WO2023219199A1 - Manufacturing method for fp-cit precursor, and manufacturing method for [18f]fp-cit using fp-cit precursor manufactured thereby - Google Patents
Manufacturing method for fp-cit precursor, and manufacturing method for [18f]fp-cit using fp-cit precursor manufactured thereby Download PDFInfo
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- WO2023219199A1 WO2023219199A1 PCT/KR2022/007221 KR2022007221W WO2023219199A1 WO 2023219199 A1 WO2023219199 A1 WO 2023219199A1 KR 2022007221 W KR2022007221 W KR 2022007221W WO 2023219199 A1 WO2023219199 A1 WO 2023219199A1
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- 239000002243 precursor Substances 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- QQXLDOJGLXJCSE-KNVOCYPGSA-N tropinone Chemical compound C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 claims abstract description 24
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims description 27
- -1 alcohol ketone Chemical class 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical group 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 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 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 3
- 150000001412 amines Chemical group 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 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 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
- 125000001424 substituent group Chemical group 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 29
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000000463 material Substances 0.000 description 14
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 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
- 238000010586 diagram Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000002372 labelling Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000018737 Parkinson disease Diseases 0.000 description 5
- 229960003920 cocaine Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 4
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000003682 fluorination reaction Methods 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 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
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-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
- 230000006872 improvement Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 238000010992 reflux Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical group C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-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
- 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
- 238000011161 development Methods 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
- 238000001914 filtration 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
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- XWIJIXWOZCRYEL-UHFFFAOYSA-M potassium;methanesulfonate Chemical compound [K+].CS([O-])(=O)=O XWIJIXWOZCRYEL-UHFFFAOYSA-M 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 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 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
- 238000005160 1H NMR spectroscopy Methods 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
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910021612 Silver iodide Inorganic materials 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 1
- 230000007177 brain activity Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125782 compound 2 Drugs 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
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000006303 iodophenyl group Chemical group 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 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 1
- 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 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
- 239000012046 mixed solvent 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
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- SIIICDNNMDMWCI-YJNKXOJESA-N rti-55 Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@H]2C(=O)OC)=CC=C(I)C=C1 SIIICDNNMDMWCI-YJNKXOJESA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Images
Classifications
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- 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
Definitions
- the present invention relates to N-(3-[18 F]fluoropropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane ([18F]), which is well known as a radiopharmaceutical for diagnosing Parkinson's disease.
- FP-CIT N-(3-[18 F]fluoropropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane
- FP-CIT N-(3-[18 F]fluoropropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane
- Positron Emission Tomography which enables functional diagnosis, diagnoses diseases by checking the dynamics of radiopharmaceuticals injected into the body.
- a diagnostic drug attached to a radioisotope that emits protons is injected into the patient and images are obtained.
- the most commonly used element that emits protons is radioisotope F-18 (fluorine, fluorine). am. This is because it has a relatively high specific radioactivity and a short half-life of about 110 minutes, so patients do not have to worry about radiation exposure.
- catecholamines are known to be related to various diseases including schizophrenia and movement disorders.
- the secretion of dopamine, a monoamine compound and a type of catecholamine is closely related to Parkinson's disease and is known to be related to the secretion and reabsorption of dopamine.
- [18F]FP-CIT is a radiopharmaceutical for diagnosing Parkinson's disease developed domestically. It is a medicine that can diagnose Parkinson's disease by imaging the dopamine transporter, which is directly related to Parkinson's disease.
- the chemical structure of [18F]FP-CIT is very similar to that of the drug cocaine. Cocaine is known to have very high selectivity for the brain's dopamine transporter. Using these characteristics, [18F]FP-CIT has a chemical structure similar to cocaine, so it has high selectivity for the dopamine transporter, but it is possible to obtain a positron emission tomography image of the dopamine transporter by using a small amount so that it has no medicinal effect as a drug. It is a material developed to allow
- [18F]FP-CIT has been used in clinical practice for about 10 years after obtaining product approval from the Ministry of Food and Drug Safety of the Republic of Korea in 2008.
- cocaine is used as the starting material for the precursor for the production of [18F]FP-CIT.
- the chemical instability (instability) of the precursor has continued to be a problem, and an azetidinium salt precursor has been developed to reduce this instability, but this material is also impossible to quantify, so there are still problems in applying it to actual manufacturing.
- the object of the present invention is N-(3-sulfonyloxypropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane (common name, IUPAC name (methyl 3-(4)) Provides a method for effectively synthesizing -iodophenyl)-8-(3-((methylsulfonyl)oxy)propyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) from the simple organic compound tropinone rather than from cocaine.
- the purpose of the present invention is to obtain this compound with optically pure stereochemistry of 1R, 2S, 3S, and 5S.
- Another object of the present invention is to produce a thermodynamically stable agent after the existing precursor N-(3-sulfonyloxypropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane is synthesized.
- N-(3-fluoropropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane is stable even after manufacturing by preventing irregular conversion to azetidinium salt. It provides for the synthesis of salts.
- the above object is achieved by a method for producing an FP-CIT precursor, which is characterized in that the compound of Formula 1 is obtained from tropinone through pure organic synthesis.
- R is C1 -6 alkyl group or C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group may be substituted with at least one of C1-3 alkyl, halogen, and nitro.
- the compound of Formula 1-1 can be obtained from the compound of Formula 1.
- R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group is C1-3 alkyl, May be substituted with at least one of halogen or nitro.
- a compound of Formula 2 corresponding to its salt can be obtained from the compound of Formula 1.
- R is a C1-6 alkyl group or a C6-12 aryl group
- the alkyl group may be substituted with halogen
- the aryl group may be substituted with at least one of C1-3 alkyl, halogen, and nitro
- Substituents that can make nitrogen and quaternary salts include alkyl aryl sulfone anions or other amine compounds
- Y includes all functional groups that can make quaternary amines other than alkyl aryl sulfone.
- the compound of Formula 1 can be obtained from the compound of Formula 2.
- the compound of Formula 3 can be obtained from tropinone.
- R includes a C1-6 alkyl group, an aryl group, or a substituted alkyl group.
- the compound of Formula 4 can be obtained from the compound of Formula 3.
- the compound of Formula 5 can be obtained from the compound of Formula 4.
- the compound of Formula 6 can be obtained from the compound of Formula 5.
- R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone.
- compounds of Formula 7 and Formula 7' can be obtained from the compound of Formula 6.
- R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone.
