AU2021106190A4 - Improved method of synthesis of 1-(3’,4’-methylene dioxyphenyl)-2-(methylamino) propane (mdma) - Google Patents
Improved method of synthesis of 1-(3’,4’-methylene dioxyphenyl)-2-(methylamino) propane (mdma) Download PDFInfo
- Publication number
- AU2021106190A4 AU2021106190A4 AU2021106190A AU2021106190A AU2021106190A4 AU 2021106190 A4 AU2021106190 A4 AU 2021106190A4 AU 2021106190 A AU2021106190 A AU 2021106190A AU 2021106190 A AU2021106190 A AU 2021106190A AU 2021106190 A4 AU2021106190 A4 AU 2021106190A4
- Authority
- AU
- Australia
- Prior art keywords
- mdma
- reaction
- mdp2p
- nitropropene
- mdp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 title claims description 8
- 230000015572 biosynthetic process Effects 0.000 title abstract description 30
- 238000003786 synthesis reaction Methods 0.000 title abstract description 17
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229940081310 piperonal Drugs 0.000 claims abstract description 29
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000009833 condensation Methods 0.000 claims abstract description 14
- 230000005494 condensation Effects 0.000 claims abstract description 14
- 238000006400 oxidative hydrolysis reaction Methods 0.000 claims abstract description 14
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 94
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 9
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 description 29
- 239000002585 base Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 21
- 239000006227 byproduct Substances 0.000 description 20
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 18
- 239000003814 drug Substances 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 17
- 229960000583 acetic acid Drugs 0.000 description 16
- ZMQAAUBTXCXRIC-UHFFFAOYSA-N safrole Chemical compound C=CCC1=CC=C2OCOC2=C1 ZMQAAUBTXCXRIC-UHFFFAOYSA-N 0.000 description 16
- SHXWCVYOXRDMCX-MRVPVSSYSA-N (2r)-1-(1,3-benzodioxol-5-yl)-n-methylpropan-2-amine Chemical compound CN[C@H](C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-MRVPVSSYSA-N 0.000 description 15
- SHXWCVYOXRDMCX-QMMMGPOBSA-N (2s)-1-(1,3-benzodioxol-5-yl)-n-methylpropan-2-amine Chemical class CN[C@@H](C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-QMMMGPOBSA-N 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 239000002775 capsule Substances 0.000 description 11
- 238000001671 psychotherapy Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000012535 impurity Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 229910052742 iron Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000010626 work up procedure Methods 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000006845 Michael addition reaction Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 208000020016 psychiatric disease Diseases 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- PKRWWZCDLJSJIF-UHFFFAOYSA-N Piperonylonitrile Chemical compound N#CC1=CC=C2OCOC2=C1 PKRWWZCDLJSJIF-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000007144 microwave assisted synthesis reaction Methods 0.000 description 5
- 208000028173 post-traumatic stress disease Diseases 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 238000006842 Henry reaction Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 238000011172 small scale experimental method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- PVXVWWANJIWJOO-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-N-ethylpropan-2-amine Chemical compound CCNC(C)CC1=CC=C2OCOC2=C1 PVXVWWANJIWJOO-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- -1 glidant Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- RIHXMHKNTLBIPJ-UHFFFAOYSA-N 1-nitroprop-1-ene Chemical compound CC=C[N+]([O-])=O RIHXMHKNTLBIPJ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- HRTRXPZBWBBZNP-UHFFFAOYSA-N 5-(2-bromopropyl)-1,3-benzodioxole Chemical compound CC(Br)CC1=CC=C2OCOC2=C1 HRTRXPZBWBBZNP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- VHVOLFRBFDOUSH-NSCUHMNNSA-N Isosafrole Chemical compound C\C=C\C1=CC=C2OCOC2=C1 VHVOLFRBFDOUSH-NSCUHMNNSA-N 0.000 description 2
- VHVOLFRBFDOUSH-UHFFFAOYSA-N Isosafrole Natural products CC=CC1=CC=C2OCOC2=C1 VHVOLFRBFDOUSH-UHFFFAOYSA-N 0.000 description 2
- QMMZSJPSPRTHGB-UHFFFAOYSA-N MDEA Natural products CC(C)CCCCC=CCC=CC(O)=O QMMZSJPSPRTHGB-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 102100029469 WD repeat and HMG-box DNA-binding protein 1 Human genes 0.000 description 2
- 101710097421 WD repeat and HMG-box DNA-binding protein 1 Proteins 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000002996 emotional effect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000004312 hexamethylene tetramine Substances 0.000 description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000506 psychotropic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical class C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- LUWHVONVCYWRMZ-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-n-methylpropan-2-amine;hydron;chloride Chemical compound Cl.CNC(C)CC1=CC=C2OCOC2=C1 LUWHVONVCYWRMZ-UHFFFAOYSA-N 0.000 description 1
- IPVYMXZYXFFDGW-UHFFFAOYSA-N 1-methylpiperidin-4-ol;hydrochloride Chemical compound Cl.CN1CCC(O)CC1 IPVYMXZYXFFDGW-UHFFFAOYSA-N 0.000 description 1
- NGBBVGZWCFBOGO-UHFFFAOYSA-N 3,4-Methylenedioxyamphetamine Chemical compound CC(N)CC1=CC=C2OCOC2=C1 NGBBVGZWCFBOGO-UHFFFAOYSA-N 0.000 description 1
- XIYKRJLTYKUWAM-UHFFFAOYSA-N 3,4-methylenedioxyphenylpropan-2-one Chemical compound CC(=O)CC1=CC=C2OCOC2=C1 XIYKRJLTYKUWAM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 238000006547 Leuckart Thiophenol synthesis reaction Methods 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 102220594896 Vasopressin-neurophysin 2-copeptin_M20A_mutation Human genes 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 230000014061 fear response Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 230000009898 traumatic memory Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/52—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to an improved method of synthesis of 1-(3',4'
methylenedioxyphenyl)-2-(methylamino)propane (MDMA) that is of sufficient purity that it can
be used for pharmaceutical applications. In particular the present invention provides a method of
synthesising MDMA comprising the steps of (a) condensation of piperonal and
nitroethane in the presence of a catalysing base to form 1-(3',4'-methylenedioxyphenyl)-2
nitroprop-1-ene (MDP-2-nitropropene), (b) oxidative hydrolysis of MDP-2-nitropropene to form
1-(3',4'methylenedioxyphenyl)-propan-2-one (MDP2P), and (c) reductive amination of
MDP2P to 1-(3',4'-methylenedioxyphenyl)-2-(methylamino)propane (MDMA).
Description
Patents Act 1990
"IMPROVED METHOD OF SYNTHESIS OF 1-(3',4'-METHYLENE DIOXYPHENYL)-2-(METHYLAMINO) PROPANE (MDMA)"
This invention is described in the following statement:-
IMPROVED METHOD OF SYNTHESIS OF 1-(3',4'-METHYLENE DIOXYPHENYL)-2-(METHYLAMINO) PROPANE (MDMA)
[0001] The present invention relates to the field of organic synthesis.
[0002] In one form, the invention relates to an improved method of synthesising a pharmaceutically active organic compound.
[0003] Any discussion of material such as documents, devices, acts or knowledge in this specification is included to explain the context of the invention in terms of the inventor's knowledge and experience and, accordingly, any such discussion should not be taken as an admission that any of the material forms part of the prior art base or the common general knowledge in the relevant art in Australia, or elsewhere, on or before the priority date of the disclosure and claims herein.
[0004] It is to be appreciated that any discussion of documents, devices, acts or knowledge in this specification is included to explain the context of the present invention. Further, the discussion throughout this specification comes about due to the realisation of the inventor and/or the identification of certain related art problems by the inventor.
