Method for producing R-MDMA

Abstract

A method for producing R-MDMA by forming a Grignard reagent from 5-bromobenzodioxole, treating this Grignard reagent with S-propylene oxide to form a chiral pure alcohol (1), activating the alcohol as a mesylate (2), converting it to a chiral pure azide (3), reducing the azide to an amine (4), protecting the amine with di-tert-butyl dicarbonate, reducing the protected amine (5) to produce the R-MDMA free base (6), and treating with an acid to form a salt (7) (>99% ee). A method for producing S-MDMA by forming a Grignard reagent from 5-bromobenzodioxole, treating this Grignard reagent with R-propylene oxide to form a chiral pure alcohol (8), activating the alcohol as a mesylate (9), converting it to a chiral pure azide (10), reducing the azide to an amine (11), protecting the amine with di-tert-butyl dicarbonate, reducing the protected amine (12) to produce the S-MDMA free base (13), and treating with an acid to form a salt (14) (>99% ee).

Description

Technical Field

[0001] The present invention relates to a method for producing R-MDMA.

Background Art

[0002] 3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive drug that alters mood and perception and has been investigated as an adjunctive agent in psychotherapy for post-traumatic stress disorder (PTSD), social anxiety, and autism (Danforth, 2016; Danforth et al., 2018; Danforth et al., 2016; Mithoefer et al., 2019; Mithoefer et al., 2010; Oehen et al., 2013), and may also be studied and used later for various other medical conditions. Such conditions for which MDMA or related substances may be useful include, but are not limited to, substance use disorders, depression, anxiety disorders (such as social anxiety), anxiety associated with life-threatening diseases, personality disorders including narcissistic and antisocial disorders, autism and other developmental disorders, and obsessive-compulsive disorder. MDMA or related substances can also be used to enhance individual or couples therapy.

[0003] There are several side effects and safety concerns regarding MDMA. The abuse of MDMA can lead to hyperthermia, neurocognitive impairment, and an increased incidence of depression. MDMA can also be neurotoxic, which limits the ability to use it chronically with repeated dosing. The use of MDMA often impairs declarative memory, prospective memory, and higher cognitive abilities. Neurocognitive deficits are associated with a decrease in SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown a local decrease in brain activity during neurocognitive abilities. Deficits in sleep, mood, vision, pain, psychomotor performance, tremors, neurohormonal activity, and mental state have also been demonstrated. These effects are more prevalent with higher doses or longer use. (Parrott, Neuroscience & Biobehavioral Reviews, Volume 37, Issue 8, 2013, Pages 1466 - 1484).

[0004] MDMA has two enantiomers, S(+)-MDMA and R(-)-MDMA. The R enantiomer is thought to be more active (Nichols, et al. J. Med. Chem. 1986, 29, 2009-2015). The neurotoxicity of racemic MDMA is thought to be caused by the S(+) enantiomer rather than the R(-) enantiomer because of the low efficacy of the R(-) enantiomer as a dopamine-releasing factor. The R(-) enantiomer also does not produce hyperthermia. The R(-) enantiomer may have a lower risk of abuse. (Pitts, et al. Psychopharmacology (2018) 235:377-392). Enantiomers have been shown to have different effects. Evaluating their effects in a Parkinson's animal model of R-MDMA and S-MDMA (Huot, et al., The Journal of Neuroscience, May 11, 2011, 31(19):7190-7198), R-MDMA is a selective compound for the 5-HT2A receptor, with a reduced severity of peak-dose dyskinesia and an increased duration of good on-time, and S-MDMA showed high affinity for SERT and moderate affinity for DAT, and the total duration of on-time was extended, but dyskinesia was found to have worsened. This indicates that racemic MDMA exerts a simultaneous effect of reducing dyskinesia and extending on-time by 5-HT2A antagonism and inhibition of SERT-selective mixed monoamine uptake, respectively, due to its R and S enantiomers. Therefore, it may be advantageous to use R-MDMA for treatment.

