Processes for the preparation of the enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and N-methyl-1,3-benzodioxolylbutanamine (MBDB)

1 . A process for preparing a compound of Formula (R)-I or (S)-I:

wherein

R is selected from CH 3 and CH 2 CH 3 ;

the process comprising:

protecting the amino group of 3,4-dihydroxy-L-phenylalanine (L-DOPA) C 1-4 alkyl ester of Formula (S)-A, or the amino group of 3,4-dihydroxy-D-phenylalanine (D-DOPA) C 1-4 alkyl ester of Formula (R)-A:

wherein R 1 is C 1-4 alkyl,

with a C 1-4 alkoxycarbonyl protecting group or a benzyloxy carbonyl protecting group to provide a compound of Formula (S)-B or (R)-B, respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

cyclizing the compound of Formula (S)-B or (R)-B to provide a compound of Formula (S)-C or (R)-C, respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-C or (R)-C with a reducing agent to provide a compound of Formula (S)-D or (R)-D, respectively:

wherein R 2 is C 1-4 alkyl or CH 2 Ph;

when R is CH 2 CH 3 , further oxidizing the compound of Formula (S)-D or (R)-D to provide a compound of Formula (S)-D ox or (R)-D ox , respectively; and

wherein R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-D ox or (R)-D ox with a methyl organometallic reagent to provide the compound of Formula (S)-D′ or (R)-D′, respectively;

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-D or (R)-D with a chlorinating agent to provide a compound of Formula (S)-E or (R)-E, respectively, or reacting the compound Formula of(S)-D′ or (R)-D′ with a chlorinating agent to provide a compound of Formula (S)-E′ or (R)-E′, respectively:

wherein R 2 is C 1-4 alkyl or CH 2 Ph; or

when R is CH 2 CH 3 , hydrolyzing the compound of Formula (S)-C or (R)-C to provide the compound of Formula (S)-C′ or (R)-C′, respectively;

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

converting the compound of Formula (S)-C′ or (R)-C′ to the compound of Formula (S)-E″ or (R)-E″, respectively

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-E or (R)-E with a reducing agent to provide the compound of Formula (R)-I or (S)-I, respectively, wherein R is CH 3 ,

reacting the compound of Formula (S)-E′ or (R)-E′ with a reducing agent to provide the compound of Formula (R)-I or (S)-I, respectively, wherein R is CH 2 CH 3 , or

reacting the compound of Formula (S)-E″ or (R)-E″ with a reducing agent to provide the compound of Formula (R)-I or (S)-I, respectively, wherein R is CH 2 CH 3 .

2 . The process of claim 1 , wherein R is CH 3 and the process is a process for preparing (R)-3,4-methylenedioxymethamphetamine ((R)-MDMA) or (S)-3,4-methylenedioxymethamphetamine ((S)-MDMA)

comprising:

protecting the amino group of 3,4-dihydroxy-L-phenylalanine (L-DOPA) C 1-4 alkyl ester of Formula (S)-A or the amino group of 3,4-dihydroxy-D-phenylalanine (D-DOPA) C 1-4 alkyl ester of Formula (R)-A:

wherein R 1 is C 1-4 alkyl,

with a C 1-4 alkoxycarbonyl protecting group or a benzyloxy carbonyl protecting group to provide a compound of Formula (S)-B or (R)-B, respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

cyclizing the compound of Formula (S)-B or (R)-B to provide a compound of Formula (S)-C or (R)-C respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-C or (R)-C with a reducing agent to provide a compound of Formula (S)-D or (R)-D, respectively:

wherein

R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-D or (R)-D with a chlorinating agent to provide a compound of Formula (S)-E or (R)-E, respectively:

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-E or (R)-E with a reducing agent to provide the (R)-MDMA or (S)-MDMA, respectively.

3 . The process of claim 1 wherein R is CH 2 CH 3 and the process is for preparing (R)—N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB) or (S)-N-methyl-1,3-benzodioxolylbutanamine ((S)-MBDB):

comprising:

protecting the amino group of 3,4-dihydroxy-L-phenylalanine (L-DOPA) C 1-4 alkyl ester of Formula (S)-A or the amino group of 3,4-dihydroxy-D-phenylalanine (D-DOPA) C 1-4 alkyl ester of Formula (R)-A:

wherein R 1 is C 1-4 alkyl,

with a C 1-4 alkoxycarbonyl protecting group or a benzyloxy carbonyl protecting group to provide a compound of Formula (S)-B or (R)-B, respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

cyclizing the compound of Formula (S)-B or (R)-B to provide a compound of Formula (S)-C or (R)-C, respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-C or (R)-C with a reducing agent to provide a compound of Formula (S)-D or (R)-D, respectively:

wherein

R 2 is C 1-4 alkyl or CH 2 Ph;

oxidizing the compound of Formula (S)-D or (R)-D to provide a compound of Formula (S)-D ox or (R)-D ox , respectively;

wherein R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-D ox or (R)-D ox with a methyl organometallic reagent to provide the compound of Formula (S)-D′ or (R)-D′, respectively;

wherein

R 2 is C 1-4 alkyl or CH 2 Ph;

reacting the compound of Formula (S)-D′ or (R)-D′ with a chlorinating agent to provide a compound of Formula (S)-E′ or (R)-E′, respectively:

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-E′ or (R)-E′ with a reducing agent to provide (R)-MBDB or (S)-MBDB, respectively.

