Method for manufacturing R-MDMA
Through a 7-step synthesis method, the existing R-MDMA synthesis method is solved, and the problem of low yield and inappropriate large-scale pharmaceuticals is achieved, efficient, robust and scalable R-MDMA synthesis is achieved, with product purity reaching >99%.
Patent Information
- Application Number
- CN202380064568.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-07-08
- Filing Date
- 2023-06-29
- Publication Date
- 2025-05-13
AI Technical Summary
Existing R-MDMA synthesis methods have low yields, use of demanding reagents and/or conditions, and are not suitable for large-scale pharmaceutical applications, making it difficult to achieve efficient, robust and scalable synthesis.
Through a 7-step synthesis method, Grignard reagent was formed using 5-bromobenzodioxolene, and a series of reactions were carried out with S-propylene oxide, methanesulfonate, azide, reducing agent, etc., and finally obtain chiral pure R-MDMA, achieving an optical purity of >99%.
It achieves efficient, robust and scalable R-MDMA synthesis, with a total yield of more than 30%, no chromatography or recrystallization required, and a product purity of >99%, making it suitable for large-scale pharmaceutical applications.
Smart Images
Figure CN119998433A_ABST
Abstract
Description
Background of the Invention 1. Technical Field
[0002] The present invention relates to a method for producing R-MDMA. 2. Background technology
[0003] 3,4-Methylenedioxymethamphetamine (MDMA) is a mood-altering and perception-altering psychoactive drug that has been studied as an adjunct to psychotherapy for post-traumatic stress disorder (PTSD), social anxiety, 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 to treat a range of other medical conditions in the future. Such conditions for which MDMA or related substances may be useful include, but are not limited to, substance use disorders, depression, anxiety disorders (including social anxiety), anxiety with life-threatening illness, personality disorders (including narcissistic and antisocial disorders), autism and other developmental disorders, and obsessive-compulsive disorder. MDMA or related substances may also be used to augment individual or couples therapy.
[0004] There are some side effects and safety issues about MDMA. Abuse of MDMA may lead to hyperthermia, neurocognitive deficits, and increase the incidence of depression. MDMA may also have neurotoxicity, which limits its ability to be used chronically with repeated administration. The use of MDMA usually impairs declarative memory, prospective memory, and advanced cognitive skills. Neurocognitive deficits are associated with a reduction in SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown that brain activity is locally reduced during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skills, tremors, neurohormonal activity, and mental state have also been confirmed. The larger the dose or the longer the use time, the more obvious these effects are. (Parrott, Neuroscience & Biobehavioral Reviews, Vol. 37, No. 8, 2013, pp. 1466-1484).
[0005] MDMA has two enantiomers, S(+)-MDMA and R(-)-MDMA. The R enantiomer is considered to be more active (Nichols et al., J. Med. Chem. 1986, 29, 2009-2015). It is believed that the neurotoxicity of racemic MDMA is caused by the S(+) enantiomer rather than the R(-) enantiomer because the R(-) enantiomer is less effective as a dopamine releaser. The R(-) enantiomer also does not produce high fever. The risk of abuse of the R(-) enantiomer may be lower. (Pitts et al., Psychopharmacology (2018) 235: 377-392). It has been shown that the enantiomers have different effects. The effects of R-MDMA and S-MDMA were evaluated in an animal model of Parkinson's disease (Huot et al., The Journal of Neuroscience, May 11, 2011, 31(19): 7190–7198), and it was found that R-MDMA, as a 5-HT2A receptor selective compound, reduced the severity of peak dose dyskinesia and increased the duration of good ON-time; S-MDMA, which exhibited high affinity for SERT and moderate affinity for DAT, prolonged the duration of total ON-time but exacerbated dyskinesia. This suggests that racemic MDMA can simultaneously play a role in reducing dyskinesia and prolonging ON-time, and these two effects are produced by 5-HT2A antagonism from its R and S enantiomers and SERT selective mixed monoamine uptake inhibition, respectively. Therefore, the use of R-MDMA in treatment can be advantageous.