[0005] For the use of R-MDMA in therapy, it is first necessary to obtain R-MDMA efficiently and in a substantially pure form. Chiral resolution of racemic MDMA is carried out to yield R-MDMA (Taschwer, Magdalena; Seidl, Yvonne; Mohr, Stefan; Schmid, Martin G., Chirality, 2014, vol. 26, #8, p. 411-418). As shown in Figure 1, enantioselective synthesis of R-MDMA has been performed (D.E. Nichols, A.J. Hoffman, R.A. Oberlender, P. Jacob, A.T. Shulgin, Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class, J. Med. Chem. 29 (1986) 2009-2015). This process requires 8 steps to obtain compound 2a with an overall yield of 23%. S. Llabres et al. (European Journal of Medicinal Chemistry 81 (2014) 35-46) teach a process with an overall yield of 32% in 7 steps for the free base at the 100 mg scale with an enantiomeric excess (ee) of 99%. This process utilizes nitromethane and two silica purifications. Neajdenko, et al. teach another process shown in Figure 2 (The Journal of Neuroscience, May 11, 2011, 31(19): 7190-7198). However, all of these processes result in low yields, use strong reagents and / or conditions, and / or require chromatographic purifications that are not suitable for large-scale pharmaceutical use.

[0006] Therefore, for pharmaceutical development, there is still a need for an efficient, robust, and scalable synthesis of R-MDMA that can achieve >99% ee. SUMMARY OF THE INVENTION

[0007] As shown in Figure 3, the present invention involves forming a Grignard reagent from 5-bromobenzodioxole, treating this Grignard reagent with S-propylene oxide to form chiral pure 1((S)-1-(benzod[d][1,3]dioxol-5-yl)propan-2-ol), activating the alcohol as a mesylate 2((S)-1-(benzod[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate), converting it to chiral pure azide 3((R)-5-(2-azidopropyl)benzod[d][1,3]dioxole), reducing the azide to an amine 4((R)-1-(benzod[d][1,3]dioxol-5-yl)propan-2-amine), protecting the amine with di-tert-butyl dicarbonate to form a protected amine 5(ethyl (R)-(1-(benzod[d][1,3]dioxol-5-yl)propan-2-yl)carbamate), reducing the protected amine 5 to produce the R-MDMA free base 6((R)-1-(benzod[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine), and treating it with an acid to form a salt such as 7(7-(R)-1-(benzod[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride)(>99% e.e), thereby providing a method for manufacturing R-MDMA.

[0008] As shown in FIG. 4, the present invention involves forming a Grignard reagent from 5-bromobenzodioxole, treating this Grignard reagent with R-propylene oxide to form chiral pure 8((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol), activating the alcohol as a mesylate 9((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate), converting it to a chiral pure azide 10((S)-5-(2-azidopropyl)benzo[d][1,3]dioxole), reducing the azide to an amine 11((S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-amine), protecting the amine with di-tert-butyl dicarbonate to form a protected amine 12(ethyl (S)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate), reducing the protected amine 12 to produce the S-MDMA free base 13((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine), and treating it with an acid to form a salt such as 14((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride)(>99% e.e), thereby providing a method for producing S-MDMA.

[0009] Other advantages of the present invention will be readily understood as they become better understood with reference to the following detailed description when considered in connection with the accompanying drawings.

Brief Description of the Drawings

[0010]

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BEST MODE FOR CARRYING OUT THE INVENTION

[0011] The present invention provides a method for manufacturing and synthesizing R-MDMA or S-MDMA, which is generally shown for R-MDMA in Figure 3 and for S-MDMA in Figure 4. In this process, seven steps with a total yield of over 30% are used on a 2 kg scale.

[0012] Generally, a Grignard reagent is formed from 5-bromobenzodioxole, which is then treated with S-propylene oxide to form chiral pure 1((S)-1-(benzodioxol-5-yl)propan-2-ol). The alcohol is activated as a mesylate 2((S)-1-(benzodioxol-5-yl)propan-2-ylmethanesulfonate) and then converted to chiral pure 3((R)-5-(2-azidopropyl)benzodioxole). The azide is reduced to 4((R)-1-(benzodioxol-5-yl)propan-2-amine), and the resulting amine is protected with di-tert-butyl dicarbonate to produce 5(ethyl (R)-(1-(benzodioxol-5-yl)propan-2-yl)carbamate). The Boc-protected amine is reduced to produce the R-MDMA free base (6)((R)-1-(benzodioxol-5-yl)-N-methylpropan-2-amine), which is treated with an acid to form a salt (7) (e.g., (R)-1-(benzodioxol-5-yl)-N-methylpropan-2-amine hydrochloride, etc.) with an ee exceeding 99%. The applicant achieved an ee exceeding 99.9% on a scale larger than 100 g.