[0005] 3,4-Methylenedioxymethamphetamine, otherwise known as 1-(3',4' methylenedioxyphenyl)-2-(methylamino)propane (MDMA), is a psychoactive drug that acts primarily by increasing the activity of neurotransmitter substances such as serotonin, dopamine and noradrenaline in parts of the brain. Early synthesis of MDMA was reported in 1912 by Merck in German patent no. 274350 filed 24 Dec.1912. At that time, Merck was not interested in MDMA as a pharmaceutical in its own right and its pharmacological effects were not substantially investigated until the 1950s and 1960s.
[0006] Recreational use of MDMA developed substantially during the 1970's and 1980's. In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the United Nations Convention on Psychotropic Substances
(1971). By the end of the 1980s the use or possession of MDMA had been formally criminalised in many countries and most legitimate medical use had ceased by the 1990s.
[0007] Nonetheless, in recent times MDMA has been investigated for clinical use, including clinical applications for enhancing psychotherapy. Administration of purified MDMA in a therapeutic setting has been found to increase the effectiveness of psychotherapy techniques, such as revisiting traumatic experiences with an appropriate level of emotional engagement.
[0008] In 2017 the United States Food and Drug Administration approved limited research on MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), designating MDMA assisted psychotherapy as a Breakthrough Therapy after their assessment of preliminary results from Phase 2 clinical trials. A Phase 3 trial is currently underway in the United States. In recent times the Australian Therapeutic Goods Administration has issued a number of approvals for the use of MDMA as part of the psychotherapy for treatment of PTSD under its Special Access Scheme-B (SAS-B). The SAS-B allows certain health practitioners to access therapeutic goods that are not included in the Australian Register of Therapeutic Goods, for a single patient who is defined as seriously ill. MDMA is also being used under expanded access schemes in the United States, Switzerland and Israel.
[0009] Relevant studies are discussed for example in Bahji et al., Progress in Neuropsychopharmacology & Biological Psychiatry 96 (2020) 109735; Jerome et al., Psychopharmacology, https://doi.org/10.1007/s00213-020-05548-2; and Mitchell et al., Nature Medicine, https://doi.ort/10.1038/s41591-021-01336-3.
[0010] Some of the studies have been sizeable. A recently completed Phase 3 study had 98 participants (half placebo) and a large effect size. This followed from a Phase 2 trial which had a similar effect size. The size of the first Phase 3 trial is likely to be statistically relevant because of the large effect size of the Phase 2 trial. All other factors being equal, the large the effect size, the small the sample size require by the regulatory authorities. A second Phase 3 trial is anticipated.
[0011] However, legitimate studies are hampered due to a lack of licit, pharmacological quality MDMA. Even when a legitimate source is available in one country, the suite of United Nations Conventions against illicit trafficking of drugs and drug precursors also hampers access of licit transport across borders.
Chemistry
[0012] MDMA is in the class of chemicals known as substituted amphetamine or substituted methylenedioxyphenethylamines. As a free base, MDMA is a colourless oil that is insoluble in water. The most common salt of MDMA is the crystalline, water soluble hydrochloride salt. MDMA is usually obtained as a racemic mixture of (R)-MDMA and (S)-MDMA enantiomers having the following structures: oCH 3 o, ON O CH3
[0013] The original synthesis described in the Merck patent mentioned above involves an initial step of brominating safrole to form 1-(3,4-methylenedioxyphenyl)-2-bromopropane according to Reaction Scheme 1(a).
oCH2 HBr < CH 3 \ 0 Bray
safrole Reaction Scheme 1(a)
[0014] The 1-(3,4-methylenedioxyphenyl)-2-bromopropane is reacted (1) with Nal and hexamine, then (2) reacted with ammonia to form 3,4-methylenedioxyamphetamine (MDA). The MDA is (3) reacted methylamine to form MDMA, then (4) transformed to 3,4-methylenedioxy N-ethylamphetamine (MDEA) by reaction with ethylamine according to Reaction Scheme 1(b):
o CH 3 2) 1) Nal, hexamine Ammonia < CH 3
0 Br 3) Methylamine 0 N 4) ethylamine R H
1) MDA; R = H 2) MDA; R = H 3) MDMA; R =CH 3 4) MDEA; R =CH 3CH 2
Reaction Scheme 1(b)
Starting Materials
[0015] Piperonal and safrole are well known starting products for MDMA production.
[0016] The starting products are usually converted to an intermediate, (3,4 methylenedioxyphenyl)-2-propanone (MDP2P),depicted in Reaction Scheme 2:
0
piperonal CH3
o CH2 MDP2P
safrole Reaction Scheme 2
[0017] One conversion method includes isomerisation of safrole to isosafrole in the presence of a strong base, followed by oxidisation of the isosafrole to MDP2P. Another method uses the Wacker process to oxidize safrole directly to the MDP2P intermediate using a palladium catalyst according to Reaction Scheme 3:
OH2 MeOH OH3
+ PdCI 2 + reflux CI 00
Reaction Scheme 3
[0018] However, this reaction sequence has a number of drawbacks. It is difficult to source safrole for use in pharmaceutical synthesis, partly due to its listing as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. Furthermore, benzoquinone is hazardous to handle in large amounts and the palladium (II) catalyst is expensive.
[0019] Another problem is that the reaction produces competing aldehyde and ketone products. Specifically, the reaction generates a large proportion of an aldehyde by-product instead of the desired ketone. Separation of the aldehyde and ketone via sodium bisulphite extraction is possible, but the yield of ketone is poor.
Use of MDP2P Precursor
[0020] The majority of illicit MDMA synthesis is based on the use of MDP2P as a precursor. The first step utilises a Leuckart reductive amination of MDP2P in the presence of N-methyl formamide and formic acid to produce N-formyl-MDMA according to the Reaction Scheme 4:
o CH 3 CH 3NHCHO O CH3 K0 HCOOHOH 160 NC 9 hrs CH 3 X CHO
Reaction Scheme 4
[0021] The Leuckart reaction sequence is challenging to perform and requires carefully controlled heating.
[0022] The next step is acid mediated hydrolysis of N-formyl-MDMA, followed by pH adjustment to produce MDIA oil according to Reaction Scheme 5:
OH 3 HCI 0 H3 N12000 N CH 3 7 ' CHO 10 hrs CH3 H
Reaction Scheme 5
[0023] However, this reaction sequence provides a low yield of low purity MDMA. Licit commercial use of this reaction scheme is not practical due to the low yield and the cost of the extensive purification process to remove multiple impurities and by-products to achieve a pharmaceutically acceptable product.
[0024] Accordingly, there is an ongoing need for a commercially practical and economically viable method of obtaining pharmaceutically acceptable MDMA.
[0025] In one aspect the present invention seeks to provide an improved method of synthesising MDMA that is of sufficient purity that it can be used for pharmaceutical applications.
[0026] In another aspect the present invention provides an improved method of synthesising MDMA that is achievable using readily available reactants or which is at least commercially practical.
[0027] The present invention also seeks to overcome or alleviate at least one of the above noted drawbacks of related art syntheses or to at least provide a useful alternative to related art syntheses.
[0028] In its broadest form, a first aspect of embodiments of the present invention provides a method of synthesising MDMA, which includes both (R)-MDMA and (S)-MDMA, in high yield in three steps from piperonal starting material. Preferably the three steps comprise a condensation reaction, followed by oxidative hydrolysis to form MDP2P as an intermediate, then reductive amination.