[0006] In order to use R-MDMA in therapy, it must first be obtained efficiently and in a substantially pure form. A chiral resolution of racemic MDMA has been performed to obtain R-MDMA (Taschwer, Magdalena; Seidl, Yvonne; Mohr, Stefan; Schmid, Martin G., Chirality, 2014, Vol. 26, No. 8, pp. 411–418). Enantioselective syntheses of R-MDMA have been performed, such as Figure 1As shown in (DENichols, AJ Hoffman, RAOberlender, P. Jacob, AT 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 method requires 8 steps to obtain compound 2a with a total yield of 23%. S. Llabrés et al. (European Journal of Medicinal Chemistry 81 (2014) 35-46) teach a method comprising 7 steps. Based on the final product on a scale of 100 mg, the total yield of the free base is 32% and the enantiomeric excess (ee) is 99%. This method utilizes nitromethane and 2 times of silica purification. Neajdenko et al. teach Figure 2 Another method shown in (The Journal of Neuroscience, May 11, 2011, 31(19):7190-7198). However, these methods all provide low yields, use harsh reagents and / or conditions, and / or require chromatographic purification, which are not suitable for large-scale pharmaceutical use.
[0007] Therefore, there remains a need for an efficient, robust, and scalable R-MDMA synthesis method for drug development that can deliver >99% ee. Summary of the invention
[0008] The present invention provides a method for producing R-MDMA, such as Figure 3, is carried out by the following steps: formation of the Grignard reagent from 5-bromobenzodioxole, treatment of the Grignard reagent with S-propylene oxide to form chirally pure 1 ((S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol), activation of the alcohol to the mesylate 2 ((S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate), conversion to the chirally pure azide 3 ((R)-5-(2-azidopropyl)benzo[d][1,3]dioxole), reduction of the azide to the amine 4 ((R)-1-(benzo[d][1,3] [d][1,3]dioxol-5-yl)propan-2-yl)carbamate), protecting the amine with di-tert-butyl dicarbonate to form protected amine 5 ((R)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)ethyl carbamate), reducing protected amine 5 to give R-MDMA free base 6 ((R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine), and treating with acid to form a salt such as 7 (7-(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride), >99% ee.
[0009] The present invention provides a method for preparing S-MDMA, such as Figure 4 , which proceeds by the following steps: formation of the Grignard reagent from 5-bromobenzodioxole, treatment of the Grignard reagent with R-propylene oxide to form chirally pure 8 ((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol), activation of the alcohol to the mesylate 9 ((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate), conversion to the chirally pure azide 10 ((S)-5-(2-azidopropyl)benzo[d][1,3]dioxole), reduction of the azide to the amine 11 ((S)-1-(benzo[d][1,3] [d][1,3]dioxol-5-yl)propan-2-yl)carbamate), protecting the amine with di-tert-butyl dicarbonate to form protected amine 12 ((S)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate), reducing protected amine 12 to give S-MDMA free base 13 ((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine), and treating with acid to form a salt such as 14 ((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride), >99% ee. BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Other advantages of the present invention will be better understood and readily appreciated by referring to the following detailed description when considered in conjunction with the accompanying drawings, in which:
[0011] Figure 1 It is a reaction schematic diagram of the prior art;
[0012] Figure 2 It is a reaction schematic diagram of the prior art;
[0013] Figure 3 is a schematic diagram of a reaction for producing R-MDMA of the present invention;
[0014] Figure 4 is a schematic diagram of a reaction for producing S-MDMA of the present invention;
[0015] Figure 5 is the HPLC chromatogram of recrystallized R-MDMA HCl;
[0016] Figure 6 is the chiral HPLC chromatogram of recrystallized R-MDMA HCl;
[0017] Figure 7 It is the recrystallized R-MDMA HCl 1 H NMR spectroscopy;
[0018] Figure 8 is the combined DSC / TGA of recrystallized R-MDMA HCl;
[0019] Fig. 9 is the HPLC chromatogram of S-MDMA;
[0020] Fig.10 is a chiral HPLC chromatogram of S-MDMA; and
[0021] Fig.11 It is S-MDMA 1 H NMR spectroscopy. DETAILED DESCRIPTION
[0022] The present invention provides a method for producing and synthesizing R-MDMA or S-MDMA. In general, the method of R-MDMA is as follows: Figure 3 As shown, the S-MDMA method is as follows Figure 4 This method uses 7 steps with an overall yield of greater than 30% at a 2 kg scale.