[0013] This method has several advantages compared to the prior art. It is an expandable process that utilizes standard pharmaceutical manufacturing reagents and processes, as well as commercially available starting materials. Chirality is introduced in the first step and chiral purity is maintained at >99% throughout the synthesis. There are minimal process impurities and the product is >99A% pure and does not require either chromatography or recrystallization, although recrystallization may be used if desired. This process does not use ICH class 1 solvents nor ICH class 1 or 2 metal catalysts. Sodium azide is utilized during the process, but this reagent and azide intermediates can be safely handled by those skilled in the art. At stage 2, MsCl can be used instead of MsO2. The amine obtained at stage 4 can be converted to a salt if required for purification or storage purposes. At stage 5, other protecting groups (i.e., ethyl chloroformate) can also be used instead of Boc2O, although Boc2O is preferred and unacceptable results were obtained with Fmoc-Cl and benzyl chloroformate. At stage 6, reducing agents other than LiAlH4 (lithium aluminum hydride) can be used.

[0014] Alternative salts can be obtained by exchanging HCl with other acids to obtain hydrobromide, maleate, L - malate, D - tartrate, meso - tartrate, citrate, phosphate, naphthalene - 1,5 - disulfonate, fumarate, sulfate, mesylate, acetate, or oxalate. In other words, acids that can be used include, but are not limited to, HCl, HBr, D - tartaric acid, L - tartaric acid, meso - tartaric acid, oxalic acid, maleic acid, malic acid, citric acid, phosphoric acid, naphthalene - 1,5 - disulfonic acid, fumaric acid, sulfuric acid, methanesulfonic acid, acetic acid, or oxalic acid. S - MDMA can be produced by the same process by exchanging S - propylene oxide with R - propylene oxide at stage 1 as shown in Figure 4. Thus, a method for manufacturing S - MDMA involves forming a Grignard reagent from 5 - bromobenzodioxole, treating this Grignard reagent with R - propylene oxide to form chiral - pure 8((R)-1-(benzod[d][1,3]dioxol - 5 - yl)propan - 2 - ol), activating the alcohol as mesylate 9((R)-1-(benzod[d][1,3]dioxol - 5 - yl)propan - 2 - ylmethanesulfonate), converting it to chiral - pure azide 10((S)-5-(2 - azidopropyl)benzod[d][1,3]dioxol), reducing the azide to amine 11((S)-1-(benzod[d][1,3]dioxol - 5 - yl)propan - 2 - amine), protecting the amine with di - tert - butyl dicarbonate to produce 12(ethyl (S)-(1-(benzod[d][1,3]dioxol - 5 - yl)propan - 2 - yl)carbamate), reducing the protected amine to produce S - MDMA free base 13((S)-1-(benzod[d][1,3]dioxol - 5 - yl)-N - methylpropan - 2 - amine), and treating with an acid to form salts 14((S)-1-(benzod[d][1,3]dioxol - 5 - yl)-N - methylpropan - 2 - amine hydrochloride etc.) (>99% e.e).

[0015] The present invention will be described in more detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting, unless otherwise specified. Therefore, the present invention should in no way be construed as being limited to the following examples, but rather should be construed as encompassing all possible variations that become apparent as a result of the teachings provided herein.

