WO2015130660A1 - Synthesis of racemic amphetamine derivatives by cuprate addition reaction with aziridine phosphoramidate compounds - Google Patents
Synthesis of racemic amphetamine derivatives by cuprate addition reaction with aziridine phosphoramidate compounds Download PDFInfo
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- WO2015130660A1 WO2015130660A1 PCT/US2015/017265 US2015017265W WO2015130660A1 WO 2015130660 A1 WO2015130660 A1 WO 2015130660A1 US 2015017265 W US2015017265 W US 2015017265W WO 2015130660 A1 WO2015130660 A1 WO 2015130660A1
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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- process according
- aryl
- alkyl
- Prior art date
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- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical class C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 title claims abstract description 64
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 13
- 238000007259 addition reaction Methods 0.000 title claims description 4
- NEKDTICQKYZRFR-UHFFFAOYSA-N aminophosphonic acid;aziridine Chemical class C1CN1.NP(O)(O)=O NEKDTICQKYZRFR-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 77
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 229940025084 amphetamine Drugs 0.000 claims abstract description 46
- 125000003118 aryl group Chemical group 0.000 claims abstract description 31
- -1 aryl-alkyl phosphoramidate Chemical compound 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 239000002243 precursor Substances 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 15
- 239000010949 copper Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229910052802 copper Inorganic materials 0.000 claims description 11
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 7
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 7
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000002105 nanoparticle Substances 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021593 Copper(I) fluoride Inorganic materials 0.000 claims description 4
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- SNIYGPDAYLBEMK-UHFFFAOYSA-M [I-].[Mg+]C1=CC=CC=C1 Chemical compound [I-].[Mg+]C1=CC=CC=C1 SNIYGPDAYLBEMK-UHFFFAOYSA-M 0.000 claims description 3
- 150000005171 halobenzenes Chemical class 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 3
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000007514 turning Methods 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 claims description 2
- 239000000428 dust Substances 0.000 claims description 2
- LJWKFGGDMBPPAZ-UHFFFAOYSA-N ethoxyethane;toluene Chemical compound CCOCC.CC1=CC=CC=C1 LJWKFGGDMBPPAZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 125000000962 organic group Chemical group 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 31
- 239000000543 intermediate Substances 0.000 abstract description 5
- 150000002902 organometallic compounds Chemical class 0.000 abstract description 4
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 abstract description 3
- 229960001252 methamphetamine Drugs 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 150000001879 copper Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 17
- 239000012230 colorless oil Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- WEXFFKIXGDHEPX-UHFFFAOYSA-N n-diethoxyphosphoryl-1-phenylpropan-2-amine Chemical compound CCOP(=O)(OCC)NC(C)CC1=CC=CC=C1 WEXFFKIXGDHEPX-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- MALAZZMAEHYRBE-UHFFFAOYSA-N 1-di(propan-2-yloxy)phosphoryl-2-methylaziridine Chemical compound CC1N(C1)P(OC(C)C)(OC(C)C)=O MALAZZMAEHYRBE-UHFFFAOYSA-N 0.000 description 6
- UILSPYZYUOXRPW-UHFFFAOYSA-N 1-dimethoxyphosphoryl-2-methylaziridine Chemical compound COP(=O)(OC)N1CC1C UILSPYZYUOXRPW-UHFFFAOYSA-N 0.000 description 6
- AYLQICSBGVRCOK-UHFFFAOYSA-N 1-diphenoxyphosphoryl-2-methylaziridine Chemical compound CC1N(C1)P(OC1=CC=CC=C1)(OC1=CC=CC=C1)=O AYLQICSBGVRCOK-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 230000000707 stereoselective effect Effects 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QEQVFBHZVPKNNW-UHFFFAOYSA-N N-di(propan-2-yloxy)phosphoryl-1-phenylpropan-2-amine Chemical compound C1(=CC=CC=C1)CC(C)NP(OC(C)C)(OC(C)C)=O QEQVFBHZVPKNNW-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000012455 biphasic mixture Substances 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- OJIVQDIJUPTQTI-UHFFFAOYSA-N 1-diethoxyphosphoryl-2-methylaziridine Chemical compound CCOP(=O)(OCC)N1CC1C OJIVQDIJUPTQTI-UHFFFAOYSA-N 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229940043232 butyl acetate Drugs 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000030609 dephosphorylation Effects 0.000 description 3
- 238000006209 dephosphorylation reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 150000001541 aziridines Chemical class 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229960000395 phenylpropanolamine Drugs 0.000 description 2
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- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
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- 125000004001 thioalkyl group Chemical group 0.000 description 2
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
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- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- 0 CC(Cc1ccccc1)N* Chemical compound CC(Cc1ccccc1)N* 0.000 description 1
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
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- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KMRCSUAUXZCVDH-UHFFFAOYSA-N [N].C1CN1 Chemical group [N].C1CN1 KMRCSUAUXZCVDH-UHFFFAOYSA-N 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- PTCGDEVVHUXTMP-UHFFFAOYSA-N flutolanil Chemical compound CC(C)OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)C(F)(F)F)=C1 PTCGDEVVHUXTMP-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- XCAAVLOGEDCHSR-UHFFFAOYSA-N n-dimethoxyphosphoryl-1-phenylpropan-2-amine Chemical compound COP(=O)(OC)NC(C)CC1=CC=CC=C1 XCAAVLOGEDCHSR-UHFFFAOYSA-N 0.000 description 1
- POARXUUKTQVRQQ-UHFFFAOYSA-N n-diphenoxyphosphoryl-1-phenylpropan-2-amine Chemical compound C=1C=CC=CC=1OP(=O)(OC=1C=CC=CC=1)NC(C)CC1=CC=CC=C1 POARXUUKTQVRQQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003236 pyrrolines Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2475—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aralkylamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/564—Three-membered rings
Definitions
- This is invention is related to processes for synthesis of amphetamine derivatives and novel intermediates thereby.
- amphetamine derivatives have led to the development of numerous synthetic methods for their synthesis and their derivatization.
- One problem with amphetamine synthesis is that amphetamines have a stereo-defined amine center, which can be difficult to resolve and subject to racemization. Accordingly, for the preparation of a single stereoisomer, only stereospecific methods are useful. However, stereospecific methods do not provide the economic requirements of high yields, high selectivity and low process costs.
- the stereo center is purchased as part of a chiral starting material or utilize tedious and expensive synthetic reactions to achieve that goal.
- Such reactions involve a coupling agent, such as Grignard or organolithium reagents.
- a coupling agent such as Grignard or organolithium reagents.
- Conventional teaching requires that the use such organometallics requires that the reaction temperature be maintained at a cold temperature, such as an ice bath at less than 10 degrees Celsius.
- racemic amphetamine To complicate the amphetamine marketplace, there are established formulations which require racemic amphetamine to obtain an extended release of elevated blood levels of the drug.
- This racemic material can be obtained by mixing equal parts of the dextrorotary and levorotary stereos isomers or running a synthetic sequence which only produces racemic amphetamine.
- the present invention addresses one or more of the shortcomings of the prior art by providing processes for the synthesis of amphetamine, dexamphetamine, methamphetamine, derivatives of these, including their salts, and novel precursors and intermediates obtained thereby, by synthesizing aziridine phosphoramidate compounds in specified solvents at specified temperatures, and then converting to a novel aryl or aryl-alkyl phosphoramidate precursors using a modified organometallic compound such as a organocopper reagent, where the novel aryl or aryl-alkyl phosphoramidate precursor is then easily converted to the target compounds using known reactions, e.g. acidification, alkylation of the nitrogen followed by dephosphorylation, etc.
- a modified organometallic compound such as a organocopper reagent
- the invention provides a synthetic pathway to amphetamine derivatives using an aziridine based process with an organometallic compound by heating the reactants in a first step, and then adding as a second step the Grignard reagent in a dosage controlled fashion.
- the reaction is heated to above 40 degrees C, preferably above about 45 degrees C, and more preferably above about 48 degrees C.
- the temperature is maintained from 48-51 deg. C for about 30 minutes and then brought to room temperature.
- the invention provides a process of making the amphetamine, said process comprising:
- R is alkyl or aryl
- the amphetamine process comprises wherein the acidic conditions are aqueous hydrochloric, sulfuric or phosphoric acids.