[0023] In general, the Grignard reagent is formed from 5-bromobenzodioxole, which is then treated with S-propylene oxide to form chirally pure 1((S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol). The alcohol is activated to the mesylate 2((S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate), which is then converted to chirally pure 3((R)-5-(2-azidopropyl)benzo[d][1,3]dioxole). The azide is reduced to 4((R)-1-(benzo[d][1,3]dioxol-5-yl)propane-2-amine), and the resulting amine is protected with di-tert-butyl dicarbonate to give 5((R)-(1-(benzo[d][1,3]dioxol-5-yl)propane-2-yl)ethylcarbamate). The Boc protected amine is reduced to give R-MDMA free base (6) ((R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine), which is treated with acid to form a salt (7) (such as (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine hydrochloride) with >99% ee. Applicants have achieved >99.9% ee on a >100 g scale.
[0024] This method has several advantages over the prior art. This is a scalable method that utilizes standard pharmaceutical manufacturing reagents and processes and commercially available starting materials. Chirality is introduced in the first step and chiral purity is maintained at >99% throughout the synthesis. Process impurities are minimal and product purity is >99A%, without any chromatography or recrystallization, although recrystallization can be used if desired. The method does not use ICH Class 1 solvents or ICH Class 1 or Class 2 metal catalysts. Although sodium azide is utilized in the method, this reagent and azide intermediate can be safely handled by those experienced in the art. In stage 2, MsCl can be used instead of MsO2. If necessary, the amine produced in stage 4 can be converted to a salt for purification or storage. In stage 5, other protecting groups (i.e., ethyl chloroformate) can be used instead of Boc2O, although Boc2O is preferred and Fmoc-Cl and benzyl chloroformate did not give acceptable results. Reducing agents other than LiAlH4 (lithium aluminum hydride) can be used in stage 6.
[0025] Alternative salts can be produced by replacing HCl with other acids to obtain hydrobromide, maleate, L-malate, D-tartrate, meso-tartrate, citrate, phosphate, naphthalene-1,5-disulfonate, fumarate, sulfate, methanesulfonate, 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 method by, for example, Figure 4 As shown, S-propylene oxide is replaced with R-propylene oxide in stage 1. Therefore, a method for producing S-MDMA is also provided, which is carried out by the following steps: forming a Grignard reagent from 5-bromobenzodioxole, treating the Grignard reagent with R-propylene oxide to form a chirally pure 8 ((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol), activating the alcohol to a mesylate 9 ((R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate), converting to a chirally 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-yl)carbamate), protecting the amine with di-tert-butyl dicarbonate to give 12 ((S)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)ethyl carbamate), reducing the protected amine to give S-MDMA free base 13 ((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine), and treating with acid to form salt 14 (such as (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride) with >99% ee.
[0026] The present invention is further described in detail by reference 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 never be interpreted as being limited to the following examples, but should be interpreted as covering any and all variations that become apparent due to the teachings provided herein.
[0027] Example 1.
[0028] Stage 1 - Preparation of (S)-1-(Benzo[d][1,3]dioxol-5-yl)propan-2-ol (1)
[0029] Magnesium turnings (948g, 39.0mol, 1.1eq) and THF (28.5L) were mixed and heated to reflux. 5-bromo-1,3-benzodioxole (142g, 0.71mol, 0.02eq) was added once. The pre-prepared Grignard reagent (356.3ml) was added once, and initiation was observed after 10 minutes. The remaining 5-bromo-1,3-benzodioxole (6983g, 0.98eq, 34.74mol) was added dropwise over 1.5 hours while maintaining the temperature at 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 iodide (114.7g, 0.60mol, 0.02eq) was added once. (S)-Propylene oxide (2235 ml, 33.10 mol, 0.9 eq) dissolved in THF (2235 ml) was added dropwise at a rate of ~1.5 L / hr (total 3 hours, T<10°C). The reaction was stirred at 5°C for 30 minutes until complete by HPLC. The contents were divided into two equal portions for work-up.
[0030] Separation and post-processing (Part 1)
[0031] To a second jacketed vessel was added acetic acid (1220 ml) followed by 10% brine (4.8 L). Half of the reaction mass was transferred to the second vessel while maintaining T < 40°C. The contents were stirred at 40°C for 1 hour and then left overnight to allow the phases to separate. The lower aqueous phase was removed from the vessel and the upper organic phase was retained in the vessel. Heptane (7.3 L) and 10% brine (7.1 L) were added in one portion and stirred at 30°C for 40 minutes. The phases were separated from the vessel. The upper organic layer was filtered and washed with heptane (2 L).
[0032] The second portion was worked up following the same procedure as portion 1. The organics from each workup portion were combined and concentrated to give a crude oil.