[0016] Example 1. Preparation of Stage 1 - (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1) Magnesium turnings (948 g, 39.0 mol, 1.1 eq) were mixed with THF (28.5 L) and heated to reflux. 5-Bromo-1,3-benzodioxole (142 g, 0.71 mol, 0.02 eq) was added all at once. The pre-prepared Grignard reagent (356.3 ml) was added all at once, and the onset was observed after 10 minutes. The remaining 5-bromo-1,3-benzodioxole (6983 g, 0.98 eq, 34.74 mol) was added dropwise over 1.5 hours while maintaining a temperature of 65 - 75 °C, and the mixture was stirred at reflux for 30 minutes. The mixture was cooled to 5 °C over 50 minutes and then stirred at 5 °C overnight. Copper(I) iodide (114.7 g, 0.60 mol, 0.02 eq) was added all at once. (S)-Propylene oxide (2235 ml, 33.10 mol, 0.9 eq) dissolved in THF (2235 ml) was added dropwise at approximately 1.5 L / hr (total 3 hours, T < 10 °C). The reaction mixture was stirred at 5 °C for 30 minutes until completion by HPLC. The contents were divided into two equal parts for work-up.

[0017] Work-up after division (first part) Acetic acid (1220 ml) was added to the second jacketed container, followed by 10% brine (4.8 L). While maintaining T < 40 °C, half of the reaction mass was transferred to the second container. The contents were stirred at 40 °C for 1 hour and then left overnight to separate the phases. The lower aqueous phase was removed from the container, and the upper organic matter was retained in the container. Heptane (7.3 L) and 10% brine (7.1 L) were added all at once and stirred at 30 °C for 40 minutes. The phases were separated from the container. The upper organic layer was filtered and washed with heptane (2 L).

[0018] The second portion was worked up following the same procedure as the first portion. The organics from each worked-up portion were combined and concentrated to obtain a crude oil.

[0019] WFE distillation The crude oil was diluted with PEG400 (800 ml) and distilled using a wiped film evaporator (3 passes were made). Each pass was analyzed by HPLC, chiral LC, and NMR. Pass 1: HPLC 92.9%, NMR assay (CDCl3) 95%, chiral purity 99.4%, active mass = 3384 g. Pass 2: HPLC 96.3%, NMR assay 99%, chiral purity 99.4%, active mass = 1598 g. Pass 3: HPLC 98.0%, NMR assay 97%, chiral purity 99.6%, 99.2% ee, active mass = 231.3 g. Total yield = 5414 g (5214 g, active, 80%).

[0020] Example 2. Preparation of stage 2 - (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate (2) Into the reactor, 1 (1300.8 g, 95% active, 6.86 mol, 1 equivalent) and EtOAc (12.4 L) were added to obtain a clear solution. Methanesulfonic anhydride (1800 g, 10.33 mol, 1.2 equivalents) was added in small portions over 10 minutes. The contents were cooled to 6 °C, and triethylamine (2.04 L, 14.63 mol, 1.5 equivalents) was added dropwise over 3 hours. After 20 minutes, the contents were sampled by HPLC. IPC1: 0.8%, 1, 98.5%, 2. Water (3.7 L) was added all at once and stirred for 10 minutes. The stirrer was stopped and each phase was allowed to stand for 5 minutes. The lower aqueous phase was removed by vacuum transfer. Water (3.7 L) was added all at once and stirred for 10 minutes. The stirrer was stopped and each phase was allowed to stand for 10 minutes. The lower aqueous phase was removed by vacuum transfer. A 10% brine solution (3.7 L, corresponding to 1 kg of NaCl dissolved in 9 L of water) was added and stirred for 10 minutes. The stirrer was stopped and the phases were allowed to stand to separate the layers. The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated. 2 was isolated as a brown oil (3791.3 g). HPLC: 88.9%. 1 1H NMR (CDCl3): Consistent with the structure.