- the compound of formula 7 is obtained together with its isomer, the compound of formula 7', in small amounts.
- the compound of Formula 8 can be obtained from the compound of Formula 7.
- the compound of Formula 9 can be obtained from the compound of Formula 8.
- the compound of Formula 1 can be obtained from the compound of Formula 9.
- the purpose is to prepare [18F]FP-CIT from an FP-CIT precursor consisting of at least one of the compounds of Formula 1, Formula 1-1, and Formula 2 by the production method according to an embodiment of the present invention. This is achieved by the manufacturing method of [18F]FP-CIT, which is characterized in that.
- the organic solvent used in the fluorine substitution reaction may be one selected from the group consisting of acetonitrile, DMF, DMSO, and alcohol.
- 18F fluoride can be eluted using an elution method using tetra-n-butylammonium or potassium mesylate.
- N-(3-sulfonyloxypropyl)-2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane salt precursor can be produced with high purity.
- it has high chemical stability and can be stored for a long time, and even in nucleophilic fluorination reactions, salt quantification is used to remove [18F] fluorine substitution and form N-(3-sulfonyloxypropyl)-2- ⁇ -carbomer.
- Figure 1 is a diagram showing the process of synthesizing a substance of Formula 1 from tropinone according to an embodiment of the present invention.
- Figure 2 is a diagram showing the process of obtaining a material of Chemical Formula 2 from a material of Chemical Formula 1 according to an embodiment of the present invention.
- Figure 3 is a diagram showing the process of obtaining a material of Chemical Formula 1 from a material of Chemical Formula 2 according to an embodiment of the present invention.
- Figure 4 is a diagram showing the process of obtaining [18F]FP-CIT from Formula 2 through a nucleophilic fluorination reaction according to an embodiment of the present invention.
- FIGS 5 to 13 are diagrams to explain experimental examples of the present invention.
- the attempt to develop a new precursor of [18F]FP-CIT is based on the existing precursor, N-(3-sulfonyloxypropyl)-2- ⁇ -carbomethoxy-3- ⁇ .
- -(4-iodophenyl)tropane is thermodynamically stable within several days to weeks after synthesis (1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbonyl ) Spiro[azetidine-1,8'-bicyclo[3.2.1]octane]-1-ium R-substituted sulfonate ⁇ , and the rate of conversion is determined by storage conditions such as room temperature, refrigeration, and freezing after synthesis.
- the production rate varies depending on the storage period, and as before, using a polar solvent, 1(1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbohydrate) N-(3-sulfonyloxypropyl)-
- a polar solvent 1(1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbohydrate) N-(3-sulfonyloxypropyl)-
- 2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane 2- ⁇ -carbomethoxy-3- ⁇ -(4-iodophenyl)tropane
- the precursor in order to label [18F] fluorine, the precursor must be transformed into a linear structure by unraveling the cyclic structure forming the azetidinium salt, so that labeling of [18F] fluorine is ultimately possible when using this precursor.
- the precursor There are bound to be limits.
- the most optimal material as a precursor for the production of [18F]FP-CIT is a tropane ring so that the propyl group to which the leaving group for [18F] fluorine labeling is bonded is linear and the chemical structure does not change even when stored for a long time. This is the development of a material that combines a quantified salt with an amine.
- the compound of Formula 1 is obtained from tropinone using a tropane precursor synthesis method through pure organic synthesis.
- R is methyl It is represented by one case, but is not limited to this, and is possible for various R, where R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted or unsubstituted with halogen, and the aryl group is C1-3 alkyl, It may be substituted or unsubstituted with at least one of halogen and nitro.
- the compound of Formula 1-1 can be obtained from the compound of Formula 1.
- R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group is C1-3 alkyl, It may be substituted with at least one of halogen and nitro.
- the compound of Formula 1-1 is naturally produced in small to fairly large amounts even if not intentionally prepared from the compound of Formula 1, but can be produced by actively dissolving the compound of Formula 1 in a polar solvent.
- 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.
- the compound of Formula 2 which is a salt thereof, can be obtained from the compound of Formula 1.
- R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted or unsubstituted with halogen, and the aryl group may be substituted or unsubstituted with at least one of C1-3 alkyl, halogen, and nitro. In addition, can do.
- the alkyl or aryl functional group generalized to the alkyl aryl sulfone anion may specifically include at least methyl, trifluoromethyl, phenyl, toluenyl, 4-bromophenyl, or 4-nitrophenyl. .
- the compound of Formula 1 can be obtained from the salt of Formula 2.
- the compound of Formula 3 can be obtained from tropinone.
- R may include all of a C1-6 alkyl group, an aryl group, or a substituted alkyl group.
- a compound of Formula 4 is obtained from the compound of Formula 3
- a compound of Formula 5 is obtained from the compound of Formula 4
- a compound of Formula 6 is obtained from a compound of Formula 5
- a compound of Formula 7 is obtained from a compound of Formula 6
- a compound of Formula 8 is obtained from a compound of Formula 7
- a compound of Formula 6 is obtained from a compound of Formula 8.
- R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone.
- the compound of Formula 7 can be obtained in small amounts along with its isomer, the compound of Formula 7'.
- the compound of Formula 9 is used as a precursor of [18F]FP-CIT, the compound of Formula 1, Formula 1-
- the compound of Formula 2, which is the compound of 1 and its salt, can be prepared.
- the compound of Formula 1, the compound of Formula 1-1, and their compounds described above are obtained through a fluorine substitution reaction (nucleophilic fluorination reaction).
- [18F]FP-CIT can be prepared from the compound of Formula 2, which is a salt.
- the organic solvent used in the fluorine (18-F or 19-F) substitution reaction is preferably one selected from the group consisting of acetonitrile, DMF, DMSO, and tertiary alcohol.
- 18F fluoride can be eluted using an elution method using tetra-n-butylammonium or potassium mesylate.
- the compound of Formula 2 can be stored in a solid state or solution state, or as a solid suspension in an insoluble solvent.
- Figure 1 is a diagram showing the process of synthesizing the substance of Chemical Formula 1 from tropinone.
- a carbomethoxy functional group was added to the alpha position of tropinone in the lasmic mixture by a known method (J. Med. Chem. 2005, 48, 7437-7444, Nucl. Med. Biol., 1996, 23, 981-986). was introduced, and then optically pure (R)-(+)-2-carbomethoxy-3-tropinone ((R)-(+)-2-carbomethoxy-3-tropinone) was obtained through optical separation using a known method.