- the amphetamine process comprises wherein the aqueous acid water content is in an amount of 50% to 90%
- the amphetamine process comprises wherein said providing a compound of Formula 6 comprises:
- R is alkyl or aryl
- the amphetamine process comprises wherein the
- regioisomeric purity of Formula 6 is > 99% and the regioisomer (Formula 8) is ⁇ 0.1%.
- the amphetamine process comprises wherein the copper catalyst is CuCl, CuCl 2 , CuBr, CuF, Cul, Cu(OAc) 2 , Cu(OMe)2, Copper nanoparticles, Copper turnings, or combinations thereof.
- the amphetamine process comprises wherein the solvent is an organic ether or an organic ether-toluene mixture.
- the amphetamine process comprises wherein the organic ether solvent is diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran.
- the amphetamine process comprises wherein the
- phenylmagnesium halide is either phenylmagnesium chloride, phenylmagnesium bromide or phenylmagnesium iodide.
- the amphetamine process comprises wherein the
- phenylmagnesium halide solutions can either be commercially supplied or prepared in situ from the corresponding halobenzene and magnesium.
- the amphetamine process comprises wherein the magnesium is be in the form of chips, granules, ribbon, turnings, dust, grit, blocks or chunks.
- the amphetamine process comprises wherein said treating is carried out at a temperature of from about -10 °C to about 70 °C.
- the amphetamine process comprises wherein said providing a compound of Formula 2 comprises:
- R is alkyl or aryl
- the amphetamine process comprises wherein the base is potassium hydroxide or potassium carbonate.
- R is alkyl or aryl
- the amphetamine process comprises wherein said providing a compound of Formula 4 comprises:
- R alkyl or aryl
- R is alkyl or aryl
- stereoselective or stereoselectivity means without limitation, by way of explanation, the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during the non-stereospecific creation of a new stereocenter or during the non-stereospecific transformation of a pre-existing one.
- the selectivity arises from differences in steric effects and electronic effects in the mechanistic pathways leading to the different products.
- Zwierzak et al. teach in Tetrahedron 1997, 53, 4935-4946 that the product from the organocuprate addition to the 2-alkyl-N-(diethylphosphoryl)aziridines is always regiospecific, always occurring with nucleophilic attack at the less substituted carbon atom of the aziridine ring.
- Zwierzak continues the paragraph by explaining that diethyl N-sec-alkylphosphoramidate products could be easily isolated in pure state after quenching the organocuprate reaction mixture with aqueous ammonium chloride solution and no further purification is necessary before deprotection. It was discovered in attempting to implement the Zwierzak procedure, that this is not the case.
- 6a readily crystallizes from hexane, heptane, isooctane or petroleum ether, but the residual 8a is still present It is required to leave a residue of the reaction solvent (THF) in the solvent mixture to separate the 6a from 8a.
- THF reaction solvent
- the other versions of 6 (b,c or d) needed other recrystallization solvent mixtures, but the common item was that it was required to leave a residue of THF in the mixture.
- NMR spectra Proton nuclear magnetic resonance spectra were obtained on a Bruker
- dimethyl (2methylaziridin-l- yl)phosphonate (2c) is prepared as a viscous colorless oil in about 70% yield (expected 95% GC minimum purity).
- diisopropyl (2methylaziridin- l-yl)phosphonate (2d) is prepared as a viscous colorless oil in about 50 % yield (expected 95% GC minimum purity).
- the reaction was quenched by slow addition to a cooled mixture of saturated aqueous ammonium chloride solution and water (50/50 v/v, 100 mL) while maintaining an internal temperature below 20 °C.
- the flask was rinsed with methyl t- butyl ether (100 mL) and the rinse was transferred to the quenched reaction mixture.
- the biphasic mixture was stirred for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed.
- the organic phase washed with saturated sodium chloride solution (50 mL) and the organic phase was dried over sodium sulfate.
- the solution (a 97:7 mixture of 6a: 8a by GC analysis) was filtered and concentrated under reduced pressure until the product began to crystallize.
- the reaction was quenched by slow addition to a cooled mixture of saturated aqueous ammonium chloride solution and water (50/50 v/v, 4.2 L) while maintaining an internal temperature below 25 °C.
- the flask was rinsed with heptanes (3.5 L) and the rinse was transferred to the quenched reaction mixture.
- the biphasic mixture was stirred for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed.
- the organic phase was concentrated under reduced pressure to a volume of about 1.0 L.
- the organic solution was azeotropically dried by two separate charges of heptanes (2 X 2.0L) was added and the solution volume was adjusted by reduced pressure distillation to a total volume of about 2.5 L.
- halobenzene and magnesium metal turnings For phenylmagnesium chloride, the solvents of choice are either THF or 2-methylTHF. For phenylmagnesium bromide, the solvents of choice are either THF, 2-methylTHF or diethyl ether. For phenylmagnesium iodide the solvent of choice is diethyl ether.
- THF trifluoride
- 2-methylTHF 2-methylTHF
- diethyl ether diethyl ether.
- reaction mixture was cooled to ambient temperature.
- the reaction was quenched by slow addition to a cooled solution of saturated aqueous ammonium chloride/water mixture (50/50 v/v, 60 mL) while maintaining the batch temperature below 20 °C.
- Heptanes 60 mL was used to rinse the reactor and was transferred to the quench mixture.
- the biphasic mixture was agitated for 15 minutes and the aqueous layer was removed.
- the organic layer washed with deionized water (20 mL) and the organic phase concentrated under reduced pressure to give viscous oil. This residue was dissolved in heptanes (50 mL) and the solution was concentrated under reduced pressure.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention includes processes for the synthesis of amphetamine, dexamphetamine, methamphetamine, derivatives of these, including their salts, and novel precursors and intermediates obtained thereby, by synthesizing aziridine phosphoramidate compounds in specified solvents at specified temperatures, and then converting to a novel aryl or aryl-alkyl phosphoramidate precursors using an organometallic compound such as a copper salt, where the novel aryl or aryl-alkyl phosphoramidate precursor is then easily converted to the target compounds using known reactions.
Description
APPLICATION FOR GRANT OF LETTERS PATENT
TITLE
Synthesis of Racemic Amphetamine Derivatives by Cuprate Addition Reaction with Aziridine Phosphoramidate Compounds
INVENTORS
MECKLER, Harold, Delmar, NY (US)
GREGG, Brian Thomas, Altamont, NY (US)
YANG, Jie, Rensselaer, NY (US)
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Application 14/189,630 filed Feb. 25, 2014, the content of which is incorporated herein in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
No federal government funds were used in the research or development of this invention.
NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT
None.
REFERENCE TO A SEQUENCE LISTING
None.
BACKGROUND
[0001 ] Field of the Invention
[0002] This is invention is related to processes for synthesis of amphetamine derivatives and novel intermediates thereby.
[0003] Background of the Invention
[0004] The commercial importance of amphetamine derivatives has led to the development of numerous synthetic methods for their synthesis and their derivatization. One problem with
amphetamine synthesis is that amphetamines have a stereo-defined amine center, which can be difficult to resolve and subject to racemization. Accordingly, for the preparation of a single stereoisomer, only stereospecific methods are useful. However, stereospecific methods do not provide the economic requirements of high yields, high selectivity and low process costs.
Typically, the stereo center is purchased as part of a chiral starting material or utilize tedious and expensive synthetic reactions to achieve that goal. Such reactions involve a coupling agent, such as Grignard or organolithium reagents. Conventional teaching requires that the use such organometallics requires that the reaction temperature be maintained at a cold temperature, such as an ice bath at less than 10 degrees Celsius.
[0005] To complicate the amphetamine marketplace, there are established formulations which require racemic amphetamine to obtain an extended release of elevated blood levels of the drug. This racemic material can be obtained by mixing equal parts of the dextrorotary and levorotary stereos isomers or running a synthetic sequence which only produces racemic amphetamine.
[0006] Another problem with amphetamine synthesis is that the intermediates are toxic as well as flammable. This requires special handling such as double-walled drums and safety accommodations to protect manufacturing personnel.
[0007] The prior art in U.S. Pat. 6,399,828 teaches the production of amphetamine using various methods. In one approach norephedrine is refluxed with hydrogen iodide and red phosphorous. In another approach norephedrine is chlorinated using thionyl chloride and then catalytically hydrogenated. In U.S. Pat. 7,705,184, amphetamine synthesis is disclosed using hydrogenation of a chlorinated phenylpropanolamine. Aziridine chemistry, and specifically aziridine phosphoramidates are not taught in the amphetamine synthesis prior art.
