologating piperonal,

, to provide a compound of Formula B'

reacting the compound of Formula B' with (S)-t-butylS(0)NH₂ to provide a compound of Formula (S)-C^im;

reacting the compound of Formula (S)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (R),(S)-C"

wherein R¹ is CH₃or CH₂CH₃; methylating the compound of Formula (R),(R)-C or the compound of Formula

(R),(S)-C" to provide a compound of Formula (R),(R)-D or a compound of Formula (R),(S)-D, respectively

wherein R¹ in the compound of Formula (R),(R)-D and in the compound of Formula (R),(S)-D is CH₃or CH₂CH₃; and reacting the compound of Formula (R),(R)-D or the compound of Formula (R),(S)- D with an acid to provide an acid salt of the compound of Formula (R)-l.

[0054] The present application also includes a process for preparing an acid salt of a compound of Formula (S)-l

B wherein R¹ is selected from CH₃ and CH₂CH₃; with (S)-t-butylS(0)NH₂ under reductive amination conditions to provide a compound of Formula (S),(S)-C

wherein R¹ is selected from CH₃ and CH₂CH₃; or homologating piperonal,

, to provide a compound of Formula B'

reacting the compound of Formula B' with (R)-t-butylS(0)NH₂ to provide a compound of Formula (R)-C^im;

reacting the compound of Formula (R)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (S),(R)-C"

wherein R¹ is CH₃or CH₂CH₃; methylating the compound of Formula (S),(S)-C or the compound of Formula (S),(R)-C" to provide a compound of Formula (S),(S)-D ora compound of Formula (S),(R)- D', respectively

wherein R¹ in the compound of Formula (S),(S)-D and in the compound of Formula (S),(R)-D' is CH₃ or CH₂CH₃; and reacting the compound of Formula (S),(S)-D or the compound of Formula (S),(R)- D' with an acid to provide an acid salt of the compound of Formula (S)-l. [0055] In some embodiments, the present application includes a process for preparing an acid salt of a compound of Formula (R)-l or (S)-l:

B wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butyiS(0)NH₂ or (S)-t-butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (R),(R)-C or (S),(S)-C to provide a compound of Formula (R),(R)-D or (S),(S)-D, respectively:

wherein R¹ is CH₃or CH₂CH₃; and reacting the compound of Formula (R),(R)-D or (S),(S)-D -with an acid to provide an acid salt of the compound of Formula (R)-l or (S)-l, respectively.

[0056] In some embodiments, the compound of Formula B is either commercially available or may be prepared using methods known in the art. For example, in some embodiments, the compound of Formula B wherein R¹ is CH₂CH_3,

j_S available from Sigma Aldrich (St. Louis, Missouri, USA).

[0057] In some embodiments, R¹ is CH₃ and the compound of Formula B is

. in some embodiments, the compound of Formula B wherein R¹ is CH₃ is prepared by a process comprising oxidizing a compound of Formula A or a compound of Formula A':

wherein indicates that the bond is in a cis and/or trans orientation to provide a compound of Formula B:

wherein R¹ is CH₃. [0058] The compound of Formula (R)-l wherein R¹ is CH₃ is (R)-3,4- methylenedioxymethamphetamine ((R)-MDMA). The compound of Formula (S)-l wherein R¹ is CH₃ is (S)-3, 4-methylenedioxymethamphetamine ((S)-MDMA). Accordingly, when R¹ is CH_3, the present application also includes a process for preparing an acid salt of (R)- 3, 4-methylenedioxymethamphetamine ((R)-MDMA) or an acid salt of (S)-3,4- methylenedioxymethamphetamine ((S)-MDMA):

the process comprising: oxidizing a compound of Formula A or a compound of Formula A':

wherein -« indicates that the bond is in a cis and/or trans orientation to provide a compound of Formula B:

wherein R¹ is CH₃; reacting the compound of Formula B with (R)-t-butylS(0)NH₂ or (S) (R)-t- butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is CH₃; methylating the compound of Formula (R),(R)-C or (S),(S)-C to provide a compound of Formula (R),(R)-D or (S),(S)-D, respectively:

wherein R¹ is CH₃; and reacting the compound of Formula (R),(R)-D or (S),(S)-D with an acid to provide the acid salt of (R)-MDMA or (S)-MDMA, respectively.

[0059] The compound of Formula (R)-l when R¹ is CH2CH3 is (R)-N-methyl-1 ,3- benzodioxolylbutanamine ((R)-MBDB). The compound of Formula (S)-l when R¹ is CH2CH3 is (S)-N-methyM ,3-benzodioxolylbutanamine ((S)-MBDB). Accordingly, when R¹ is CH₂CH_3, the present application includes a process for preparing an acid salt of (R)-N- methyl-1 ,3-benzodioxolylbutanamine ((R)-MBDB) or (S)-N-methyl-l ,3- benzodioxolylbutanamine ((S)-MBDB):

the process comprising: reacting a compound of Formula B:

B wherein R¹ is CH₂CH₃; with (R)-t-butyiS(0)NH₂ or (S) (R)-t-butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C. respectively:

wherein R¹ is CH₂CH₃; methylating the compound of Formula (R),(R)-C or (S),(S)-C to provide a compound of Formula (R),(R)-D or (S),(S)-D, respectively:

wherein R¹ is CH₂CH₃; and reacting the compound of Formula (R),(R)-D or (S),(S)-D with an acid to provide the acid salt of (R)-MBDB or the acid salt of (S)-MBDB, respectively.

[0060] The present application also includes a process for preparing an acid salt of a compound of Formula (R)-l or (S)-l:

wherein R¹ is selected from CFh and CFhCFh; the process comprising:

reacting the compound of Formula B' with (S)-t-butyiS(0)NH₂ or (R)-t- butyiS(0)NH₂ to provide a compound of Formula (S)-C^im or (R)-C^im, respectively:

reacting the compound of Formula (S)-C^im or (R)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (R),(S)-C" or (S)(R)-C", respectively:

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (R),(S)-C" or (S)(R)-C" to provide a compound of Formula (R),(S)-D' or (S),(R)-D', respectively:

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (R),(S)-D', with an acid to provide the acid salt of a compound of Formula (R)-l or reacting the compound of Formula (S),(R)-D', with an acid to provide the acid salt of a compound of Formula (S)-l. [0061] In some embodiments, R¹ is CH_3, and the compound of Formula I is (R)-

3, 4-methylenedioxymethamphetamine ((R)-MDMA). Accordingly, the present application includes a process for preparing an acid salt of (R)-3,4- methylenedioxymethamphetamine ((R)-MDMA)

the process comprising: homologating piperonal,

, to provide a compound of Formula (B')

reacting the compound of Formula B' with (S)-t-butylS(0)NH₂ to provide a compound of Formula S-C^im:

reacting the compound of Formula (S)-C^im with a methyl organometallic reagent to provide the compound of (R),(S)-C":

wherein R¹ is CH₃; methylating the compound of Formula (R),(S)-C" to provide a compound of

Formula (R),(S)-D':

wherein R¹ is CH₃; and reacting the compound of Formula (R),(S)-D', with an acid to provide the acid salt of (R)-MDMA.

[0062] In some embodiments, R¹ is CH₂CH₃ and the compound of Formula I is

(R)-N-methyl-1 ,3-benzodioxolylbutanamine ((R)-MBDB). Accordingly, when R¹ is CH₂CH_3, the present application includes a process for preparing an acid salt of (R)-N- methyl-1 ,3-benzodioxolylbutanamine ((R)-MBDB):

the process comprising:

< 1 j ⁰ homologating piperonal, , to provide a compound of Formula B':

reacting the compound of Formula B' with (S)-t-butylS(0)NH₂ to provide a compound of Formula (S)-C^im:

reacting the compound of Formula (S)-C^im with an ethyl organometallic reagent to provide the compound of (R),(S)-C":

wherein R¹ is CH₂CH₃; methylating the compound of Formula (R),(S)-C" to provide a compound of Formula (R),(S)-D'

wherein R¹ is CH₂CH₃; and reacting the compound of Formula (R),(S)-D' with an acid to provide the acid salt of (R)-MBDB.

[0063] In some embodiments, the compound of Formula A is known as safrole.

In some embodiments, the compound of Formula A is either commercially available or may be prepared using methods known in the art. For example, the compound of Formula A (safrole) is available from Sigma Aldrich (St. Louis, Missouri, USA).

[0064] In some embodiments, the compound of Formula A is oxidized to provide a compound of Formula B using any suitable conditions for oxidizing the compound of Formula A to provide the compound of Formula B known in the art, for example, using the synthetic procedures found in Advanced Synthesis & Catalysis 361(11) p2582-2593, 2019 or Forensic Science International, 248, 140-147; 2015.

[0065] In some embodiments, the compound of Formula A is oxidized to provide a compound of Formula B using Wacker oxidation or Wacker-Tsuji oxidation conditions. In some embodiments, the compound of Formula A is oxidized to provide a compound of Formula B in the presence of a palladium (II) catalyst and water or an iron (III) catalyst and water, or a combination thereof at temperatures and at times to provide the compound of Formula B. In some embodiments, the palladium (II) catalyst is selected from palladium chloride (PdCI₂) or palladium (II) trifluoroacetate ((CF₃C0₂)₂Pd). In some embodiments, the iron (III) catalyst is iron (III) chloride (FeCI₃). In some embodiments, the suitable conditions further comprise a co-oxidant. In some embodiments, the co-oxidant is benzoquinone. In some embodiments, the oxidation conditions further comprise a co solvent. In some embodiments, the co-solvent is selected from dimethylformamide, acetonitrile and methanol, and combinations thereof. As representative, non-limiting examples, the temperature for oxidizing the compound of Formula A to provide the compound of Formula B is about 10 °C, about 20 °C, about 30 °C, about 40 °C, about 50 °C, about 60 °C or about 70 °C.

[0066] In some embodiments, the compound of Formula A is oxidized to provide a compound of Formula B in the presence of an excess amount (for example about 2% to 5% molar equivalents, or a 2.5% molar equivalent) of a palladium (II) catalyst, an excess amount (for example about 1 to 3 molar equivalent, or 1.5 molar equivalent) of an iron (III) catalyst and water at temperatures and at times to provide the compound of Formula B. In some embodiments, the palladium (II) catalyst is palladium (II) trifluoroacetate ((CF₃C0₂)₂Pd) and the iron (III) catalyst is iron chloride (FeCI₃). In some embodiments, the suitable conditions further comprise using acetonitrile as the co solvent. As representative, non-limiting examples, the temperature for oxidizing the compound of Formula A in the presence of a palladium (II) catalyst, and an iron (III) catalyst to provide the compound of Formula B is about 40 °C, about 50 °C, or about 60 °C and representative, non-limiting example of reaction time, is about 4 hour to about 24 hours, about 8 hours to about 18 hours, about 12 hours to about 18 hours, about 14 hours to about 18 hours or about 16 hours.