[0033] WFE Distillation
[0034] The crude oil was diluted with PEG400 (800 ml) and distilled on a wiped film evaporator (three passes). Each pass was analyzed by HPLC, chiral LC and NMR. Pass 1: HPLC 92.9%, NMR analysis (CDCl3) 95%, chiral purity 99.4%, active substance = 3384 g. Pass 2: HPLC 96.3%, NMR analysis 99%, chiral purity 99.4%, active substance = 1598 g. Pass 3: HPLC 98.0%, NMR analysis 97%, chiral purity 99.6%, 99.2% ee, active substance = 231.3 g. Total yield = 5414 g (5214 g active substance, 80%).
[0035] Example 2.
[0036] Stage 2 - Preparation of (S)-1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate (2)
[0037] 1 (1300.8 g, 95% effective, 6.86 mol, 1 eq) and EtOAc (12.4 L) were added to the reactor to give a clear solution. Methanesulfonic anhydride (1800 g, 10.33 mol, 1.2 eq) was added in batches over 10 minutes. The contents were cooled to 6 ° C and triethylamine (2.04 L, 14.63 mol, 1.5 eq) was added dropwise over 3 hours. The contents were sampled by HPLC after 20 minutes. IPC 1: 0.8% 1, 98,5% 2. Water (3.7 L) was added once and stirred for 10 minutes. The agitator was stopped to allow each phase to stand for 5 minutes. The lower aqueous phase was removed by vacuum transfer. Water (3.7 L) was added once and stirred for 10 minutes. The agitator was stopped to allow each phase to stand for 10 minutes. The lower aqueous phase was removed by vacuum transfer. 10% saline solution (3.7 L, equivalent to 1 kg NaCl dissolved in 9 L water) was added and stirred for 10 minutes. The stirrer was stopped to allow the phases to settle and the layers to separate. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated. 2,3791.3 g were isolated as a brown oil. HPLC: 88.9%. 1 H NMR (CDCl3): consistent with the structure.
[0038] Example 3.
[0039] Stage 3 / 4 - Preparation of (R)-1-(Benzo[d][1,3]dioxol-5-yl)propane-2-amine (4)
[0040] The reactor was charged with the second stage material (770 g crude material, 81% effective, 2.41 mol, 1 eq) and DMF (2.7 L). Sodium azide (230.2 g, 35.54, 1.4 eq) was added at one time. The contents were heated to 60 ° C for 45 minutes and stirred overnight. The contents were cooled to 15 ° C and water (3.4 L) was added dropwise for 45 minutes. The phases were separated and the aqueous phase was treated with TBME (1.35 L). The phases were allowed to stand and the aqueous phase was removed. 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 added to the container. The phases were allowed to stand and separated. The organic layer was washed with water (3.4 L) and the aqueous layer was removed. Organic layer analysis showed <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 eq) was added in batches over 1 hour. The contents were stirred and cooled to 15 ° C after 24 hours. Analysis showed 87.5% of 4, and no 3 remained. Water (1.9 L) was added once, and then concentrated HCl (250 ml) was added dropwise over 40 minutes. Each phase was separated and the aqueous phase was washed with isopropyl acetate (3 x 1.9 L). 85% KOH (315 g) was added in batches 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 give 4 = 383.6 g as a brown oil. HPLC: 98.8%. Chiral purity: 99.3%, 98.6% ee NMR analysis (CDCl3): 96%, effective yield = 368.3 g (85% yield).
[0041] Example 4.
[0042] Stage 5 - Preparation of (R)-(1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (5)
[0043] 4 (1691 g crude, 95% effective, 8.93 mol, 1 eq) and THF (4 L) were added to the 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, and the contents were heated to room temperature (RT) and stirred until the reaction was complete by HPLC detection. The crude reaction was concentrated by rotary evaporator to obtain a beige solid, which was dried at 40 ° C to obtain 2297.6 g. HPLC: 98.9 area%. NMR analysis (CDCl3): 97%. Effective yield = 2228.7 g (89% yield).
[0044] Example 5.