[0029] In a second aspect of embodiments described herein there is provided a method of synthesising MDMA comprising the steps of;
(a) condensation of piperonal and nitroethane in the presence of a catalysing base to form 1-(3',4'-methylenedioxyphenyl)-2-nitroprop-1-ene (MDP-2 nitropropene),
(b) oxidative hydrolysis of MDP-2-nitropropene to form 1 (3',4'methylenedioxyphenyl)-propan-2-one(MDP2P),and
(c) reductive amination of MDP2P to 1-(3',4'-methylenedioxyphenyl)-2 (methylamino)propane(MDMA).
[0030] Optionally, the MDMA formed according to the above methods is converted to a pharmaceutically acceptable salt, preferably a hydrochloride salt - 1-(3',4' methylenedioxyphenyl)-2-(methylamino)propanehydrochloridemonohydrate(MDMA.HC).
[0031] Preferably, the yield of MDP-2-nitropropene from piperonal according to Step (a) is greater than 90%, more preferably greater than 95%.
[0032] Preferably, the yield of MDP2P from MDP-2-nitropropene according to Step (b) is greater than 75%, more preferably greater than 85%.
[0033] Preferably, the yield of MDMA from MDP2P according to Step (c) is at least 90%, more preferably 95%.
[0034] It has advantageously been found that the Step (a) condensation of piperonal and nitroethane in the presence of a catalysing base can be carried out in the absence of solvent to form MDP-2-nitropropene in high yield. This is contrary to previous teaching that the reaction must be carried out in the presence of an acid, such as an acid solvent. Preferably Step (a) comprises reacting piperonal and base in a mole ratio of 1:0.01- 2 of piperonal to catalysing base. This is preferably carried out in the presence of an excess of nitroethane, in a mole ratio of about 1:8 of piperonal to nitroethane, more preferably about 2:6 of piperonal to nitroethane.
[0035] Preferably, the catalysing base of Step (a) is an amine. It is preferred that the amine is a cycloamine such as cyclohexylamine or alkylamine such as ethylene diamine.
[0036] The Step (a) condensation is typically carried out at 115-125 °C, preferably about 120 °C. In a particularly preferred embodiment Step (a) is microwave assisted.
[0037] Preferably, Step (b) comprises oxidative hydrolysis of MDP-2-nitropropene in the presence of an excess of an oxidative catalyst. Contrary to prior art teaching that recommends a to 12 fold excess of catalyst, the present invention may be carried out using, for example, an iron catalyst in no more than a 5 fold excess.
[0038] Advantageously, the reactions of steps (b) and (c) may proceed at ambient temperature without requiring special heating or cooling conditions.
[0039] The intermediates formed during the synthesis Steps (a), (b), and (c) are all readily isolable solid materials and may be crystallised to reduce the content of impurities, without the need for recrystallisation or chromatography. However, preferably the MDP2P product of Step (b) and the MDMA product of Step (c) are recrystallised to further reduce unwanted by-products.
[0040] In a third aspect of embodiments described herein there is provided a method of producing MDMA according to the Reaction Scheme 6:
0 Step (a) Step (b)
<cC O H H NHCH2NO, NH2CH2CH2NH2 O2CH3 N))2 CHFeO FeCOH <0. OO CH3
Step (c)
o CH 3 CH 3 NH 2 CH NaBH 3CN O CH
O MeOH O MeOH O CH 3 CH H
Reaction Scheme 6
[0041] Step (c), the reductive amination of MDP2P to MDMA with sodium cyanoborohydride in the presence of methylamine hydrochloride, should be conducted at ambient temperature. It has been found that increasing the temperature of reaction is likely to cause the further, undesirable reduction of the ketone (MDP2P)to the corresponding alcohol 1-(3',4'-MDP)-2-propanol.
[0042] Preferably Step (c) comprises reacting MDP2P with a slight molar excess of sodium cyanoborohydride, in the presence of a large excess of methylamine hydrocholoride. Preferably the methylamine hydrochloride is present in a mole ratio of 10:12 of MDP2P to methylamine hydrochloride.
[0043] In a fourth aspect of embodiments described herein there is provided MDMA comprising (R)-MDMA and (S)-MDMA, produced according to any of the aforementioned methods.
[0044] In a fifth aspect of embodiments described herein there is provided a pharmaceutical composition comprising a therapeutically effective amount of MDMA, (R)-MDMA or (S) MDMA produced according to any of the aforementioned methods, and at least one pharmaceutically acceptable excipient.
[0045] In a sixth aspect of embodiments described herein there is provided a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of MDMA, (R)-MDMA or (S)-MDMA produced according to any of the aforementioned methods, and at least one pharmaceutically acceptable excipient.
[0046] In a seventh aspect of embodiments described herein there is provided the use of MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof produced according to any of the aforementioned methods in the preparation of a medicament for MDMA- assisted psychotherapy. The medicament may be used in combination with one or more other kinds of therapeutic agents and /or therapeutic methods for the treatment, amelioration and/or prevention of psychological disorders.
[0047] Typically, the medicament would be in the form of capsules containing a powder mix or tablets, typically pressed tablets. The powder mix for a capsule would typically include MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof combined with any excipients, such as binders, disintegrants, fillers, glidant and preservatives. The press mix for a tablet would typically include MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof combined with excipients, such as binders, disintegrants, fillers, glidant, lubricant and preservatives.
[0048] In an eighth aspect of embodiments described herein there is provided a method of treating, ameliorating and/or preventing a psychological disorder comprising administering to a subject in need thereof, a therapeutically effective amount of MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof, produced according to any of the aforementioned methods. The method may be used in combination with one or more other kinds of therapeutic agents and /or therapeutic methods for the treatment, amelioration and/or prevention of psychological disorders. A typical treatment regimen would include a patient receiving an initial dose of 1 to 250 mg, more typically 60 to 150 mg, preferably 80 to 120 mg, the exact amount depending on body mass. If the patient and clinician believe it would be helpful, after a couple of hours the patient may receive a subsequent dose of between 20 to 80 mg, 40mg to 60mg.
[0049] Other aspects and preferred forms are disclosed in the specification and/or defined in the appended claims, forming a part of the description of the invention.
[0050] In essence, embodiments of the present invention stem from the realization that it is possible to isolate high yields of MDMA from piperonal in three synthetically straightforward steps by careful control of the acid and base components of the synthesis. Specifically, it has been found that it is advantageous to use a first step involving condensation of piperonal and nitroethane in the presence of a base, but the absence of an acid. It has also been realised that careful control of the temperature of reaction advantageously avoids undesirable side reactions and much of the synthesis can be carried out at ambient temperature.
[0051] Advantages provided by the synthetic method of the present invention comprise the following:
• readily available and cost-effective precursors and reaction materials;
• provides desired compounds in useful yields; • improved production of MDP-2-nitropropene by removal of acid catalyst; • has a small number of synthetic steps; • piperonal (in contrast to safrole) is commercially available because it is used in other industries, notably the flavour and fragrance industries; • minimal side-reactions with concomitant reduction in by-products; • scalable; and * manageable chemical risks associated with reaction materials and methods.
[0052] Further scope of applicability of embodiments of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure herein will become apparent to those skilled in the art from this detailed description.
