CN117088868A - Preparation method of FP-CIT precursor and preparation using the same 18 F]Method of FP-CIT - Google Patents
Preparation method of FP-CIT precursor and preparation using the same 18 F]Method of FP-CIT Download PDFInfo
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- CN117088868A CN117088868A CN202210650146.5A CN202210650146A CN117088868A CN 117088868 A CN117088868 A CN 117088868A CN 202210650146 A CN202210650146 A CN 202210650146A CN 117088868 A CN117088868 A CN 117088868A
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- 239000002243 precursor Substances 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000000126 substance Substances 0.000 claims abstract description 127
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 15
- QQXLDOJGLXJCSE-KNVOCYPGSA-N tropinone Chemical compound C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 claims abstract description 12
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 alkylaryl sulfone anions Chemical class 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000000524 functional group Chemical group 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- SHWAZDVCGJVDIW-UHFFFAOYSA-N methyl 3-(4-iodophenyl)-8-(3-methylsulfonyloxypropyl)-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound COC(=O)C1C(N2CCCOS(C)(=O)=O)CCC2CC1C1=CC=C(I)C=C1 SHWAZDVCGJVDIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- XWIJIXWOZCRYEL-UHFFFAOYSA-M potassium;methanesulfonate Chemical compound [K+].CS([O-])(=O)=O XWIJIXWOZCRYEL-UHFFFAOYSA-M 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 3
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 claims description 2
- 229960004394 topiramate Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 11
- 238000010586 diagram Methods 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 5
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 5
- 208000018737 Parkinson disease Diseases 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 229960003920 cocaine Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical class C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 239000012217 radiopharmaceutical Substances 0.000 description 3
- 229940121896 radiopharmaceutical Drugs 0.000 description 3
- 230000002799 radiopharmaceutical effect Effects 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 150000003871 sulfonates Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical group C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 150000003943 catecholamines Chemical class 0.000 description 2
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- IBOZZWGMZPMXBO-DGAVXFQQSA-N methyl (1s,3s,4s,5r)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3)[C@H]2C(=O)OC)=CC=C(I)C=C1 IBOZZWGMZPMXBO-DGAVXFQQSA-N 0.000 description 2
- WXEMSGQRTGSYOG-PMDVUHRTSA-N methyl (1s,5r)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound C1C(=O)C(C(=O)OC)[C@@]2([H])CC[C@]1([H])N2C WXEMSGQRTGSYOG-PMDVUHRTSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229930004006 tropane Natural products 0.000 description 2
- OXDSKEQSEGDAFN-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenylmethanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NC1=CC=CC=C1 OXDSKEQSEGDAFN-UHFFFAOYSA-N 0.000 description 1
- QKIHLPFZYGFMDK-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F QKIHLPFZYGFMDK-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 1
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910021612 Silver iodide Inorganic materials 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- SWJBITNFDYHWBU-UHFFFAOYSA-N [I].[I] Chemical compound [I].[I] SWJBITNFDYHWBU-UHFFFAOYSA-N 0.000 description 1
- 230000007177 brain activity Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- HEYOUZKOHYRGEV-GXTWGEPZSA-N methyl (1s,5r)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]oct-3-ene-4-carboxylate Chemical compound COC(=O)C([C@H]1CC[C@H](N1C)C1)=C1C1=CC=CC=C1 HEYOUZKOHYRGEV-GXTWGEPZSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- MXVIRUOHPRXGTG-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1.OB(O)C1=CC=CC=C1 MXVIRUOHPRXGTG-UHFFFAOYSA-N 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a preparation method of an FP-CIT precursor and preparation of the FP-CIT precursor 18 F]FP-CIT method. The preparation method of the FP-CIT precursor of one embodiment of the invention is characterized in that the compound of the chemical formula 1, the compound of the chemical formula 1-1 and the compound of the chemical formula 2 are obtained from tropinone (tropinone) through pure organic synthesis, wherein the chemical formula 1:chemical formula 1-1:chemical formula 2:
Description
Technical Field
The present invention relates to the preparation of N- (3- [ known as a radiopharmaceutical for diagnosing Parkinson's disease ] 18 F]Fluoropropyl) -2-beta-carbonylmethoxy-3-beta- (4-iodophenyl) tropane (e.g. [ solution ] 18 F]FP-CIT), in particular for the preparation of [ 18 F]A method for preparing a precursor of FP-CIT.
Background
Among various diagnostic methods for properly treating a patient, positron emission tomography (Positron Emission Tomography, hereinafter referred to as PET) capable of functional diagnosis diagnoses diseases by confirming the dynamics of a radiopharmaceutical injected into the body. The method is to inject a diagnostic drug with a proton-releasing radioisotope attached thereto to a patient to obtain an image, in which case the proton-releasing element is most commonly radioisotope F-18 (fluorine, fluorine element). The isotope has a relatively high non-radioactivity and a half-life of about 110 minutes, which is short, so that the patient does not have to worry about overexposure to radioactivity.
The brain of animals is associated with a variety of signaling substances, the proper secretion of which and their relationship to receptors and transmitters are essential for brain activity. Among these, catecholamines are known to be involved in various diseases including schizophrenia (schizophrenia) and dyskinesia. One of these catecholamines has a close relationship with parkinson's disease as dopamine which is a monoamine compound, and is known to be involved in secretion and resorption of dopamine.
[ 18 F]FP-CIT is a radiopharmaceutical developed in Korea for diagnosing Parkinson's disease, and is a drug capable of diagnosing Parkinson's disease by imaging a dopamine transporter (dopamine transporter) directly associated with Parkinson's disease. [ 18 F]FP-CIT has a chemical structure very similar to cocaine as an anesthetic. Cocaine is known to have very high selectivity (selectivity) for dopamine transporter in the brain. Due to [ 18 F]FP-CIT has similar chemical results to cocaine and thus utilizes thisIs characterized by high selectivity for dopamine transporter, and thus can be developed as a substance for obtaining proton emission tomography images of dopamine transporter in a trace amount without anesthetic effect.