[0067] In some embodiments, the compound of Formula A is oxidized to provide a compound of Formula B in the presence of a catalytic amount (for example about 1 to about 15 mole percent) of a palladium (II) catalyst, an excess amount (for example, about 1.1 to about 5 molar equivalents) of a co-oxidant and water at temperatures and at times to provide the compound of Formula B. In some embodiments, the palladium (II) catalyst is palladium (II) chloride (PdCI₂) and the co-oxidant is benzoquinone. In some embodiments, the suitable conditions further comprise using methanol as the co-solvent. As representative, non-limiting examples, the temperature for oxidizing the compound of Formula A in the presence of a palladium (II) catalyst and a co-oxidant to provide the compound of Formula B is about 10 °C, about 10 °C, about 20 °C, or about 30 °C, and representative, non-limiting example of reaction time, is about 1 hour to about 5 hours, about 1 hours to about 4 hours, about 2 hours to about 4 hours, or about 3 hours.

[0068] In some embodiments, the compound of Formula A' is known as isosafrole. In some embodiments, the compound of Formula A' is either commercially available or may be prepared using methods known in the art. For example, the compound of Formula A' (isosafrole) is available from Sigma Aldrich (St. Louis, Missouri, USA).

[0069] In some embodiments, the compound of Formula A' is a mixture of cis and trans isomers. [0070] In some embodiments, the compound of Formula A' is prepared by isomerizing the compound of Formula A. Therefore, alternatively, in some embodiments, the process comprises isomerizing the compound of Formula A:

to provide a compound of Formula A':

wherein indicates that the bond is in a cis and/or trans orientation; and oxidizing the compound of Formula A' to provide a compound of Formula B:

wherein R¹ is CH₃.

[0071] In some embodiments, the compound of Formula A is isomerized to provide a compound of Formula A' using any suitable conditions for isomerizing the compound of Formula A to provide the compound of Formula A' known in the art, for example, using the synthetic procedures found in Forensic Science International 155 (2005) 141-157. [0072] In some embodiments, the step of isomerizing a compound of Formula A to provide a compound of Formula A' comprises reacting the compound of Formula A in the presence of a base and an inert solvent at a temperature and for a time to provide the compound of Formula A'. In some embodiments, the base is potassium tert-butoxide, sodium hydroxide or potassium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the inert solvent is DMSO. In some embodiments, the step of isomerizing a Formula A to provide a compound of Formula A' is in the presence of potassium tert-butoxide in DMSO at a temperature and for a time to provide the compound of Formula A'. As representative, non-limiting example of temperature and reaction times for the step of isomerizing a Formula A to provide a compound of Formula B in the presence of a base in an insert solvent, the temperature is maintained at boiling point of the solvent (reflux) for about 1 hour to about 6 hours, about 2 hours to about 5 hours, about 3 hours to about 5 hours, or about 4 hours to provide the compound of Formula B.

[0073] In some embodiments, the step of isomerizing a compound of Formula A to provide a compound of Formula A' comprises reacting the compound of Formula A in the presence of a base and a phase transfer catalyst at a temperature and for a time to provide the compound of Formula A'. In some embodiments, the phase transfer catalyst is an ionic liquid. In some embodiments, the phase transfer catalyst is aliquot 336 (Stark’s catalyst). In some embodiments, the step of isomerizing a Formula A to provide a compound of Formula A' comprises reacting the compound of Formula A in the presence of a potassium hydroxide and aliquot 336 at a temperature and for a time to provide the compound of Formula A'. In some embodiments, the compound of Formula A, the base and the phase transfer catalyst are combined at room temperature and are agitated for about 15 minutes to about 30 minutes, or about 20 minutes, followed by heating to a temperature of about 50°C to about 90°C, about 60°C to about 90°C, or about 80°C for about 30 minutes to about 2 hours, about 45 minutes to about 90 minutes, about 60 minutes to about 90 minutes or about 75 minutes to provide the compound of Formula A'.

[0074] In some embodiments, the compound of Formula A' is oxidized to provide a compound of Formula B using any suitable conditions for oxidizing the compound of Formula A' to provide the compound of Formula B known in the art, for example, using the synthetic procedures found in Forensic Science International 155 (2005) 141-157.

[0075] In some embodiments, the compound of Formula A' is oxidized to provide a compound of Formula B in the presence of hydrogen peroxide and formic acid in water at a time and a temperature to provide the compound of Formula B. In some embodiments, the step of oxidizing a compound of Formula A' to provide a compound of Formula B further comprises an inert solvent. In some embodiments, the inert solvent is acetone. In some embodiments, the hydrogen peroxide and formic acid in water is added, for example, dropwise to a solution of the compound of Formula B in an inert solvent to provide a reaction mixture which is maintained with cooling at a temperature of from about 18 °C to about 45 °C, about 25°C to about 40 °C, or about 30 °C to about 40 °C. In some embodiments, after the addition of the hydrogen peroxide and formic acid in water, the reaction mixture is maintained at room temperature (e.g., about 18 °C to about 25 °C) for about 14 to about 20hours, or about 16 hours. In some embodiments, the reaction mixture is concentrated and then dissolved in a solvent and treated with an acid for a time and at a temperature to provide the compound of Formula B. In some embodiments, the solvent is methanol or ethanol. In some embodiments, the solvent is methanol. In some embodiments, the acid is sulfuric acid. As representative, non-limiting example of temperature and reaction times, the reaction is heated to about 30 °C to about 80°C, about 30 °C to about 60 °C, or about 40 °C to about 60 °C for about 1 hour to about 6 hours, about 2 hours to about 4 hours or about 3 hours.

[0076] In some embodiments, the (R)-t-butylS(0)NH₂ has an enantiomeric purity of about 97% or greater or of about 98% or greater. In some embodiments, the (R)-t- butyiS(0)NH₂ has an enantiomeric purity of about 97% to about 99.9%, about 97% to about 99.8%, about 97% to about 99.5%, about 97% to about 99%, about 97% to about 98%, about 98% to about 99.8%, about 98% to about 99.5%, or about 98% to about 99%. In some embodiments, the (R)-t-butyiS(0)NH₂ having an enantiomeric purity of about 97% or greater or of about 98% or greater is either commercially available or may be prepared using methods known in the art. For example, (R)-t-butyiS(0)NH₂with a purity of about 98% or greater is available from Sigma Aldrich (St. Louis, Missouri, USA) or Fischer Scientific (Waltham, Massachusetts, USA).

[0077] In some embodiments, the (S)-t-butyiS(0)NH₂ has an enantiomeric purity of about 97% or greater. In some embodiments, the (S) -t-butyiS(0)NH₂ has an enantiomeric purity of about 97% to about 99.9%, about 97% to about 99.8%, about 97% to about 99.5%, about 97% to about 99%, about 97% to about 98%, or about 98% to about 99%. In some embodiments, the (S)-t-butyiS(0)NH₂ having an enantiomeric purity of about 97% or greater is either commercially available or may be prepared using methods known in the art. For example, (S)-t-butyiS(0)NH₂with a purity of about 97% or greater is available from Sigma Aldrich (St. Louis, Missouri, USA). [0078] In some embodiments, the compound of Formula B is reacted with (R)-t- butyiS(0)NH₂ or (S)-t-butylS(0)NH₂ under any suitable reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively, for example, using the synthetic procedures found in Llabres et al (2014), European Journal of Medicinal Chemistry 81 (2014) 35-46.

[0079] In some embodiments, the suitable reductive amination conditions comprise a first step of reacting a compound of Formula B with (R)-t-butylS(0)NH₂ or (S)- t-butyiS(0)NH₂ in the presence of a titanium catalyst followed by a second step of adding a suitable reducing agent to provide the compound of Formula (R),(R)-C or (S),(S)-C. In some embodiments, the suitable reductive amination conditions comprise a first step of reacting a compound of Formula B with (R)-t-butylS(0)NH₂ or (S)-t-butylS(0)NH₂ in the presence of a titanium catalyst to provide a compound of Formula C:

wherein R¹ is selected from CH₃ and CH₂CH₃; followed by a second step of adding a suitable reducing agent to provide the compound of Formula (R),(R)-C or (S),(S)-C.

[0080] In some embodiments, the suitable reductive amination conditions comprise a first step of reacting a compound of Formula B with an excess amount (for example, about 1.1 to about 2 molar equivalents) of (R)-t-butylS(0)NH₂ or (S)-t- butyiS(0)NH₂ in the presence of an excess amount (for example, about 1.1 to about 10 equivalents) of a titanium catalyst in a solvent at a temperature and a time to react the compound of Formula B with (R)-t-butylS(0)NH₂ or (S)-t-butylS(0)NH₂ to provide a compound of Formula C, followed by a second step of adding a suitable reducing agent to the compound of Formula C to provide the compound of Formula (R),(R)-C or (S),(S)- C. In some embodiments, the compound of Formula C is not isolated. As representative, non-limiting example of temperature and reaction times, the reaction of the compound of Formula B with the titanium catalyst is maintained at boiling point of the solvent (reflux) for about 1 hour to about 8 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, or about 5 hours to provide the compound of Formula C, and then cooled to about -25 °C to about 15 °C, or about -20°C before the second step of adding a suitable reducing agent to provide the compounds of Formula (R),(R)-C or (S),(S)-C. In some embodiments, the reduction reaction to provide the compound of Formula (R),(R)-C or (S),(S)-C is maintained at about -25 °C to about -15 °C, or about -20°C for about 1 hour to about 4 hours or about 2 to about 3 hours or about 3 hours and then at room temperature (e.g., about 18 °C to 25 °C) for about 8 to about 12 hours.

[0081] In some embodiments, the first and second step of the reduction amination of the compound of Formula B to provide the compound of Formula (R),(R)-C or (S),(S)- C occur sequentially in one reaction vessel (one pot). In some embodiments, the compound of Formula C, is isolated before proceeding with the second step.

[0082] Accordingly, in some embodiments, the suitable reductive amination conditions comprise reacting the compound of Formula B with (R)-t-butylS(0)NH₂or (S)- t-butylS(0)NH₂ to provide a compound of Formula C, and

wherein R¹ is selected from CH₃ and CH₂CH₃; reducing the compound of Formula C with a reducing agent to provide a compound of Formula (R),(R)-C or (S),(S)-C.

[0083] In some embodiments, the titanium catalyst is selected from titanium (IV) isopropoxide (Ti(OiPr)4) and titanium (IV) ethoxide (Ti(OEt)4). In some embodiments, the titanium catalyst is titanium (IV) ethoxide (Ti(OEt) In some embodiments, the inert solvent is tetrahydrofuran, toluene or xylene. In some embodiments, the inert solvent is tetrahydrofuran.

[0084] In some embodiments, the suitable reducing agent to provide the compound of Formula (R),(R)-C or (S),(S)-C is any suitable reducing agent that reduces the fe/f-butanesulfinyl imine compound of Formula C to provide a compound of Formula (R),(R)-C or (S),(S)-C. In some embodiments, the suitable reducing agent is sodium borohydride.

[0085] In some embodiments, piperonal is either commercially available or may be prepared using methods known in the art. For example, piperonal is available from Sigma Aldrich (St. Louis, Missouri, USA).

[0086] In some embodiments, piperonal is homologated to provide a compound of Formula B' using any suitable conditions for homologating piperonal to provide a compound of Formula B' known in the art, for example, using the synthetic procedures found in Tetrahedron: Asymmetry, 27(6), 274-284; 2016.

[0087] In some embodiments, the step of homologating piperonal to provide a compound of Formula (B') is with the Wittig reagent methoxymethylenetriphenylphosphine under Wittig reaction conditions. Accordingly, in some embodiments, the process comprises homologating piperonal with methoxymethylenetriphenylphosphine under Wittig reaction conditions to provide a compound of Formula (B').