[0053] Further disclosure, objects, advantages and aspects of preferred and other embodiments of the present application may be better understood by those skilled in the relevant art by reference to the following description of embodiments taken in conjunction with the accompanying drawings, which are given by way of illustration only, and thus are not limitative of the disclosure herein, and in which:
Figure 1 illustrates spectral analyses for the condensation of piperonal and nitroethane in the presence of a cyclohexylamine base to form MDP-2-nitropropene as described in Example 1A including: Fig.lA - 1H NMR spectrum; Fig.1B - 1 3 C NMR spectrum
Figure 2 illustrates analyses for the condensation of piperonal and nitroethane in the presence of ethylenediamine base to form MDP-2-nitropropene as described in Example 1B including: Fig.2A - 1H NMR spectrum; Fig.2B - 1 3C NMR spectrum; Fig.2C - HPLC; Fig.2D - HPLC-MS; Fig.2E - HPLC-nMS 2 Collision energy -10 Volts; Fig.2F - HPLC-nMS 2 Collision energy -20 Volts; Fig.2G - HPLC-nMS 2 Collision energy -35 Volts;
Figure 3 illustrates analyses for the oxidative hydrolysis of MDP-2-nitropropene with iron to form MDP2-propanone as described in Example 2 including: Fig.3A- IH NMR spectrum; Fig.3B13 C NMR spectrum; Fig.3C - HPLC-UV; Fig.3D - HPLC-MS; Fig.3E - HPLC nMS 2 Collision energy -10 Volts; Fig.3F - HPLC-nMS 2 Collision energy -20 Volts; Fig.3G - HPLC-nMS 2 Collision energy -35 Volts;
Figure 4 illustrates analyses for the reductive amination of MDP2P with sodium cyanoborohydride in the presence of methylamine hydrochloride as described in Example 3 including: Fig.4A - 'H NMR spectrum; Fig.4B1 3 C NMR spectrum; Fig.4C - HPLC-UV; Fig.4D - HPLC-MS; Fig.4E - HPLC-nMS 2 Collision energy 10 Volts; Fig.4F - HPLC-nMS 2 Collision energy 20 Volts; Fig.4G - HPLC-nMS 2 Collision energy 35 Volts; Fig.4H HPLC-nMS 3 Collision energy -10 Volts; Fig.41 - HPLC-nMS 3 Collision energy -20 Volts; Fig.4J - HPLC-nMS 3 Collision energy -35 Volts;
Figure 5 illustrates analyses for the formation of the hydrochloride salt of MDMA from MDMA free base as described in Example 4 including: Fig.5A - 'H NMR spectrum; Fig.5B - 1 3C NMR spectrum; Fig.5C - HPLC-nMS 2 , collision energy -10 Volts; Fig.5D - HPLC
nMS 2 , collision energy -20 Volts; Fig.5E - HPLC-nMS 2, collision energy -35 Volts;
[0054] It is to be understood that the specific devices and processes illustrated in the attached Figures and described in the following specification are simply exemplary embodiments of the inventive concepts defined in the appended claims. Hence, specific physical characteristics relating to the embodiments disclosed herein are not to be considered as limiting, unless the claims expressly state otherwise.
[0055] The preparation of MDMA according to the present invention comprises subjecting piperonal to three steps, preferably a condensation step, followed by oxidative hydrolysis of the condensate, then reductive amination.
[0056] Preferably, the preparation of MDMA involves synthesis of MDP2P as intermediate.
Steps (a) & (b) - Preparation of MDP2P Intermediate
[0057] Piperonal is a preferred starting material because it is readily available in high purity and comparatively inexpensive.
[0058] In a preferred embodiment, the MDP2P is prepared by the following two steps; (a) condensation of piperonal and nitroethane in the presence of a catalysing base to form MDP-2-nitropropene, and
(b) oxidative hydrolysis of MDP-2-nitropropene with iron to form MDP2P.
[0059] This two-step reaction has the advantage of having a relatively simple reaction work up.
Step (a) - Condensation of piperonal
[0060] Preferably, the condensation step is a modified Henry reaction. The prior art as described in Yang et al. (2012) Chin.J.Chem. 30, 2827-2833 (DOI: 10.1002/cjoc. 20120194) teaches the use of ethylene diamine as a highly effective catalysing base for one-pot synthesis of aryl nitroalkenes via the Henry reaction.
[0061] Similarly, PiHKAL A Chemical Love Story by Shulgin and Shulgin, (1991) Transform Press describes the reaction of piperonal in glacial acetic acid with nitroethane in the presence of cyclohexylamine.
[0062] In respect to the present invention, as described at Example 1A and Example 1B, it has been found that the preferred catalysing base is an amine. It has further been found that in a particularly preferred embodiment the catalysing base is cyclohexylamine (as per the following Reaction Scheme 7 described at Example 1A)
0 NH 2 reflux 0 CH 3 H + CH3CH2NO2 + O 3COOH -.- 'C 00 C) NO 2
Reaction Scheme 7
or more preferably, ethylene diamine (as per the following reaction Scheme 8 described at Example 1B):
0 oNH 2 reflux 0CH 3 H + CH 3CH NO 2 2 + H2N N HReactonc 0 2 NO
Reaction Scheme 8
Step (b) - Oxidative Hydrolysis of MDP-2-nitropropene with Iron.
[0063] The second step comprises oxidative hydrolysis of MDP-2-nitropropene in acetic acid with iron catalyst to form MDP2P according to Reaction Scheme 9 as described at Example 2:
CH 3 Fe CH3
a O 2 CH 3COOH < Reaction Scheme 9
[0064] A number of prior art publications describe the general synthesis including Gallager et al. (2012) Forensic Sci. Int. Vol.223, Issues 1-3, 30 Nov. 2012, pp. 3 0 6 - 3 1 3 (DOI:http://dx.doi.org/10.1016/j.forsciint.2012.10.006)
[0065] MDP2P can be generated easily and in high purity from MDP-2-nitropropene with few side-reactions. The second step is highly tolerant of lower purity feedstock.
Step (c) - Reductive Amination of MDP2P to MDMA
[0066] The third step, step (c), comprises the reductive amination of MDP2P in methanol with sodium cyanoborohydride in the presence of methylamine hydrochloride according to Reaction Scheme 10:
o CH 3 CH 3NH 2 O CH 3 NaBH 3 CN 0 CH 3 .-
MeOH MeOH CHf Ambient - 36 hrs CH3 `H
Reaction Scheme 10
[0067] Step (c) needs to be conducted at ambient temperatures because elevated temperatures of reaction have been observed to cause the further, undesirable reduction of the ketone (MDP2P) to the corresponding alcohol l-(3',4'-MDP)-2-propanol. Without wishing to be bound by theory it is postulated that two factors are important here. The first is driving of the Schiff's base formation with excess amine. The cyanoborohydride acts upon the Schiff's base to reduce it to the corresponding amine and so the second fact is a consequential reduction reaction being driven to proceed after the formation of the Schiff's base. Typically, the reduction step is conducted in the same vessel but is intended to proceed after the formation of the Schiff's base or imine (the central structure in the Reaction Scheme 10). The alcohol is a likely competitive product if the sequence is compressed so that it does not reach equilibrium or if an excess of methylamine is not allowed (which would cause an equilibrium portion of the ketone to remain).
Preparation of MDMA salt
[0068] The MDMA prepared according to the present invention may be in the form of a liquid and may optionally be converted to a desired salt. In particular, hydrochloride salt of MDMA free base is well known and characterised.
[0069] The present invention will be further described with reference to the following non limiting examples. Analysis:
[0070] The examples include reference to use of1 H and1 3 C nuclear magnetic resonance spectroscopy (NMR) to establish structure of key intermediates and products and HPLC-UV-MS to test the purity and detect by-products.
[0071] HPLC-UV-MS has been used to further identify the structures of any products obtained.