Since the approval of the project was obtained in the korean food and drug security hall in 2008 [ 18 F]FP-CIT has been used in clinical practice for 10 years. However, as a method for preparing [ 18 F]The precursor of the starting material of FP-CIT in most cases uses cocaine as starting material. Further, since chemical instability (instability) of the precursor continues to be a problem, an azetidinium salt precursor has been developed to reduce such instability, but this substance is not quantifiable and therefore has a problem in practical application to production.
Related prior art is U.S. publication No. 2010-0292478 (title of the invention: method for producing a radioactive compound containing a fluorine 18isotope (Process of preparing a radioactive compound containing a fluorine-18 isotope), publication date: 11/18/2010).
Disclosure of Invention
The object of the present invention is to provide a method for the efficient synthesis of N- (3-sulfonyloxypropyl) -2- β -carboxymethoxy-3- β - (4-iodophenyl) tropane (commonly known as International Association of pure and applied chemistry (IUPAC) name: methyl3- (4-iodophenyl) -8- (3- ((methylsulfonyl) oxy) propyl) -8-azabicyclo [3.2.1] octane-2-carboxylate (methyl 3- (4-iodophenyl) -8- (3- ((methyl sulfonyl) oxy) propyl) -8-azabicyclo [3.2.1] octane-2-carboxylate)) not by cocaine but by the simple organic compound tolenone. In particular, the present invention aims to obtain the compound in such a way that it has optically pure stereochemical structure of the compound 1R,2S,3S, 5S.
It is another object of the present invention to provide a process for preventing the irregular conversion of the existing N- (3-sulfonyloxypropyl) -2- β -carboxymethoxy-3- β - (4-iodophenyl) tropane (commonly known, international Union of Pure and Applied Chemistry (IUPAC) name: 3- (4-iodophenyl) -8- (3- ((methylsulfonyl) oxy) propyl) -8-azabicyclo [3.2.1] octane-2-carboxylate) as a precursor into a thermodynamically stable azetidinium salt after synthesis, but an N- (3-fluoropropyl) -2- β -carboxymethoxy-3- β - (4-iodophenyl) tropane salt which is still stable after preparation (commonly known, IUPAC name: synthesis of ((methyl 3- (4-iodophenyl) -8- (3- ((methylsulfonyl) oxy) propyl) -8-azabicyclo [3.2.1] octane-2-carboxylate) (methyl 3- (4-iodophenyl) -8- (3- ((methyl sulfonyl) oxy) propyl) -8-azabicyclo [3.2.1] octane-2-carboxylate salt).
In order to achieve the above object, an embodiment of the present invention provides a method for preparing an FP-CIT precursor, characterized in that a compound of chemical formula 1 is obtained from topinone through pure organic synthesis.
Chemical formula 1:
in methyl N- (3-methylsulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate represented by the above chemical formula 1, R is a C1-C6 alkyl group or a C6-C12 aryl group, the above alkyl group may be substituted with halogen, and the above aryl group may be substituted with at least one of C1-C3 alkyl group, halogen, and nitro group.
Preferably, the compound of chemical formula 1-1 can be obtained from the compound of chemical formula 1 described above.
Chemical formula 1-1:
in (1 'R,2' S,3'S,5' S) -3 '-4-iodophenyl) -2' -methoxycarbonyl-spiro [ azetidine-1, 8 '-bicyclo [3.2.1] octane ] -1-' methanesulfonate represented by the above chemical formula 1-1, R is a C1-C6 alkyl group or a C6-C12 aryl group, the above alkyl group may be substituted with halogen, and the above aryl group may be substituted with at least one of a C1-C3 alkyl group, halogen, and nitro group.
Preferably, a compound of chemical formula 2 corresponding to a salt thereof may be obtained from the compound of chemical formula 1 described above.
Chemical formula 2:
wherein R is a C1-C6 alkyl or C6-C12 aryl group, said alkyl group being capable of being substituted by a halogen, said aryl group being capable of being substituted by at least one of a C1-C3 alkyl, halogen, nitro group, X is a substituent capable of forming a quaternary salt with the nitrogen of the amine, including alkylaryl sulfone anions or other stable anions, Y includes all functional groups capable of forming quaternary amines other than alkylaryl sulfone.
Preferably, the compound of formula 1 above may be obtained from the compound of formula 2 above.
Preferably, the compound of formula 3 is obtained from topirane (tropinone).
Chemical formula 3:
wherein R comprises a C1-C6 alkyl group, an aryl group or a substituted alkyl group.
Preferably, the compound of formula 4 may be obtained from the compound of formula 3 described above.
Chemical formula 4:
preferably, the compound of formula 5 may be obtained from the compound of formula 4 described above.
Chemical formula 5:
preferably, the compound of formula 6 may be obtained from the compound of formula 5 described above.
Chemical formula 6:
wherein R is a C1-C6 alkyl group or a C6-C12 aryl group, said alkyl group being capable of being substituted by halogen or a functional group comprising a substituted alcohol ketone.
Preferably, compounds of chemical formula 7 and chemical formula 7' may be obtained from the compound of chemical formula 6 described above.
Chemical formula 7:
chemical formula 7':
wherein R is a C1-C6 alkyl group or a C6-C12 aryl group, said alkyl group being capable of being substituted by halogen or a functional group comprising a substituted alcohol ketone. Moreover, a small amount of the compound of formula 7' as an isomer of the compound of formula 7 is simultaneously obtained.
Preferably, the compound of formula 8 may be obtained from the compound of formula 7 described above.
Chemical formula 8:
preferably, the compound of formula 9 may be obtained from the compound of formula 8 described above.
Chemical formula 9:
preferably, the compound of formula 1 above may be obtained from the compound of formula 9 above.
In order to achieve the above object, an embodiment of the present invention provides 18 F]A process for producing FP-CIT, which comprises preparing a precursor of FP-CIT from at least one compound selected from the group consisting of the compounds of chemical formula 1, chemical formulae 1-1 and chemical formula 2 by the above-mentioned production process 18 F]FP-CIT。
Preferably, the organic solvent used in the above-mentioned fluorine substitution reaction may be one selected from the group consisting of acetonitrile, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and alcohol.