[0088] In some embodiments, the methoxymethylenetriphenylphosphine is generated in situ, for example, by the deprotonation of, for example, methoxymethyl(triphenyl)phosphonium chloride with a suitable base. Accordingly, in some embodiments, the Wittig reaction conditions comprise combining methoxymethyl(triphenyl)phosphonium chloride with an excess amount (for example, about 1.1 to about 2 molar equivalents) of suitable base in an inert solvent at a temperature of about 0 °C to about 15°C, about 0 °C to about 10 °C, or about 0 °C to about 5 °C or about 0 °C and then stirring at about room temperature (e.g., about 18 °C to 25 °C) for about 15 minutes to about 1 hour, about 30 minutes to about 1 hour, about 30 minutes to about 45 minutes, or about 30 minutes, to provide the methoxymethylenetriphenylphosphine. In some embodiments, the suitable base is selected from alkyllithiums; alkoxides such as sodium methoxide or potassium tert- butoxide; dimsyl sodium; hydrides such as sodium hydride, amides; and amines such as triethylamine. In some embodiments, the suitable base is an alkoxide such as sodium methoxide or potassium tert-butoxide. In some embodiments, the suitable base potassium tert-butoxide. In some embodiments, the suitable inert solvent is THF or toluene.

[0089] In some embodiments, the Wittig reaction conditions further comprise reacting piperonal with the methoxymethylenetriphenylphosphine for a time and at temperature to provide a vinyl ether intermediate,

reacting the vinyl ether intermediate with a suitable acid for a time and at a temperature to provide the compound of Formula B'. [0090] As representative, non-limiting examples of temperature and reaction times to provide the vinyl ether intermediate, the piperonal is reacted with the methoxymethylenetriphenylphosphine at about room temperature (e.g., about 18 °C to 25 °C) for about 8 to about 20 hours, about 10 to about 16 hours, about 10 to about 14 hours or about 12 hours (e.g. overnight).

[0091] As representative, non-limiting examples of temperature and reaction times for reacting the vinyl ether intermediate with a suitable acid, the vinyl ether intermediate is reacted with a suitable acid at room temperature (e.g., about 18 °C to 25 °C) for about 24 hours about 72 hours, about 36 to about 60 hours, about 40 hours to about 50 hours, about 36 hours to about 72 hours, about 48 hours to about 72 hours, or about 72 hours. In some embodiments, the suitable acid is selected from hydrochloric acid and formic acid. In some embodiments, the suitable acid is formic acid.

[0092] In some embodiments, the compound of Formula B' is reacted with (S)-t- butyiS(0)NH₂ or (R)-t-butylS(0)NH₂ under any suitable conditions to provide a compound of Formula (S)-C^im or (R)-Ci^m, respectively, for example, using the synthetic procedures found in Angewandte Chemie, International Edition, 53(48), 13215-13219; 2014 and Wakefield, Bryan Hall (2008) Synthetic studies on (E)-alkene peptide isosteres and thiophene-containing furanosteroids [Ph.D Thesis, University of Pittsburgh]

[0093] In some embodiments, the compound of Formula B' is reacted with (S)-t- butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of a catalyst such as pyridinium p- toluenesulfonate (PPTS) or a titanium catalyst to provide the compound of Formula (S)- C^im or (R)-C^im. In some embodiments, the compound of Formula B' is reacted with (S)-t- butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of a catalyst such as pyridinium p- toluenesulfonate or a titanium catalyst in an inert solvent at a temperature and a time to provide the compound of Formula (S)-C^im or (R)-C^im . In some embodiments, the compound of Formula B' is reacted with (S)-t-butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of pyridinium p-toluenesulfonate in an inert solvent at a temperature and a time to provide the compound of Formula (S)-C^im or (R)-C^im . In some embodiment, the compound of Formula B' is reacted with (S)-t-butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of pyridinium p-toluenesulfonate and a dehydrating agent in an inert solvent at a temperature and a time to provide the compound of Formula (S)-C^im or (R)-C^im .

[0094] In some embodiments, the compound of Formula B' is reacted with a slight excess (for example, about 1.1 to about 1.5 molar equivalents) of (S)-t-butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of catalytic amounts (for example, 0.1 to 1 , or about 0.25 to about 0.75 molar equivalents) of pyridinium p-toluenesulfonate in the present of an excess amount (for example, about 7 to about 12 molar equivalents, or about 9 to about 11 molar equivalents) of a dehydrating agent in an inert solvent at a temperature and a time to provide the compound of Formula (S)-C^im or (R)-C^im . In some embodiments, the dehydrating reagent is magnesium sulfate. As representative, non-limiting example of temperature and reaction times, the reaction of the compound of Formula B' with (S)-t- butyiS(0)NH₂ or (R)-t-butylS(0)NH₂ in the presence of pyridinium p-toluenesulfonate and a dehydrating agent in an inert solvent at room temperature (e.g., about 18 °C to 25 °C) for about 36 hours to about 60 hours, about 40 to about 56 hours, about 45 to about 50 hours, about 48 hours to about 60 hours, or about 60 hours to provide the compounds of Formula (S)-C^im or (R)- C^im. In some embodiments, the inert solvent is methylene chloride.

[0095] In some embodiments, the compound of Formula B' is reacted with excess amount (for example, about 1.1 to about 2 molar equivalents) of (S)-t-butylS(0)NH₂ or (R)-t-butylS(0)NH₂ in the of an excess amount (for example, about 1.1 to about 10 molar equivalents) of a titanium catalyst in a solvent at a temperature and a time to react the compound of Formula B with (R)-t-butylS(0)NH₂ (R)-t-butylS(0)NH₂ to provide a compound of Formula (S)-C^im or (R)-C^im . As representative, non-limiting example of temperature and reaction times, the reaction of the compound of Formula B' with the titanium catalyst is maintained at boiling point of the solvent (reflux) for about 1 hour to about 8 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, or about 5 hours to provide the compound of Formula (S)-C^im or (R)-C^im .

[0096] In some embodiments, the titanium catalyst is selected from titanium (IV) isopropoxide (Ti(OiPr)4) and titanium (IV) ethoxide (Ti(OEt)4). In some embodiments, the titanium catalyst is titanium (IV) ethoxide (Ti(OEt) In some embodiments, the inert solvent is tetrahydrofuran, toluene or xylene. In some embodiments, the inert solvent is tetrahydrofuran.

[0097] In some embodiments, the conditions for providing the compound of formula (R),(S)-C" or (S),(R)-C" are any suitable conditions for reacting the compound of Formula (S)-C^im or (R)-C^im, respectively, with a methyl or ethyl organometallic reagent to provide a compound of Formula (R),(S)-C" or (S),(R)-C" known in the art, for example, using the synthetic procedures found Tetrahedron, 55(29), 8883-8904; 1999.

[0098] In some embodiments, the compound of Formula (S)-C^im or (R)-C^im is reacted with an excess amount (for example, about 1.1 to about 3, or about 2 molar equivalent) of the methyl or ethyl organometallic reagent in a suitable inert solvent for a time and a temperature to provide the compound of Formula (R),(S)-C" or (S),(R)-C" . In some embodiments, the suitable inert solvent is selected from methylene chloride, tetrahydrofuran, and diethyl ether. In some embodiments, the suitable inert solvent is methylene chloride.

[0099] In some embodiments, the methyl or ethyl organometallic reagents is a

Grignard reagent or methyl lithium or ethyllithium, respectively. In some embodiments, the methyl or ethyl organometallic reagents is a Grignard reagent. In some embodiments, the methyl or .ethyl organometallic reagent is methyl lithium or ethyllithium, respectively.

[00100] In some embodiments, the methyl or ethyl organometallic reagent is a Grignard reagent. In some embodiments, the methyl or ethyl Grignard reagent is Ch MgBr or CH₃CH₂MgBr, respectively. In some embodiments, the methyl or ethyl organometallic reagent is a Grignard reagent and the compound of Formula C^im is reacted with the methyl or ethyl Grignard reagent at a temperature of about -60 °C to about -20 °C, about -50 °C to about -30 °C , -50 °C to about -40 °C or about -50 °C for about 2 to about 6 hours, about 3 to about 5 hours, or about 4 hours and then at about room temperature (e.g., about 18 °C to 25 °C) for about 4 hours to about 18 hours, about 6 hours to about 16 hours, about 8 hours to about 14 hours, or about 12 hours (e.g., overnight) to provide the compound of Formula (R),(S)-C" or (S),(R)-C".

[00101] In some embodiments, the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" is methylated under any suitable methylation conditions to methylate the compound of Formula R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" provide the compound of Formula

(R),(R)-D or (S),(S)-D or the compound of Formula (R),(S)-D' or (S),(R)-D', respectively, known in the art, for example, using the synthetic procedures found in European Journal of Medicinal Chemistry, 81 , 35-46; 2014.

[00102] In some embodiments, the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" is methylated with a methyl halide in the presence of a base in an inert solvent at a temperature and a time to react the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or

(S),(R)-C" with the methyl halide to provide the compound of Formula R),(R)-D or (S),(S)- D or the compound of Formula (R),(S)-D' or (S),(R)-D'. In some embodiments, the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" is methylated with an excess amount (for example, about 1.1 to about 8, or about 6 molar equivalents) of a methyl halide such as methyl iodide (Mel) in the presence of an excess amount (for example, about 1.1 to about 2 equivalents) of a base such as sodium hydride in an inert solvent at a temperature and a time to react the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" with the methyl halide to provide the compound of Formula (R),(R)-D or (S),(S)-D or the compound of Formula (R),(S)-D' or (S),(R)-D'. In some embodiments, the inert solvent is dimethylformamide. As representative, non-limiting example of temperatures and reaction times, the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" is reacted with the base at about 0 °C to about 10 °C or 0 °C to about 5 °C and then at room temperature (e.g., about 18 °Cto 25 °C) for about 15 minutes to about 1 hours, about 20 minutes to about 45 minutes, or about 20 minutes to about 30 minutes to form a reaction mixture which is then cooled to at a temperature of about 0 °C to about 10 °C or 0 °C to about 5 °C and reacted with the methyl halide such as methyl iodide and then at about room temperature (e.g., about 18 °C to 25 °C) for about 4 hours to about 18 hours, about 6 hours to about 16 hours, about 8 hours to about 14 hours, or about 12 hours (e.g., overnight) to provide the compound of Formula (R),(R)-D or (S),(S)- D or the compound of Formula (R),(S)-D' or (S),(R)-D'.

[00103] In some embodiments, the compound of Formula (R),(R)-D or (S),(S)-D or the compound of Formula (R),(S)-D' or (S),(R)-D' is reacted with an acid under any suitable conditions to provide the acid salt of the compound of Formula (R)-l (i.e., (R)- MDMA and (R)-MBDB) or (S)-l (i.e., (S)-MDMA and (S)-MBDB), respectively, known in the art, for example, using the synthetic procedures found in European Journal of Medicinal Chemistry, 81 , 35-46; 2014.