[0045] Stage 6 - Preparation of (R)-1-(Benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine (6)
[0046] Add 5 (572 g, 97% effective, 1.99 mol, 1 eq) and THF (1.1 L) to the reactor. Cool the resulting solution to 10 ° C, and add 1M LiAlH4 (4.44 L, 4.44 mol, 2.2 eq) dropwise. Heat the contents to 40 ° C and stir until HPLC detection is complete. Add MTBE (2.78 L) in one go, and cool the contents to 0 ° C. Add water (166 ml) dropwise over 1 hour. Add 15% NaOH (166 ml, equivalent to dissolving 150 g NaOH in 850 ml water) dropwise over 20 minutes. Add water (500 ml) dropwise over 15 minutes. Heat the contents to 20 ° C and stir for 2 hours. Add magnesium sulfate (677 g) in batches over 10 minutes: +5 ° C exotherm. Stir the contents at 20 ° C for 1 hour. Filter the contents, wash with MTBE (0.5 L), and drain. The filtrate was dried over magnesium sulfate and filtered. The dry filtrate was concentrated by rotary evaporation to give an amber oil = 324.5 g: bath temp = 40°C. HPLC: 98.0% stage 6. NMR analysis (CDCl3): 97%. Effective yield = 314.8 g (82% yield).
[0047] Example 6.
[0048] Stage 7 - Preparation of (R)-1-(Benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine hydrochloride (7)
[0049] The reactor was charged with 6 (1227.1 g, 95% active, 6.09 mol, 1 eq) and IPA (9.47 L). 5-6 M HCl in IPA (1023 ml, 5.77 mol, 1 eq) was added dropwise. The resulting solid was isolated by filtration, washed with the mother liquor, then with IPA (300 ml), and dried under vacuum to give a white solid. Dry matter = 1231 g. HPLC: 99.4% ( Figure 5 ). Chiral purity: 99.6% ( Figure 6 ), 99.2%ee 1 H NMR ( Figure 7 ) and MS were consistent with the expected structure.
[0050] Example 7.
[0051] Recrystallization of R-MDMA HCl
[0052] R-MDMA HCl (150 g) was added to 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 in a preheated container and balanced at 70°C for 30 minutes. The temperature was lowered to 55-60°C and R-MDMA HCl mode A was added for seeding and allowed to develop for 15 minutes, during which time the formation of a suspension was observed. The suspension was then cooled to 0°C. Two volumes of IPA were added. After balancing for about 2 hours, the suspension was filtered. The filter cake was washed with 1 volume of cold IPA and the solid (wet material 155 g) was vacuum dried at 60°C for 18 hours (dry material 137.7 g, yield 91.8%). HPLC: 100.0%. Chiral purity: 100%, 100% ee. 1 H NMR was consistent with the expected structure. Figure 8 Shown are the DSC and TGA thermograms of Pattern A of R-MDMA HCl recrystallized from IPA / water.
[0053] Example 8.
[0054] Direct preparation of crystalline R-MDMA HCl salt from R-MDMA free base
[0055] R-MDMA free base (effective amount: 3.98g) was added to a 100ml container. Water (0.84ml) and IPA (22.39ml) were added and the mixture was heated to 70°C to form a light yellow solution. After reaching the temperature, HCl (4.4M, 4.77ml) in IPA was added to the container over a period of 1 hour, and then the pipeline was flushed with IPA (0.5 volume, 2ml). After adding the acid, the solution was stirred for 30 minutes and then cooled to 58°C. The solution was seeded and developed. The resulting suspension was cooled to 0°C. IPA was added to a container (6ml, 1.5 volumes in total) and stirred for 2 hours. The solid was filtered and dried in vacuo at 60°C for 18 hours. A white solid (3.74g, 79.4%) was obtained. HPLC: 100.0%. 1 H NMR was consistent with the expected structure.
[0056] Example 9.
[0057] Preparation of S-MDMA Phase 1 - (R)-1-(Benzo[d][1,3]dioxol-5-yl)propan-2-ol (8)
[0058] S-MDMA Stage 1 was carried out as described in Example 1 on a 90 g scale using R-propylene oxide instead of S-propylene oxide. This material was purified by distillation (instead of WFE distillation due to smaller scale) to give 62.32 g of a light blue oil (77% yield, target = 78%) with 98.1% HPLC purity.1 H NMR is consistent with the expected structure. NMR analysis = 100%
[0059] Example 10.
[0060] Preparation of S-MDMA Phase 2 - (R)-1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl methane sulfonate (9)
[0061] S-MDMA Stage 2 was run as described in Example 2 on a 60 g scale to give 84.94 g of a brown oil with 97.8% HPLC purity. NMR analysis = 85%, effective yield 72.20 g, 85% yield (target = 80%).