[0072] Method of analysis for UHPLC with UV detection: Analysis of samples was performed using a LC-30 UHPLC with SPD M20A diode array detector in series with a LCMS-8030 triple quadrupole mass spectrometer (Shimadzu Corporation, Kyoto Japan). The separation was achieved using a Luna Omega C18 column (150 x 2.1 mm.id., 1.6 micron particles) from Phenomenex (Torrence, CA, USA) operated at 50 °C. The mobile phase consisted of Solvent A (0.1%v/v formic acid in MilliQ water) and Solvent B (0.1 % v/v formic acid in acetonitrile). A linear solvent gradient was programmed from an initial composition of 0% B (0.0-5.0 min) to 100 % B (5.0-25.0 min) and held at the final composition (25.0-26.0 min) before returning to the starting composition (26.0-30.0 min). The flow rate was 0.300 mL/min. Solvents were membrane degassed using a LC-30 degasser (Shimadzu)
[0073] The injection volume was 10 L using a needle in line SIL-30AC autosampler (Shimadzu). The UV detection wavelength was 2.54 nm. Samples for analysis were reconstituted in methanol at a concentration of 0.1 mg/mL immediately prior to analysis (standing time was less than 2 hours at ambient temperature). Data was collected and processed using LabSolutions software (Shimadzu).
[0074] The LCMS-8300 (Shimadzu Corporation, Kyoto, Japan) was operated in line with the UV detector with 100% of the sample flowing to the ion source. Ionisation was in electrospray mode using an ESI-8030 source. The gas flows were nebulising gas flow (3 L/min) and drying gas (15 L/min). The DL temperature was 150 °C and the Heater Block was set to 400 °C. The interface voltage was 4.5 kV.
[0075] For scanning experiments, Q3 scan was used across three mass ranges of 100-200 mass units at a scan rate of 15000 micron/sec, 200-300 mass units at a scan rate of 15000 micron/sec, and 300-500 mass units at a scan rate of 15000 micron/sec. The different mass ranges were used to allow the management of chemical noise and the detection of by-products.
[0076] Collision experiments were carried out using precursor ions identified by correlation of significant peaks detected with the UV detector (>0.5% of the height of the peak of interest) and the corresponding significant masses detected at that retention time (corrected for the retention gap between detectors). Collision was at -10, -20, and -35 Volts acceleration potential difference and the product ions were scanned at 15000 micron/sec. In some cases, where the Q-Array resulted in the generation of significant fragmentation, MS3 experiments were also performed using the MS 2 conditions and selection of the Q-Array generated fragment as the Q2 precursor ion. Data was collected and processed using LabSolutions software (Shimadzu).
Example 1 - Preparation of MDP2P Intermediate
[0077] Example 1 illustrates a two-step reaction to form MDP2P according to Reaction Scheme 7 or Reaction Scheme 8.
[0078] The first step is the formation of 3',4'-methylenedioxy-2-nitroprop-1-ene and two variations of the condensation reaction namely:
- a Henry reaction utilising cyclohexylamine as the catalysing base in the presence of acetic acid (Example 1A); or
- use of ethylenediamine as the catalysing base as a neat reaction (Example 1B).
[0079] The second step is the oxidative hydrolysis of the nitropropene adduct (MDP-2 nitropropene) in the presence of iron dust and acetic acid to form MDP2P (Example 2).
Example 1A- Condensation of Piperonal and Nitroethane in the presence of a Cyclohexylamine Base to Form MDP-2-nitropropene
[0080] A nitroaldol reaction was carried out according to the following reaction:
0 H2 reflux 0 CH 3 o ~N H + CH 3CH 2NO 2 + N CHK>OH OO 2CH
Reaction Scheme 7
[0081] By comparison with other examples herein, Example 1A illustrates the surprising novelty of the reaction continuing in a non-acidic environment intended to protect the nitroethane from degradation.
[0082] The reaction was carried out by combining the following reagents in a round bottom flask and refluxing at approximately 120°C for 6-8 hours: Reagent Equivalents Piperonal 1.00 Nitroethane 2-4 Cyclohexylamine 1.02 Acetic acid Solvent
[0083] The progress of the reaction was monitored to completion using a TLC system (100% dichloromethane on silica). A by-product, piperonylonitrile, was identified.
[0084] NMR spectroscopy of the materials isolated from the reaction (FIG.1) shows the presence of both the desired product and piperonylonitrile. The nitrile is a by-product produced by the degradation of nitroethane. Conditions that prevent the breakdown of the nitroethane will prevent the formation of the nitrile.
[0085] High purity MDP-2-nitropropene product was crystallised from the reaction mixture however the yield was relatively low (50-60%). Poor yield, particularly on scale up can be explained by crystallisation during work up and a significant production of the by product, piperonylonitrile. An alternative workup involving a base wash to remove acetic acid may increase the yield, but concomitantly decrease purity.
[0086] Prior art wisdom as embodied in PiHKAL, A Chemical Love Story by Shulgin and Shulgin, (1991) Transform Press, at pages 298 and 320 is that the reaction of piperonal, nitroethane and cyclohexylamine should be carried out by reflux in glacial acetic acid solvent. Hitherto there has been no readily apparent reason to diverge from this practice.
[0087] However, it was surprisingly found that refluxing in the absence of acetic acid solvent significantly improved suppression of by-product formation. Without wishing to be bound by theory it is believed that the formation of piperonylonitrile is acid catalysed - the result of conversion of the aldehyde to a corresponding oxime and subsequent dehydration of the oxime to the nitrile. The formation of hydroxylamine from nitroalkanes is well understood and proceeds in an acidic environment according to the following reaction:
O'Zz' - acidcatalysed HO-- O HONH2 tauomeis N+ -H 20 +H20 and acid 2
HYCH 3 H CCH 3COOH H"" H H H.- C H3
nitroethane CH3
[0088] The formation of piperonylonitrile is therefore a competing acid-catalysed reaction that may be reduced by the elimination of acetic acid as the solvent as follows:
0 NOH 0 CN + HONH 2 H H
- H2 0 0 -o2
piperonal MD-benzonitrile
[0089] Again, without wishing to be bound by theory, the reagents are liquids and the intended reaction kinetics are likely determined by bimolecular collision which is enhanced at higher concentrations.
Example IB- Condensation of Piperonal and Nitroethane in the Presence of Ethylenediamine Base to Form MDP-2-nitropropene
[0090] The following nitroaldol condensation reaction was carried out:
0 ONNH 2 reflux 0 CH 3 / H CH 3CH 2NO 2 +KC'ONO 0 H2N 0NO
Reaction Scheme 8
[0091] The reaction was carried out by combining the following reagents. Initial small scale experiments were successfully scaled up to 30 g.
Reagent Equivalents 30 g scale reaction Piperonal 1.00 30.00g, 199.82 mmol Nitroethane 6 90.00g, 85.70 mL, 1200 mmol Ethylenediamine 0.01-0.2 120mg, 0.133 mL, 2.00 mmol
[0092] The reagents were combined in a round bottom flask and the reaction performed under reflux at approximately 120°C for 12-16 hours. The progress of the reaction was monitored to completion using a TLC system (100% dichloromethane on silica). The desired product was detected as a bright yellow spot (RF = 0.91) and consumption of the starting material (RM = 0.71). The TLC did not indicate the presence of by-products.
[0093] Importantly, the reaction was monitored for end point. Allowing the reaction to continue beyond this point results in formation of a Michael addition by product. The amount of catalyst added is also critical, preferably 1-2% , in order to avoid formation of by-products.
[0094] The reaction slowed at around the 10 hour mark. Addition of an equal portion of ethylenediamine allowed the reaction to continue. Upon complete consumption of the starting material (monitored by the same TLC method) the reaction was allowed to cool.
[0095] The reaction mixture was worked up by removing half of the remaining nitroethane using rotary evaporation (ca. 40mbar @ 50 0C). Upon cooling an orange slurry formed. To the slurry, a 1:2 mixture of methanol: water was added to remove the remaining nitroethane and promote precipitation of the desired MDP-2-nitropropene.
[0096] The precipitate was collected by filtration and the filtrate washed with a 1:1 methanol: water solution. The product was dried in a vacuum oven for 1-3 hours at 700 C. The bright yellow MDP-2-nitropropene product was recovered in high yield (90-95%).