4 . The process of claim 1 , wherein R is CH 2 CH 3 and the process is for preparing (R)—N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB) or (S)-N-methyl-1,3-benzodioxolylbutanamine ((S)-MBDB):

and the process comprises:

protecting the amino group of 3,4-dihydroxy-L-phenylalanine (L-DOPA) C 1-4 alkyl ester of Formula (S)-A or the amino group of 3,4-dihydroxy-D-phenylalanine (D-DOPA) C 1-4 alkyl ester of Formula (R)-A:

wherein R 1 is C 1-4 alkyl,

with a C 1-4 alkoxycarbonyl protecting group or a benzyloxy carbonyl protecting group to provide a compound of Formula (S)-B or (R)-B, respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

cyclizing the compound of Formula (S)-B or (R)-B to provide a compound of Formula (S)-C or (R)-C respectively:

wherein

R 1 is C 1-4 alkyl, and

R 2 is C 1-4 alkyl or CH 2 Ph;

hydrolyzing the compound of Formula (S)-C or (R)-C to provide the compound of Formula (S)-C′ or (R)-C′, respectively;

wherein R 2 is C 1-4 alkyl or CH 2 Ph;

converting the compound of Formula (S)-C′ or (R)-C′ to the compound of Formula (S)-E″ or (R)-E″, respectively

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-E″ or (R)-E″ with a reducing agent to provide (R)-MBDB or (S)-MBDB, respectively.

5 . The process of claim 1 , wherein the C 1-4 alkoxycarbonyl protecting group is methoxycarbonyl or ethoxycarbonyl.

6 . The process of claim 1 , wherein the reducing agent to provide the compound of Formula (R)-I or (S)-I from the compound of Formula (S)-E or (R)-E, the compound of Formula (S)-E′ or (R)-E′ or the compound of Formula (S)-E″ or (R)-E″, respectively is a metal hydride.

7 . The process of claim 6 , wherein the reducing agent for reacting with the compound of Formula (S)-C or (R)-C to provide the compound of Formula (S)-D or (R)-D, respectively is lithium aluminium hydride.

8 . The process of claim 1 , wherein the chlorinating reagent is selected from thionyl chloride (SOCl 2 ), phosphorus trichloride (PCl 3 ), phosphorus pentachloride (PCl 5 ) and oxalyl chloride (COCl) 2 .

9 . The process of claim 8 , wherein the chlorinating reagent is SOCl 2 .

10 . The process of claim 1 , wherein reacting the compound of Formula (S)-E or (R)-E or the compound of Formula (S)-E′ or (R)-E′ with a reducing agent to provide the compound of Formula (R)-I or (S)-I respectively comprises

reacting the compound of Formula (S)-E or (R)-E or a compound of Formula (S)-E′ or (R)-E′ with a first reducing agent to provide a compound of Formula (S)-F or (R)-F, respectively;

wherein R is selected from CH 3 and CH 2 CH 3 ;

R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-F or (R)-F with a second reducing agent to provide the compound of Formula (R)-I or (S)-I, respectively.

11 . The process of claim 4 , wherein the step of converting the compound of Formula (S)-C′ or (R)-C′ to the compound of Formula (S)-E″ or (R)-E″ comprises;

reacting the compound of Formula (S)-C′ or (R)-C′ with N, O-dimethylhydroxylamine,

 to provide the amide compound of Formula (S)-E′″ or (R)-E′″, respectively

wherein R 2 is C 1-4 alkyl or CH 2 Ph; and

reacting the compound of Formula (S)-E″ or (R)-E′″ with a methyl organometallic reagent to provide the compound of Formula (S)-E″ or (R)-E″

wherein R 2 is C 1-4 alkyl or CH 2 Ph.

12 . The process of claim 3 , wherein the compound of Formula (S)-D or (R)-D is oxidized in the presence of a suitable oxidizing agent in a suitable inert solvent for a time and a temperature to provide the compound of formula (S)-D ox or (R)-D ox , respectively, wherein the suitable oxidizing agent is phosgene, Dess-Martin periodinane, sodium hypochlorite with 2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) or oxalyl chloride with dimethylsulfoxide.

13 . The process of claim 1 , wherein the process provides compound of Formula (R)-I or (S)-I in greater than 60% ee, 65% ee, 70% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 98% ee or 99% ee.