- the reaction mixture was reacted with stirring in a hydrogen environment for 12 hours. After confirming the completion of the reaction, a small amount of MeOH was added to the reaction solution.
- the reaction product is filtered through a celite-coated filter with the addition of MeOH, and the filtered solution is concentrated under reduced pressure.
- the reactant thus prepared is stirred for 15 hours in a dark hood at room temperature. Solids such as silver iodide formed in the reaction vessel are removed by filtration, and the reaction product is extracted with CH 2 Cl 2 (4 * 30 mL). The organic CH 2 Cl 2 solution obtained in this way was washed with diluted NH 4 OH, 1M Na 2 SO 3 and 20 ml of water, then the moisture was removed with anhydrous sodium sulfate (Na 2 SO 4 ) and then filtered. The filtrate was concentrated under reduced pressure and passed through a silica gel column to obtain the title compound (1.15 g, 90%) as a yellow liquid.
- reaction mixture is filtered to remove solids, and the passed organic solution is concentrated under reduced pressure and purified by the desired silica gel column chromatography to obtain 1.0 g of the pure title compound in 86% yield.
- N-(3-hydroxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (0.9 g, 2.0 mmol) was dissolved in 10 mL of anhydrous CH 2 Cl. 2 Add (10mL) anhydrous methanesulfonate (0.8g, 4.6mmol) and diisopropylamine (0.4mL, 2.3mmol) to the solution dissolved in 2 at room temperature in a nitrogen environment and stir. After stirring for 3 hours, the reaction mixture was concentrated under reduced pressure, and the product was purified by silica gel column chromatography to obtain 0.92 g of the pure labeled compound in the form of a colorless oil in 86% yield.
- Figure 2 is a diagram showing the process of obtaining a material of Chemical Formula 2 from a material of Chemical Formula 1.
- the process of obtaining a substance of Formula 2 from a substance of Formula 1-1 can be said to be substantially the same as the process of obtaining a substance of Formula 2 from a substance of Formula 1.
- Figure 3 is a diagram showing the process of obtaining a material of Chemical Formula 1 from a material of Chemical Formula 2
- Figure 4 is a diagram showing the process of obtaining [18F]FP-CIT from a material of Chemical Formula 2 through a nucleophilic fluorination reaction. .
- the present invention can be used in a method for producing an FP-CIT precursor and a method for producing [18F]FP-CIT using the FP-CIT precursor produced thereby.
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Abstract
Disclosed are a manufacturing method for a FP-CIT precursor, and a manufacturing method for [18F]FP-CIT using a FP-CIT precursor manufactured thereby. The manufacturing method for a FP-CIT precursor, according to one embodiment of the present invention, comprises obtaining a compound of chemical formula 1, a compound of chemical formula 1-1, and a compound of chemical formula 2 from tropinone through pure organic synthesis.
Description
본 발명은 파킨슨병 진단용 방사성의약품으로 잘 알려진 N-(3-[18 F]플루오로프 로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판([18F]FP-CIT)를 제조하는 방법에 관한 것으로, 특히 [18F]FP-CIT의 제조에 사용되는 전구체의 제조방법에 관한 것이다.The present invention relates to N-(3-[18 F]fluoropropyl)-2-β-carbomethoxy-3-β-(4-iodophenyl)tropane ([18F]), which is well known as a radiopharmaceutical for diagnosing Parkinson's disease. FP-CIT), and in particular, relates to a method of producing a precursor used in the production of [18F]FP-CIT.
환자의 적절한 치료를 위한 여러가지 다양한 진단 방법 중에서 기능적 진단을 가능하게 하는 양전자방출단층촬영기(Positron Emission Tomography, 이하 PET)는 체내에 주입된 방사성의약품의 동태를 확인하여 질병을 진단한다. 이를 위한 진단의약품은 양성자를 방출하는 방사선 동위 원소를 부착한 진단의약품을 환자에게 주입하고 영상을 얻게 되는데, 이때 양성자를 내는 원소로 가장 많이 사용되는 것이 방사성동위원소 F-18(플루오린, 불소)이다. 이는 상대적으로 높은 비방사능을 가지면서도 반감기가 110분 정도로 짧기 때문에 환자가 피폭을 걱정하지 않아도 되기 때문이다.Among the various diagnostic methods for appropriate treatment of patients, Positron Emission Tomography (PET), which enables functional diagnosis, diagnoses diseases by checking the dynamics of radiopharmaceuticals injected into the body. For this purpose, a diagnostic drug attached to a radioisotope that emits protons is injected into the patient and images are obtained. At this time, the most commonly used element that emits protons is radioisotope F-18 (fluorine, fluorine). am. This is because it has a relatively high specific radioactivity and a short half-life of about 110 minutes, so patients do not have to worry about radiation exposure.
동물의 뇌에는 여러가지의 신호전달물질이 관계되며 이들 신호전달물질의 적절한 분비와 수용체 및 전달체와 관계는 정상적인 뇌의 활동에 필수적이다. 이러한 물질 중에서 카테콜아민으로 대표되는 물질은 정신분열증(schizophrenia)이나 운동장애 등을 포함하는 다양한 질환과 관계가 있다고 알려져 있다. 이러한 카테콜아민의 일종으로 모노아민 화합물인 도파민의 분비는 파킨슨병과 밀접한 관련을 가지며 도파민의 분비 및 재흡수와 관련된 것으로 알려져 있다.Various signal transmitters are involved in the animal brain, and proper secretion of these signal transmitters and their relationship with receptors and transmitters are essential for normal brain activity. Among these substances, those represented by catecholamines are known to be related to various diseases including schizophrenia and movement disorders. The secretion of dopamine, a monoamine compound and a type of catecholamine, is closely related to Parkinson's disease and is known to be related to the secretion and reabsorption of dopamine.