[0021] Example 3. Preparation of stage 3 / 4-(R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-amine (4) The reactor was charged with stage 2 (770 g crude mass, 81% active, 2.41 mol, 1 equivalent) and DMF (2.7 L). Sodium azide (230.2 g, 35.54, 1.4 equivalents) was added all at once. The contents were heated to 60 °C over 45 minutes and stirred overnight. The contents were cooled to 15 °C and water (3.4 L) was added dropwise over 45 minutes. The phases were separated and the aqueous phase was treated with TBME (1.35 L). The phases were allowed to stand to remove the aqueous substances. The organic layers were combined and water (3.4 L) was added. The phases were allowed to stand and the lower layer was removed. Saturated sodium bicarbonate solution (3.4 L) was added and stirred. Stirring was stopped and the phases were allowed to stand for 10 minutes. The lower layer was removed and fresh water was placed in the vessel. The phases were allowed to stand and separated. The organic layer was washed with water (3.4 L) and the aqueous layer was removed. Analysis of the organic layer showed less than 129 ppm of NaN3. THF (676 ml) and water (1.35 L) were added. The contents were heated to 40 °C over 20 minutes and triphenylphosphine (726 g, 2.77 mol, 1.15 equivalents) was added in portions over 1 hour. After 24 hours, the contents were stirred while cooling to 15 °C. Analysis showed 87.5% 4 and indicated that 3 was not remaining. Water (1.9 L) was added all at once, followed by dropwise addition of concentrated HCl (250 ml) over 40 minutes. The phases were separated and the aqueous solution was washed with iso-propyl acetate (3 x 1.9 L). 85% KOH (315 g) was added in portions over 15 minutes. The aqueous phase was extracted with MTBE (3 x 1.9 L). The organics were combined, dried over MgSO4, filtered, and concentrated to produce 4 as a brown oil = 383.6 g. HPLC: 98.8%. Chiral purity: 99.3%, 98.6% ee. NMR assay (CDCl3): 96%, active yield = 368.3 g (85% yield).

[0022] Example 4. Preparation of stage 5 - ethyl (R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (5) 4 (1691 g crude, 95% active, 8.93 mol, 1 eq) and THF (4 L) were charged into a reactor. The resulting solution was cooled to 0 °C. Boc anhydride (2065 g, 9.46 mol, 1.05 eq) dissolved in THF (4 L) was added dropwise, the contents were heated to room temperature, and stirred until the reaction was complete by HPLC. The crude reaction was concentrated by rotary evaporator to give a beige solid, which was dried at 40 °C to yield 2297.6 g. HPLC: 98.9 area %. NMR assay (CDCl3): 97%. Active yield = 2228.7 g (89% yield).

[0023] Example 5. Preparation of (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine (6) at Stage 6 5 (572 g, 97% active, 1.99 mol, 1 eq) and THF (1.1 L) were charged into a reactor. The resulting solution was cooled to 10 °C and 1 M LiAlH4 (4.44 L, 4.44 mol, 2.2 eq) was added dropwise. The contents were heated to 40 °C and stirred until complete by HPLC. MTBE (2.78 L) was added all at once and the contents were cooled to 0 °C. Water (166 ml) was added dropwise over 1 hour. 15% NaOH (166 ml, corresponding to dissolving 150 g of NaOH in 850 ml of water) was added dropwise over 20 minutes. Water (500 ml) was added dropwise over 15 minutes. The contents were heated to 20 °C and stirred for 2 hours. Magnesium sulfate (677 g) was added in portions over 10 minutes: exotherm to +5 °C. The contents were stirred at 20 °C for 1 hour. The contents were filtered, washed with MTBE (0.5 L) and suction dried. The filtrate was dried over magnesium sulfate and filtered. The dried filtrate was concentrated by rotary evaporator to give an amber oil = 324.5 g. Bath temperature = 40 °C. HPLC: 98.0%, Stage 6. NMR assay (CDCl3): 97%. Active yield = 314.8 g (82% yield).

[0024] Example 6. Preparation of (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride (7) at Stage 7 6 (1227.1 g, 95% active, 6.09 mol, 1 equivalent) and IPA (9.47 L) were placed into the reactor. IPA (1023 ml, 5.77 mol, 1 equivalent) containing 5 - 6 M HCl was added dropwise. The resulting solid was isolated by filtration, washed with the mother liquor and then IPA (300 ml), and dried under vacuum to obtain a white solid. Dried mass = 1231 g. HPLC: 99.4% (Figure 5). Chiral purity: 99.6% (Figure 6), 99.2% ee 1 1H NMR (Figure 7) and MS are consistent with the predicted structure.