[0008] Zwierzak et al. disclose a method of reacting N-phosphorylated aziridines with copper-modified Grignard reagents as a new route to substituted pyrrolines and pyrrolidines. However, Zwierzak et al discloses this method as being regiospecific, which it is not. Synthetic Communications: An Int'l J. for Rapid Commun. of Syn. Org. Chem., 28:7, 1127-1137 (1998).
[0009] Additionally, the use of protecting groups and leaving groups is well known.
However, it has been discovered that there is significant variation among the various standard protecting groups. Specifically, where a carbonyl moiety is used as the amine protecting group (i.e. acetyl t-Boc or CBZ), the reaction must be kept at or below -10 degrees Celsius or the carbonyl
will react with the organometallic reagent. Where a sulfonyl moiety is used as an amine protecting group (i.e. methanesulfonyl or p-toluenesulfonyl), it is difficult to remove the protecting group without destroying the molecule.
[00010] Accordingly, there is a need for synthetic processes and useful compounds for the manufacture of amphetamine and its derivatives that have high chemical yield, high selectivity, low cost, lower toxicity and are less dangerous to handle.
BRIEF SUMMARY OF THE INVENTION
[00011] The present invention addresses one or more of the shortcomings of the prior art by providing processes for the synthesis of amphetamine, dexamphetamine, methamphetamine, derivatives of these, including their salts, and novel precursors and intermediates obtained thereby, by synthesizing aziridine phosphoramidate compounds in specified solvents at specified temperatures, and then converting to a novel aryl or aryl-alkyl phosphoramidate precursors using a modified organometallic compound such as a organocopper reagent, where the novel aryl or aryl-alkyl phosphoramidate precursor is then easily converted to the target compounds using known reactions, e.g. acidification, alkylation of the nitrogen followed by dephosphorylation, etc.
[00012] In one preferred aspect the invention provides a synthetic pathway to amphetamine derivatives using an aziridine based process with an organometallic compound by heating the reactants in a first step, and then adding as a second step the Grignard reagent in a dosage controlled fashion. In a preferred embodiment, the reaction is heated to above 40 degrees C, preferably above about 45 degrees C, and more preferably above about 48 degrees C. In one embodiment, the temperature is maintained from 48-51 deg. C for about 30 minutes and then brought to room temperature.
[00013] In another preferred embodiment, the invention provides a process of making the amphetamine, said process comprising:
[00014] roviding a compound of Formula 6:
[00016]
[00017] wherein R is alkyl or aryl; and
[00018] deprotecting the compound of Formula 6 under acidic conditions effective to produce amphetamine of Formula 7:
[00019] 7
[00020]
[00021] In preferred aspects, the amphetamine process comprises wherein the acidic conditions are aqueous hydrochloric, sulfuric or phosphoric acids.
[00022] In preferred aspects, the amphetamine process comprises wherein the aqueous acid water content is in an amount of 50% to 90%
[00023] In preferred aspects, the amphetamine process comprises wherein the R= methyl, ethyl, isopropyl or phenyl.
[00024] In preferred aspects, the amphetamine process comprises wherein said providing a compound of Formula 6 comprises:
[00025] providing a compound of Formula 2:
P(0)(OR)2
N
H3C
[00026] 2 ;
[00027] wherein R is alkyl or aryl and
[00028] reacting the compound of Formula 2 with phenylmagnesium halide and a copper catalyst under solvent and temperature conditions effective to produce a compound of Formula 6 in a purity substantially free of any regioisomeric impurities.
[00029] In preferred aspects, the amphetamine process comprises wherein the
regioisomeric purity of Formula 6 is > 99% and the regioisomer (Formula 8) is < 0.1%.
[00030] In preferred aspects, the amphetamine process comprises wherein the R= methyl, ethyl, isopropyl or phenyl.
[00031] In preferred aspects, the amphetamine process comprises wherein the copper catalyst is CuCl, CuCl2, CuBr, CuF, Cul, Cu(OAc)2, Cu(OMe)2, Copper nanoparticles, Copper turnings, or combinations thereof.
[00032] In preferred aspects, the amphetamine process comprises wherein the solvent is an organic ether or an organic ether-toluene mixture.
[00033] In preferred aspects, the amphetamine process comprises wherein the organic ether solvent is diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran.
[00034] In preferred aspects, the amphetamine process comprises wherein the
phenylmagnesium halide is either phenylmagnesium chloride, phenylmagnesium bromide or phenylmagnesium iodide.
[00035] In preferred aspects, the amphetamine process comprises wherein the
phenylmagnesium halide solutions can either be commercially supplied or prepared in situ from the corresponding halobenzene and magnesium.
[00036] In preferred aspects, the amphetamine process comprises wherein the magnesium is be in the form of chips, granules, ribbon, turnings, dust, grit, blocks or chunks.
[00037] In preferred aspects, the amphetamine process comprises wherein said treating is carried out at a temperature of from about -10 °C to about 70 °C.
[00038] In preferred aspects, the amphetamine process comprises wherein said treating is carried out at a temperature of from about 30 °C to about 60 °C.
[00039] In preferred aspects, the amphetamine process comprises wherein said providing a compound of Formula 2 comprises:
[00040] roviding a compound of Formula 5:
[00041] 5 ;
[00042] wherein R is alkyl or aryl; and
[00043] reacting the compound of Formula 5 with the base under conditions effective to produce a compound of Formula 2.
[00044] In preferred aspects, the amphetamine process comprises a compound of Formula 5 wherein the R= methyl, ethyl, isopropyl or phenyl.
[00045] In preferred aspects, the amphetamine process comprises wherein the base is potassium hydroxide or potassium carbonate.
[00046] In preferred aspects, the amphetamine process comprises wherein said providing a compound of Formula 5 comprises:
[00047] roviding a compound of Formula 4:
[00048] wherein R is alkyl or aryl; and
[00049] reacting the compound of Formula 4 with methanesulfonyl chloride and a base under conditions effective to produce a compound of Formula 5.
[00050] In preferred aspects, the amphetamine process comprises a compound of Formula 4 wherein the R= methyl, ethyl, isopropyl or phenyl.
[00051] In preferred aspects, the amphetamine process comprises wherein said providing a compound of Formula 4 comprises:
[00052] providing a compound of Formula 3:
NH2
, . . OH
H3C
[00053] 3 ; and
[00054] reacting the compound of Formula 3 with the appropriate
O
I I
/P-Cl
RO OR
[00055]
[00056] wherein R= alkyl or aryl
[00057] under conditions effective to produce a compound of Formula 4.
[00058] In preferred aspects, the amphetamine process involving Formula 4 comprises wherein the R= methyl, ethyl, isopropyl or phenyl.
[00060]
[00061] prepared according to one or more processes herein, in a regioisomeric purity of > 1700:1
[00062] wherein:
[00063] R is alkyl or aryl
[00065]
[00066] wherein the alkyl group is selected from the group consisting of methyl, ethyl or isopropyl.
[00068]
[00069] wherein the aryl group is phenyl.
[00070] In another preferred embodiment, the invention provides a compound of formula 2:
P(0)(OR)2
N
H3C
2
[00071]
[00072] wherein: R is alkyl or aryl
[00073] In preferred aspects, the invention further comprises a compound of formula 2:
P(0)(OR)2
N
[00074]
[00075] wherein the alkyl group is selected from the group consisting of methyl, ethyl or isopropyl.
[00076] In preferred aspects, the invention further comprises a compound of formula 2:
P(0)(OR)2
N
H3C
[00077] 2
[00078] wherein the aryl group is phenyl.
[00079] In yet another preferred embodiment, there is provided a process for the synthesis of amphetamine derivatives comprising the step of performing an organo cuprate addition reaction upon an aziridine phosphoramidate compound to obtain an aryl or aryl-alkyl
phosphoramidate amphetamine precursor.
[00080] In yet another preferred embodiment, there is provided a process for crystallization of compounds 6a-d from a mixture of compounds 6a-d and 8a-d, comprising the step of performing a crystallization using a mixture of two or more solvents wherein at least one of the two or more solvents is THF.