[18F]FP-CIT는 국내에서 개발된 파킨슨병 진단용 방사성의약품으로서 파킨슨병과 직접적인 연관성을 가지는 도파민 운반체(dopamine transporter)를 영상화하여 파킨슨병을 진단할 수 있는 의약품이다. [18F]FP-CIT의 화학 구조는 마약인 코카인과 매우 유사한 화학 구조를 가지고 있다. 코카인은 뇌의 도파민 운반체에 매우 높은 선택성(selectivity)을 가지는 것으로 알려져 있다. 이러한 특징을 이용하여 [18F]FP-CIT는 코카인과 유사한 화학적 구조를 가지므로 도파민 운반체에 대한 높은 선택성을 가지지만, 마약으로서의 약효는 없도록 소량을 사용하여 도파민 운반체의 양전자방출 단층촬영 영상을 얻을 수 있도록 개발된 물질이다.[18F]FP-CIT is a radiopharmaceutical for diagnosing Parkinson's disease developed domestically. It is a medicine that can diagnose Parkinson's disease by imaging the dopamine transporter, which is directly related to Parkinson's disease. The chemical structure of [18F]FP-CIT is very similar to that of the drug cocaine. Cocaine is known to have very high selectivity for the brain's dopamine transporter. Using these characteristics, [18F]FP-CIT has a chemical structure similar to cocaine, so it has high selectivity for the dopamine transporter, but it is possible to obtain a positron emission tomography image of the dopamine transporter by using a small amount so that it has no medicinal effect as a drug. It is a material developed to allow
[18F]FP-CIT는 대한민국 식품의약품안전처에서 2008년 품목 허가를 취득 후 10 여년간 임상 진료에 사용되었다. 그러나 [18F]FP-CIT의 제조를 위한 원료물질인 전구체는 대부분의 경우 코카인을 그 출발물질로 만들어 사용하고 있다. 또한, 전구체는 화학적 불안정성(instability)이 지속적으로 문제가 되었으며, 이러한 불안정성을 낮추기 위하여 아제티디늄 염 전구체가 개발되기도 하였으나, 이 물질 역시 정량화가 불가능하므로 실제 제조에 적용하기에는 여전히 문제를 가지고 있다.[18F]FP-CIT has been used in clinical practice for about 10 years after obtaining product approval from the Ministry of Food and Drug Safety of the Republic of Korea in 2008. However, in most cases, cocaine is used as the starting material for the precursor for the production of [18F]FP-CIT. In addition, the chemical instability (instability) of the precursor has continued to be a problem, and an azetidinium salt precursor has been developed to reduce this instability, but this material is also impossible to quantify, so there are still problems in applying it to actual manufacturing.
관련 선행기술로는 미국 공개특허공보 제2010-0292478호(발명의 명칭: Process of preparing a radioactive compound containing a fluorine-18 isotope, 공개일자: 2010.11.18.)가 있다.Related prior art includes U.S. Patent Publication No. 2010-0292478 (title: Process of preparing a radioactive compound containing a fluorine-18 isotope, publication date: 2010.11.18.).
본 발명의 목적은, N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판(일상명칭, IUPAC 명칭 (methyl 3-(4-iodophenyl)-8-(3-((methylsulfonyl)oxy)propyl)-8-azabicyclo[3.2.1]octane-2-carboxylate)을 코카인으로부터가 아니라 간단한 유기화합물인 트로피논으로부터 효과적으로 합성하는 방법을 제공하는 것이다. 특히 본 발명의 목적은 이 화합물을 광학적으로 순수하게 1R,2S,3S,5S의 입체화학을 가지도록 얻는 것이다.The object of the present invention is N-(3-sulfonyloxypropyl)-2-β-carbomethoxy-3-β-(4-iodophenyl)tropane (common name, IUPAC name (methyl 3-(4) Provides a method for effectively synthesizing -iodophenyl)-8-(3-((methylsulfonyl)oxy)propyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) from the simple organic compound tropinone rather than from cocaine. In particular, the purpose of the present invention is to obtain this compound with optically pure stereochemistry of 1R, 2S, 3S, and 5S.
본 발명의 다른 목적은, 기존의 전구체인 N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판이 합성된 후 열역학적으로 안정한 아제티디늄 염(azetidinium salt)으로 불규칙하게 전환되는 것을 방지하여, 제조 후에도 안정적인 N-(3-플루오로프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판 염의 합성을 제공하는 것이다.Another object of the present invention is to produce a thermodynamically stable agent after the existing precursor N-(3-sulfonyloxypropyl)-2-β-carbomethoxy-3-β-(4-iodophenyl)tropane is synthesized. N-(3-fluoropropyl)-2-β-carbomethoxy-3-β-(4-iodophenyl)tropane is stable even after manufacturing by preventing irregular conversion to azetidinium salt. It provides for the synthesis of salts.
상기 목적은 본 발명의 일 실시예에 따라, 화학식 1의 화합물을 순수 유기합성을 통해 트로피논(tropinone)으로부터 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법에 의해 달성된다.According to an embodiment of the present invention, the above object is achieved by a method for producing an FP-CIT precursor, which is characterized in that the compound of Formula 1 is obtained from tropinone through pure organic synthesis.
<화학식 1><Formula 1>
상기 화학식 1로 표시되는 메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트에서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있으며 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있음.In methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate represented by Formula 1, R is C1 -6 alkyl group or C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group may be substituted with at least one of C1-3 alkyl, halogen, and nitro.
바람직하게, 상기 화학식 1의 화합물로부터 화학식 1-1의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 1-1 can be obtained from the compound of Formula 1.
<화학식 1-1><Formula 1-1>
상기 화학식 1-1로 표시되는 (1'R,2'S,3'S,5'S)-3'-(4-아이오도페닐)-2'-(메톡시카보닐)스파이로[아제티딘-1,8'-바이사이클로[3.2.1]옥탄]-1-'메탄설포네이트에서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있으며 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있음.(1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbonyl)spiro[azetidine-1,8' represented by the formula 1-1 -Bicyclo[3.2.1]octane]-1-' In methanesulfonate, R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group is C1-3 alkyl, May be substituted with at least one of halogen or nitro.
바람직하게, 상기 화학식 1의 화합물로부터 그 염에 해당하는 화학식 2의 화합물을 얻어낼 수 있다.Preferably, a compound of Formula 2 corresponding to its salt can be obtained from the compound of Formula 1.
<화학식 2><Formula 2>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있고, 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있으며, X는 아민의 질소와 4차염을 만들 수 있는 치환체로서 알킬 아릴 술폰 음이온이나 다른 아민 화합물을 포함하고, Y는 알킬 아릴 술폰 이외 4차 아민을 만들 수 있는 작용기 모두를 포함함.Here, R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, the aryl group may be substituted with at least one of C1-3 alkyl, halogen, and nitro, and Substituents that can make nitrogen and quaternary salts include alkyl aryl sulfone anions or other amine compounds, and Y includes all functional groups that can make quaternary amines other than alkyl aryl sulfone.
바람직하게, 상기 화학식 2의 화합물로부터 상기 화학식 1의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 1 can be obtained from the compound of Formula 2.