Preferably, the elution may be performed by elution using tetra-n-butylammonium or potassium methanesulfonate 18 F fluoride.
Drawings
Fig. 1 is a diagram illustrating a process of synthesizing a substance of chemical formula 1 by tropanone according to an embodiment of the present invention.
Fig. 2 is a diagram illustrating a process of obtaining a substance of chemical formula 2 from a substance of chemical formula 1 according to an embodiment of the present invention.
Fig. 3 is a diagram illustrating a process of obtaining a substance of chemical formula 1 from a substance of chemical formula 2 according to an embodiment of the present invention.
FIG. 4 is a diagram showing the reaction of nucleophilic fluoride from a substance of chemical formula 2 [ according to one embodiment of the present invention 18 F]A diagram of the process of FP-CIT.
Fig. 5 to 13 are diagrams for explaining experimental examples of the present invention.
Detailed Description
The advantages, features and methods of accomplishing the same may be understood clearly by reference to the detailed description of embodiments that follow. However, the present invention is not limited to the embodiments disclosed below, but can be embodied in various forms, which are provided only for the sake of completeness of the disclosure and to fully inform a person of ordinary skill in the art of the scope of the present invention, which is defined only by the scope of the claimed invention. Throughout the specification, like reference numerals refer to like structural elements.
In order to effectively explain the technical elements for realizing the present invention, the functional configuration provided in each system in the preferred embodiment of the present invention or the system functions normally provided in the technical field of the present invention will be omitted, and the functional configuration additionally provided for the present invention will be mainly described below. In the case of a conventional functional structure, the functions of the components that have been conventionally used in the functional structure described below for illustration and description are easily understood by those skilled in the art to which the present invention pertains, and the relationship between the components that have been omitted and the components added for the present invention is clearly understood.
Before explaining an embodiment of the invention, so as to develop 18 F]Novel precursors of FP-CIT are based on the fact that they are existing precursorsIs converted thermodynamically to stable (1 ' R,2' S,3' S,5' S) -3' - (4-iodophenyl) -2' - (methoxycarbonyl) spiro [ azetidine-1, 8' -bicyclo [3.2.1] within days to weeks after synthesis]Octane (octane)]The conversion ratio of the (1-ium R-substituted sulfonate) varies depending on the storage conditions and storage time such as normal temperature, cold storage and freezing after the synthesis, and even if only (1 ' R,2' S,3' S,5' S) -3' - (4-iodophenyl) -2' - (methoxycarbonyl) spiro [ azetidine-1, 8' -bicyclo [3.2.1] is synthesized in a conventional manner using a polar solvent]Octane (octane)]-1-ium R-substituted sulfonate, the residual amount of N- (3-sulfonyloxypropyl) -2-beta-carboxymethoxy-3-beta- (4-iodophenyl) tropane is still present, and therefore cannot be found in the presence of both substances at the same time 18 F]In the development of the synthesis conditions of FP-CIT, both substances are properly used simultaneously 18 F]Fluorine substitution conditions.
Therefore, it is only possible to set the mode in which the presence of one form of the precursor substance is judged 18 F]Fluorine labeling conditions, ultimately, even if only (1 ' R,2' S,3' S,5' S) -3' - (4-iodophenyl) -2' - (methoxycarbonyl) spiro [ azetidine-1, 8' -bicyclo [3.2.1] is artificially synthesized]Octane (octane)]-1-ium R-substituted sulfonate as precursor for improvement [ 18 F]The yield of fluorine labeling is also limited. In particular, for [18 ]]Marking of fluorine, the precursor is obtained by deforming the ring (cyclic) structure forming the azetidinium salt into a linear structure 18 F]Fluorine is labeled, so that when such a precursor is used, the increase in yield is limited.
Therefore, it is most suitable for preparation 18 F]The precursor of FP-CIT is a material for binding a salt (salt) to an amine of a tropane ring in an amount sufficient to bind 18 F]A substance in which the propyl group of the fluorine-labeled leaving group does not undergo a change in chemical structure during long-term storage even when it exists in a linear form. In particular, this material is described in [ [ 18 F]Only the salt is removed before fluorine marking, and the method is used for [ 18 F]In the case of the fluorine labeling reaction, it is possible to produce [ under the same conditions as in the case of the conventional N- (3-sulfonyloxypropyl) -2- β -carboxymethoxy-3- β - (4-iodophenyl) tropane ] 18 F]FP-CIT, therefore, is most desirable for preparation[ 18 F]A precursor of FP-CIT.
According to a preparation method of an FP-CIT precursor according to an embodiment of the present invention, the compound of chemical formula 1 is obtained by tropanone using a synthesis method by pure organic synthesis of tropane (tropane) precursor.
Chemical formula 1:
methyl N- (3-methylsulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate represented by the above chemical formula 1 is represented by, but is not limited to, the case where R is a methyl group, R may be plural, R is a C1-C6 alkyl group or a C6-C12 aryl group, the alkyl group may be substituted with halogen, and the aryl group may be substituted with at least one of a C1-C3 alkyl group, halogen, and nitro group.
Also, according to a preparation method of the FP-CIT precursor of an embodiment of the present invention, the compounds of chemical formula 1-1 may be obtained from the compound of chemical formula 1 described above.
Chemical formula 1-1:
in (1 'R,2' S,3'S,5' S) -3 '-4-iodophenyl) -2' -methoxycarbonyl-spiro [ azetidine-1, 8 '-bicyclo [3.2.1] octane ] -1-' methanesulfonate represented by the above chemical formula 1-1, R is a C1-C6 alkyl group or a C6-C12 aryl group, the above alkyl group may be substituted with halogen, and the above aryl group may be substituted with at least one of a C1-C3 alkyl group, halogen, and nitro group.