DETAILED DESCRIPTION OF THE INVENTION
[00081] Accordingly, the present invention relates to processes for the synthesis of amphetamine, dexamphetamine, methamphetamine, derivatives of these, including their salts, and novel precursors and intermediates obtained thereby, by synthesizing aziridine phosphoramidate compounds in specified solvents at specified temperatures, and then converting to a novel aryl or aryl-alkyl phosphoramidate precursor using an organometallic compound such as a copper salt, where the novel aryl or aryl-alkyl phosphoramidate precursor is then easily converted to the target compounds using known reactions, e.g. acid dephosphorylation, alkylation of the nitrogen followed by acid dephosphorylation, etc.
[00082] Alkyl means any C1-C10 straight or branched chain alkyl, wherein said alkyl, is optionally substituted with CI -C6 alkyl, C2 -C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl.
[00083] Aryl means any alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group including, but not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, CI -C9 straight or branched chain alkyl, CI -C9 alkoxy, C2 -C9 alkenyloxy, C2 -C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.
[00084] R may also be in certain preferred embodiments any C2-C10 straight or branched chain alkenyl or C1-C10 alkoxy, unsubstituted or optionally substituted with moieties listed above.
[00085] Copper includes CuCl, CuCl2, CuBr, CuF, Cul, Cu(OAc)2, Cu(OMe)2, Copper
nanoparticles, Copper turnings, or combinations thereof. Copper nanoparticles means particles having an average diameter of about lnm -lOOnm.
[00086] Alkyl Phosphonic Acid Protecting group means any group attached to the aziridine nitrogen having one or more alkyl groups attached to a phosphorous atom thereby having the formula P-0-(OR)2, where Rl and R2 can be the same or different, and include without limitation any alkyl, alkoxy or aryl group as defined herein, and including any and all equivalents thereof.
[00087] Solvents, as used and exemplified herein, are not intended to be limiting and may include without limitation solvents selected from Ligroine, Pentane, Hexane, Heptane, Octane,
Cyclopentane, Cyclohexane, Cycloheptane, Cyclooctane, Dichloromethane, Chloroform, Carbon tetrachloride, 1,2-Dichloroethane, 1,1,2,2-Tetrachloroethane, Methylacetate, Ethylacetate, Propylacetate, Butylacetate, Dimethylformamide, Diethylformamide, Dimethylacetamide,
20
Diethylacetamide, Diethylether, Diisopropylether, methyl tert-Butyl ether, THF, Dioxane, Acetonitrile, Sulfolane, DMSO, HMPT, NMP or mixtures of these solvents. Preferred solvents are Dichloromethane, Chloroform, Ethyl acetate, Propyl acetate, Butyl acetate, Dimethylformamide, Diethylformamide, Dimethylacetamide, Diethylacetamide, Diisopropylether, methyl tert-Butyl ether, THF, Dioxane, Acetonitrile or mixtures of these. Especially preferred solvents are
Dichloromethane, Chloroform, Ethyl acetate, Butyl acetate, Dimethylformamide,
Dimethylacetamide, methyl tert-Butyl ether, THF, Dioxane, Acetonitrile or mixtures of these.
[00088] The term, regioselective or regioselectivity, means without limitation, by way of explanation, the preference of one direction of chemical bond making or breaking over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base will abstract from an organic molecule, or where on a substituted benzene ring a further substituent will add. Because of the preference for the formation of one product over another, the reaction is selective. This reaction is regioselective because it selectively generates one constitutional isomer rather than the other. When a reaction is regioselective to the point that no other regioisomers are observed, the reaction is defined as being regiospecific.
[00089] The term, stereoselective or stereoselectivity, means without limitation, by way of explanation, the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during the non-stereospecific creation of a new stereocenter or during the non-stereospecific transformation of a pre-existing one. The selectivity arises from differences in steric effects and electronic effects in the mechanistic pathways leading to the different products.
[00090] Zwierzak et al. teach in Tetrahedron 1997, 53, 4935-4946 that the product from the organocuprate addition to the 2-alkyl-N-(diethylphosphoryl)aziridines is always regiospecific, always occurring with nucleophilic attack at the less substituted carbon atom of the aziridine ring. Zwierzak continues the paragraph by explaining that diethyl N-sec-alkylphosphoramidate products could be easily isolated in pure state after quenching the organocuprate reaction mixture with aqueous ammonium chloride solution and no further purification is necessary before
deprotection. It was discovered in attempting to implement the Zwierzak procedure, that this is not the case. In fact, irrespective of the esters on the phosphoramidate, the crude product (6a,b,c or d) is not of acceptable purity to proceed with. Further, it has also been discovered that, where the process generates 3-5% of 8 (a,b,c or d respectively) in the crude product, that it could not be readily removed after the deprotection or later in the synthetic sequence. It was also found that if you used a single solvent recrystallization of 6a, then you did not remove the corresponding 8a. As example, 6a readily crystallizes from hexane, heptane, isooctane or petroleum ether, but the residual 8a is still present It is required to leave a residue of the reaction solvent (THF) in the solvent mixture to separate the 6a from 8a. Interestingly, it has been discovered that a ratio of specific solvents yielded the most preferred embodiment. This ratio comprises about 7 part heptane and 1 part THF for 6a. The other versions of 6 (b,c or d) needed other recrystallization solvent mixtures, but the common item was that it was required to leave a residue of THF in the mixture.
[00091] Experimental Introduction :
[00092] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.
[00093] NMR spectra: Proton nuclear magnetic resonance spectra were obtained on a Bruker
AV 300 or a Bruker AV 500 spectrometer at 300 MHz and 500 MHz, respectively. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane was used as an internal standard for proton spectra.
[00094] HPLC analyses: Analyses were obtained on a Varian Prostar 210 HPLC system using a
Prevail C18 column (53 x 7 mm, Alltech) with PDA detection at 208-210 nm and solvent gradient program Method A.
10.0 2.0 5.0 95.0
11.5 2.0 5.0 95.0
11.6 2.0 95.0 5.0
13.0 2.0 95.0 5.0
[00096] A = Water with 0.05% v/v Trifluoro acetic Acid
[00097] B = Acetonitrile with 0.05% v/v Trifluoro acetic Acid
[00098] Method B
[00099] Flow rate: 0.7 rnL/min
[000100] Run time : 35 min
[000101] Temp: ambient
[000102] Mobile phase: 90% water pH = 1.5 (perchloric acid): 10% Methanol
[000103] GC (FID): Analyses were obtained on a Varian CP 3800 GC using a Supleco (Cat #
24048) SPB-5 30 x 0.320; 0.25 μιη column.
[000104] Column temperature initial: 50 °C
[000105] Column temperature final: 275 °C
[000106] Ramp profile: 20.0 deg/min
[000107] Injector temperature: 250 °C
[000108] Detector temperature: 250 °C
[000109] Carrier Gas/ flow rate: Helium, 2 mL/min
[000110] Example 1: Preparation of diethyl (2methylaziridin-l-yl)phosphonate (2a):
[000111]
[000112] A 12 L 4-neck flask fitted with an overhead mechanical stirrer, temperature probe and 1 L pressure equalizing addition funnel was charged with 2-methylaziridine (300 g, 5,25 mol purchased from Menadiona SL of Barcelona, Spain), triethylamine (880 mL, 6.3 mol) and dichloromethane (3.0 L).
The stirred solution was cooled to 5 °C and diethoxyphosphoryl chloride (804 mL, 5.51 mol) was added over 2.5 hours while maintain the internal temperature below 15 °C. The reaction was then stirred for 18 hours, at which point the reaction was complete reaction was complete by TLC analysis (silica gel plate, 93:6: 1 dichloromethane/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMn04 stain). Water (3 L) was charged and the biphasic mixture was stirred for 20 minutes. The layers were separated and the organic layer was concentrated under reduced pressure. The remaining yellow oil was clarified by filtration. The filtrate (1028 g) was purified by short path vacuum distillation at 66-67 °C, 1.0 mm Hg. to afford 2a as a colorless liquid (864.8 g, 85% yield, 99.0% GC purity). Ή NMR (300 MHz, CDC13) δ 4.15 (dq, J= 8.0, 7.1 Hz, 4H), 2.64 - 2.45 (m, 1H), 2.33 (ddd, J= 17.9, 5.9, 1.3 Hz, 1H), 1.91 - 1.81 (m, 1H), 1.34 (dt, J= 7.1, 0.9 Hz, 6H), 1.28 (dd, J= 5.4, 1.4 Hz, 3H).