[0062] Example 11.
[0063] Preparation of S-MDMA Phase 4 - (R)-1-(Benzo[d][1,3]dioxol-5-yl)propane-2-amine (11)
[0064] S-MDMA Stages 3 and 4 were carried out as described in Example 3 on a 84.9 g scale to give 45.81 g (88% yield, target = 80%) of a yellow oil with 99.0% HPLC purity, 99.0% chiral purity, 98.0% ee.
[0065] Example 12.
[0066] S-MDMA Stage 5 - Preparation of (S)-(1-(Benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamic acid ethyl ester (12)
[0067] S-MDMA Stage 5 was carried out as described in Example 4 on a 45.7 g scale to give 60.05 g (83% yield, target = 92%) of a white solid with HPLC purity of 99.6%. 1 H NMR was consistent with the expected structure.
[0068] Example 13.
[0069] S-MDMA Stage 6 - Preparation of (S)-1-(Benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine (13)
[0070] S-MDMA Stage 6 was carried out as described in Example 5 on a 60.0 g scale to give 36.80 g of a pale yellow oil with a HPLC purity of 98.3% ( Fig. 9 ), chiral purity is 99.7% (99.4% ee, Fig.10 ).1 H NMR ( Fig.11 ) and MS were consistent with the expected structure. S-MDMA free base 13 can be converted to S-MDMA salts, such as the hydrochloride salt (14), by the methods described in Examples 6 to 8.
[0071] Throughout this application, various publications (including U.S. patents) are cited by author and year, and patents are cited by number. The full citations of the publications are listed below. These publications and patents are incorporated into this application by reference with their full disclosures to more fully describe the state of the art in the field to which the invention belongs.
[0072] The present invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation.
[0073] Obviously, many modifications and variations of the present invention are possible in light of the above teachings.It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.
Claims
1. A method for producing R-MDMA by the steps shown in FIG3 , the method comprising the following steps: Formation of Grignard reagent from 5-bromobenzodioxole; Treating the Grignard reagent with S-propylene oxide to form the chirally pure alcohol (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1); activating the alcohol to the mesylate (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate (2); converting the mesylate to the chirally 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)propane-2-amine (4); Protecting the amine as (R)-ethyl(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (5); Reducing the protected amine to provide R-MDMA free base ((R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine) (6); and The free base was treated with acid to form the salt of (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine in >99% enantiomeric excess.
2. The method of claim 1, 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.
3. The method of claim 1, wherein the reducing step is further defined as reducing the protected amine 5 with LiAlH4.
4. The method of 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, naphthalene-1,5-disulfonate, fumarate, sulfate, methanesulfonate, acetate and oxalate.
5. The method of claim 1, wherein the method provides an overall yield of R-MDMA of at least 30%.
6. The method of claim 1, further comprising the step of converting the amine 4 into a salt for purification or storage.
7. The method of claim 6, wherein the salt is (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine hydrochloride (7).
8. A method for producing S-MDMA by the steps shown in FIG. 4, the method comprising the following steps: Formation of Grignard reagent from 5-bromobenzodioxole; treating the Grignard reagent with R-propylene oxide to form chirally pure (R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (8); activating the alcohol (8) to the mesylate (R)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl methanesulfonate (9); The mesylate (9) is converted into the chirally pure azide ((S)-5-(2-azidopropyl)benzo[d][1,3]dioxole) (10); Reducing the azide (10) to the amine (S)-1-(benzo[d][1,3]dioxol-5-yl)propane-2-amine (11); The amine (11) is protected as (S)-(1-(benzo[d][1,3]dioxol-5-yl)propan-2-yl)carbamate (12) with di-tert-butyl dicarbonate; Reducing the protected amine (12) to provide S-MDMA free base ((S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine) (13); and Treatment with acid formed the salt of (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine in >99% enantiomeric excess.
9. The method of 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. The method of claim 8, wherein the reducing step is further defined as reducing the protected amine 5 with LiAlH4.
11. The method of 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, methanesulfonate, acetate and oxalate.
12. The method of claim 8, wherein the method provides an overall yield of S-MDMA of at least 30%.
13. The method of claim 8, further comprising the step of converting the amine 11 into a salt for purification or storage.
14. The method of claim 13, wherein the salt is (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-methylpropane-2-amine hydrochloride (14).