[0097] FIG 2 incudes 1 H and 1 3 C NMR spectra, consistent with the structure of MDP-2 nitropropene with no significant evidence of impurities or by-products.
Example 2 - oxidative hydrolysis of MDP-2-nitropropene with iron
[0098] The following oxidative hydrolysis was carried out:
CH 3 Fe O CH3 CH 3000H N.' NO2 1000C Rcncm Reaction Scheme 9
[0099] The reaction was carried out by combining the following reagents. Initial small scale experiments were successfully scaled up to 5 g and 10 g.
Reagent Equivalents 5g scale reaction 10g scale reaction MDP-2-nitropropene 1.00 5.00g 24.13 mmol 10.00g, 48.27 mmol Iron powder 5-10 13.48g, 33 mmol 13.48g, 241.33 mmol Acetic acid Solvent Solvent Solvent
[0100] Very fine iron powder as to be interchangeable with 'iron dust' was combined with acetic acid in a round bottom flask and stirred with heating to100°C. Immediately upon reaching this temperature, MDP-2-nitropropene solution (-0.25g/mL) in acetic acid was added dropwise. Upon full addition, the solution was refluxed until the reaction reached completion after 1.5-2.0 hours.
[0101] The progress of the reaction was monitored to completion using a TLC system (100% dichloromethane on silica) for the formation of the desired product (RF = 0.61) and consumption of the starting material (RF = 0.91). No by-products were detected.
[0102] Advantageously, although published prior art methods teach 10-12 equivalents of iron, the present invention has been successfully conducted using no more than a 5-fold excess or iron which greatly simplifies the purification method over the prior art.
[0103] Two work up methods were carried out:
Work Up Method 1:
[0104] In this method, the 5g scale reaction was worked up. The reaction solution was filtered to remove undissolved salts. The precipitate was washed with dichloromethane to give a dark filtrate. Saturated sodium bicarbonate was added to the filtrate to neutralise excess acetic acid, creating gas and some precipitate, which was filtered off.
[0105] Further, saturated sodium hydrogen carbonate was added to the filtrate to fully neutralise the acid present. The organic layer was dried over magnesium sulphate, filtered and the solvent removed via rotary evaporation. The MDP2P produced was a light brown oil (3.247g, 18.22mmol, 76% yield).
Work Up Method 2:
[0106] In this work up method the reaction solution was added to a large volume of water to dissolve iron salts and residual acetic acid. The aqueous layer was extracted with dichloromethane
(DCM). The combined organic fractions were washed with a base (saturated sodium bicarbonate/dilute (5%) sodium hydroxide solution) to neutralise the acid.
[0107] The organic layer was dried over magnesium sulphate, filtered and the solvent removed via rotary evaporation to yield the product as a light brown oil (7.525g, 42.33mmol, 87.48% yield).
[0108] Although recovery Method 2 provides a significantly higher product yield than Method 1, Method 2 requires a large volume of water to dilute the acetic acid and consequently presents more significant handling and waste disposal issues.
[0109] FIG 3 incudes 1 H and 13 C NMR spectra, consistent with the structure of MDP2P with no significant evidence of impurities or by-products.
[0110] Accordingly, MDP2P can be generated easily and in high purity from MDP-2 nitropropene with little evidence of side reactions. The yield of recovered product was as high as % depending on the extraction (work up) method.
Example 3 - reductive amination of MDP2P with sodium cyanoborohydride in the presence of methylamine hydrochloride.
[0111] The following reductive amination reaction was carried out:
o CH 3 CH 3NH 2 0 CH3 NaBH 3CN O ,CH3
O MeOH 2 MeOH O CH 3 f Ambient - 36 hrs CH3 "-H
Reaction Scheme 10
[0112] The reaction was carried out by combining the following reagents. Initial small scale experiments were successfully scaled up to 5 g.
Reagent Equivalents 5g scale reaction MDP2P 1.0 5.0g, 28.06 mmol Methylamine hydrochloride 11.0 20.22g, 308.66 mmol Sodium cyanoborohydride 1.3 2.29g, 36.48 mmol Methanol Solvent Solvent
[0113] The reaction was carried out by combining the reagents at ambient temperature to create a suspended solution. The suspension was stirred at ambient temperature and the pH measured and adjusted to between 6 and 7 using methanoic HCl. The pH was measured and readjusted every 3-4 hours, the system slowly becoming basic over time, and the reaction becoming complete in 30-40 hours.
[0114] The progress of the reaction was monitored to completion using a TLC system (100% dichloromethane on silica) via consumption of the MDP2P (R = 0.61) and product formation (R= 0.14).
[0115] The reaction mixture was worked up by removing the methanol solvent using rotary evaporation. The evolved solids were redissolved in a volume of water approximately equal to the reaction volume. Concentrated HCl (38%) was added to the crude material to make the solution strongly acidic (<pH 1) to decompose the excess borohydride. Significant gas was evolved from the crude material.
[0116] The aqueous layer containing the product was washed with dichloromethane, then the organic layer was re-extracted with IM HCl. Combined aqueous fractions were made basic (~pH ) using a strong NaOH solution, causing a cloudy suspension to form. The final step was extraction with dichloromethane and removal of the solvent via rotary evaporator to isolate the MDMA product as a light brown oil in 70% yield. Re-extracting the organic layer with additional acid improved the yield of product by -10%.
[0117] FIG 4 incudes 1H and 13C NMR spectra, consistent with the structure of MDMA with no significant evidence of impurities or by-products.
Example 4 - formation of hydrochloride salt from MDMA free base
[0118] MDMA produced according to the procedural steps set out in Examples 1 to 3 can be readily converted to the hydrochloride salt according to Reaction Scheme 11:
O CH 3 HCI O CH 3
<0 O N ~ N- 0N OmCI _ CH 3 H CH3 \N H H Oily liquid Crystalline solid Reaction Scheme 11
[0119] The method is based on the titration of methanolic hydrochloric acid up to a stoichiometric quantity in a solvent that is able to sequester water (from the hydrochloric acid) while also being a poor solvent for the MDMA hydrochloride. In this case, diethyl ether was used for convenience but could be replaced with acetone or a higher alcohol.
[0120] The salt formation was carried out by combining the following reagents. Initial small scale experiments were successfully scaled up to 700mg.
Reagent Equivalents 700mg scale reaction MDMA 1.0 700mg, 3.23 mmol 2M HCl in methanol 1.0
[0121] MDMA was dissolved in diethyl ether at ambient temperature. Methanoic HCl was added dropwise, resulting in precipitation of light brown to cream coloured MDMA.HCl precipitate.
[0122] The solid was collected via centrifugation and supernatant decanted. The separated solid was placed in a vacuum oven at 70°C for 1 hour to provide light brown to cream coloured MDMA.HCl crystalline solid in 52% yield. A further crop of crystalline solid was recovered upon concentration of the supernatant.
[0123] FIGs 5A and 5B include1 H and1 3 C NMR spectra obtained in CD 30D, consistent with the structure of MDMA.HCl with no significant evidence of impurities or by-products. The peak (arrow) at -5.Oppm in the 1H spectrum has an integral of two and is attributable to one water of hydration. This identifies the salt as a monohydrate. Microscopy shows the solid to be crystalline.
[0124] MDMA released from the hydrochloride salt yields identical chromatographic retention and LC-MS and LC-MS2 spectra to the free base.
Example 5 - Microwave Assisted Synthesis
[0125] Microwave assisted synthesis makes use of a microwave reactor system instead of using conductive heating from an electrical or gas-powered source. Use of a microwave source provides more uniform heating. In general, for every 10°C increase in temperature in a microwave reactor, the reaction time halves as compared with conductive heating. This is important because higher applied temperatures can cause unexpected or continued (secondary) reactions that generate different chemical species compared to conventional heating methods.