Example 2: Preparation of diphenyl (2methylaziridin-l-yl)phosphonate (2b):
[000115] Compound 2b is prepared as described in Stephens, Moffett, Vaughan, Hill and Brown in the Journal of Chemical and Engineering Data, 1969, 14, 114-116, but substituting toluene for benzene, and is obtained as a thick colorless oil in about 55% yield after vacuum distillation. Expected JH NMR (300 MHz, CDC13) 5 7.40- 7.15 (m, 10H), 2.81 - 2.69 (m, 1H), 2.62 - 2.49 (dd, J= 17.6, 5.6 Hz, 1H), 2.10 - 2.00 (dd, J= 14.1, 4.9 Hz, 1H) and 1.28 - 1.24 ppm (m, 3H).
[000116] Example 3: Preparation of dimethyl (2methylaziridin-l-yl)phosphonate (2c):
[000117]
1.05 eq ClP(0)(OMe)2 D/nwnil .
H 1.20 eq Et3N P(0)(OMe)2
N N
1 CH2C12 . 2c
[000118] Compound 2c is prepared following the general procedure in Stephens, Moffett,
Vaughan, Hill and Brown in the Journal of Chemical and Engineering Data, 1969, 14, 114-116 but substituting toluene for benzene, and is obtained as a colorless oil in about 73% yield after vacuum distillation (75-80 °C @ 10 mm Hg vacuum). Expected *H NMR (300 MHz, CDC13) δ 3.80 (s, 3H), 3.76
(s, 3H), 2.65-2.50 (m, 1H), 2.42-2.31 (dd, J= 17.6, 5.6 Hz, 1H), 1.92 - 1.85 (dd, J= 14.1, 4.9 Hz, 1H), 1.28 (dd,/ = 5.4, 1.2 Hz, 3H).
[000119] Example 4: Preparation of diisopropyl (2methylaziridin-l-yl)phosphonate (2d):
[000120]
[000121] Compound 2d is prepared following the general procedure in Stephens, Moffett,
Vaughan, Hill and Brown in the Journal of Chemical and Engineering Data, 1969, 14, 114-116 but substituting toluene for benzene, and is obtained as a colorless oil in about 80% yield after vacuum distillation (79 - 82 °C @ 3 mm Hg vacuum). Expected !H NMR (300 MHz, CDC13) δ 4.71 (m, 2H), 2.64 - 2.41 (m, 1H), 2.28 (dd, J= 17.6, 5.6 Hz, 1H), 1.81 (dd, J= 14.1, 4.9 Hz, 1H), 1.34 (m, 12H) and 1.22 (dd, J= 5.6, 1.2 Hz, 3H).
Example 5: Preparation of diethyl (2methylaziridin-l-yl)phosphonate (2a), alternate
in. 4.0 eq KOH
(3 M) P(0)(OEt)2
>~ N
5-10 °C 2 h
then
2a
40 °C 6 h
[000124] A 2 L 3 -neck flask fitted with an overhead mechanical stirrer and 50 mL pressure equalizing addition funnel was charged with 2-aminopropanol (25.0 g, 332 mmol), triethylamine (57.8 mL, 416 mmol, 1.25 equivalents) and tetrahydrofuran (800 mL). The stirred solution was cooled to +4
°C and diethoxyphosphoryl chloride (57.9 mL, 399 mmol, 1.20 equivalents) was added over 20 minutes while maintaining an internal temperature <+15°C. The reaction mixture was stirred an additional 30 minutes at which point the reaction was complete by TLC analysis (silica gel plate, 93 :6: 1
dichloromethane/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMn04 stain). Additional triethylamine (57.8 mL, 416 mmol, 1.10 equivalents) was added to the reaction mixture and
methanesulfonyl chloride (32.3 mL, 416 mmol, 1.25 equivalents) was added drop-wise over 25 minutes while maintaining an internal temperature <+18 °C. The resulting reaction mixture was stirred for 1.5 hours at which time TLC analysis (see above methods) indicated the reaction was complete. Potassium hydroxide solution (3 M solution, 555 mL, 1.6 mo 1, 5.0 equivalents) was slowly added to the stirred reaction mixture while maintaining an internal temperature < +20°C. The reaction was stirred for 30 minutes and diluted with ethyl acetate (300 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic extract was washed with saturated sodium chloride solution (300 mL) and dried over anhydrous sodium sulfate. The solution was clarified and then concentrated under reduced pressure to afford crude 2 as an orange oil. The oil was purified by short path distillation (72-74 °C, 10 mm Hg vacuum) to afford purified 2a as a colorless oil (48.2 g,
75% yield, 99.0 % GC purity). Ή NMR (300 MHz, CDC13) δ 4.15 (dq, J = 8.0, 7.1 Hz, 4H), 2.64 - 2.45 (m, 1H), 2.33 (ddd, J = 17.9, 5.9, 1.3 Hz, 1H), 1.91 - 1.81 (m, 1H), 1.34 (dt, J= 7.1, 0.9 Hz, 6H), 1.28 (dd, J= 5.4, 1.4 Hz, 3H).
[000125] Example 6: Preparation of diphenyl (2methylaziridin-l-yl)phosphonate (2b) alternate route:
Hi. 4.0 eq KOH
(3 M) P(0)(OPh)2
[000127] Following the procedure for the alternate preparation of 2a, diphenyl (2methylaziridin-l- yl)phosphonate (2b) is prepared as a thick colorless oil in about 30% yield (expected minimum 97% GC purity). Expected Ή NMR (300 MHz, CDC13) δ 7.40- 7.15 (m, 10H), 2.81 - 2.69 (m, 1H), 2.62 - 2.49 (dd, J= 17.6, 5.6 Hz, 1H), 2.10 - 2.00 (dd, J= 14.1, 4.9 Hz, 1H) and 1.28 - 1.24 ppm (m, 3H).
[000128] Example 7: Preparation of dimethyl (2methylaziridin-l-yl)phosphonate (2c) alternate route:
Hi. 4.0 eq KOH
(3 M) P(0)(OMe)2
*► N
5-10 °C 2 h J-^
then
40 °C 6 h 2c
[000130] Following the procedure for the alternate preparation of 2a, dimethyl (2methylaziridin-l- yl)phosphonate (2c) is prepared as a viscous colorless oil in about 70% yield (expected 95% GC minimum purity). Expected Ή NMR (300 MHz, CDCI3) δ 3.80 (s, 3H), 3.76 (s, 3H), 2.65-2.50 (m, 1H), 2.42-2.31 (dd, J= 17.6, 5.6 Hz, 1H), 1.92 - 1.85 (dd, J = 14.1, 4.9 Hz, 1H), 1.28 (dd,/ = 5.4, 1.2 Hz, 3H).
[000131] Example 8: Preparation of diisopropyl (2methylaziridin-l-yl)phosphonate (2d) alternate route:
[000132]
NH, 1
Hi. 4.0 eq KOH
(3 M) P(0)(OMe)2
N
5-10 °C 2 h
then
40 °C 6 h 2d
[000133] Following the procedure for the alternate preparation of 2a, diisopropyl (2methylaziridin- l-yl)phosphonate (2d) is prepared as a viscous colorless oil in about 50 % yield (expected 95% GC minimum purity). Expected Ή NMR (300 MHz, CDC13) δ 4.71 (m, 2H), 2.64 - 2.41 (m, 1H), 2.28 (ddd, J = 17.6, 5.6, 1.3 Hz, 1H), 1.81 (dd, J = 14.1, 4.9, 1.3 Hz, 1H), 1.34 (m, 12H) and 1.22 (dd, J = 5.6, 1.2 Hz, 3H).