[00104] In some embodiments, the compound of Formula (R),(R)-D or (S),(S)-D or the compound of Formula (R),(S)-D' or (S),(R)-D' is reacted with an excess amount (for example, about 1.1 to about 6 equivalents) of acid in a solvent at a temperature and a time to provide the acid salt of the compound of Formula (R)-l (i.e., (R)-MDMA and (R)- MBDB) or (S)-l (i.e., (S)-MDMA and (S)-MBDB)). In some embodiments, the solvent is water, methanol, dioxane, and mixtures thereof. In some embodiments, the solvent is methanol and dioxane. In some embodiments, the solvent is methanol. As representative, non-limiting examples of temperature and reaction times, the compound of Formula (R),(R)-D or (S),(S)-D or the compound of Formula (R),(S)-D' or (S),(R)-D' is combined with the acid at a temperature of about 0 °C to about 10 °C or 0 °C to about 5 °C and then at then (at about room temperature (e.g., about 18 °C to 25 °C) for about for about 1 hours to about 24 hours, about 3 hours to about 16 hours, about 4 hours to about 14 hours, about 6 hours to about 12 hours, about 8 hours to about 12 hours, or about 10 hours to about 12 hours(e.g overnight).

[00105] In some embodiments, the acid is sulfuric acid (H₂S0 ), trifluoroacetic acid (TFA) or hydrochloric acid (HCI). In some embodiments, the acid is HCI. Accordingly, in some embodiments the compound of Formula (R),(R)-D or (S),(S)-D or the compound of Formula (R),(S)-D' or (S),(R)-D' is reacted with HCI to provide an HCI salt of the compound of Formula (R)-l (i.e., (R)-MDMA.HCI and (R)-MBDB.HCI) or (S)-l (i.e., (S)- MDMA.HCI and (S)-MBDB).HCI). In some embodiments the compound of Formula

(R),(R)-D or (S),(S)-D wherein R¹ is CH₃ is reacted with HCI to provide an HCI salt of (R)- MDMA ((R)-MDMAHCI) or (S)-MDMA ((S)-MDMA.HCI). In some embodiments the compound of Formula (R),(R)-D or (S),(S)-D or compound of Formula (R),(S)-D' or

(S),(R)-D' wherein R¹ is CH₂CH₃ is reacted with HCI to provide an HCI salt of (R)-MBDB ((R)-MBDB HCI) or (S)-MBDB ((S)-MBDB.HCI).

[00106] In an exemplary embodiment, the present application includes a process for preparing an HCI salt of a compound of Formula (R)-l:

wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butyiS(0)NH₂ under reductive amination conditions in the presence of a titanium catalyst to provide a compound of Formula (R),(R)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (R),(R)-C to provide a compound of Formula (R),(R)-D:

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (R),(R)-D with hydrochloric acid to provide the

HCI salt of the compound of Formula (R)-l.

[00107] In an exemplary embodiment of the process of the application, the application includes a process for preparing an HCI salt of (R)-N-methyl-1 ,3- benzodioxolylbutanamine ((R)-MBDB):

wherein /v/v/vr indicates that the bond is in a cis and/or trans orientation, to provide a compound of Formula B:

wherein R¹ is CH₃; reacting the compound of Formula B with (R)-t-butylS(0)NH₂ under reductive amination conditions in the presence of a titanium catalyst to provide a compound of Formula (R),(R)-C:

wherein R¹ is CH₃; methylating the compound of Formula (R),(R)-C to provide a compound of Formula (R),(R)-D:

wherein R¹ is CH3; and reacting the compound of Formula (R),(R)-D with hydrochloric acid to provide (R)- MDMAHCI.

[00108] In an exemplary embodiment, the present application includes a process for preparing an HCI salt of (R)-N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB):

the process comprising: reacting the compound of Formula B with (R)-t-butyiS(0)NH₂ under reductive amination conditions in the presence of a titanium catalyst to provide a compound of Formula (R),(R)-C:

wherein R¹ is CH₂CH₃; methylating the compound of Formula (R),(R)-C to provide a compound of Formula (R),(R)-D:

wherein R¹ is CH₂CH₃; and reacting the compound of Formula (R),(R)-D with hydrochloric acid to provide the (R)- MBDB.HCI. [00109] In an exemplary embodiment of the process of the application, the present application also includes a process for preparing an HCI salt of a compound of Formula (R)-l:

wherein R¹ is selected from CH₃ and CH₂CH₃; the process comprising: homologating piperonal,

, with methoxymethylenetriphenylphosphine under Wittig reaction conditions to provide a compound of Formula B':

reacting the compound of Formula (S)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (R),(S)-C":

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (R),(S)-C" to provide a compound of Formula (R),(S)-D':

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (R),(S)-D' with hydrochloric acid to provide the HCI salt of a compound of Formula (R)-l.

[00110] In some embodiments, the Wittig reaction conditions further comprise reacting piperonal with the methoxymethylenetriphenylphosphine to provide a vinyl ether intermediate,

reacting the vinyl ether intermediate with a suitable acid the compound of Formula B'.

[00111] In some embodiments, the compound of Formula B' is reacted with (S)-t- butylS(0)NH₂ or (R)-t-butylS(0)NH₂ in the presence of a catalyst such as pyridinium p- toluenesulfonate to provide the compound of Formula (S)-C^im or (R)-C^im, respectively.

[00112] In some embodiments, the compound of Formula (R),(S)-D' or (S),(R)-D' is reacted hydrochloric acid to provide the hydrochloric acid salt of the compound of Formula (R)-l or (S)-l, respectively.

[00113] In an exemplary embodiment of the process of the application, the present application includes a process for preparing an HCI salt of (R)- 3,4- methylenedioxymethamphetamine ((R)-MDMA):

the process comprising: homologating piperonal,

, with methoxymethylenetriphenylphosphine under Wittig reaction condition to provide a compound of Formula B':

reacting the compound of Formula B' with (S)-t-butyiS(0)NH₂ to provide a compound of Formula (S)-C^im:

wherein R¹ is CH₃; methylating the compound of Formula (R),(S)-C" to provide a compound of Formula (R),(S)-D':

wherein R¹ is CH₃; and reacting the compound of Formula (R),(S)-D', with hydrochloric acid to provide the HCI salt of (R)-MDMA ((R)-MDMA.HCI).

[00114] In some embodiments, the compound of Formula B' is reacted with (S)-t- butyiS(0)NH₂ in the presence of a catalyst such as pyridinium p-toluenesulfonate to provide the compound of Formula (S)-C^im. [00115] In an exemplary embodiment of the process of the application, when R¹ is

CFhCFh_, the present application includes a process for preparing an HCI salt of (R)-N- methyl-1 ,3-benzodioxolylbutanamine ((R)-MBDB):

the process comprising: homologating piperonal,

with methoxymethylenetriphenylphosphine under Wittig reaction conditions to provide a compound of Formula B':

wherein R¹ is CH₂CH₃; methylating the compound of Formula (R),(S)-C" to provide a compound of Formula (R),(S)-D':

wherein R¹ is CH₂CH₃; and reacting the compound of Formula (R),(S)-D', with hydrochloric acid to provide the HCI salt of (R)-MBDB ((R)-MBDB.HCI). [00116] In an exemplary embodiment, the present application includes a process for preparing an acid salt of a compound of Formula (S)-l:

B wherein R¹ is selected from CH₃ and CH₂CH₃; with (S)-t-butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (S),(S)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (S),(S)-C to provide a compound of Formula (S),(S)-D:

wherein R¹ is CH₃or CH₂CH₃; and reacting the compound of Formula (S),(S)-D with an acid to provide an acid salt of the compound of Formula (S)-l.

[00117] When R¹ is CH_3, the present application also includes an exemplary process for preparing (S)-3, 4-methylenedioxymethamphetamine (S-MDMA):

wherein R¹ is CH₃; reacting the compound of Formula B with (S)-t-butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (S),(S)-C:

wherein R¹ is CH₃; methylating the compound of Formula (S),(S)-C to provide a compound of Formula (S),(S)-D:

wherein R¹ is CH₃; and reacting the compound of Formula (S),(S)-D with an acid to provide an acid salt of (S)-MDMA.

[00118] When R¹ is CH₂CH_3, the present application also includes an exemplary process for preparing an acid salt of (S)-N-methyl-1 ,3-benzodioxolylbutanamine (S- MBDB):

the process comprising: reacting a compound of Formula B:

wherein R¹ is CH₂CH₃; with (S)-t-butylS(0)NH₂ under reductive amination conditions to provide a compound of Formula (S),(S)-C:

wherein R¹ is CH₂CH₃; methylating the compound of Formula (S),(S)-C to provide a compound of

Formula (S),(S)-D:

wherein R¹ is CH₂CH₃; and reacting the compound of Formula (S),(S)-D with an acid to provide an acid salt of (S)-MBDB.

[00119] The present application also includes an exemplary process for preparing an acid salt of a compound of Formula (S)-l:

wherein R¹ is selected from CH₃ and CH₂CH₃; the process comprising:

reacting the compound of Formula B' with (R)-t-butyiS(0)NH₂ to provide a compound of Formula (R)-C^im:

reacting the compound of Formula (R)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (S),(R)-C":

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (S),(R)-C" to provide a compound of Formula (S),(R)-D':

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (S),(R)-D', with an acid to provide an acid salt of the compound of Formula (S)-l.

[00120] In some embodiments, the process further comprises converting the acid salt of S-MDMA to S-MDMA.

[00121] In some embodiments, the acid salt of the compound of Formula (R)-l or (S)-l prepared by a process of the application is further converted to a solvate and/or prodrug thereof, for example, a pharmaceutically acceptable salt, solvate and/or prodrug thereof. In some embodiments, the acid salt of (R)-MDMA or (S)-MDMA prepared by a process of the application is further converted to a solvate and/or prodrug thereof, for example, a pharmaceutically acceptable salt, solvate and/or prodrug thereof. In some embodiments, the acid salt of (R)-MBDB or (S)-MBDB prepared by a process of the application is further converted to a solvate and/or prodrug thereof, for example, a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

[00122] In some embodiments, the process of the application further comprises converting the acid salt of the compound of Formula (R)-l or (S)-l to the free base of the compound of Formula (R)-l or (S)-l, respectively. In some embodiments, the process of the application further comprises converting the acid salt of (R)- or (S)-MDMA to the free base of (R)- or (S)-MDMA. In some embodiments, the process of the application further comprises converting the acid salt of (R)- or (S)-MBDB to the free base of (R)- or (S)- MBDB.

[00123] In some embodiments, the acid salt of the compound of Formula (R)-l or (S)-l is converted to the free base, for example, using any suitable base under any suitable conditions known in the art, for example, using a suitable base and conditions known in the art as described below.

[00124] In some embodiments, the free base of the compound of Formula (R)-l or (S)-l, (i.e. (R)- or (S)-MDMA and (R)- or (S)-MBDB), prepared by a process of the application is further converted to a salt, solvate and/or prodrug thereof, for example, a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

[00125] In some embodiments, the process provides the R or S enantiomer as the major isomer. In some embodiments, the process provides the R or S enantiomer in greater than 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 98% ee or 99% ee. In some embodiments, the process provides the R or S enantiomer of the MDMA ((R)-MDMA or (S)-MDMA) or the acid salt of (R)-MDMA or (S)-MDMA such as (R)-MDMAHCI or (S)-MDMA.HCI as the major isomer. In some embodiments, the process provides (R)-MDMA or (S)-MDMA or acid salt of (R)-MDMA or (S)-MDMA in greater than 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 98% ee or 99% ee. In some embodiments, the process provides the R or S enantiomer of the MBDB ((R)- MBDB or (S)-MBDB) or the acid salt of (R)-MBDB or (S)-MBDB such as (R)- MBDB.HCI or (S)-MBDB.HCI as the major isomer. In some embodiments, the process provides (R)-MBDB or (S)-MBDB or acid salt of (R)-MBDB or (S)-MBDB in greater than 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 98% ee or 99% ee.