[0025] Example 7. Recrystallization of R - MDMA HCl R - MDMA HCl (150 g) was placed into a flask. IPA / water (97:3, 7 volumes, 1050 ml) was added and the suspension was heated to 70 °C. The resulting solution was clarified and placed into a pre - heated container and equilibrated at 70 °C for 30 minutes. The temperature was lowered to 55 - 60 °C, a seed of R - MDMA HCl pattern A was added, and it was allowed to develop for 15 minutes, during which time the formation of a suspension was observed. Then the suspension was cooled to 0 °C. 2 volumes of IPA were added. After equilibration for about 2 hours, the suspension was filtered. The filter cake was washed with 1 volume of cold IPA and the solid (wet mass 155 g) was dried in vacuo at 60 °C for 18 hours (dried mass 137.7 g, yield 91.8%). HPLC: 100.0%. Chiral purity: 100%, 100% ee 1 1H NMR is consistent with the predicted structure. The DSC and TGA thermograms of R - MDMA HCl pattern A recrystallized from IPA / water are shown in Figure 8.

[0026] Example 8. Direct preparation of crystalline R - MDMA HCl salt from R - MDMA free base The free base of R-MDMA (active charge: 3.98 g) was placed in a 100 ml container. Water (0.84 ml) and IPA (22.39 ml) were added, and the mixture was heated to 70 °C to form a pale yellow solution. After reaching the predetermined temperature, IPA containing HCl (4.4 M, 4.77 ml) was added to the container over 1 hour, and then the line was rinsed with IPA (0.5 volume, 2 ml). After the addition of the acid, the solution was stirred for 30 minutes and then cooled to 58 °C. Seeds were added to the solution and it was developed. The resulting suspension was cooled to 0 °C. IPA was added to the container (6 ml, total volume 1.5 volumes) and stirred for 2 hours. The solid was filtered and dried in vacuo at 60 °C for 18 hours. A white solid (3.74 g, 79.4%) was obtained. HPLC: 100.0%. 1 The 1H NMR is consistent with the expected structure.

[0027] Example 9. Preparation of S-MDMA Stage 1 - (R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (8) S-MDMA Stage 1 was carried out on a 90 g scale according to the process described in Example 1 using R-propylene oxide instead of S-propylene oxide. The material was purified by distillation (instead of WFE distillation due to the small scale) to produce 62.32 g of a pale blue oil with an HPLC purity of 98.1% (yield 77%, target = 78%). 1 The 1H NMR is consistent with the expected structure. NMR assay = 100%

[0028] Example 10. Preparation of S-MDMA Stage 2 - (R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate (9) S-MDMA Stage 2 was carried out on a 60 g scale according to the process described in Example 2 to obtain 84.94 g of a brown oil with an HPLC purity of 97.8%. An NMR assay = 85% and an active yield of 72.20 g (yield 85%) was obtained (target = 80%).

[0029] Example 11. Preparation of (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-amine (11) at Stage 4 of S-MDMA Stages 3 and 4 of S-MDMA were carried out on an 84.9 g scale according to the process described in Example 3 to obtain 45.81 g (yield 88%, target = 80%) of a yellow oil (HPLC purity 99.0%). Chiral purity 99.0%, 98.0% ee.

[0030] Example 12. Preparation of ethyl (S)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (12) at Stage 5 of S-MDMA Stage 5 of S-MDMA was carried out on a 45.7 g scale according to the process described in Example 4 to obtain 60.05 g (yield 83%, target = 92%) of a white solid (HPLC purity 99.6%). 1 1H NMR is consistent with the predicted structure.

[0031] Example 13. Preparation of (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine (13) at Stage 6 of S-MDMA Stage 6 of S-MDMA was carried out on a 60.0 g scale according to the process described in Example 5 to obtain 36.80 g as a pale yellow oil (HPLC purity 98.3% (Figure 9), chiral purity 99.7% (99.4% ee, Figure 10). 1 1H NMR (Figure 11) and MS are consistent with the predicted structure. The free base 13 of S-MDMA can be converted into salts of S-MDMA such as hydrochloride (14) according to the processes described in Examples 6 to 8.

[0032] Throughout this application, various publications, including U.S. patents, are referenced by author, year, and patent number. The complete citations of the publications are listed below. For the purpose of more fully explaining the current state of the art related to the present invention, the disclosures of these publications and patents are hereby incorporated by reference in their entirety into this specification.