[000134] Example 9: Preparation of diethyl (l-phenylpropan-2-yl)phosphoramidate (6a) [Cul catalyst):
[000135]
GC ratio = 97:3
6a purified
[000136] A 250 mL, jacketed, three necked flask equipped with an overhead stirrer, 50 mL pressure equalizing addition funnel and a temperature probe was charged with 2a (10 g, 51.7
mmol), THF (50 mL) and Cul (98 mg, 1.0 mol%) and the stirred mixture was heated to 30 °C. The pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 32.36 mL) and the solution was added over 20 minutes while maintaining an internal temperature of 30 - 32 °C. After the addition was complete, the reaction mixture was heated to 45-50 °C for an additional 30 minutes and then cooled to ambient temperature. The reaction was quenched by slow addition to a cooled mixture of saturated aqueous ammonium chloride solution and water (50/50 v/v, 100 mL) while maintaining an internal temperature below 20 °C. The flask was rinsed with methyl t- butyl ether (100 mL) and the rinse was transferred to the quenched reaction mixture. The biphasic mixture was stirred for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed. The organic phase washed with saturated sodium chloride solution (50 mL) and the organic phase was dried over sodium sulfate. The solution (a 97:7 mixture of 6a: 8a by GC analysis) was filtered and concentrated under reduced pressure until the product began to crystallize. Heptane (40 mL) was added to the slurry and the mixture was heated until a solution was obtained. The stirred solution allowed to cool to room temperature and stirred for 18 hours. The solid was collected by filtration and dried under reduced pressure at 30°C for 18 hours affording diethyl (l-phenylpropan-2-yl)phosphoramidate (6a) as a white crystalline solid (9.12 g, 65% yield; 99.72% GC purity with 0.04% 8a present). Mp 66-67°C (lit1 57-58 °C). *H NMR (300 MHz, CDCls) δ 7.36 - 7.08 (m, 5H), 4.14 - 3.85 (m, 3H), 3.85 - 3.66 (m, 1H), 3.58 - 3.32 (m, 1H), 2.81 - 2.61 (m, 2H), 2.38 (t,/ = 9.8 Hz, 1H), 1.38 - 1.18 (m, 6H), 1.15 (d,/ = 6.4 Hz, 3H).
[000137] Example 10: Preparation of diethyl (l-phenylpropan-2-yl)phosphoramidate (6a) [CuCl catalyst]:
[000138]
GC ratio = 97:3
6a purified
[000139] A 12 L, jacketed, bottom outlet flask was charged with 2a (700 g, 3.62 mol), THF (3.5 L) and CuCl (3.58 g, 1.0 mol%) and the stirred mixture was heated to 45 °C. A pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 2.26 L) and the solution was added slowly while maintaining an internal temperature below 52°C. After the addition was complete, the reaction mixture was stirred at 48-51 °C for an additional 30 minutes. GC analysis indicated the consumption of 2a (< 1.0%) and the reaction mixture was cooled to ambient temperature. The reaction was quenched by slow addition to a cooled mixture of saturated aqueous ammonium chloride solution and water (50/50 v/v, 4.2 L) while maintaining an internal temperature below 25 °C. The flask was rinsed with heptanes (3.5 L) and the rinse was transferred to the quenched reaction mixture. The biphasic mixture was stirred for 5 minutes, allowed to separate for 20 minutes and then the aqueous phase was removed. The organic phase was concentrated under reduced pressure to a volume of about 1.0 L. The organic solution was azeotropically dried by two separate charges of heptanes (2 X 2.0L) was added and the solution volume was adjusted by reduced pressure distillation to a total volume of about 2.5 L. The slurry was heated to 60-65 °C until the solids dissolved and then stirrer was slowed and the crystallization was allowed to proceed for about 24 hours as the batch cooled to ambient temperature. The slurry was cooled to 5 °C for about 1.5 hours. The resulting crystalline solid was collected by vacuum filtration and washed with cold heptanes (2 x 350 mL). After drying under vacuum at 35 °C for 48 hours the diethyl (l-phenylpropan-2-yl)phosphoramidate (6a) was obtained as a white crystalline solid
(806.1 g, 82% yield; 99.90% GC purity with 0.04% 8a present). Mp 64-65°C (lit1 57-58 °C). *H NMR (300 MHz, CDC13) δ 7.36 - 7.08 (m, 5H), 4.14 - 3.85 (m, 3H), 3.85 - 3.66 (m, 1H), 3.58 - 3.32 (m, 1H), 2.81 - 2.61 (m, 2H), 2.38 (t,/ = 9.8 Hz, 1H), 1.38 - 1.18 (m, 6H), 1.15 (d,/ = 6.4 Hz, 3H).
[000140] The phenyl Grignard can be either be purchased commercial solutions, at about 2 moles of active reagent per liter of solution, or prepared in situ from the corresponding
halobenzene and magnesium metal turnings. For phenylmagnesium chloride, the solvents of choice are either THF or 2-methylTHF. For phenylmagnesium bromide, the solvents of choice are either THF, 2-methylTHF or diethyl ether. For phenylmagnesium iodide the solvent of choice is diethyl ether. The use of any of these ether solvents (alone or mixed with toluene) in conversion to 2a to 6a, following the established procedure, affords 6a in comparable isolated yield, GC purity and devoid of the regioisomer 8a.
[000141] The use of other copper sources (CuCl2, CuBr, CuF, Cu(OAc)2, Cu(acac)2, Cu(OMe)2, Copper nanoparticles and Copper turnings) in conversion to 2a to 6a, following the established procedure, affords 6a in comparable isolated yield, GC purity and devoid of the regioisomer 8a.
Example 11: Preparation of diphenyl (l-phenylpropan-2-yl)phosphoramidate
6b purified
[000144] A 100 mL, 3-necked flask equipped with an overhead stirrer, reflux condenser and pressure equalizing addition funnel was charged with 2b (10.0 g, 34.6 mmol), THF (50 mL) and CuCl (42 mg, 1 mol%) and the stirrer was started. The stirred mixture was heated to 48 °C and the pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 17.4 mL). This solution was added slowly while maintaining a reaction temperature of 48-51 °C. The reaction was
allowed to stir at 48-51 °C for an additional 2 hours until the GC analysis indicated the
consumption of 2b (< 1.0%) and the reaction mixture was cooled to ambient temperature. The reaction was quenched by slow addition to a cooled solution of saturated aqueous ammonium chloride/water mixture (50/50 v/v, 60 mL) while maintaining the batch temperature below 20 °C. Heptanes (60 mL) was used to rinse the reactor and was transferred to the quench mixture. The biphasic mixture was agitated for 15 minutes and the aqueous layer was removed. The organic layer washed with deionized water (20 mL) and the organic phase concentrated under reduced pressure to give viscous oil. This residue was dissolved in heptanes (50 mL) and the solution was concentrated under reduced pressure. The residue was crystallized from ethanol (1 g/5 mL) to give 6b as a white solid (9.05 g, 72% yield, 99.85% GC purity containing 0.05% of 8b). Mp 102- 103 °C (lit1 101-102 °C). H NMR (300 MHz, CDC13) δ 7.38 - 7.11 (m, 15H), 3.83 - 3.65 (m, 1H), 3.00-2.89 (m, 1H), 2.86-2.78 (m, 1H), 2.73-2.62 (m, 1H), 1.15 (d,/ = 10.1 Hz, 3H).
Example 12: Preparation of dimethyl (l-phenylpropan-2-yl)phosphoramidate
GC ratio = 97.5:2.5
H3C
6c purifled
[000147] A 100 mL, 3-necked flask equipped with an overhead stirrer, reflux condenser and pressure equalizing addition funnel was charged with 2c (10.0 g, 60.5 mmol), THF (60 mL) and CuCl (70 mg, 1 mol%) and the stirrer was started. The mixture was heated to 48 °C and the pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 13 mL). This solution was added slowly while maintaining an internal temperature of 48-51 °C. The reaction was stirred at 48-51 °C for an additional 30 minutes until the GC analysis indicated the consumption of 2c (< 1.0%) and the reaction mixture was cooled to ambient temperature. The reaction was
quenched by slow addition to a cooled solution of saturated aqueous ammonium chloride in water (50/50 v/v, 100 mL) while maintaining the temperature below 20 °C. Heptanes (100 mL) was used to rinse the reactor and the rinse solution was transferred to the quenched reaction mixture. The mixture was agitated for 15 minutes, allowed to separate for 30 minutes then the aqueous phase was discarded. The organic phase washed with deionized water (30 mL) and the organic phase concentrated under reduced pressure to give an oil. The residue was dissolved in heptanes (100 mL) and the solution was concentrated under reduced pressure. The residue was
crystallized from methyl tert-butyl ether (lg/3mL), filtered and dried to give 6c as white needles (10.2 g; 74.8 % yield), with 99.90% GC purity containing 0.06% 8c. Mp 86-88 °C. *H NMR (300 MHz, CDCls) δ 7.32 - 7.17 (m, 5H), 3.66 (d,/ = 6.4 Hz, 3H), 3.50-3.83 (m, 1H), 2.71 (d,/ = 6.6 Hz, 2H), 2.45 (m, 1H), 1.15 (d,/ = 6.6 Hz, 3H).