14 . The process of claim 1 , wherein the compound of Formula (R)-I or (S)-I is further converted to a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

15 . The process of claim 2 , wherein in the process is for preparing (R)-3,4-methylenedioxymethamphetamine ((R)-MDMA):

the process comprising:

protecting the amino group of the compound of Formula (S)-A:

wherein R 1 is CH 3 or CH 2 CH 3 ;

with a methoxycarbonyl protecting group or ethoxycarbonyl protecting group to provide the compound of Formula (S)-B:

wherein

R 1 is CH 3 or CH 2 CH 3 , and

R 2 is CH 3 or CH 2 CH 3 ;

cyclizing the compound of Formula (S)-B to provide the compound of Formula (S)-C:

wherein

R 1 is CH 3 or CH 2 CH 3 ; and

R 2 is CH 3 or CH 2 CH 3 ;

reacting the compound of Formula (S)-C with a reducing agent to provide the compound of Formula (S)-D:

wherein R 2 is CH 3 or CH 2 CH 3 ;

reacting the compound of Formula (S)-D with a chlorinating agent to provide the compound of Formula (S)-E:

wherein R 2 is CH 3 or CH 2 CH 3 ; and

reacting the compound of Formula (S)-E with a reducing agent to provide the (R)-MDMA.

16 . The process of claim 3 , wherein the process is for preparing (R)—N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB)

the process comprising:

protecting the compound of Formula (S)-A:

wherein R 1 is CH 3 or CH 2 CH 3 ,

with a methoxycarbonyl protecting group or ethoxycarbonyl protecting group to provide the compound of Formula (S)-B:

wherein

R 1 is CH 3 or CH 2 CH 3 , and

R 2 is CH 3 or CH 2 CH 3 ;

cyclizing the compound of Formula (S)-B to provide the compound of Formula (S)-C:

wherein

R 1 is CH 3 or CH 2 CH 3 , and

R 2 is CH 3 or CH 2 CH 3 ;

reacting the compound of Formula (S)-C with a reducing agent to provide the compound of Formula (S)-D:

wherein R 2 is CH 3 or CH 2 CH 3

oxidizing the compound of Formula (S)-D to provide the compound of Formula (S)-D ox ;

wherein R 2 is CH 3 or CH 2 CH 3 ;

reacting the compound of Formula (S)-D ox with a methyl organometallic reagent to provide the compound of Formula (S)-D′;

wherein R 2 is CH 3 or CH 2 CH 3 ;

reacting the compound of Formula (S)-D′ with a chlorinating agent to provide the compound of Formula (S)-E′:

wherein R 2 is CH 3 or CH 2 CH 3 ; and

reacting the compound of Formula (S)-E′ with a reducing agent to provide the (R)-MBDB.

17 . The process of claim 4 , wherein the process is for preparing (R)—N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB)

the process comprising:

protecting the amino group of 3,4-dihydroxy-L-phenylalanine (L-DOPA) C 1-4 alkyl ester of Formula (S)-A:

wherein

R 1 is CH 3 or CH 2 CH 3 ,

with a methoxycarbonyl or ethoxycarbonyl protecting group or a benzyloxy carbonyl protecting group to provide the compound of Formula (S)-B:

wherein

R 1 is CH 3 or CH 2 CH 3 ; and

R 2 is CH 3 or CH 2 CH 3 ;

cyclizing the compound of Formula (S)-B to provide the compound of Formula (S)-C:

wherein

R 1 is CH 3 or CH 2 CH 3 ; and

R 2 is CH 3 or CH 2 CH 3 ;

hydrolyzing the compound of Formula (S)-C to provide the compound of Formula (S)-C′;

wherein R 2 is CH 3 or CH 2 CH 3 ;

converting the compound of Formula (S)-C′ to the compound of Formula (S)-E″

wherein R 2 is CH 3 or CH 2 CH 3 ; and

reacting the compound of Formula (S)-E″ with a reducing agent to provide the (R)-MBDB.

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

wherein R 1 is C 1-4 alkyl; and R 2 is CH 3 ; or

R 1 is CH 2 CH 3 and R 2 is CH 2 CH 3 ; or

a compound of Formula (S)-C′ or (R)-C′:

wherein R 2 is CH 3 ; or

a compound of Formula (S)-D or (R)-D:

wherein R 2 is CH 3 or CH 2 CH 3 ; or

a compound of Formula (S)-D′ or (R)-D′;

wherein R 2 is CH 3 , CH 2 CH 3 or C(CH 3 ) 3 ; or

a compound of Formula (S)-D ox or (R)-D ox ;

wherein R 2 is CH 3 .

19 . The compound of claim 18 , wherein R 1 and R 2 are both CH 3 and the compound of Formula (S)-C or (R)-C has the following structure:

respectively.

20 . A compound of Formula (S)-E or (R)-E

wherein R 2 is CH 3 , CH 2 CH 3 or CH 2 Ph, or

a compound of Formula (S)-E′ or (R)-E′

wherein R 2 is CH 3 ; or

a compound of Formula (S)-E″ or (R)-E″

wherein R 2 is CH 3 ; or

a compound of Formula (S)-E″ or (R)-E″

wherein R 2 is CH 3 ; or

a compound of Formula (S)-F or (R)-F:

wherein R is CH 3 or CH 2 CH 3 ; and

R 2 is CH 3 or CH 2 Ph.