Further, even if the compound of the chemical formula 1-1 is not intentionally prepared from the compound of the chemical formula 1, the compound of the chemical formula 1 can be naturally formed from a small amount to a considerable amount, and the compound of the chemical formula 1 can be actively dissolved in a polar solvent to prepare the compound. In this case, the polar solvent may be one selected from the group consisting of dimethylformamide, t-butanol, acetonitrile, methanol, ethanol, isopropanol, dimethyl sulfoxide, t-amyl alcohol, and water.
According to a preparation method of an FP-CIT precursor of an embodiment of the present invention, a compound of chemical formula 2 corresponding to a salt thereof may be obtained from the compound of chemical formula 1 described above.
Chemical formula 2:
wherein R is a C1-C6 alkyl group or a C6-C12 aryl group, said alkyl group being capable of being substituted by a halogen, said aryl group being capable of being substituted by at least one of a C1-C3 alkyl group, a halogen, a nitro group, X is an alkylaryl sulfone anion or other stable anion as a substituent capable of forming a quaternary salt with the nitrogen of the amine, Y may include all functional groups capable of forming a quaternary amine except alkylaryl sulfone.
In this case, the alkyl or aryl functionality typically described above as alkylaryl sulfone anions includes at a minimum methyl, trifluoromethyl, phenyl, tolyl, 4-bromophenyl, or 4-nitrophenyl or more.
On the other hand, according to a preparation method of an FP-CIT precursor according to an embodiment of the present invention, the compound of chemical formula 1 described above may be obtained from the salt of chemical formula 2 described above.
The following describes the efficient synthesis of topiramate from a simple organic compound for use as [ according to a preparation method of an FP-CIT precursor of an embodiment of the present invention 18 F]A method of preparing the compound of formula 1, the compound of formula 1-1, and the compound of formula 2 as a salt thereof, which are precursors of FP-CIT.
First, according to a preparation method of an FP-CIT precursor according to an embodiment of the present invention, the compound of chemical formula 3 may be obtained by topirane.
Chemical formula 3:
wherein R may include all C1-C6 alkyl groups, aryl groups, substituted alkyl groups, and the like.
Then, according to the preparation method of the FP-CIT precursor of an embodiment of the present invention, the compound of formula 4 may be obtained from the compound of formula 3, the compound of formula 5 may be obtained from the compound of formula 4, the compound of formula 6 may be obtained from the compound of formula 5, the compound of formula 7 may be obtained from the compound of formula 6, the compound of formula 8 may be obtained from the compound of formula 7, and the compound of formula 6 may be obtained from the compound of formula 8.
Chemical formula 4:
chemical formula 5:
chemical formula 6:
chemical formula 7:
chemical formula 8:
chemical formula 9:
wherein R is a C1-C6 alkyl group or a C6-C12 aryl group, which alkyl group can be substituted with halogen or a functional group comprising a substituted alcohol ketone.
On the other hand, the above compound of formula 7 can simultaneously obtain a small amount of the compound of formula 7' as an isomer thereof.
Chemical formula 7':
finally, according to a preparation method of the FP-CIT precursor of an embodiment of the present invention, the compound of the above chemical formula 9 can be used for the preparation of [ [ 18 F]The compound of formula 1, the compound of formula 1-1, and the compound of formula 2 as salts thereof, which are precursors of FP-CIT.
Hereinafter, an embodiment of the present invention will be described 18 F]A preparation method of FP-CIT.
According to one embodiment of the invention 18 F]The preparation method of FP-CIT can be carried out by fluorine substitution reaction (nucleophilic fluorination reaction) from the above-described compound of formula 1, the above-described compounds of formula 1-1 and the above-described compound of formula 2 as a salt thereof 18 F]FP-CIT。
Among them, the organic solvent used in the above-mentioned fluorine (18-F or 19-F) substitution reaction is preferably one selected from the group consisting of acetonitrile, N-dimethylformamide, dimethyl sulfoxide and triol. Can be eluted by elution using tetra-n-butylammonium or potassium methanesulfonate 18 F fluoride. Further, the compound of the above chemical formula 2 can be stored in a solid state or a solution state, or in a state of a solid suspension in an insoluble solvent.
Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
Fig. 1 is a diagram showing a process of synthesizing a substance of chemical formula 1 by tropinone.
EXAMPLE 1 (R) -2-methoxycarbonyl-3-tropanone-3-trifluoromethylsulfonate (R) -2-carbomethoxy-3-tropinone 3-triflate) (see chemical formula 3 of FIG. 1)
After introducing a methoxycarbonyl function to the α position of the tropanone (tropinone) of the racemic mixture using known methods (J.Med. Chem.2005,48,7437-7444, nucl. Med. Biol.,1996,23,981-986), optically pure (R) - (+) -2-methoxycarbonyl-3-tropanone ((R) - (+) -2-carbomethoxy-3-tropinone) was obtained by optical separation using known methods, 3.5g (17.7 mmol) of this material was placed in 100mL of anhydrous Tetrahydrofuran (THF) and 21.3mL of NaN (TMS) formed from a 1M solution of tetrahydrofuran at a temperature of-78 ℃ 2 Slowly drop by drop over 10 minutes.
After stirring the solution for 30 minutes, the solution was slowly dropped drop by drop (7.6 g,21.3 mmol)N-phenyl trifluoro methanesulfonamide (N-phenyl trifluoro methyl sulfonamide) (15.4 g,43 mmol) for 10 min. After completion of the dripping, the reaction solution was stirred at a temperature of 0℃for 1 hour, and then stirred at room temperature for 4 hours. After the completion of the reaction, the solvent was volatilized, and then 50mL of water was added to the remaining reaction mass, and the organic matter was extracted 4 times with 100mL of ethyl acetate to collect the organic solvent. After washing the solvent with 20mL of concentrated brine (brine), anhydrous sodium sulfate (Na 2 SO 4 ) Removing water and filtering. After concentrating the filtrate under reduced pressure, it was passed through a silica gel column to prepare 4.6g of the title compound in 78% yield.