[000148] Example 13: Preparation of diisopropyl (l-phenylpropan-2- yljphosphoramidate (6d):
[000149]
6d purified
[000150] Following the procedure for the alternate preparation of 6a, diisopropyl (1- phenylpropan-2-yl)phosphoramidate (6d) is prepared as a viscous colorless oil in about 50 % yield (expected GC purity: > 99.7% 6d with < 0.1% 8d). Expected *H NMR (300 MHz, CDC13) δ 7.32 - 7.17 (m, 5H), 4.59 - 4.41 (m, 2H), 3.53 - 3.41 (m, 1H), 2.86 - 2.80 (m, 1H), 2.69 - 2.61 (m, 1H), 2.36 (t,/ = 9.6 Hz, 1H), 1.32 - 1.26 (m, 12H), 1.08 (d,/ = 10.1 Hz, 3H).
[000151] Example 14: Preparation of amphetamine (7) from 6a:
[000152]
v. distillation
[000153] A 12 L, jacketed, bottom outlet valve flask was charged with 6a (800 g, 2.95 mol) and 3 M hydrochloric acid (3.0 L) and the reaction mixture was heated to 80 °C for 1.5 hours at which point HPLC analysis indicated that the reaction was complete, and then cooled to room temperature. The brown solution was washed with ethyl acetate (1.5 L) and the organic extract layer was discarded. Sodium hydroxide solution (50% solution, 560 mL) was slowly added to the remaining aqueous layer, keeping the temperature below 25 °C. Methyl tert-butyl ether (1.0 L) was added and the mixture was agitated for 20 minutes then allowed to separate for 30 minutes. The aqueous layer was removed and the organic layer was concentrated under reduced pressure to afford a light yellow oil. This oil was short path distilled (75-78°C at 10 mmHg vacuum) to give racemic amphetamine (7) as a clear colorless oil (335.76 g, 84.3% yield; 99.93% pure by GC). Ή
NMR (300 MHz, CDC13) δ 7.36 - 7.26 (m, 2H), 7.23 - 7.13 (m, 3H), 3.26 - 3.03 (m, 1H), 2.72 (dd,/ = 13.2, 5.4 Hz, 1H), 2.53 (dd,/ = 13.2, 8.0 Hz, 1H), 1.20 (br s, 2H), 1.13 (d, / = 6.3 Hz, 3H).
[000154] Example 15: Preparation of amphetamine (7) from 6b:
[000155]
v. distillation
[000156] A 50 mL flask is charged with 6b (7.5 g, 20.41 mmol) and 3 M HCl (20.0 mL) and the stirred reaction mixture is heated to 80 °C for 32 hours, at which point HPLC analysis should indicate the reaction is complete, and it is cooled to room temperature. The organic layer is
washed with ethyl acetate (2 x 25 mL) and the organic extracts are discarded. The aqueous layer is treated with sodium hydroxide solution (50%, 12.0 mL) keeping the temperature below 25 °C. Methyl tert-butyl ether (50 mL) is added and the reaction mixture is agitated for 5 minutes and then separated. A second portion of methyl tert-butyl ether (50 mL) is added and the reaction mixture is agitated for 5 minutes. The combined organic extracts are washed with water (10 mL) and the organic layer is concentrated under reduced pressure to give 7 as a colorless oil in about 80% yield. The expected purity is > 99% by GC purity and 99% by HPLC. The expected Ή NMR spectra (300 MHz, CDC13) is δ 7.36 - 7.26 (m, 2H), 7.23 - 7.13 (m, 3H), 3.26 - 3.03 (m, 1H), 2.72 (dd,/ = 13.2, 5.4 Hz, 1H), 2.53 (dd,/ = 13.2, 8.0 Hz, 1H), 1.20 (br s, 2H), 1.13 (d,/ = 6.3 Hz, 3H) and matches the reference spectra.
[000157] Example 16: Preparation of amphetamine (7) from 6c:
[000158]
v. distillation
[000159] A 50 mL flask is charged with 6c (5.0 g, 20.6 mmol) and 3 M HCl (20.0 mL) and the stirred reaction mixture is heated to 80 °C for 1 hour, at which point HPLC analysis indicates the reaction is complete, and it is cooled to room temperature. The reaction mixture is washed with ethyl acetate (2 x 20 mL) and the organic extracts are disposed. The aqueous layer is treated with sodium hydroxide solution (50%, 12.0 mL) keeping the internal temperature below 25 °C. Methyl tert-butyl ether (15 mL) is added and the reaction mixture is agitated for 15 minutes then allowed to separate. The organic layer is washed with water (10 mL) and organic layer is concentrated under reduced pressure to give 7 as a colorless oil in about 88.0% yield. The expected purity is
>99.5 % by GC and >99% by HPLC. The expected *H NMR spectra (300 MHz, CDC13) is δ 7.36 - 7.26 (m, 2H), 7.23 - 7.13 (m, 3H), 3.26 - 3.03 (m, 1H), 2.72 (dd,/ = 13.2, 5.4 Hz, 1H), 2.53 (dd,/ = 13.2, 8.0 Hz, 1H), 1.20 (br s, 2H), 1.13 (d,/ = 6.3 Hz, 3H) and matches the reference spectra.
[000160] Example 17: Preparation of amphetamine (7) from 6d:
[000161]
iv. M BE extraction
6(1
v. distillation
[000162] Following the procedure for the preparation of amphetamine (7) from 6a,
amphetamine (7) is prepared from diisopropyl (l-phenylpropan-2-yl)phosphoramidate (6d) as a colorless oil. The expected *H NMR spectra (300 MHz, CDC13) is δ 7.36 - 7.26 (m, 2H), 7.23 - 7.13 (m, 3H), 3.26 - 3.03 (m, 1H), 2.72 (dd,/ = 13.2, 5.4 Hz, 1H), 2.53 (dd,/ = 13.2, 8.0 Hz, 1H), 1.20 (br s, 2H), 1.13 (d,/ = 6.3 Hz, 3H) and matches the reference spectra.
Example 18: Preparation of Impurities 8a-d:
a R=Et 8a R=Et
b R=P 8b R=Ph
c R=Me 8c R=Me
d R=iPr 8d R=iPr
[000165] A 100 mL 3-neck flask was charged with commercial 8 (1.0 g, 7.4 mmol, from Aldrich Chemical), Et3N (1.23 mL, 8.8 mmol), and dichloromethane (25 mL). The solution was cooled to 0-5 °C and a solution of the appropriate chlorophosphate (8.15 mmol of a through d) in dichloromethane (5 mL) was added over 5 minutes. The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was then quenched by adding water (20 mL) and the organic layer was separated. The organic extract was washed with IN HC1 solution (10 mL), saturated NaHC03 solution (10 mL), and saturated sodium chloride solution (10 mL). The organic phase was concentrated to dryness to afford the desired product, 8a-d.
[000166] 8a: 81% yield, colorless oil. 95.8% GC purity.1!! NMR (300 MHz, CDC13) δ 7.30-7.19 (m, 5H), 3.68 (d,/ = 11.1 Hz, 3H), 3.63 (d,/ = 11.1 Hz, 3H), 3.20-3.00 (m, 2 H), 2.95-2.80 (m, 1H), 2.45 (s, br, 1H), 1.26 (d,/ = 6.9 Hz, 3H).
[000167] 8b: 91% yield, colorless oil. 95.16% GC purity.iH NMR (300 MHz, CDCI3) δ 7.26- 7.04 (m, 15H), 3.48 (s, br, 1H), 3.35-3.22 (m, 1 H), 3.03-2.90 (m, 2H), 1.21 (m, 3H).