[00126] In some embodiments the pharmaceutically acceptable salt is an acid addition salt and the selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[00127] An acid addition salt that is pharmaceutically acceptable, that is suitable for, or compatible with, the treatment of subjects, is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p- toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In some embodiments, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[00128] Solvates include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[00129] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[00130] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[00131] Prodrugs may be, for example, conventional esters formed with the available amino group. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters. [00132] Examples of inert solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, ethyl ether, ethyl acetate, dimethyl formamide (DMF), acetonitrile, Ci_ ₆alkylOH (e.g. methanol, ethanol, n-propanol, 2-propanol, n-butanol, butan-2-ol and 2- methyl-1 -propanol), diethylcarbonate, hexane and dimethylsulfoxide (DMSO). Further examples can include aqueous solutions, such as water and dilute acids and bases, and ionic liquids, provided that such solvents do not interfere with the reaction.

III. Compounds of the Application

[00133] The present application also includes compound of Formula (R)-C', (S)-C', (R),(R)-C, (S),(S)-C and (R),(R)-D and (S),(S)-D, useful forthe preparation of compounds of Formula (R)-l or (S)-l.

[00134] Accordingly, the present application also includes a compound of Formula (R)-C':

wherein R¹ is CH_{3 or}CH₂CH₃. [00135] The present application also includes a compound of Formula (S)-C':

wherein R¹ is CH_{3 o}rCH₂CH₃.

[00136] In some embodiments, R¹ in the compound of Formula (R)-C' or (S)C' is CH₃ In some embodiments, R¹ in the compound of Formula (R)-C' or (S)-C' is CH₂CH₃ [00137] The present application also includes a compound of Formula (R),(R)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃.

[00138] The present application also includes a compound of Formula (S),(S)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃

[00139] In some embodiments, R¹ in the compound of Formula (R),(R)-C or (S),(S)-C is CH₃ In some embodiments, R¹ in the compound of Formula (R),(R)-C or (S),(S)-C is CH₂CH₃

[00140] The present application includes a compound of Formula (S)-C^im:

[00141] The present application also includes a compound of Formula (R)-C^im:

[00142] The present application includes a compound of Formula (R),(S)-C":

wherein R¹ is CH₃or CH₂CH₃.

[00143] The present application also includes a compound of Formula (S),(R)-C":

wherein R¹ is selected from CH₃ and CH₂CH₃.

[00144] In some embodiments, R¹ in the compound of Formula (R),(S)-C" or (S),(R)-C" is CH₃ In some embodiments, R¹ in the compound of Formula (R),(S)-C" or (S),(R)-C" is CH₂CH₃

[00145] The present application also includes a compound of Formula (R),(R)-D:

wherein R¹ is CH₃or CH₂CH₃.

[00146] The present application also includes a compound of Formula (S),(S)-D:

wherein R¹ is CH₃or CH₂CH₃.

[00147] In some embodiments, R¹ in the compound of Formula (R),(R)-D or (S),(S)-D is CH₃ In some embodiments, R¹ in the compound of Formula (R),(R)-D or (S),(S)-D is CH₂CH₃

[00148] The present application also includes a compound of Formula (R),(S)-D':

wherein R¹ is CH₃or CH₂CH₃.

[00149] The present application also includes a compound of Formula (S),(R)-D':

[00150] wherein R¹ is CH₃or CH₂CH₃.ln some embodiments, R¹ in the compound of Formula (R),(S)-D' or (S),(R)-D' is CH₃ In some embodiments, R¹ in the compound of Formula (R),(S)-D' or (S),(R)-D' is CH₂CH₃

[00151] As the process of the application provides a compound of Formula (R)-l or (S)-! or an acid salt of compound of Formula (R)-l or (S)-l, the application also includes compound of Formula (R)-l or (S)-l or an acid salt of compound of Formula (R)-l or (S)-l prepared by process of the application as described above. As the process of the application provides (R)-MDMA, (S)-MDMA or an acid salt of (R)-MDMA or (S)-MDMA, the application also includes (R)-MDMA, (S)-MDMA or an acid salt of (R)-MDMA or (S)- MDMA prepared by process of the application as described above. As the process of the application provides (R)-MBDB or (S)-MBDB or an acid salt of (R)-MBDB or (S)-MBDB, the application also includes (R)-MBDB, (S)-MBDB or an acid salt of (R)-MBDB, (S)- MBDB or an acid salt of (R)-MBDB or (S)-MBDB prepared by process of the application as described above.

[00152] In some embodiments, the acid salt is the HCI salt.

EXAMPLES

[00153] The following non-limiting examples are illustrative of the present application.

Example 1. Exemplary process for preparing (R)-MDMA

[00154] (R)-MDMA can be prepared according to the following synthetic scheme.

Step 1

[00155] A solution of 5-(prop-2-en-1-yl)-2h-1,3-benzodioxole (4.055 g, 25 mmol) in acetonitrile (50 ml) is added under nitrogen atmosphere to a Schlenk flask containing a mixture of palladium(ll) trifluoroacetate (208 mg, 0.625 mmol, 2.5 mol% eq.), sodium trifluoroacetate (680 mg, 5 mmol, 0.2 eq.) and iron(lll) chloride (6.1 g, 37.6 mmol, 1.5 eq.) in water (400 mL). The reaction is stirred at 60 °C for 16 h in the absence of light and with the closed flask using crystal cap. After this time, the mixture is extracted with EtOAc (2 x 100 mL) and the organic phases are combined, dried over sodium sulfate and filtered off. The solvent is removed under reduced pressure and the resulting reaction crude is purified by column chromatography on silica gel (10% EtOAc/hexane) to give the desired compound.

Steps 2 and 3

[00156] In a 2 necked 250 mL round bottomed flask was dissolved (R)-tert- butylsulfinamide (485 mg, 4.0 mmol, 2 equiv) in anhydrous THF (11 mL). To this solution is added Ti(OEt) ( 4.607 g, 20.2 mmol, 10 equiv) and the product of step 1 (356.4 mg, 2.0 mmol) in anhydrous THF (13 mL). The solution is heated to reflux and monitored by TLC. After 5 h the reaction is allowed to cool to room temperature. The reaction is then cooled down to -20 C, NaBH₄ (75.7 mg, 2.0 mmol, 1 equiv) is added and the reaction is stirred 3 h at 20 °C and overnight at room temperature. The solution is then filtered through celite and the solvent evaporated under reduced pressure to provide the desired compound.

Step 4

[00157] In a 100mL round bottomed flask, NaH (60 % dispersion in mineral oil) (68 mg, 1.7 mmol) is suspended in anhydrous DMF (15 mL). A solution of the product of Step 3 (211 mg, 0.75 mmol) in anhydrous DMF (3.5 mL) is added and the reaction is stirred 20 min under ice bath. Mel (280 mL, 4.5 mmol) is added via syringe and the reaction is monitored by TLC. When the starting material is consumed, water (50 mL) and EtOAc (50 mL) are added. The organic phase is dried (MgS0₄) and evaporated and purified to give the desired compound.

Step 5

[00158] A solution of the product of Step 4 (1.136 g, 3.82 mmol) in MeOH (15 mL) is added to a 250 mL round bottomed flask. 4 M HCI in dioxane (10 mL, 40 mmol) is added to the flask at room temperature. The reaction is stirred overnight. The reaction mixture is concentrated, and the residue is triturated with ether to give (R)-MDMA as the HCI salt.

Example 2. Exemplary process for preparing (S)-MDMA

[00159] (S)-MDMA can be prepared according to the following synthetic scheme.

Step 1

[00160] A solution of 5-(prop-2-en-1-yl)-2h-1,3-benzodioxole (4.055 g, 25 mmol) in acetonitrile (50 ml) is added under nitrogen atmosphere to a Schlenk flask containing a mixture of palladium(ll) trifluoroacetate (208 mg, 0.625 mmol, 2.5 mol% eq.), sodium trifluoroacetate (680 mg, 5 mmol, 0.2 eq.) and iron(lll) chloride (6.1 g, 37.6 mmol, 1.5 eq.) in water (400 mL). The reaction is stirred at 60 °C for 16 h in the absence of light and with the closed flask using crystal cap. After this time, the mixture is extracted with EtOAc (2 x 100 mL) and the organic phases are combined, dried over sodium sulfate and filtered off. The solvent is removed under reduced pressure and the resulting reaction crude is purified by column chromatography on silica gel (10% EtOAc/hexane) to give the desired compound.

Steps 2 and 3

[00161] In a 2 necked 250 mL round bottomed flask was dissolved (S)-tert- butylsulfinamide (485 mg, 4.0 mmol, 2 equiv) in anhydrous THF (11 mL). To this solution is added Ti(OEt) ( 4.607 g, 20.2 mmol, 10 equiv) and the product of step 1 (356.4 mg, 2.0 mmol) in anhydrous THF (13 mL). The solution is heated to reflux and monitored by TLC. After 5 h the reaction is allowed to cool to room temperature. The reaction is then cooled down to -20 C, NaBH₄ (75.7 mg, 2.0 mmol, 1 equiv) is added and the reaction is stirred 3 h at 20 °C and overnight at room temperature. The solution is then filtered through celite and the solvent evaporated under reduced pressure to provide the desired compound.

Step 4

[00162] In a 100mL round bottomed flask, NaH (60 % dispersion in mineral oil) (68 mg, 1.7 mmol) is suspended in anhydrous DMF (15 mL). A solution of the product of Step

3 (211 mg, 0.75 mmol) in anhydrous DMF (3.5 mL) is added and the reaction is stirred 20 min under ice bath. Mel (280 mL, 4.5 mmol) is added via syringe and the reaction is monitored by TLC. When the starting material is consumed, water (50 mL) and EtOAc (50 mL) are added. The organic phase is dried (MgS0 ) and evaporated and purified to give the desired compound. Step 5

A solution of the product of Step 4 (1.136 g, 3.82 mmol) in MeOH (15 mL) is added to a 250 mL round bottomed flask. 4 M HCI in dioxane (10 mL, 40 mmol) is added to the flask at room temperature. The reaction is stirred overnight. The reaction mixture is concentrated, and the residue is triturated with ether to give (S)-MDMA as the HCI salt. Example 3: Exemplary synthesis of a compound of Formula B

Step 1

[00163] To 20 g of safrole are added 8.3 g of solid KOH and 3 g of aliquot 336 (phase transfer catalyst). After a vigorous shaking (20 min) at room temperature, the mixture is left at 80°C within 1 h 15min. After cooling to room temperature, the mixture is diluted with 500 ml of methylene chloride and filtered through celite. The filtrate is then dried (MgS04) and concentrated by a rotary evaporation. The crude product is then purified in vacuum to yield 14.9 g (75%) of isosafrole as colorless oil.

Step 2 [00164] To a well stirred solution of 29 g of 35% hydrogen peroxide in 136 g of formic acid (88%) and 20.5 g of water, is added dropwise to a solution of 32.4 g isosafrole in 120 ml acetone, with cooling to keep the mixture from exceeding 40 °C. After stirring for 16 h at room temperature, the mixture is concentrated under vacuum without heating. The crude product is dissolved in 55 ml of methyl alcohol, treated with 240 g of 15% sulfuric acid and heated for 3 h. After cooling, the reaction mixture is extracted with diethyl ether. Organic layers are washed with water and then with dilute sodium hydroxide. Solvent is removed by rotary evaporation. The residue is distilled under vacuum to provide 17.4 g (50%) of the title compound as pale yellow oil.