바람직하게, 트로피논(tropinone)으로부터 화학식 3의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 3 can be obtained from tropinone.
<화학식 3><Formula 3>
여기서, R은 C1-6 알킬기 아릴기 또는 치환된 알킬기를 포함함.Here, R includes a C1-6 alkyl group, an aryl group, or a substituted alkyl group.
바람직하게, 상기 화학식 3의 화합물로부터 화학식 4의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 4 can be obtained from the compound of Formula 3.
<화학식 4><Formula 4>
바람직하게, 상기 화학식 4의 화합물로부터 화학식 5의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 5 can be obtained from the compound of Formula 4.
<화학식 5><Formula 5>
바람직하게, 상기 화학식 5의 화합물로부터 화학식 6의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 6 can be obtained from the compound of Formula 5.
<화학식 6><Formula 6>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐이나 치환된 알코올올 케톤을 포함하는 작용기로 치환될 수 있음.Here, R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone.
바람직하게, 상기 화학식 6의 화합물로부터 화학식 7 및 화학식 7'의 화합물을 얻어낼 수 있다.Preferably, compounds of Formula 7 and Formula 7' can be obtained from the compound of Formula 6.
<화학식 7><Formula 7>
<화학식 7'><Formula 7'>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐이나 치환된 알코올올 케톤을 포함하는 작용기로 치환될 수 있음. 그리고 화학식 7의 화합물은 그 이성질체인 화학식 7’의 화합물이 적은 양으로 함께 얻어짐.Here, R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone. And the compound of formula 7 is obtained together with its isomer, the compound of formula 7', in small amounts.
바람직하게, 상기 화학식 7의 화합물로부터 화학식 8의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 8 can be obtained from the compound of Formula 7.
<화학식 8><Formula 8>
바람직하게, 상기 화학식 8의 화합물로부터 화학식 9의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 9 can be obtained from the compound of Formula 8.
<화학식 9><Formula 9>
바람직하게, 상기 화학식 9의 화합물로부터 상기 화학식 1의 화합물을 얻어낼 수 있다.Preferably, the compound of Formula 1 can be obtained from the compound of Formula 9.
상기 목적은, 본 발명의 일 실시예에 따라, 상기 제조방법에 의해 상기 화학식 1, 상기 화학식 1-1 및 상기 화학식 2의 화합물 중 적어도 하나로 이루어진 FP-CIT 전구체로부터 [18F]FP-CIT를 제조하는 것을 특징으로 하는 [18F]FP-CIT의 제조방법에 의해 달성된다.The purpose is to prepare [18F]FP-CIT from an FP-CIT precursor consisting of at least one of the compounds of Formula 1, Formula 1-1, and Formula 2 by the production method according to an embodiment of the present invention. This is achieved by the manufacturing method of [18F]FP-CIT, which is characterized in that.
바람직하게, 상기 불소 치환 반응에 사용되는 유기 용매는 아세토니트릴, DMF, DMSO 및 알코올로 이루어진 군으로부터 선택되는 1종일 수 있다.Preferably, the organic solvent used in the fluorine substitution reaction may be one selected from the group consisting of acetonitrile, DMF, DMSO, and alcohol.
바람직하게, 테트라-n-부틸암모늄 또는 포타슘 메질레이트를 이용한 용리 방법을 활용하여 18F 플루오르화물을 용리할 수 있다.Preferably, 18F fluoride can be eluted using an elution method using tetra-n-butylammonium or potassium mesylate.
본 발명의 일 실시예에 따르면, N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판 염 전구체는 순도 높게 제조할 수 있을 뿐만 아니라, 화학 안정성이 높아 장기간 보관이 가능하며, 친핵성 플루오르화 반응에서도 염의 정량화를 통해 [18F]불소 치환 전 염을 제가하여 N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판의 [18F]불소 표지 조건과 동일하게 훨씬 빠르고 높은 수율로 FP-CIT를 합성할 수 있기 때문에 [18F]FP-CIT 제조에 매우 유용하다.According to one embodiment of the present invention, N-(3-sulfonyloxypropyl)-2-β-carbomethoxy-3-β-(4-iodophenyl)tropane salt precursor can be produced with high purity. In addition, it has high chemical stability and can be stored for a long time, and even in nucleophilic fluorination reactions, salt quantification is used to remove [18F] fluorine substitution and form N-(3-sulfonyloxypropyl)-2-β-carbomer. It is very useful in producing [18F]FP-CIT because FP-CIT can be synthesized much faster and with higher yield under the same [18F]fluorine labeling conditions of toxin-3-β-(4-iodophenyl)tropane. .
도 1은 본 발명의 일 실시예에 따라 화학식 1의 물질을 트로피논으로부터 합성하는 과정을 나타내는 도면이다.Figure 1 is a diagram showing the process of synthesizing a substance of Formula 1 from tropinone according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에 따라 화학식 1의 물질로부터 화학식 2의 물질을 얻어내는 과정을 나타내는 도면이다.Figure 2 is a diagram showing the process of obtaining a material of Chemical Formula 2 from a material of Chemical Formula 1 according to an embodiment of the present invention.
도 3은 본 발명의 일 실시예에 따라 화학식 2의 물질로부터 화학식 1의 물질을 얻어내는 과정을 나타내는 도면이다.Figure 3 is a diagram showing the process of obtaining a material of Chemical Formula 1 from a material of Chemical Formula 2 according to an embodiment of the present invention.
도 4는 본 발명의 일 실시예에 따라 화학식 2로부터 친핵성 플루오르화 반응을 통해 [18F]FP-CIT를 얻어내는 과정을 나타내는 도면이다.Figure 4 is a diagram showing the process of obtaining [18F]FP-CIT from Formula 2 through a nucleophilic fluorination reaction according to an embodiment of the present invention.
도 5 내지 도 13은 본 발명의 실험예를 설명하기 위해 도시한 도면이다.Figures 5 to 13 are diagrams to explain experimental examples of the present invention.
본 발명의 이점 및/또는 특징, 그리고 그것들을 달성하는 방법은 첨부되는 도면과 함께 상세하게 후술되어 있는 실시예들을 참조하면 명확해질 것이다. 그러나, 본 발명은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 것이며, 단지 본 실시예들은 본 발명의 개시가 완전하도록 하며, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다. 명세서 전체에 걸쳐 동일 참조 부호는 동일 구성요소를 지칭한다.The advantages and/or features of the present invention and methods for achieving them will become clear by referring to the embodiments described in detail below in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and will be implemented in various different forms, but the present embodiments only serve to ensure that the disclosure of the present invention is complete and are within the scope of common knowledge in the technical field to which the present invention pertains. It is provided to fully inform those who have the scope of the invention, and the present invention is only defined by the scope of the claims. Like reference numerals refer to like elements throughout the specification.