1 H NMR(CDCl 3 )：δ 1 H NMR(400MHz,CDCl 3 )δ3.94(d,J＝5.4Hz,2H)，3.82(s，6H)，3.44(dd，J＝6.0，5.1Hz，2H)，2.88(d，J＝4.6Hz，1H)，2.83(d，J＝4.6Hz，1H)，2.40(s，6H)，2.18(dd，J＝6.5，5.5Hz，4H)，2.02–1.92(m，4H)，1.65–1.57(m，2H)；13C NMR(CDCl 3 )δ163.8，149.1，125.2，118.2(q，J＝319.8Hz)，60.0，57.4，52.0，34.8，33.0，30.0。
EXAMPLE 2 (R) -2-methoxycarbonyl-3-phenyl-2-tolylene (R) -2-carbomethoxy-3-phenyl-2-tropene) (see section 4 of FIG. 1)
(R) -2-methoxycarbonyl-3-tropanone-3-trifluoromethylsulfonate (4.0 g,12.1 mmol), phenylboronic acid (phenyl boronicacid) (1.77 g,14.5 mmol), pd (PPh) 3 ) 4 (0.42 g,0.36 mmol) and cesium fluoride (4.0 g,26.8 mmol) were placed in 30mL of DEM and stirred at 70℃for 2 hours. After the reaction was completed, 200mL of dimethyl ether was added to the reaction solution, followed by filtration and removal of the formed solid. After washing the passed organic solvent twice with 10mL of water, it was washed with anhydrous sodium sulfate (Na 2 SO 4 ) Removing water and filtering. After concentrating the filtrate under reduced pressure, it was passed through a silica gel column to prepare 2.7g of the title compound in 87% yield.
[α]D 20 ＝-60.5(c＝1.0,CHCl 3 )(lit.[α]D20＝-61.4(c＝7.25,CHCl3)。 1 H NMR(400MHz,CDCl 3 )：δ7.37-7.23(m，3H)，7.14(m，2H)，3.87(m，1H)，3.47(s，3H)，3.34(m，1H)，2.77(dd，J＝18.9，4.3Hz，1H)，2.47(s，3H)，2.34-2.14(m，2H)，2.10-1.90(m，2H)，1.66(m，1H)；13C NMR(CDCl 3 )：δ168.3，143.6，141.1，130.3，127.9，127.3，126.6，60.2，57.3，51.1，37.3，35.8，34.1，30.0。
EXAMPLE 3 (1R, 5S) -methyl3-phenyl-8-azabicyclo [3.2.1] oct-2-ene-2-dicarboxylic acid ester) (see chemical formula 5 of FIG. 1).
(R) -2-methoxycarbonyl-3-phenyl-2-tolene ((R) -2-carbomethoxy-3-phenyl-2-tropene 4 (2.5 g,9.7 mmol) was dissolved in dichloroethane (40 mL) under nitrogen, sodium bicarbonate (sodium bicarbonate) (1.1 g,13.8 mmol) was added thereto in three portions while heating and convection stirring, and the reaction was further heated by convection for 48 hours after adding 8.9mL of 1-chloroethyl chloroformate (l-chloroethyl chloroformate).
After the reaction was completed, all volatile matters were removed in a vacuum concentrator, and 100mL of methanol was added thereto and heated and convection stirred for 12 hours. After the reaction, the reaction solvent was concentrated under reduced pressure, and NH was used 4 OH and CH 2 Cl 2 And (5) diluting. Then, CH is used 2 Cl 2 The reaction product was extracted 5 times in 100ml portions. Then, the organic solvent was washed 3 times with 50mL of water, and then dried over anhydrous sodium sulfate (Na 2 SO 4 ) Removing water and filtering. The filtrate was concentrated under reduced pressure and used in the next reaction without purification.
To this was added 20mL of methanol, followed by sodium hydrogencarbonate (3.0 g,25.9 mmol) and di-tert-butyl dicarbonate (di-tert-butyl dicarbonate) (2.6 g,12.3 mmol), and then stirred at room temperature for 3 hours. After completion of the reaction, 60mL of CH was used 2 Cl 2 After dilution, the mixture was washed with 50mL of CH each time 2 Cl 2 Is extracted twice by way of (a) a pattern. Anhydrous sodium sulfate (Na 2 SO 4 ) Removing water and filtering. After concentrating the filtrate under reduced pressure, it was passed through a silica gel column to prepare 2.8g of the title compound in 85% yield.
1 H NMR(400MHz，CDCl3)：δ7.42–7.24(m,3H)，7.14–7.00(m，2H)，4.90(m，1H)，4.43(s，4H)，3.52(s，3H)，3.09(m，1H)，2.33–2.02(m，4H)，1.77(m，1H)，1.50(s，9H)。
EXAMPLE 4 (1R, 2S,3S, 5S) -8-tert-butyl 2-methyl3-phenyl-8-azabicyclo [3.2.1] octane-2, 8-dicarboxylic acid ester ((1R, 2S,3S, 5S) -8-tert-butyl 2-methyl3-phenyl-8-azabicyclo [3.2.1] octane-2, 8-dicarboxylate) (see chemical formula 6, chemical formula 7, and isomer chemical formula 7' thereof in FIG. 1)
2.5g (7.2 mmol) of the previously prepared (R) -8-tert-butyl-2-methyl-3-phenyl-8-azabicyclo [3.2.1]Oct-2-ene-2, 8-dicarboxylic acid ester ((1R, 5S) -8-tert-butyl-2-methyl3-phenyl-8-azabicyclo [3.2.1]]oct-2-ene-2,8-dicarboxylate (5) 2.5g (7.2 mmol) was placed in 40mL of CH 2 Cl 2 In (2) stirring for 1 hour under nitrogen atmosphere to obtain the compound of chemical formula 6 in fig. 1. The compound was then used for the next reaction. To the compound obtained in the state of solution, 50% Pd (OH) was added 2 after/C (1.0 g,7.2 mmol), nitrogen was removed and a hydrogen atmosphere was produced at normal pressure.