Example 4: Exemplary process for preparing (R)-MBDB

[00165] (R)-MBDB.HCI can be prepared starting from 1-(benzo[d][1 ,3]dioxol-5- yl)butan-2-one following steps 2 to 5 of Example 1 .

Example 5: Exemplary process for preparing (S)-MBDB

[00166] (S)-MBDB.HCI can be prepared starting from 1-(benzo[d][1 ,3]dioxol-5- yl)butan-2-one following steps 2 to 5 of Example 2.

Example 6: Exemplary process for preparing compounds of Formula (R)-l

*R¹ is CH₃or CH2CH3

Step 1: Homopiperonal

[00167] Homopiperonal can be prepared using the synthetic procedures found in Tetrahedron: Asymmetry, 27(6), 274-284; 2016.

[00168] KOtBu (6.48 g, 66.6 mmol) was added portionwise to a stirred suspension of [MeOCH₂PPh₃]⁺ [Cl] (12.6 g, 36.6 mmol) in THF (50 mL) at 0°C. The resultant mixture was stirred for 30 min at rt and then a solution of piperonal (5.00 g, 33.3 mmol) in THF (50 mL) was added dropwise. The resultant mixture was stirred at rt for 12 h and then quenched by the addition of satd aq NH4CI (50 mL). The aqueous layer was extracted with Et₂0 (375 mL) and the combined organics were washed with brine (2 100 mL), then dried and concentrated in vacuo. Pentane (50 mL) was added to the residue and the resultant suspension was stirred at rt for 30 min. The resultant solution was filtered and the filtrate was concentrated in vacuo. This trituration process was repeated three times to give a vinyl ether intermediate {65:35 dr [(E):(Z) ratio]} as a pale yellow oil (5.93 g).

[00169] Formic acid (12.5 mL) was added to a stirred solution of the vinyl ether intermediate (5.93 g) in CH₂CI₂ (50 mL) at rt. The resultant solution was stirred in the dark for 48 h. H₂0 (25 mL) was added and the aqueous layer was extracted with CH₂CI₂ (335 mL). The combined organics were washed with brine (2 100 mL), then dried and concentrated in vacuo. Purification by vacuum distillation gave the homopiperonal as a pale yellow oil (4.37 g, 80% from piperonal).

Step 2

[00170] A 300-mL round-bottomed flask equipped with a magnetic stirring bar was charged with the aldehyde (the product of Step 1) (4.11 g , 25 mmol), (S_s)-2- methylpropane-2-sulfinamide (3.95 g, 32.6 mmol), anhydrous MgS0 (30.2 g, 251 mmol), and CH2CI2 (25 mL). To the suspension was added PPTS (Pyridinium p-toluenesulfonate) (315 mg, 1.25 mmol) at room temperature. The reaction mixture was stirred for 36 h. The brown suspension was filtered through celite pad. The filtrate was concentrated under reduced pressure to give a crude oil, which was purified by silica gel column chromatography to provide (S_s)-A/-[(1£)-2-(2/-/-1 ,3-benzodioxol-5-yl)ethylidene]-2- methylpropane-2-sulfinamide

Step 3

[00171] To a solution of the product of Step 2 (300 mg , 1.12 mmol) in dichloromethane (7 ml) at -48 °C was added EtMgBr (2.9 M in Et₂0, 0.46 mL, 1.33 mmol, 1.2 eq.) dropwise. The reaction mixture was stirred at -48 °C for 4-6 h and then warmed to r.t.When complete, the mixture was quenched by addition of sat’d aq. NH₄CI and with extrated EtOAc. The organic layer was dried over Na₂S0₄, filtered. The filtrate was concentrated and purified to give A/-[(S_s,2R)-1-(2/-/-1,3-benzodioxol-5-yl)butan-2-yl]-2- methylpropane-2-sulfinamide.

Step 4

[00172] In a 100mL round bottomed flask, NaH (60 % dispersion in mineral oil) (68 mg, 1 .7 mmol) is suspended in anhydrous DMF (15 mL). A solution of the product of Step 3 (211 mg, 0.75 mmol) in anhydrous DMF (3.5 mL) is added and the reaction is stirred 20 min under ice bath. Mel (280 mL, 4.5 mmol) is added via syringe and the reaction is monitored by TLC. When the starting material is consumed, water (50 mL) and EtOAc (50 mL) are added. The organic phase is dried (MgS0₄) and evaporated and purified to give the desired compound.

Step 5

[00173] A solution of the product of Step 4 (1.136 g, 3.82 mmol) in MeOH (15 mL) is added to a 250 mL round bottomed flask. 4 M HCI in dioxane (10 mL, 40 mmol) is added to the flask at room temperature. The reaction is stirred overnight. The reaction mixture is concentrated, and the residue is triturated with ether to give the compound of Formula (R)-l as the HCI salt ((R)-MDMA.HCI or (R)-MBDB.HCI).

Example 7: Exemplary process for preparing compounds of Formula (S)-l

*R¹ is CH₃or CH2CH3

Step 1: Homopiperonal

[00174] Homopiperonal can be prepared using the synthetic procedures found in Tetrahedron: Asymmetry, 27(6), 274-284; 2016.

[00175] KOt Bu (6.48 g, 66.6 mmol) was added portionwise to a stirred suspension of [MeOCH₂PPh₃]⁺ [Cl] (12.6 g, 36.6 mmol) in THF (50 mL) at 0°C. The resultant mixture was stirred for 30 min at rt and then a solution of piperonal (5.00 g, 33.3 mmol) in THF (50 mL) was added dropwise. The resultant mixture was stirred at rt for 12 h and then quenched by the addition of satd aq NH4CI (50 mL). The aqueous layer was extracted with Et₂0 (375 mL) and the combined organics were washed with brine (2 100 mL), then dried and concentrated in vacuo. Pentane (50 mL) was added to the residue and the resultant suspension was stirred at rt for 30 min. The resultant solution was filtered and the filtrate was concentrated in vacuo. This trituration process was repeated three times to give a vinyl ether intermediate {65:35 dr [(E):(Z) ratio]} as a pale yellow oil (5.93 g).

[00176] Formic acid (12.5 mL) was added to a stirred solution of the vinyl ether intermediate (5.93 g) in CH₂CI₂ (50 mL) at rt. The resultant solution was stirred in the dark for 48 h. H₂0 (25 mL) was added and the aqueous layer was extracted with CH₂CI₂ (335 mL). The combined organics were washed with brine (2 100 mL), then dried and concentrated in vacuo. Purification by vacuum distillation gave the homopiperonal as a pale yellow oil (4.37 g, 80% from piperonal).

Step 2

[00177] A 300-mL round-bottomed flask equipped with a magnetic stirring bar was charged with the aldehyde (the product of Step 1) (4.11 g , 25 mmol), (S_s)-2- methylpropane-2-sulfinamide (3.95 g, 32.6 mmol), anhydrous MgS0 (30.2 g, 251 mmol), and CH2CI2 (25 mL). To the suspension was added PPTS (Pyridinium p-toluenesulfonate) (315 mg, 1.25 mmol) at room temperature. The reaction mixture was stirred for 36 h. The brown suspension was filtered through celite pad. The filtrate was concentrated under reduced pressure to give a crude oil, which was purified by silica gel column chromatography to provide (Rs)-A/-[(1£)-2-(2/-/-1 ,3-benzodioxol-5-yl)ethylidene]-2- methylpropane-2-sulfinamide

Step 3

[00178] To a solution of the product of Step 2 (300 mg , 1.12 mmol) in dichloromethane (7 ml) at -48 °C was added EtMgBr (2.9 M in Et₂0, 0.46 mL, 1.33 mmol, 1.2 eq.) dropwise. The reaction mixture was stirred at -48 °C for 4-6 h and then warmed to r.t.When complete, the mixture was quenched by addition of sat’d aq. NH₄CI and with extrated EtOAc. The organic layer was dried over Na₂S0₄, filtered. The filtrate was concentrated and purified to give A/-[(R_s,2S)-1-(2/-/-1,3-benzodioxol-5-yl)butan-2-yl]-2- methylpropane-2-sulfinamide.

Step 4

[00179] In a 100mL round bottomed flask, NaH (60 % dispersion in mineral oil) (68 mg, 1 .7 mmol) is suspended in anhydrous DMF (15 mL). A solution of the product of Step 3 (211 mg, 0.75 mmol) in anhydrous DMF (3.5 mL) is added and the reaction is stirred 20 min under ice bath. Mel (280 mL, 4.5 mmol) is added via syringe and the reaction is monitored by TLC. When the starting material is consumed, water (50 mL) and EtOAc (50 mL) are added. The organic phase is dried (MgS0₄) and evaporated and purified to give the desired compound.

Step 5

[00180] A solution of the product of Step 4 (1.136 g, 3.82 mmol) in MeOH (15 mL) is added to a 250 mL round bottomed flask. 4 M HCI in dioxane (10 mL, 40 mmol) is added to the flask at room temperature. The reaction is stirred overnight. The reaction mixture is concentrated, and the residue is triturated with ether to give the compound of Formula (S)-l as the HCI salt ((S)-MDMA.HCI or (S)-MBDB.HCI).

Example 8: Exemplary process for preparing (R)-MBDB

Step 5 Step 6

Step 1: Preparation of 5-(2-methoxyvinyl)benzo[d][1 ,3]dioxole

[00181] A white suspension of methoxymethyltriphenylphosphonium chloride (25.22 g, 73.6 mmol) in tetrahydrofuran (100 mL) was cooled to 0 °C (ice bath) then treated with potassium fe/f-butoxide (13.06 g, 116.4 mmol) in portions. The suspension slowly darkened to a brown suspension then became a clear brown solution. The resulting mixture was stirred at 0 °C for 30 minutes then piperonal 1 (10.01 g, 66.7 mmol) in tetrahydrofuran (100 mL) was added dropwise to give a yellow suspension. The mixture was stirred at room temperature overnight, then quenched with saturated ammonium chloride solution. The aqueous solution was extracted with diethyl ether and the organic layer was washed with brine, dried (sodium sulphate), filtered and the filtrate was concentrated to a yellow oil. The oil was triturated with hexanes to precipitate out triphenylphosphine oxide, which was removed by filtration. The filtrate was concentrated to give 5-(2-methoxyvinyl)benzo[d][1 ,3]dioxole (11.98 g, crude, quantitative) as a yellow oil .

[00182] Ή NMR (CDCI₃, 400 MHz): 87.27 (d, 0.55H, J= 1.6 Hz), 6.89-6.96 (m, 1 H), 6.67-6.78 (m, 1 9H), 6.04 (d, 0.55H, J= 7.0 Hz), 5.92 (d, 2H), 5.76 (d, 0.45H, J= 12.9 Hz), 5.15 (d, 0.55H, J= 7.0 Hz), 3.76 (s, 1.65H), 3.65 (s, 1.35H).