또한, 이하 실시되는 본 발명의 바람직한 실시예는 본 발명을 이루는 기술적 구성요소를 효율적으로 설명하기 위해 각각의 시스템 기능구성에 기 구비되어 있거나, 또는 본 발명이 속하는 기술분야에서 통상적으로 구비되는 시스템 기능 구성은 가능한 생략하고, 본 발명을 위해 추가적으로 구비되어야 하는 기능 구성을 위주로 설명한다. 만약 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면, 하기에 도시하지 않고 생략된 기능 구성 중에서 종래에 기 사용되고 있는 구성요소의 기능을 용이하게 이해할 수 있을 것이며, 또한 상기와 같이 생략된 구성 요소와 본 발명을 위해 추가된 구성 요소 사이의 관계도 명백하게 이해할 수 있을 것이다.In addition, the preferred embodiments of the present invention to be implemented below are provided in each system function configuration in order to efficiently explain the technical components constituting the present invention, or system functions commonly provided in the technical field to which the present invention pertains. The configuration will be omitted whenever possible, and the description will focus on the functional configuration that must be additionally provided for the present invention. If a person has ordinary knowledge in the technical field to which the present invention pertains, he or she will be able to easily understand the functions of conventionally used components among the functional configurations not shown and omitted below, as well as the omitted configurations as described above. The relationships between elements and components added for the present invention will also be clearly understood.
본 발명의 일 실시예를 설명하기에 앞서서, [18F]FP-CIT의 신규 전구체를 개발하려는 것은 기존 전구체인 N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판이 합성 후 수일에서 수주 이내에 열역학적으로 안정한 (1'R,2'S,3'S,5'S)-3'-(4-아이오도페닐)-2'-(메톡시카보닐)스파이로[아제티딘-1,8'-바이사이클로[3.2.1]옥탄]-1-윰 R-치환된 설포네이트}로 전환되며, 전환의 비율은 합성 후 상온, 냉장, 냉동 등 보관 조건과 보관 기간에 따라 생성비율이 다르고, 기존과 같이 극성의 용매를 사용하여 1(1'R,2'S,3'S,5'S)-3'-(4-아이오도페닐)-2'-(메톡시카보닐)스파이로[아 제티딘-1,8'-바이사이클로[3.2.1]옥탄]-1-윰 R-치환된 설포네이트}만으로 합성을 하여도 N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판의 잔류량이 존재하며, 이 두가지 물질이 동시에 존재할 때 [18F]FP-CIT의 합성 조건 개발에서 두 가지 물질 모두에 대해 [18F]불소 치환을 위한 최적의 조건 설정은 불가능하기 때문이다.Before explaining an embodiment of the present invention, the attempt to develop a new precursor of [18F]FP-CIT is based on the existing precursor, N-(3-sulfonyloxypropyl)-2-β-carbomethoxy-3-β. -(4-iodophenyl)tropane is thermodynamically stable within several days to weeks after synthesis (1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbonyl ) Spiro[azetidine-1,8'-bicyclo[3.2.1]octane]-1-ium R-substituted sulfonate}, and the rate of conversion is determined by storage conditions such as room temperature, refrigeration, and freezing after synthesis. The production rate varies depending on the storage period, and as before, using a polar solvent, 1(1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbohydrate) N-(3-sulfonyloxypropyl)- There is a residual amount of 2-β-carbomethoxy-3-β-(4-iodophenyl)tropane, and when these two substances exist simultaneously, in the development of conditions for the synthesis of [18F]FP-CIT, both substances are used. This is because it is impossible to set optimal conditions for [18F]fluorine substitution.
따라서 한 가지 형태의 전구물질에 존재하는 것을 추정하여 [18F]불소의 표지조건을 설정할 수밖에 없으며, 결국 인위적으로 (1'R,2'S,3'S,5'S)-3'-(4-아이오도페닐)-2'-(메톡시카보닐)스파이로[아제티딘-1,8'-바이사이클로[3.2.1]옥탄]-1-윰 R-치환된 설포네이트}를 합성하여 전구체로 사용한다고 하여도 [18F]불소 표지의 수율 상승에는 한계가 있을 수밖에 없다. 특히 상기 전구체는 [18F]불소의 표지를 위해서는 아제티디늄 염을 형성하는 고리(cyclic) 구조를 풀어서 선형 구조로 변형하여야 [18F]불소의 표지가 가능하므로, 결국 이러한 전구체를 활용할 경우에는 수율 상승에는 한계가 존재할 수밖에 없다.Therefore, there is no choice but to set the labeling conditions for [18F] fluorine by estimating its presence in one type of precursor, and in the end, artificially (1'R,2'S,3'S,5'S)-3'-(4-iodophenyl) Even if -2'-(methoxycarbonyl)spiro[azetidine-1,8'-bicyclo[3.2.1]octane]-1-ium R-substituted sulfonate} is synthesized and used as a precursor, There is bound to be a limit to the increase in yield of [18F] fluorine labeling. In particular, in order to label [18F] fluorine, the precursor must be transformed into a linear structure by unraveling the cyclic structure forming the azetidinium salt, so that labeling of [18F] fluorine is ultimately possible when using this precursor. There are bound to be limits.
따라서 [18F]FP-CIT의 제조를 위한 전구체로서 가장 최적의 물질은 [18F]불소 표지를 위한 이탈기가 결합된 프로필 그룹이 선형으로 존재하면서도 장시간 보관하여도 화학 구조의 변화가 없도록 트로판 고리의 아민에 정량화된 염(salt)을 결합한 물질의 개발이다. 특히 이러한 물질은 [18F]불소 표지 전 염만 제거하여 [18F]불소 표지 반응에 활용할 경우 기존의 N-(3-설포닐옥시프로필)-2-β-카보메톡시-3-β-(4-아이오도페닐)트로판과 동일 조건에서 [18F]FP-CIT의 제조가 가능하므로, 가장 이상적인 [18F]FP-CIT 제조를 위한 전구체이다.Therefore, the most optimal material as a precursor for the production of [18F]FP-CIT is a tropane ring so that the propyl group to which the leaving group for [18F] fluorine labeling is bonded is linear and the chemical structure does not change even when stored for a long time. This is the development of a material that combines a quantified salt with an amine. In particular, when these substances are used in the [18F] fluorine labeling reaction by removing only the salt before the [18F] fluorine labeling, the existing N-(3-sulfonyloxypropyl)-2-β-carbomethoxy-3-β-(4- Since [18F]FP-CIT can be produced under the same conditions as iodophenyl)tropane, it is the most ideal precursor for producing [18F]FP-CIT.