After the reaction mixture was stirred under a hydrogen atmosphere and allowed to react for 12 hours, a small amount of methanol (MeOH) was added to the reaction mixture after completion of the reaction. After methanol was added to the reaction product and the mixture was filtered through a celite-coated filter, the filtered solution was concentrated under reduced pressure. After passing the concentrated product through a silica gel column, two partial stereoisomers were obtained, namely, 1.32g (yield 60%) of a colorless liquid and 0.88g of a solid-state substance (yield 40%) (dr=60:40), respectively. In this case, the main product obtained is the title compound, which is used for the next reaction.
Major product isomer (formula 7): 1 H NMR(400MHz,CDCl 3 )：δ7.40–7.13(m,5H),4.68(m,1H),4.55(m,1H),3.46(s,3H),3.29(dt,J＝12.5,5.2Hz,1H),2.92(d,J＝11.4Hz,1H),2.81(m,1H),2.26–1.95(m,2H),1.94-1.63(m,3H),1.47(s,9H)；13C NMR(101MHz,CDCl 3 )δ171.3,152.2,141.7,128.1,127.4,126.3,79.1,54.9,53.5,52.3,51.2,34.6,31.7,29.3,28.3,27.4,27.2。
byproduct isomer (chemical formula 7')： 1 H NMR(400MHz,CDCl 3 )δ7.36–7.09(m,5H),4.57(m,1H),4.36(m,1H),3.60(m,1H),3.44(s,3H),3.11(m,1H),2.46(m,1H),2.22–1.80(m,5H),1.66(m,1H),1.49(s,9H)。
EXAMPLE 5 (1R, 2S,3S, 5S) -methyl3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate ((1R, 2S,3S, 5S) -methyl3- (4-iodophenyl) -8-azabicyclo [3.2.1] octa-2-carbox ylate) (see chemical formula 8 of FIG. 1)
(1R, 2S,3S, 5S) -8-tert-butyl 2-methyl3-phenyl-8-azabicyclo [3.2.1] as starting material]Octane-2, 8-dicarboxylic acid ester (1.2 g,3.4 mmol) was dissolved in 10mL of CH 2 Cl 2 After that, acetic acid (4 mL), iodine (iodine) (2.3 g,9.3 mmol) and silver triflate (1.7 g,7.0 mmol) were added thereto.
The reaction prepared above was stirred under a dark hood at room temperature for 15 hours. Filtering and removing solid such as silver iodide formed in the reaction vessel, and using CH 2 Cl 2 (4X 30 mL) the reaction product was extracted. Using diluted NH 4 Na of OH, 1M 2 SO 3 And 20ml of water to obtain organic CH 2 Cl 2 After the solution, anhydrous sodium sulfate (Na 2 SO 4 ) Removing water and filtering. After concentrating the filtrate under reduced pressure, it was passed through a silica gel column to obtain the title compound (1.15 g, 90%) as a yellow liquid.
1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.4Hz,2H),6.96(d,J＝8.3Hz,2H),3.79–3.66(m,2H),3.41(s,3H),3.25–3.11(m,1H),2.76–2.66(m,2H),2.38(td,J＝13.0,2.8Hz,1H),2.18–1.96(m,3H),1.79–1.58(m,3H)；13C NMR(101MHz,CDCl 3 )δ173.5,142.1,137.2,129.4,91.7,56.3,53.6,51.2,50.9,35.2,29.1,27.7.
EXAMPLE 6 (1R, 2S,3S, 5S) -methyl N- (3-hydroxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate) (see chemical formula 9 of FIG. 1)
After 1.0g (2.6 mmol) of (1R, 2S,3S, 5S) -methyl3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate dissolved in 20mL of toluene, 0.86mL (9.4 mmol) of 3-bromo-1-propanol and 5.6mL (40.4 mmol) of triethylamine were added under nitrogen, the reaction mixture was heated to reflux for 4 hours.
After the reaction was completed, the reaction was filtered to remove solids, and the passed organic solution was concentrated under reduced pressure and purified using a desired silica gel tube chromatography to obtain 1.0g of the pure title compound in 86% yield.
1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝8.4Hz,2H),6.97(d,J＝8.2Hz,2H),3.82–3.73(m,2H),3.67–3.56(m,2H),3.49(s,3H),2.98(dt,J＝10.8,5.1Hz,1H),2.91–2.85(m,1H),2.63–2.37(m,3H),2.19–1.98(m,2H),1.80–1.47(m,5H)；13C NMR(101MHz,CDCl 3 )δ172.1,142.2,137.0,129.4,91.3,64.7,64.4,59.2,54.6,53.0,51.4,33.7,29.1,26.3,24.8。
EXAMPLE 7 (1R, 2S,3S, 5S) -methyl N- (3-methylsulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate ((1R, 2S,3S, 5S) -methyl N- (3-methylsulfonyloxypropyl-3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate) (see chemical formula 1 of FIG. 1)
To N- (3-hydroxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] under nitrogen at room temperature]Octane-2-carboxylate (0.9 g,2.0 mmol) was dissolved in 10mL of anhydrous CH 2 Cl 2 Anhydrous methanesulfonate (0.8 g,4.6 mmol) and diisopropylamine (0.4 mL,2.3 mmol) were added and stirred. After stirring for 3 hours, the reaction mixture was concentrated under reduced pressure to give the product, which was purified using silica gel chromatography to give 0.92g of the title compound as a pure colorless oil in 86% yield.
1 H NMR(400MHz,CDCl 3 )：δ1.60-1.88(m,5H),1.94-2.15(m,2H),2.30-2.42(m,2H),2.50(td,1H,J＝12.4,2.8Hz),2.87–2.92(m,1H),2.94–2.99(m,1H),2.98(s,3H),3.34–3.40(m,1H),3.49(s,3H),3.62–3.66(m,1H),4.24–4.38(m,2H),6.99(d,2H,J＝8.4Hz),7.58(d,2H,J＝8.4Hz).13C NMR(100MHz,CDCl 3 )δ25.9,26.0,28.5,33.8,33.9,37.0,49.0,51.1,52.6,61.5,61.8,62.8,68.4,91.1,129.4,136.9,142.8,171.9。
Fig. 2 is a diagram showing a process of obtaining a substance of chemical formula 2 from a substance of chemical formula 1.