[0033] The present invention is described illustratively, and it should be understood that the terminology used is intended to be of the nature of words stated rather than of limitation.

[0034] Obviously, many modifications and variations of the present invention are possible in light of the above teachings. Therefore, within the scope of the appended claims, it is understood that the invention can be practiced otherwise than as specifically described.

Claims

**Claim 1** A method for producing R - MDMA according to the steps shown in FIG. 3, comprising: forming a Grignard reagent from 5 - bromobenzodioxole; treating the Grignard reagent with S - propylene oxide to form the chiral pure alcohol (S) - 1 - (benzo[d][1,3]dioxol - 5 - yl)propan - 2 - ol (1); activating the alcohol as the mesylate (S) - 1 - (benzo[d][1,3]dioxol - 5 - yl)propan - 2 - yl methanesulfonate (2); converting the mesylate to the chiral pure azide ((R) - 5 - (2 - azidopropyl)benzo[d][1,3]dioxole) (3); reducing the azide to the amine (R) - 1 - (benzo[d][1,3]dioxol - 5 - yl)propan - 2 - amine) (4); protecting the amine as ethyl (R) - (1 - (benzo[d][1,3]dioxol - 5 - yl)propan - 2 - yl)carbamate (5); reducing the protected amine to produce the R - MDMA free base ((R) - 1 - (benzo[d][1,3]dioxol - 5 - yl) - N - methylpropan - 2 - amine) (6); treating the free base with an acid to form a salt of (R) - 1 - (benzo[d][1,3]dioxol - 5 - yl) - N - methylpropan - 2 - amine with > 99% enantiomeric excess. The method as described above. **Claim 2** The method according to claim 1, further defined in that the protecting step is to protect the amine with a compound selected from the group consisting of di - tert - butyl dicarbonate and ethyl chloroformate. **Claim 3** wherein the reduction step further comprises reducing the protected amine 5 with LiAlH ４ as defined in claim 1. **Claim 4** The method according to claim 1, wherein the salt formed in the treating step is selected from the group consisting of hydrochloride, hydrobromide, maleate, L - malate, D - tartrate, meso - tartrate, citrate, phosphate, naphthylene - 1,5 - disulfonate, fumarate, sulfate, mesylate, acetate, and oxalate. **Claim 5** The method according to claim 1, which provides R - MDMA with a total yield of at least 30%. **Claim 6** The method according to claim 1, further comprising the step of converting the amine 4 to a salt for purification or storage. **Claim 7** The method according to claim 6, wherein the salt is (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride (7).

8. A method for producing S-MDMA according to the steps shown in Figure 4, comprising: forming a Grignard reagent from 5-bromobenzodioxole; treating the Grignard reagent with R-propylene oxide to form chiral pure (R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (8); activating the alcohol (8) as mesylate (R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ylmethanesulfonate (9); converting the mesylate (9) to chiral pure azide ((S)-5-(2-azidopropyl)benzo[d][1,3]dioxole) (10); reducing the azide (10) to amine ((S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-amine) (11); protecting the amine (11) with di-tert-butyl dicarbonate as ethyl (S)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (12); reducing the protected amine (12) to produce S-MDMA free base ((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine) (13); treating with an acid to form a salt of (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine with >99% enantiomeric excess.

9. The method according to claim 8, wherein the protecting step is further defined as protecting the amine with a compound selected from the group consisting of di-tert-butyl dicarbonate and ethyl chloroformate.

10. wherein the reduction step further comprises reducing the protected amine 5 with LiAlH ４ as defined in claim 8.

11. The method according to claim 8, wherein the salt formed in the treating step is selected from the group consisting of hydrochloride, hydrobromide, maleate, L-malate, D-tartrate, meso-tartrate, citrate, phosphate, naphthalene-1,5-disulfonate, fumarate, sulfate, mesylate, acetate, and oxalate.

12. The method according to claim 8, which provides S-MDMA with a total yield of at least 30%.

13. The method according to claim 8, further comprising the step of converting the amine 11 into a salt for purification or storage.

14. The method according to claim 13, wherein the salt is (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride (14).

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