Step 2: Preparation of 2-(benzo[d][1 ,3]dioxol-5-yl)acetaldehyde [00183] Crude 5-(2-methoxyvinyl)benzo[d][1 ,3]dioxole was diluted with dichloromethane (100 mL) and treated with formic acid (30 mL, 660 mmol). The mixture was stirred at room temperature for 3 days, then quenched with water, extracted with dichloromethane, dried (sodium sulphate), filtered and concentrated to a brown oil. Purification by column chromatography (10-20 % ethyl acetate in hexanes) gave 2- (benzo[d][1 ,3]dioxol-5-yl)acetaldehyde (1.6 g, 15 %) as a yellow oil.

[00184] Ή NMR (CDCI₃, 400 MHz): d 9.72 (app td, 1H, J= 2.3, 0.6 Hz), 6.81 (d, 1 H, J= 7.8 Hz), 6.66-6.70 (m, 2H), 5.97 (s, 2H), 3.61 (d, 2H, J= 2.3 Hz).

Step 3: Preparation of(S)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2- sulfinamide

[00185] A suspension of 2-(benzo[d][1 ,3]dioxol-5-yl)acetaldehyde (0.18 g, 1.1 mmol), (S)-(-)2-methylpropane-2-sulfinamide (0.173 g, 1.4 mmol), and magnesium sulphate (1.32 g, 10.9 mmol) in dichloromethane (5 mL) was treated with pyridinium p- toluenesulfonate (PPTS) (0.019 g, 0.076 mmol). The mixture was stirred at room temperature for 2.5 days. The solids were filtered away through a Celite pad and the filtrate was concentrated in vacuo. Purification by column chromatography (10-15 % ethyl acetate in hexanes) afforded (S)-N-(2-(benzo[d][1 ,3]dioxol-5-yl)ethylidene)-2- methylpropane-2-sulfinamide 4 (0.17 g, 58 %) as a yellow oil.

[00186] Ή NMR (CDCI₃, 400 MHz): d 8.06 (t, 1H, J= 5.2 Hz), 6.75 (d, 1H, J= 7.8 Hz), 6.70 (s, 1 H), 6.66 (d, 1H, J= 7.8 Hz), 5.93 (s, 2H), 3.74 (m, 2H), 1.18 (s, 9H).

Step 4: Preparation of (S)-N-((R)-1-(benzo[d][1,3]dioxol-5-yl)butan-2-yl)-2- methylpropane-2-sulfinamide

[00187] A solution of (S)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2- methylpropane-2-sulfinamide (0.28 g, 1.05 mmol) in anhydrous dichloromethane (5 mL) was treated at -50 °C with ethyl magnesium bromide (2 M solution in diethyl ether; 0.70 mL, 2.1 mmol) dropwise. The mixture was stirred at -50 °C for 4 hours, then at room temperature overnight. The mixture was carefully quenched with saturated ammonium chloride dropwise, extracted with ethyl acetate, dried (sodium sulphate), filtered and concentrated in vacuo to a brown oil. Purification by column chromatography (10-100% ethyl acetate/hexanes) afforded (S)-N-((R)-1-(benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-2- methylpropane-2-sulfinamide 5 (0.149 g, 48 %) as a colourless oil.

[00188] ¹H NMR (CDCI₃, 400 MHz): d 6.73 (d, 1H, J= 7.9 Hz), 6.66 (d, 1H, J= 1.6 Hz), 6.63 (dd, 1H, J= 7.8. 1.6 Hz), 5.92 (s, 2H), 3.33 (m, 1H), 3.07 (d, 1H, J= 6.1 Hz), 2.71 (d, 2H, J= 6.7 Hz), 1.56-1.69 (m, 2H), 1.12 (s, 9H), 1.00 (t, 3H, J= 7.4 Hz).

Step 5: Preparation of (S)-N-((R)-1-(benzo[d][1,3]dioxol-5-yl)butan-2-yl)-N,2- dimethylpropane-2-sulfinamide [00189] An ice-cold solution of (S)-N-((R)-1-(benzo[d][1,3]dioxol-5-yl)butan-2-yl)-2- methylpropane-2-sulfinamide (0.14 g, 0.47 mmol) in A/-A/-dimethylformamide (5 mL) was treated with sodium hydride (60% suspension in mineral oil, 0.037 g, 0.92 mmol) in portions. The mixture was stirred at room temperature for 30 minutes, then cooled to 0 °C. Methyl iodide (0.20 mL, 3.21 mmol) was added dropwise and the resulting mixture was stirred at room temperature overnight. The mixture was carefully quenched with saturated ammonium chloride solution, then concentrated in vacuo to a brown oil. Purification by column chromatography eluting with 25-50 % ethyl acetate/hexanes afforded the (S)-N-((R)-1-(benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-N,2-dimethylpropane-2- sulfinamide 6 (0.112 g, 76 %) as a colourless oil.

[00190] ¹H NMR (CDCI₃, 400 MHz): 86.72 (d, 1H, J= 7.8 Hz), 6.66 (d, 1H, J= 1.6 Hz), 6.62 (dd, 1H, J= 7.8, 1.6 Hz), 5.91 (s, 2H), 3.20-3.35 (m, 1H), 2.80-64 (m, 2H), 2.50 (s, 3H), 1.42-1.66 (m, 2H), 1.01 (s, 9H), 0.97 (t, 3H, J= 7.4 Hz).

Step 6: Preparation of (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylbutan-2-amine hydrochloride

[00191] An ice-cold solution of (S)-N-((R)-1-(benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-

N,2-dimethylpropane-2-sulfinamide 6 (0.10 g, 0.32 mmol)in methanol was treated with hydrogen chloride (2 M solution in diethyl ether, 1 mL, 2.0 mmol). The mixture was stirred at 0 °C to room temperature overnight, then concentrated with vacuo to a brown oil. The oil was triturated with methanol and diethyl ether. The off-white solid (R)-1- (benzo[d][1 ,3]dioxol-5-yl)-N-methylbutan-2-amine hydrochloride 7 (0.066 g, 85 %) was collected by vacuum filtration.

[00192] ¹H NMR (DMSO-cfe, 400 MHz): 88.80 (br s, 2H), 6.88 (d, 1H, J= 1.6 Hz), 6.85 (d, 1 H, J= 7.8 Hz), 6.72 (dd, 1H, J= 7.8, 1.6 Hz), 5.97 (s, 2H), 3.19-3.25 (m 1H), 2.96 (dd, 1 H, J= 13.8, 5.1 Hz), 2.69 (dd, 1H, J= 13.8, 8.9 Hz), 2.51 (s, 3H), 1.44-1.60 (m, 2H),

O.87 (t, 3H, J= 7.4 Hz).

[00193] MS (ESI) m/z: [M + H]⁺ Calcd for CI₂HI₈N0₂208.13; Found 208.0.

[00194] HPLC: >99 %

[00195] Melting point 182.5-183.6 °C

[00196] Specific rotation [a]_D ²⁰ -26.64 (c 1 , H₂0)

[00197] Anal. Calcd forCi₂Hi₇N0₂ HCI: C, 59.14; H, 7.44; N, 5.75; Found: C, 59.16; H, 7.38; N, 5.78. Example 9: Exemplary process for preparing (S)-MBDB.HCI ((S)-1-

(Benzo[d][1 ,3]dioxol-5-yl)-N-Methylbutan-2-amine Hydrochloride)

Step 1 : (R)-N-(2-{benzo[d][l,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

[00198] A suspension of 2-(benzo[d][l,3]dioxol-5-)acetaldehyde (10.1 g, 61.5 mmol), (R)-(+)2- methylpropane-2-sulfinamide (9.5 g, 78.4 mmol) in dichloromethane (280 ml) was treated with pyridinium p-toluenesulfonate (1.5 g, 6.0 mmol) and magnesium sulfate (73.4 g, 609.8 mmol). The mixture was stirred at room temperature for 2 days. The solid was filtered away through a Celite pad and the filtrate was concentrated in vacuo. Purification by column chromatography (10-35 % ethyl acetate/hexanes) afforded (R)-N-(2-(benzo[d][1 ,3]dioxol-5-yl)ethylidene)-2- methylpropane-2-sulfinamide (9.3 g, 57 %) as a yellow oil. [00199] 1 H NMR (CDCb, 400 MHz): d= 8.08 (t, 1H, J = 5.2 Hz), 6.78 (d, 1H, J =

7.8 Hz), 6.71 (d, 1H, J = 1.6Hz), 6.68 (dd, 1H, J = 7.8, 1.8 Hz), 5.96 (s, 2H), 3.81 - 3.67 (m, 2H), 1.20 (s, 9H).

Step 2: (R)-N-((S)-1-(benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-2-methylpropane-2- sulfinamide

[00200] A solution of (R)-N-(2-(benzo[d][1 ,3]dioxol-5-yl)ethylidene)-2- methylpropane-2-sulfinamide (15.7 g, 58.7 mmol) in anhydrous dichloromethane (282 ml) was treated at -50 °C with ethyl magnesium bromide (3M solution in diethyl ether; 59 ml, 177 mmol) dropwise. The mixture was stirred at -50 °c for 4 hours, then at room temperature overnight. The mixture was carefully quenched with saturated ammonium chloride dropwise in an ice bath, extracted with ethyl acetate, dried (sodium sulphate), filtered and concentrated in vacuo to a brown oil. Purification by column chromatography (10-50 % ethyl acetate/hexanes) afforded (R)-N-((S)-1- (benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (10 .7 g, 61 %) as a pale-yellow oil.

[00201] ¹ H NMR (CDCI3, 400 MHz): =6.74 (d, 1H, J = 7.8 Hz), 6.69 (d, 1H, J =

1.6 Hz), 6.64 (dd, 1 H, J = 7.8, 1.8 Hz), 5.93 (s, 2H), 3.39 - 3.30 (m, 1H), 3.10 (d, 1H, J = 6.5 Hz), 2.72 (d, 2H, J =6.8 Hz), 1.71 -1.59 (m, 2H), 1.14 (s, 9H), 1.01 (t, 3H, J = 7.4 Hz).

Step 3: (R)-N-((S)-1-(benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-N, 2-dimethylpropane-2- sulfinamide

[00202] An ice-cold solution of (R)-N-((S)-1-(benzo[d][1 , 3]dioxol-5-yl)butan-2-yl)- 2-methylpropane-2- sulfinamide (24.4 g, 82.0 mmol) in N-N-dimethylformamide (150 ml) was treated with sodium hydride (60 % suspension in mineral oil, 6.6 g, 165.0 mmol) in portions. The mixture was stirred at room temperature for 30 minutes, then cooled to 0 oC. Methyl iodide (15.3 ml, 245.8 mmol) was added dropwise and the resulting mixture was stirred at room temperature overnight. The mixture was carefully quenched with saturated ammonium chloride solution in an ice bath, then concentrated in vacuo to a brown oil. Purification by column chromatography eluting with 10-50 % ethyl acetate/hexanes afforded (R)-N-((S)-1-(benzo[d][1 ,3]dioxol-5-yl)butan-2-yl)-N, 2- dimethylpropane-2-sulfinamide (16.0 g, 62 %) as a pale-yellow oil.

[00203] ¹H NMR (CDC , 400 MHz): d= 6.74 (d, 1H, J = 7.8 Hz), 6.68 (d, 1H, J = 1.8 Hz), 6.64 (dd, 1H, J = 7.8, 1.8 Hz), 5.93 (s, 2H), 3.36 - 3.24 (m, 1H), 2.83 - 2.65 (m, 2H), 2.52 (s, 3H), 1.70 - 1.42 (m, 2H), 1.03 (s, 9H), 0.99 (t, 3H, J = 7.4 Hz).