본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따르면, 순수 유기합성을 통한 트로판(tropane) 전구체 합성 방법을 이용하여, 화학식 1의 화합물을 트로피논(tropinone)으로부터 얻어낸다.According to the method for producing an FP-CIT precursor according to an embodiment of the present invention, the compound of Formula 1 is obtained from tropinone using a tropane precursor synthesis method through pure organic synthesis.
<화학식 1><Formula 1>
상기 화학식 1로 표시되는 메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트, 즉 R이 메틸일 경우로 대표되지만 이에 국한하지는 않으며 다양한 R에 대해 가능하며, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환 또는 비치환될 수 있으며 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환 또는 비치환될 수 있다.Methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate represented by Formula 1, that is, R is methyl It is represented by one case, but is not limited to this, and is possible for various R, where R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted or unsubstituted with halogen, and the aryl group is C1-3 alkyl, It may be substituted or unsubstituted with at least one of halogen and nitro.
또한, 본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따르면, 상기 화학식 1의 화합물로부터 화학식 1-1의 화합물을 얻어낼 수 있다.In addition, according to the method for producing an FP-CIT precursor according to an embodiment of the present invention, the compound of Formula 1-1 can be obtained from the compound of Formula 1.
<화학식 1-1><Formula 1-1>
상기 화학식 1-1로 표시되는 (1'R,2'S,3'S,5'S)-3'-(4-아이오도페닐)-2'-(메톡시카보닐)스파이로[아제티딘-1,8'-바이사이클로[3.2.1]옥탄]-1-'메탄설포네이트에서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있으며 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있다.(1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbonyl)spiro[azetidine-1,8' represented by the formula 1-1 -Bicyclo[3.2.1]octane]-1-' In methanesulfonate, R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group is C1-3 alkyl, It may be substituted with at least one of halogen and nitro.
그리고, 상기 화학식 1-1의 화합물은 상기 화학식 1의 화합물로부터 의도적으로 제조하지 않더라도 소량에서부터 제법 많은 양으로 자연스럽게 생성되지만, 적극적으로 상기 화학식 1의 화합물을 극성 용매에 용해시켜서 제조할 수 있다. 이때, 상기 극성 용매는 다이메틸포름아미드, t-부탄올, 아세토나이트릴, 메탄올, 에탄올, 아이소프로판올, 다이메틸설폭사이드, t-아밀 알코올 및 물로 이루어지는 군으로부터 선택되는 1종일 수 있다.In addition, the compound of Formula 1-1 is naturally produced in small to fairly large amounts even if not intentionally prepared from the compound of Formula 1, but can be produced by actively dissolving the compound of Formula 1 in a polar solvent. At this time, 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.
본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따르면, 상기 화학식 1의 화합물로부터 그 염에 해당하는 화학식 2의 화합물을 얻어낼 수 있다.According to the method for producing an FP-CIT precursor according to an embodiment of the present invention, the compound of Formula 2, which is a salt thereof, can be obtained from the compound of Formula 1.
<화학식 2><Formula 2>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환 또는 비치환될 수 있고, 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환 또는 비치환될 수 있으며, X는 아민의 질소와 4차염을 만들 수 있는 치환체로서 다양한 치환체의 알킬 아릴 술폰 음이온이나 다른 일반적인 안정한 음이온이며, Y는 다양한 치환체의 알킬 아릴 술폰 이외 4차 아민을 만들 수 있는 작용기 모두를 포함할 수 있다.Here, R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted or unsubstituted with halogen, and the aryl group may be substituted or unsubstituted with at least one of C1-3 alkyl, halogen, and nitro. In addition, can do.
이때, 상기 알킬 아릴 술폰 음이온으로 일반화 되는 알킬이나 아릴 작용기는 구체적으로 메틸, 트라이플루오로메틸, 페닐, 톨루에닐, 4-브로모페닐, 또는 4-나이트로페닐 이상을 최소로 포함할 수 있다.At this time, the alkyl or aryl functional group generalized to the alkyl aryl sulfone anion may specifically include at least methyl, trifluoromethyl, phenyl, toluenyl, 4-bromophenyl, or 4-nitrophenyl. .
한편, 본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따르면, 상기 화학식 2의 염으로부터 상기 화학식 1의 화합물을 얻어낼 수도 있다. Meanwhile, according to the method for producing an FP-CIT precursor according to an embodiment of the present invention, the compound of Formula 1 can be obtained from the salt of Formula 2.
이하, 본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따라, [18F]FP-CIT의 전구체로 사용되는 상기 화학식 1의 화합물, 상기 화학식 1-1의 화합물 및 이들의 염인 상기 화학식 2의 화합물을 간단한 유기화합물인 트로피논으로부터 효과적으로 합성하는 방법에 대하여 설명한다.Hereinafter, according to a method for producing an FP-CIT precursor according to an embodiment of the present invention, a compound of the formula 1, a compound of the formula 1-1, and a salt thereof used as a precursor of [18F]FP-CIT. A method for effectively synthesizing compound 2 from tropinone, a simple organic compound, will be explained.
먼저, 본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따르면, 트로피논 (tropinone)으로부터 화학식 3의 화합물을 얻어낼 수 있다.First, according to the method for producing an FP-CIT precursor according to an embodiment of the present invention, the compound of Formula 3 can be obtained from tropinone.
<화학식 3><Formula 3>
여기서, R은 C1-6 알킬기 아릴기 또는 치환된 알킬기 등을 모두 포함할 수 있다.Here, R may include all of a C1-6 alkyl group, an aryl group, or a substituted alkyl group.