[0126] In the present case, microwave assisted synthesis is suitable for Step (a) - the preparation of MDP-2-nitropropene, such as using cyclohexylamine as the catalysing base according to Reaction Scheme 7,
0 0/NH refl ux 0 H3
H + CH 3CH 2NO 2 + 2CH OH ONO 2
Reaction Scheme 7
or ethylenediamine according to reaction Scheme 8.
0 O NH 2 reflux 0 OH 3 H + CH 3CH 2NO 2 + H2N OO 2CH3
Reaction Scheme 8
Example 5A - Step (a) using cyclohexylamine as catalysing base
[0127] Microwave assisted synthesis was investigated as a source of heating using the synthetic route described for Step (a) at Example IA. Specifically, it was unclear whether the thermodynamics would favour production of the desired product MDP-2-nitropropene, or whether it would promote a Michael addition reaction, leading to an undesirable Michael addition by product according to Reaction Scheme 12:
0 2N CH 3
O CH 3 Michael addition 0 CH 3 <~ N' NO + CH 3CH 2NO 2 N NO 2
Reaction Scheme 12
[0128] Reactions fully consumed the starting material after 20mins at 160°C, in contrast to the 6 to 8 hours at110°C reported in Example 1A when conventional heating was used.
[0129] Further analogous experiments were carried out with variations to the temperature, time, equivalents of nitroethane and volume of solvent (acetic acid). None of the experiments produced the desired product in excess of 70% yield.
Example 5B - Step (a) using ethylenediamine as catalysing base
[0130] As noted in Example lB conventional heating provided the desired product in very high purity, but the reaction is slow. Microwave assisted synthesis was investigated as a source of heating using the synthetic route described for Step (a) at Example lB to see if an increased reaction rate could be obtained.
[0131] Reactions were carried out according to the synthesis steps reported in Example 1B but using microwave heating at several temperatures (140°C, 160°C and 180°C).
[0132] In each case TLC monitoring indicated that significant amounts of impurities formed before all the starting material had been consumed. Furthermore, the reaction mixture developed a brown tint, instead of clear deep orange; a similar effect being noted during conventional heating if the reaction is heated for too long. However, in this case the impurity only appears after the starting material is fully consumed and it is postulated that the impurity may be the nitropropene product reacting with a second molecule of ethylenediamine to form the undesirable Michael addition by-product. The presence of the Michael addition product was confirmed by LCMSMS analysis and is a very minor product if the conventionally heated reaction is monitored and stopped as appropriate.
Preparation of a Medicament
[0133] MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof produced according to any of the aforementioned methods may be used in the preparation of a medicament for MDMA-assisted psychotherapy. The medicament may be used in combination with one or more other kinds of therapeutic agents and /or therapeutic methods for the treatment, amelioration and/or prevention of psychological disorders.
Example 6a - Capsules
[0134] In one embodiment, the medicament would be in the form of capsules, preferably two piece capsules telescoping gelatin capsules containing a powder mix.
[0135] During manufacture, typically the MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof combined with any excipients, such as binders, disintegrants, fillers, glidant and preservatives would be loaded as a powder in one half of the capsule. The other of the capsule would then be pressed on to close the powder inside the capsule.
[0136] In a preferred embodiment the excipient would be a filler such as dextrose, lactose, glucose or sucrose.
[0137] In one embodiment, a #3 capsule would be filled with 60 to 120 mg of active produced according to the present invention and 80 to 140 mg of excipient. In another embodiment, a #3 capsule would be filled with 20 to 60 mg of active produced according to the present invention and 140 to 180 mg of excipient.
Example 6b - Tablets
[0138] In one embodiment, the medicament would be in the form of tablets, typically pressed tablets. The press mix for a tablet would typically include MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof combined with excipients, such as binders, disintegrants, fillers, glidant, lubricant and preservatives.
[0139] A preferred direct compression formulation would typically include;
- 40 to 60 wt%, preferably 55 wt% of MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt
- 30 to 50 wt%, preferably 41 wt% binder,
- 0.01 to 5 wt%, preferably 1 wt% lubricant,
- 1 to 5 wt%, preferably 3 wt% disintegrant.
[0140] The exact proportions of component would be varied according to the desired dissolution profile, tablet hardness, friability, disintegration profile and dissolution profiles. The preferred proportions mentioned above would be likely to have low hardness (soft) but would probably have a desirable disintegration profile.
[0141] In one embodiment, the tablet would contain 60 to 120 mg of active produced according to the present invention and 80 to 140 mg of excipients. In another embodiment, the tablet would contain 20 to 60 mg of active produced according to the present invention and 140 to 180 mg of excipients.
Example 7 - Treatment
[0142] MDMA has been investigated in clinical settings for enhancing psychotherapy. A combined treatment of MDMA administration and psychotherapy may be effective for treating trauma relates conditions such as post-traumatic stress disorder (PTSD). MDMA appears to diminish some patient's fear response and decrease the patient's defensiveness without blocking memories. During a psychotherapy session, a patient may be better able to remain emotionally engaged with traumatic memories without being overwhelmed by anxiety or other painful emotions or avoiding them by dissociation or emotional numbing
[0143] In an eighth aspect of embodiments described herein there is provided a method of treating, ameliorating and/or preventing a psychological disorder comprising administering to a subject in need thereof, a therapeutically effective amount of MDMA, (R)-MDMA or (S)-MDMA or a pharmaceutically acceptable salt thereof, produced according to any of the aforementioned methods. The method may be used in combination with one or more other kinds of therapeutic agents and /or therapeutic methods for the treatment, amelioration and/or prevention of psychological disorders.
[0144] A typical treatment regimen would include a patient receiving an initial dose during a clinically supervised psychotherapy session, of 60 or 150 mg, preferably 80 to 120 mg, the exact amount depending on body mass. If the patient and clinician believe it would be helpful, after a couple of hours the patient may receive a subsequent dose of between 20 to 80 mg, 40mg to 60mg. Typically the dose would be delivered in the form of a capsule or tablet as described herein.
[0145] While this invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modification(s). This application is intended to cover any variations uses or adaptations of the invention following in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.
[0146] As the present invention may be embodied in several forms without departing from the spirit of the essential characteristics of the invention, it should be understood that the above described embodiments are not to limit the present invention unless otherwise specified, but rather should be construed broadly within the spirit and scope of the invention as defined in the appended claims. The described embodiments are to be considered in all respects as illustrative only and not restrictive.
[0147] Various modifications and equivalent arrangements are intended to be included within the spirit and scope of the invention and appended claims. Therefore, the specific embodiments are to be understood to be illustrative of the many ways in which the principles of the present invention may be practiced.
[0148] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.
[0149] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. The broad term "comprising" is intended to encompass the narrower "consisting essentially of and the even narrower "consisting of." Thus, in any recitation herein of a phrase "comprising one or more claim element" (e.g., "comprising A), the phrase is intended to encompass the narrower, for example, "consisting essentially of A" and "consisting of A" Thus, the broader word "comprising" is intended to provide specific support in each use herein for either "consisting essentially of or "consisting of." The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.
[0150] One of ordinary skill in the art will appreciate that materials and methods, other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by examples, preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
[0151] Each references cited herein is incorporated by reference herein in their entirety. Such references may provide sources of materials; alternative materials, details of methods, as well as additional uses of the invention.
Claims (5)
1. A method of synthesising MDMA or a pharmaceutically acceptable salt thereof from piperonal, the method comprising a first, condensation reaction step, followed by second, oxidative hydrolysis to form 1-(3',4'methylenedioxyphenyl)-propan-2-one (MDP2P) as an intermediate, followed by a third reductive amination step.