[000168] 8c: 85% yield, colorless oil. 97.47% GC purity!H NMR (300 MHz, CDCI3) δ 7.32-7.19 (m, 5H), 4.04-3.91 (m, 4 H), 3.20-3.95 (m, 2 H), 2.92-2.80 (m, 1H), 2.45 (s, br, 1H), 1.26 (d,/ = 6.9 Hz, 3H).
[000169] 8d: The residue was chromatographed on a 40 g Combiflash Gold column eluting with 100% heptanes to 100% ethyl acetate over a 20-minute gradient. Combined clean fractions we concentrated to dryness to give the desired product as a clear colorless oil in 42% yield, 97.3% purity GC. *H NMR (300 MHz, CDCI3) δ 7.37 - 7.10 (m, 5H), 4.61 - 4.44 (m, 2H), 3.20-2.91 (m, 2H), 2.90-2.78 (m, 1H), 2.41-2.28 (m, 1H), 1.35-1.16 (m, 15H).
[000170] 1) Cates, L. A.; Lawrence, W. H.; McClain, R. J. Journal of Pharmaceutical Sciences, 1966, 55, 1400 - 1403.
[000171] The references recited herein are incorporated herein in their entirety, particularly as they relate to teaching the level of ordinary skill in this art and for any disclosure necessary for the commoner understanding of the subject matter of the claimed invention. It will be clear to a person of ordinary skill in the art that the above embodiments may be altered or that insubstantial changes may be made without departing from the scope of the invention. Accordingly, the scope of the invention is determined by the scope of the following claims and their equitable
Equivalents.
Claims
1. A process of making the amphetamine, said process comprising: providing a compound of Formula 6:
wherein R is alkyl or aryl; and
deprotecting the compound of Formula 6 under acidic conditions effective to produce
7
2. The process according to claim 1 wherein the acidic conditions are aqueous hydrochloric, sulfuric or phosphoric acids.
3. The process according to claim 2 wherein the aqueous acid water content is in an amount of 50% to 90%
4. The process according to claim 1 wherein the R= methyl, ethyl, isopropyl or phenyl.
5. The process according to claim 1, wherein said providing a compound of Formula 6 comprises:
providing a compound of Formula 2:
P(0)(OR)2
N
H3C
2 wherein R is alkyl or aryl and
reacting the compound of Formula 2 with phenylmagnesium halide and a copper catalyst under solvent and temperature conditions effective to produce a compound of Formula 6 in a purity substantially free of any regioisomeric impurities.
6. The process according to claim 5 wherein the regioisomeric purity of Formula 6 is > 99% and the regioisomer (Formula 8) is < 0.1%.
7. The process according to claim 6 wherein the R= methyl, ethyl, isopropyl or phenyl.
8. The process according to claim 5 wherein the copper catalyst is CuCl, CuCl2, CuBr, CuF, Cul, Cu(OAc)2, Cu(acac)2, Cu(OMe)2, Copper nanoparticles, Copper turnings, or combinations thereof.
9. The process according to claim 5 wherein the solvent is an organic ether or an organic ether - toluene mixture.
10. The process according to claim 9 wherein the organic ether solvent is diethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran.
11. The process according to claim 5 wherein the phenylmagnesium halide is either
phenylmagnesium chloride, phenylmagnesium bromide or phenylmagnesium iodide.
12 The process according to claim 11 wherein the phenylmagnesium halide solutions can either be commercially supplied or prepared in situ from the corresponding halobenzene and magnesium.
13. The process according to claim 12 wherein the magnesium can be in the form of chips, granules, ribbon, turnings, dust, grit, chunks, or combinations thereof.
14. The process according to claim 5 wherein said treating is carried out at a temperature of from about -10 °C to about 70 °C.
15. The process according to claim 11 wherein said treating is carried out at a temperature of from about 30 °C to about 60 °C.
16. The process according to claim 2, wherein said providing a compound of Formula 2 comprises:
providing a compound of Formula 5:
5
wherein R is alkyl or aryl; and
reacting the compound of Formula 5 with the base under conditions effective to produce a compound of Formula 2.
17. The process according to claim 16 wherein the R= methyl, ethyl, isopropyl or phenyl.
18. The process according to claim 16, wherein the base is potassium hydroxide or potassium carbonate.
19. The process according to claim 16, wherein said providing a compound of Formula 5 comprises:
4
wherein R is alkyl or aryl; and
reacting the compound of Formula 4 with methanesulfonyl chloride and a base under conditions effective to produce a compound of Formula 5.
20. The process according to claim 19 wherein the R= methyl, ethyl, isopropyl or phenyl.
21. The process according to claim 19, wherein said providing a compound of Formula 4 comprises:
providing a compound of Formula 3:
NH2
, . . OH
H3C
3 and
reacting the compound of Formula 3 with the appropriate
O
I I
/P-Cl
RO VOR
wherein R= alkyl or aryl
under conditions effective to produce a compound of Formula 4
22. The process according to claim 21 wherein the R= methyl, ethyl, isopropyl or phenyl.
6
prepared as per claim 5 in a regioisomeric purity of > 1700:1
wherein:
R is alkyl or aryl.
24. A compound according to claim 23, wherein the alkyl group is selected from the group consisting of methyl, ethyl or isopropyl.
25. A compound according to claim 23 wherein the aryl group is phenyl.
26. A compound of the formula 2:
2
wherein: R is alkyl or aryl.
27. A compound according to claim 26, wherein the alkyl group is selected from the group consisting of methyl, ethyl or isopropyl.
28. A compound according to claim 26 wherein the aryl group is phenyl.
29. A process for the synthesis of amphetamine derivatives comprising the step of performing a organo cuprate addition reaction upon an aziridine phosphoramidate compound to obtain an aryl or aryl-alkyl phosphoramidate amphetamine precursor.
30. A process for the crystallization of compounds 6a-d from a mixture of compounds 6a-d and 8a-d, comprising the step of performing a crystallization using a mixture of two or more solvents wherein at least one of the two or more solvents is THF.
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US14/327,209 US9321794B2 (en) | 2013-12-31 | 2014-07-09 | Synthesis of racemic amphetamine derivatives by cuprate addition reaction with aziridine phosphoramidate compounds |
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Cited By (3)
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US9657041B2 (en) | 2013-12-31 | 2017-05-23 | Chemapotheca, Llc | Chiral aryl or aryl-alkyl phosphoramidate dexamphetamine precursors having a regioisomeric purity >99% |
WO2017098533A3 (en) * | 2015-12-11 | 2017-08-10 | Sun Pharmaceutical Industries Limited | Process for preparation of lisdexamphetamine |
US11717498B2 (en) | 2013-12-31 | 2023-08-08 | Pharmapotheca A, Inc. | Methods of treatment using amphetamine controlled release, prodrug, and abuse deterrent dosage forms |
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US3584085A (en) * | 1967-07-18 | 1971-06-08 | Atlas Chem Ind | Phosphoramidates |
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US3584085A (en) * | 1967-07-18 | 1971-06-08 | Atlas Chem Ind | Phosphoramidates |
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Title |
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LI XINYAO ET AL.: "An Improved and Mild WenkerSynthesis of Aziridines", SYNTHESIS, vol. 20, 1 January 2010 (2010-01-01), pages 3423 - 3428 * |
ZWIERZAK A . ET AL.: "Communications, ''Phosphoramidomercuration_Demercuration: A Simple, Two-Step Conversion of Alkenes into Alkamnines, November, 918-920, 1982.", SYNTHESIS, 1 January 1982 (1982-01-01), pages 918,920 * |
ZWIERZAK A. ET AL.: "Synthesis of Primary sec-Alkylamines via Nucleophilic Ring-opening of N-Phosphorylated Aziridines", TETRAHEDRON, vol. 53, no. 13, 1997, pages 4935 - 4946, XP004771912, ISSN: 0040-4020 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9657041B2 (en) | 2013-12-31 | 2017-05-23 | Chemapotheca, Llc | Chiral aryl or aryl-alkyl phosphoramidate dexamphetamine precursors having a regioisomeric purity >99% |
US11717498B2 (en) | 2013-12-31 | 2023-08-08 | Pharmapotheca A, Inc. | Methods of treatment using amphetamine controlled release, prodrug, and abuse deterrent dosage forms |
WO2017098533A3 (en) * | 2015-12-11 | 2017-08-10 | Sun Pharmaceutical Industries Limited | Process for preparation of lisdexamphetamine |
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