Example 8 1R,2S,3S, 5S) -methyl N- (3-methanesulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1]Octane-2-carboxylic acid methyl ester (1R, 2S,3S, 5S) -N- (3-methanesulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1]Octane-2-carboxylate methanesulfonate anhydride salt ((1R, 2S,3S, 5S) -methyl N- (3-methanesulphonyl-oxypropyl) -3- (4-iodophenyl) -8-azabicyclo [ 3.2.1)]octane-2-carboxylate methanesulfonic anhydride salt：(X＝CH 3 SO 3 -，Y＝SO 2 CH 3 ))
Referring to FIG. 2, 150mg of (1R, 2S,3S, 5S) -methyl N- (3-methylsulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1]Octane-2-carboxylate is added into 2mL of mixed hexane and CH in a ratio of 10:1 2 Cl 2 To which 48mg of methanesulfonyl anhydride was added and stirred for 10 minutes. In this case, after the solvent was volatilized by distillation under reduced pressure, 190mg of the title compound salt was obtained as a solid after washing with hexane.
1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝6.9Hz,2H),6.96(d,J＝7.2Hz,2H),5.26(s,3H),4.55–4.46(m,2H),4.43–4.38(m,2H),3.59(m,1H),3.43(s,3H),3.31(s,1H),3.18(s,3H),3.06(m,1H),2.94(d,J＝14.3Hz,1H),2.88(s,3H),2.62(m,1H),2.55–1.90(m,6H)；13C NMR(101MHz,CDCl 3 )δ173.5,137.9,137.5,129.3,93.3,68.0,63.5,62.2,52.7,49.7,49.2,39.4,37.3,34.3,31.8,25.4,24.7,23.6。
On the other hand, the process of obtaining the substance of chemical formula 2 by the substance of chemical formula 1-1 may be substantially the same as the process of obtaining the substance of chemical formula 2 by the substance of chemical formula 1.
EXAMPLE 9 (1R, 2S,3S, 5S) -methyl N- (3-methanesulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1]Octane-2-carboxylate nonafluorobutanesulfonic anhydride salt ((1R, 2S,3S, 5S) -methyl N- (3-methysulfoformopyl-3- (4-iodophenyl) -8-azabicyclo [ 3.2.1)]octane-2-carboxylate nonafluorobutanesulfonic anhydride salt：(X＝n-C 4 F 9 SO 3 -，Y＝n-C 4 F 9 SO 2 ))
Referring to fig. 2, after (1 r,2s,3s,5 s) -methyl N- (3-methanesulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate was added to stir with all molar conditions and solvents and the like identical to example 8 except that nonafluorobutanesulfonic anhydride was used instead of methanesulfonic anhydride. In this case, the title compound salt was obtained after volatilizing the solvent by distillation under the reduced pressure.
EXAMPLE 10 methyl (1R, 2S,3S, 5S) -N- (3-methylsulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate (1R, 2S,3S, 5S) -methyl N- (3-methylsulfonyloxypropyl-3- (4-iodophenyl) -8-azabicyclo [3.2.1] octant-2-carboxylate) (see chemical formula 1 of FIG. 1)
200mg of (1R, 2S,3S, 5S) -N- (3-methanesulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1]Methyl octane-2-carboxylate methanesulfonate (all salts represented by chemical formula 2) was dissolved in 5mL of CH 2 Cl 2 After the solvent is used NaHCO 3 The saturated solution was dropped. Then, another 10mL of CH was added 2 Cl 2 The whole solution was then passed through a small silicone tube. In this case, CH is distilled by reduced pressure 2 Cl 2 After evaporation of the solvent from the solution, the title compound was obtained in a quantitative manner as a salt.
FIG. 3 is a diagram showing a process of obtaining a substance of chemical formula 1 from a substance of chemical formula 2 according to an embodiment of the present invention, and FIG. 4 is a diagram showing a process of obtaining a substance of chemical formula 2 from a substance of chemical formula 2 by nucleophilic fluorination according to an embodiment of the present invention 18 F]A diagram of the process of FP-CIT.
Experimental example
DATA SET 1 (DATA SET 1)
1-1. Precursor information (Precursor Information)
-date of preparation (Date of Manufacturing): 2022, 2, 28
-Weight (Weight): 8mg of
-Physical State): white slurry (white syrup)
1-2 Test results (see Table 1 and FIG. 5)
Date of Test: 2022, 3, 28
Test Site (Site): duchembiochil-gokkyungbuk RP center
-synthesis conditions (Synthesis condition): AIO+AMA+8mg (use of 8mg precursor to improve impurities)
TABLE 1
Referring to fig. 6 and 7, in the case of purification chromatography (chromatography), no unknown peak (unknown peak) observed in the precursor before impurity improvement was observed.
Data set 2
2-1. Premise information
-date of preparation: 2022, 2, 28
-weight: 8mg of
-physical state: white slurry
2-2 test results (see Table 2 and FIG. 8)
Test date: 2022, 4, 11 days
Test site: duchembiochil-gokkyungbuk RP center
-synthesis conditions: AIO+AMA+8mg (use of 8mg impurity-ameliorating precursor)
TABLE 2
| Batch of | FP-CIT 22041101-DC05 |
| mCi | |
| Start the operation | 4430 |
| Production operation | 1144 |
| Yield (n.d.c) | 25.82％ |
Referring to fig. 9 and 10, in the case of purification chromatography, no unknown peaks observed in the precursor before improvement of impurities were observed.
Data set 3
3-1. Premise information
-date of preparation: 2022, 2, 28
-weight: 8mg of
-physical state: white slurry
3-2. Test results (see Table 3 and FIG. 11)
Test date: 2022, 4 and 25 days
Test site: duchembiochil-gokkyungbuk RP center
-synthesis conditions: AIO+AMA+8mg (use of 8mg impurity-ameliorating precursor)
TABLE 3 Table 3
| Batch of | FP-CIT 22042501-DC05 |
| mCi | |
| Start the operation | 4260 |
| Production operation | 1055 |
| Yield (n.d.c) | 24.77％ |
Referring to fig. 12 and 13, in the case of purification chromatography, no unknown peaks observed in the precursor before improvement of impurities were observed.