Step 4: (S)-1 -(benzo[d][1 ,3]dioxol-5-yl)-N-methylbutan-2-amine hydrochloride

[00204] An ice-cold solution of (R) -N-((S)-1 -(benzo[d ][ 1 ,3]dioxol-5-yl)but an-2- yl)-N, 2-dimethylpropane-2-sulfinamide (1 6.0 g, 51.4 mmol) in methanol (121 ml) was treated with hydrogen chloride (aqueous 3 M solution, 103 ml, 309 mmol) dropwise at 0 °C. The reaction mixture was raised to room temperature and stirred for 2 hours. The mixture was concentrated in vacuo to a brown semi-solid. The slurry was triturated with methanol and diethyl et her. The off-white solid (5)-1- (benzo[d][l, 3]dioxol-5-yl) -N-met hylbutan-2-amine hydrochloride (9.7 g, 77 %) was collected by vacuum filtration.

[00205] ¹H NMR (DMSO-d6, 400 MHz): d= 8.67 (s, 2H), 6.89 (d, 1H, J = 1.8 Hz), 6.85 (d, 1 H, J = 7.9 Hz), 6.72 (dd, 1H, J = 7.9, 1.8 Hz), 5.98 (s, 2H), 3.27 - 3.18 (m, 1H), 2.94 (dd, 1 H, J = 13.9, 4.1 Hz), 2.69 (dd, 1 H, J = 13.9, 8.8 Hz), 2.52 (s, 3H), 1.58 - 1.45 (m, 2H), 0.87 (t , 3H, J = 7.5 Hz).

[00206] MS (ESI) m/z: [M + H]+ Calcd for C12H18SN02 208.13; Found 208.0. HPLC: 98.65 %

[00207] Melting point: 181.4 - 182.4 °C

[0100] Specific rotation [a]_D ²⁰ 26.06 (c 1 , H₂0) [00208] While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

[00209] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Claims

CLAIMS:

1. A process for preparing an acid salt of a compound of Formula (R)-l or (S)-l:

wherein R¹ is selected from CH3 and CH2CH3; the process comprising: reacting a compound of Formula B:

wherein R¹ is selected from CH₃ and CH₂CH₃; or homologating piperonal,

, to provide a compound of Formula B':

reacting the compound of Formula B' with (S)-t-butylS(0)NH₂ or (R)-t- butyiS(0)NH₂ to provide a compound of Formula (S)-C^im or(R)-C^im respectively:

2. The process of claim 1 , wherein the process comprises: reacting a compound of Formula B:

B wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is CH₃or CH₂CH₃; and reacting the compound of Formula (R),(R)-D or (S),(S)-D with an acid to provide an acid salt of the compound of Formula (R)-l or (S)-l, respectively.

3. The process of claim 1 or claim 2, wherein the (R)-t-butylS(0)NH₂ or (S)-t- butyiS(0)NH₂ has an enantiomeric purity of about 97% or greater or of about 98% or greater.

4. The process of any one of claims 1 to 3, wherein the reductive amination conditions comprise a first step of reacting a compound of Formula B with (R)-t- butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of a titanium catalyst to provide a compound of Formula C:

wherein R¹ is selected from CH₃ and CH₂CH₃; followed by a second step of adding a suitable reducing agent to provide the compound of Formula (R),(R)-C or (S),(S)-C, respectively.

5. The process of claim 4, wherein the compound of Formula C is not isolated.

6. The process of claim 4 or claim 5, wherein the titanium catalyst is selected from titanium (IV) isopropoxide (Ti(OiPr)4) and titanium (IV) ethoxide (Ti(OEt)4).

7. The process of any one of claims 1 to 6, wherein the reducing agent is sodium borohydride.

8. The process of any one of claims 1 to 7, wherein R¹ is CH₃ and the process further comprises oxidizing a compound of Formula A or a compound of Formula A':

wherein R¹ is CH₃.

9. The process of claim 8, wherein R¹ is CH₃ and the process is a process for preparing an acid salt of (R)-methylenedioxymethamphetamine ((R)-MDMA) or (S)- methylenedioxymethamphetamine ((S)-MDMA) comprising: oxidizing a compound of Formula A or a compound of Formula A':

wherein LLLR indicates that the bond is in a cis and/or trans orientation to provide a compound of Formula B:

wherein R¹ is CH₃; reacting the compound of Formula B with (R)-t-butyiS(0)NH₂ or (S)-t- butylS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is CH₃; and reacting the compound of Formula (R),(R)-D or (S),(S)-D with an acid to provide an acid salt of (R)-MDMA or an acid salt of (S)-MDMA, respectively.

10. The process of claim 8 or claim 9, wherein the compound of Formula A is oxidized in the presence of a palladium (II) catalyst and water or an iron (III) catalyst and water, or a combination thereof at temperatures and at times to provide the compound of Formula B.

11. The process of claim 10, wherein the palladium (II) catalyst is selected from palladium chloride (PdCI₂) or palladium (II) trifluoroacetate ((CF₃C0₂)₂Pd), and/or the iron (III) catalyst is iron (III) chloride (FeCI₃).

12. The process of any one of claims 1 to 7, wherein R¹ is CH₂CH₃ and the process is for preparing an acid salt of (R)-N-methyl-1 ,3-benzodioxolylbutanamine ((R)-MBDB) or (S)-N-methyl-1,3-benzodioxolylbutanamine ((S)-MBDB) comprising: reacting a compound of Formula B:

wherein R¹ is CH₂CH₃; with (R)-t-butyiS(0)NH₂ or (S)-t-butyiS(0)NH₂ under reductive amination conditions to provide a compound of Formula (R),(R)-C or (S),(S)-C, respectively:

wherein R¹ is CFhCFh; and reacting the compound of Formula (R),(R)-D or (S),(S)-D with an acid to provide an acid salt of (R)-MBDB or an acid salt of (S)-MBDB, respectively.

13. The process of claim 1 , wherein the process comprises: homologating piperonal,

, to provide a compound of Formula B':

wherein R¹ is selected from CH₃ and CH₂CH₃; methylating the compound of Formula (R),(S)-C" or (S),(R)-C" to provide a compound of Formula (R),(S)-D or (S),(R)-D, respectively:

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (R),(S)-D' or (S),(R)-D', with an acid to provide an acid salt of the compound the acid salt of a compound of Formula (R)-l or the acid salt of a compound of Formula (S)-l, respectively.

14. The process of claim 13, wherein the process comprises homologating piperonal with methoxymethylenetriphenylphosphine under Wittig reaction conditions to provide a compound of Formula B'.

15. The process of claim 13 or claim 14, wherein the (S)-t-butyiS(0)NH₂ or (R)-t- butylS(0)NH₂ has an enantiomeric purity of about 97% or greater.

16. The process of any one of claims 13 to 15, wherein the compound of Formula B' is reacted with (S)-t-butyiS(0)NH₂ or (R)-t-butyiS(0)NH₂ in the presence of a catalyst selected from pyridinium p-toluenesulfonate or a titanium catalyst to provide the compound of Formula (S)-C^im or (R)-C^im.

17. The process of claim 16, wherein the catalyst is pyridinium p-toluenesulfonate.

18. The process of any one of claims 1, and 13 to 17, wherein the methyl or ethyl organometallic reagent is a Grignard reagent, or methyl lithium or ethyllithium, respectively.

19. The process of claim 18, wherein the methyl or ethyl organometallic reagent is a Grignard reagent.

20. The process of any one of claims 1 to 19, wherein the compound of Formula (R),(R)-C or (S),(S)-C or the compound of Formula (R),(S)-C" or (S),(R)-C" is methylated with a methyl halide in the presence of a base in an inert solvent at a temperature and a time to react the compound of Formula (R),(R)-C or (S),(S)-C with the methyl halide to provide the compound of Formula (R),(R)-D or (S),(S)-D or to react the compound of Formula R),(S)-C" or (S),(R)-C" with the methyl halide to provide the compound of Formula R),(S)-D' or (S),(R)-D\

21. The process of any one of claims 1 to 20, wherein the acid is sulfuric acid (H₂S0 ), trifluoroacetic acid (TFA) or hydrochloric acid (HCI).

22. The process of any one of claims 1 to 21 , wherein the process further comprises converting the acid salt of the compound of Formula (R)-l or (S)-l to the free base of the compound of Formula (R)-l or (S)-l, respectively.

23. A process for preparing an HCI salt of a compound of Formula (R)-l:

wherein R¹ is selected from CH3 and CH2CH3; the process comprising: reacting a compound of Formula B

wherein R¹ is selected from CH₃ and CH₂CH₃; with (R)-t-butylS(0)NH₂ under reductive amination conditions in the presence of a titanium catalyst to provide a compound of Formula (R),(R)-C:

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (R),(R)-D with hydrochloric acid to provide the HCI salt of the compound of Formula (R)-l.

24. The process of claim 23, wherein R¹ is CH₃ and the process further comprises oxidizing a compound of Formula A or a compound of Formula A':

wherein R¹ is CH₃.

25. The process of claim 23 or claim 24, wherein R¹ is CH₃ and the process is for preparing an HCI salt of (R)-3, 4-methylenedioxymethamphetamine ((R)-MDMAHCI):

wherein R¹ is CH₃; reacting the compound of Formula B with (R)-t-butyiS(0)NH₂ under reductive amination conditions in the presence of a titanium catalyst to provide a compound of Formula (R),(R)-C:

wherein R¹ is CH₃; and reacting the compound of Formula (R),(R)-D with hydrochloric acid to provide (R)- MDMAHCI.

26. The process of claim 23, wherein R¹ is CH₂CH₃ and the process is for preparing the HCI salt of (R)-N-methyM ,3-benzodioxolylbutanamine ((R)-MBDB):

wherein R¹ is CH₂CH₃; and reacting the compound of Formula (R),(R)-D with hydrochloric acid to provide the (R)- MBDB.HCI.

27. A process for preparing an HCI salt of a compound of Formula (R)-l:

, with methoxymethylenetriphenylphosphine under Wittig reaction conditions to provide a compound of Formula B';

reacting the compound of Formula (S)-C^im with a methyl or ethyl organometallic reagent to provide the compound of Formula (R),S)-C":

wherein R¹ is selected from CH₃ and CH₂CH₃; and reacting the compound of Formula (R),(S)-D', with hydrochloric acid to provide the HCI salt of a compound of Formula (R)-l.

28. The process of claim 27 wherein R¹ is CH₃ and the process if or preparing an HCI salt of (R)-3, 4-methylenedioxymethamphetamine ((R)-MDMAHCI).

29. The process of claim 27, wherein R¹ is CH₂CH₃ and the process is for preparing the HCI salt of (R)-N-methyM ,3-benzodioxolylbutanamine ((R)-MBDB.HCI).

30. The process of any one of claims 1 to 22, wherein the process provides the compound of Formula (R)-l or (S)-l or the acid salt of the compound of Formula (R)-l or

(S)-l in greater than 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 98% ee or 99% ee.

31. The process of any one of claims 22 to 29, wherein the process provides the compound of Formula (R)-l or the acid salt of the compound of Formula (R)-l in greater than 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 98% ee or 99% ee.

32. A compound of Formula (R)-C' or (S)-C':