2. A method of synthesising MDMA or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of;
(a) condensation of piperonal and nitroethane in the presence of a catalysing base to form 1-(3',4'-methylenedioxyphenyl)-2-nitroprop-1-ene (MDP-2 nitropropene),
(b) oxidative hydrolysis of MDP-2-nitropropene to form 1 (3',4'methylenedioxyphenyl)-propan-2-one(MDP2P),and
(c) reductive amination of MDP2P to 1-(3',4'-methylenedioxyphenyl)-2 (methylamino)propane(MDMA).
3. A method of producing MDMA according to the following reaction scheme:
0 O CH 3 CH 2 NO 2 0 CH 3 Fe O CH 33 H O 1NH 2 CH 2 CH 2 NH 2 ON 2 CH3COOH
00
O CH3 CH3NH2 O0.(N. CH3 NaBH3CN 0 -- CH3
O zt MeOH O MeO OY CH3 CH3 H
4. MDMA produced according to the method of any one of the preceding claims.
5. A pharmaceutical composition comprising a therapeutically effective amount of MDMA produced according to the method of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
FIG 1B FIG 1A 1/16
FIG 2B FIG 2A 2/16
FIG 2C
FIG 2D 3/16
FIG 2F FIG 2E 4/16
FIG 3A FIG 2G 5/16
FIG 3B
FIG 3C 6/16
FIG 3E FIG 3D 7/16
FIG 3F
FIG 3G 8/16
FIG 4B FIG 4A 9/16
FIG 4D FIG 4C 10/16
FIG 4F FIG 4E 11/16
FIG 4H FIG 4G 12/16
FIG 4I
FIG 4J 13/16
FIG 5B FIG 5A 14/16
FIG 5D FIG 5C 15/16
FIG 5E 16/16
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2021106190A AU2021106190A4 (en) | 2021-08-20 | 2021-08-20 | Improved method of synthesis of 1-(3’,4’-methylene dioxyphenyl)-2-(methylamino) propane (mdma) |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2021106190A AU2021106190A4 (en) | 2021-08-20 | 2021-08-20 | Improved method of synthesis of 1-(3’,4’-methylene dioxyphenyl)-2-(methylamino) propane (mdma) |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2021106190A4 true AU2021106190A4 (en) | 2021-10-28 |
Family
ID=78207547
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2021106190A Active AU2021106190A4 (en) | 2021-08-20 | 2021-08-20 | Improved method of synthesis of 1-(3’,4’-methylene dioxyphenyl)-2-(methylamino) propane (mdma) |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2021106190A4 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022232949A1 (en) * | 2021-05-06 | 2022-11-10 | Pharmala Biotech Inc. | Processes for the preparation of the enantiomers of 3,4-methylenedioxymethamphetamine (mdma) and n-methyl-1,3-benzodioxolylbutanamine (mbdb) |
WO2023092044A3 (en) * | 2021-11-17 | 2023-06-22 | Terran Biosciences, Inc. | Phenethylamine compounds salts, polymorphic forms and methods of use thereof |
CN111909134B (en) * | 2019-05-07 | 2024-04-26 | 北京鼎材科技有限公司 | Compound and application thereof, and organic electroluminescent device comprising compound |
-
2021
- 2021-08-20 AU AU2021106190A patent/AU2021106190A4/en active Active
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111909134B (en) * | 2019-05-07 | 2024-04-26 | 北京鼎材科技有限公司 | Compound and application thereof, and organic electroluminescent device comprising compound |
WO2022232949A1 (en) * | 2021-05-06 | 2022-11-10 | Pharmala Biotech Inc. | Processes for the preparation of the enantiomers of 3,4-methylenedioxymethamphetamine (mdma) and n-methyl-1,3-benzodioxolylbutanamine (mbdb) |
WO2023092044A3 (en) * | 2021-11-17 | 2023-06-22 | Terran Biosciences, Inc. | Phenethylamine compounds salts, polymorphic forms and methods of use thereof |
US11958821B2 (en) | 2021-11-17 | 2024-04-16 | Terran Biosciences Inc. | Phenethylamine compounds salts, polymorphic forms and methods of use thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2021106190A4 (en) | Improved method of synthesis of 1-(3’,4’-methylene dioxyphenyl)-2-(methylamino) propane (mdma) | |
US11634377B2 (en) | Fenfluramine compositions and methods of preparing the same | |
Kawamura et al. | Synthesis of (2S, 3S)-β-(trifluoromethyl)-α, β-diamino acid by Mannich addition of glycine Schiff base Ni (II) complexes to N-tert-butylsulfinyl-3, 3, 3-trifluoroacetaldimine | |
WO2022006186A1 (en) | Phenalkylamines and methods of treating mood disorders | |
KR20130002316A (en) | New crystalline form of a cyclopropyl benzamide derivative | |
US11365195B2 (en) | Atypical inhibitors of monoamine transporters; method of making; and use thereof | |
Khobare et al. | One pot oxidative dehydration-oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: a versatile methodology for the facile access of azasugar alkaloids | |
KR20200117952A (en) | Highly enantioselective bifunctional chiral organocatalytic compound, method for preparing the same, and method for preparing non-natural gamma-amino acid from nitrocompound using thereof | |
US20120059179A1 (en) | Palladium-catalyzed ortho-fluorination | |
AU2022328454A1 (en) | Improved method of synthesis of 1-(3',4'-methylene dioxyphenyl)-2-(methylamino) propane (mdma) | |
CN100443466C (en) | Cycloalkylaminoacid compounds, processes for making and uses thereof | |
Kamo et al. | Synthesis of enantiomerically pure juglomycin C and NHAB | |
US11566000B2 (en) | Crystalline form of sofpironium bromide and preparation method thereof | |
Kuga et al. | Expedient Entry to 1-Aminoadamantane Derivatives via Aza-Prins Cyclization of 7-Methylenebicyclo [3.3. 1] nonan-3-one Oximes | |
CN110105238B (en) | Synthesis method of 16-methyl-2, 6, 6, 8-tetramethyl tricyclo-8-alkenoxime-O- (4-chlorobenzyl) ether | |
JP6747653B2 (en) | 11C-labeled catechol derivative, PET probe for phosphorylated tau aggregation inhibitor using the same, and method for producing the same | |
RU2488577C1 (en) | Method of producing 3-amino-1-adamantanol and acid addition salts thereof | |
Backes et al. | Synthesis and Sensory Studies of Umami‐Active Scaffolds | |
RU2537361C1 (en) | Optic isomers of (+) and (-)-benzhydrylureas and (+) and (-)-1-[(3-chlorophenyl)-phenyl-methyl]urea, pharmaceutical composition based on thereof and method of thereof obtaining | |
RU2676098C1 (en) | METHOD OF 1,2,3,4,6,7,8,9-OCTAHYDRO-4a,5b,10,12-TETRAAZAINDENO[2,1-b]FLUOREN-5,11-DIONE SYNTHESIS | |
Lee et al. | Identification of a new M-ALPHA analog and MDMA in an illegal health product | |
ES2354355T3 (en) | PROCEDURE FOR THE CLORATION OF TERTIARY ALCOHOLS. | |
EP2739610B1 (en) | Process for the manufacture of ivabradine and of intermediates of synthesis thereof | |
Nádvorník et al. | Syntheses, X-ray, MSn, NMR and CD structure determination of nickel (II) complexes of Schiff bases of (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide and aromatic α-amino acids | |
US9994523B2 (en) | Salts of Saxagliptin with organic acids |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FGI | Letters patent sealed or granted (innovation patent) |