While the present invention has been described with reference to the above-described embodiments and drawings, it should be apparent to those skilled in the art that various modifications and variations can be made therein without departing from the spirit and scope of the invention. Accordingly, these modifications and variations should also be construed as being the term for the scope of the invention as claimed.
Claims (14)
1. A preparation method of an FP-CIT precursor is characterized in that a compound of a chemical formula 1 is obtained by pure organic synthesis of tropinone,
chemical formula 1:
in methyl N- (3-methylsulfonyloxypropyl) -3- (4-iodophenyl) -8-azabicyclo [3.2.1] octane-2-carboxylate represented by the above chemical formula 1, R is a C1-C6 alkyl group or a C6-C12 aryl group, the above alkyl group may be substituted with halogen, and the above aryl group may be substituted with at least one of C1-C3 alkyl group, halogen, and nitro group.
2. The method for producing an FP-CIT precursor according to claim 1, wherein the compound of formula 1-1 is obtained from the compound of formula 1,
chemical formula 1-1:
in (1 'R,2' S,3'S,5' S) -3 '-4-iodophenyl) -2' -methoxycarbonyl-spiro [ azetidine-1, 8 '-bicyclo [3.2.1] octane ] -1-' methanesulfonate represented by the above chemical formula 1-1, R is a C1-C6 alkyl group or a C6-C12 aryl group, the above alkyl group may be substituted with halogen, and the above aryl group may be substituted with at least one of a C1-C3 alkyl group, halogen, and nitro group.
3. The method for producing an FP-CIT precursor according to claim 1, wherein the compound of formula 2 corresponding to a salt thereof is obtained from the compound of formula 1,
chemical formula 2:
wherein R is a C1-C6 alkyl or C6-C12 aryl group, said alkyl group being capable of being substituted by a halogen, said aryl group being capable of being substituted by at least one of a C1-C3 alkyl, halogen, nitro group, X is a substituent capable of forming a quaternary salt with the nitrogen of the amine, including alkylaryl sulfone anions or other stable anions, Y includes all functional groups capable of forming quaternary amines other than alkylaryl sulfone.
4. A method for producing an FP-CIT precursor according to claim 3, wherein the compound of formula 1 is obtained from the compound of formula 2.
5. The method for preparing a FP-CIT precursor according to claim 1, wherein the compound of formula 3 is obtained from topiramate,
chemical formula 3:
wherein R comprises a C1-C6 alkyl group, an aryl group or a substituted alkyl group.
6. The method for producing a FP-CIT precursor according to claim 5, wherein the compound of formula 4 is obtained from the compound of formula 3,
chemical formula 4:
7. the method for producing a FP-CIT precursor according to claim 6, wherein the compound of formula 5 is obtained from the compound of formula 4,
chemical formula 5:
8. the method for producing a FP-CIT precursor according to claim 7, wherein the compound of formula 6 is obtained from the compound of formula 5,
chemical formula 6:
wherein R is a C1-C6 alkyl group or a C6-C12 aryl group, said alkyl group being capable of being substituted by halogen or a functional group comprising a substituted alcohol ketone.
9. The method for producing an FP-CIT precursor according to claim 8, wherein the compound of formula 7 is obtained from the compound of formula 6,
chemical formula 7:
wherein R is a C1-C6 alkyl group or a C6-C12 aryl group, said alkyl group being capable of being substituted by halogen or a functional group comprising a substituted alcohol ketone.
10. The method for producing a FP-CIT precursor according to claim 9, wherein the compound of formula 8is obtained from the compound of formula 7,
chemical formula 8:
11. the method for producing an FP-CIT precursor according to claim 10, wherein the compound of formula 1 is obtained from the compound of formula 8.
12. [ solution ] 18 F]A process for producing FP-CIT, characterized in that the FP-CIT precursor produced by the process for producing a FP-CIT precursor as claimed in any one of claims 1 to 11 is produced by a fluorine substitution reaction 18 F]FP-CIT。
13. According to claim 12 18 F]The method for producing FP-CIT is characterized in that the organic solvent used in the fluorine substitution reaction is one selected from the group consisting of acetonitrile, N-dimethylformamide, dimethyl sulfoxide and alcohol.
14. According to claim 13 18 F]A process for producing FP-CIT, characterized by eluting by an elution method using tetra-n-butylammonium or potassium methanesulfonate 18 F fluoride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220059011A KR20230159083A (en) | 2022-05-13 | 2022-05-13 | Manufacturing method for fp-cit precursor and manufacturing method for [18f]fp-cit using the same |
| KR10-2022-0059011 | 2022-05-13 |
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|---|---|
| CN117088868A true CN117088868A (en) | 2023-11-21 |
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| CN202210650146.5A Pending CN117088868A (en) | 2022-05-13 | 2022-06-10 | Preparation method of FP-CIT precursor and preparation using the same 18 F]Method of FP-CIT |
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| KR (1) | KR20230159083A (en) |
| CN (1) | CN117088868A (en) |
| WO (1) | WO2023219199A1 (en) |
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| US20100292478A1 (en) * | 2009-05-18 | 2010-11-18 | Gachon University Of Medicine & Science Industry- Academic Cooperation Foundation | Process of preparing a radioactive compound containing a fluorine-18 isotope |
| KR101269588B1 (en) * | 2010-10-13 | 2013-06-05 | (주)퓨쳐켐 | Azetidinium salt as fp-cit precursor, selective preparation method thereof, and synthesis of fp-cit |
| KR102063498B1 (en) * | 2019-06-25 | 2020-01-08 | (주)퓨쳐켐 | Process for producing fluorinated compounds using alcohol solvent having unsaturated hydrocarbon |
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- 2022-05-20 WO PCT/KR2022/007221 patent/WO2023219199A1/en unknown
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