다음으로, 본 발명의 일 실시예에 따른 FP-CIT 전구체 제조방법에 따르면, 상기 화학식 3의 화합물로부터 화학식 4의 화합물을 얻어내고, 상기 화학식 4의 화합물로부터 화학식 5의 화합물을 얻어내고, 상기 화학식 5의 화합물로부터 화학식 6의 화합물을 얻어내고, 상기 화학식 6의 화합물로부터 화학식 7의 화합물을 얻어내고, 상기 화학식 7의 화합물로부터 화학식 8의 화합물을 얻어내고, 상기 화학식 8의 화합물로부터 화학식 6의 화합물을 얻어낼 수 있다.Next, according to the FP-CIT precursor manufacturing method according to an embodiment of the present invention, a compound of Formula 4 is obtained from the compound of Formula 3, a compound of Formula 5 is obtained from the compound of Formula 4, and A compound of Formula 6 is obtained from a compound of Formula 5, a compound of Formula 7 is obtained from a compound of Formula 6, a compound of Formula 8 is obtained from a compound of Formula 7, and a compound of Formula 6 is obtained from a compound of Formula 8. can be obtained.
<화학식 4><Formula 4>
<화학식 5><Formula 5>
<화학식 6><Formula 6>
<화학식 7><Formula 7>
<화학식 8><Formula 8>
<화학식 9><Formula 9>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐이나 치환된 알코올올 케톤을 포함하는 작용기로 치환될 수 있다.Here, R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone.
한편, 상기 화학식 7의 화합물은 적은 양으로 그 이성질체인 화학식 7’의 화합물과 함께 얻어질 수 있다.Meanwhile, the compound of Formula 7 can be obtained in small amounts along with its isomer, the compound of Formula 7'.
<화학식 7'><Formula 7'>
마지막으로, 본 발명의 일 실시예에 따른 FP-CIT 전구체의 제조방법에 따르면, 상기 화학식 9의 화합물을 이용하여 [18F]FP-CIT의 전구체로 사용되는 상기 화학식 1의 화합물, 상기 화학식 1-1의 화합물 및 이들의 염인 상기 화학식 2의 화합물을 제조할 수 있다.Finally, according to the method for producing an FP-CIT precursor according to an embodiment of the present invention, the compound of Formula 9 is used as a precursor of [18F]FP-CIT, the compound of Formula 1, Formula 1- The compound of Formula 2, which is the compound of 1 and its salt, can be prepared.
이하, 본 발명의 일 실시예에 따른 [18F]FP-CIT의 제조방법에 대하여 설명한다.Hereinafter, a method for manufacturing [18F]FP-CIT according to an embodiment of the present invention will be described.
본 발명의 일 실시예에 따른 [18F]FP-CIT의 제조방법에 따르면, 불소 치환 반응(친핵성 플루오르화 반응)을 통해 앞서 설명한 상기 화학식 1의 화합물, 상기 화학식 1-1의 화합물 및 이들의 염인 상기 화학식 2의 화합물로부터 [18F]FP-CIT를 제조할 수 있다.According to the method for producing [18F]FP-CIT according to an embodiment of the present invention, the compound of Formula 1, the compound of Formula 1-1, and their compounds described above are obtained through a fluorine substitution reaction (nucleophilic fluorination reaction). [18F]FP-CIT can be prepared from the compound of Formula 2, which is a salt.
여기서, 상기 불소(18-F 또는 19-F) 치환 반응에 사용되는 유기 용매는 아세토니트릴, DMF, DMSO 및 3차 알코올로 이루어진 군으로부터 선택되는 1종인 것이 바람직하다. 테트라-n-부틸암모늄 또는 포타슘 메질레이트를 이용한 용리 방법을 활용하여 18F 플루오르화물을 용리할 수 있다. 그리고, 상기 화학식 2의 화합물은 고체 상태 또는 용액 상태로 보존하거나 불용성 용매 중에서 고체의 현탁액으로 보존할 수 있다.Here, the organic solvent used in the fluorine (18-F or 19-F) substitution reaction is preferably one selected from the group consisting of acetonitrile, DMF, DMSO, and tertiary alcohol. 18F fluoride can be eluted using an elution method using tetra-n-butylammonium or potassium mesylate. In addition, the compound of Formula 2 can be stored in a solid state or solution state, or as a solid suspension in an insoluble solvent.
이하에서는 첨부된 도면을 참조하여 본 발명의 실시예들을 상세히 설명하기로 한다.Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings.
도 1은 화학식 1의 물질을 트로피논으로부터 합성하는 과정을 나타내는 도면이다.Figure 1 is a diagram showing the process of synthesizing the substance of Chemical Formula 1 from tropinone.
실시예 1. (R)-2-카보메톡시-3-트로피논-3-트리플레이트 ((R)-2-carbomethoxy-3-tropinone 3-triflate) (도 1의 화학식 3 참조):Example 1. (R)-2-carbomethoxy-3-tropinone-3-triflate ((R)-2-carbomethoxy-3-tropinone 3-triflate) (see Formula 3 in FIG. 1):
공지의 방법 (J. Med. Chem. 2005, 48, 7437-7444, Nucl. Med. Biol., 1996, 23, 981-986)으로 라스믹 혼합체의 트로피논(tropinone) 알파 위치에 카보메톡시 작용기를 도입하고 이후 알려진 방법으로 광학 분리를 통하여 광학적으로 순수한 (R)-(+)-2-카보메톡-3-트로피논 ((R)-(+)-2-carbomethoxy-3-tropinone)을 얻은 후 이 물질 3.5g (17.7mmol)을 100mL 의 무수 THF (100 mL)에 녹이고 -78℃에서 1M THF 용액으로 된 NaN(TMS)2를 21.3mL를 10분 동안 천천히 방울방울 적하한다.A carbomethoxy functional group was added to the alpha position of tropinone in the lasmic mixture by a known method (J. Med. Chem. 2005, 48, 7437-7444, Nucl. Med. Biol., 1996, 23, 981-986). was introduced, and then optically pure (R)-(+)-2-carbomethoxy-3-tropinone ((R)-(+)-2-carbomethoxy-3-tropinone) was obtained through optical separation using a known method. Then, 3.5 g (17.7 mmol) of this material was dissolved in 100 mL of anhydrous THF (100 mL), and 21.3 mL of NaN(TMS)2 as a 1 M THF solution was slowly added dropwise at -78°C over 10 minutes.
이 용액을 30분 동안 교반하고서 (7.6g, 21.3mmol)의 N-페닐트라이플로로메탄술폰아마이드 (N-phenyltrifluoromethanesulfonamide) (15.4g, 43mmol)를 10분 동안 천천히 방울방울 적하한다. 적하가 끝난 후 반응 용액을 0℃에서 1시간 동안 교반하고 이후 상온에서 4시간 교반한다. 반응을 마치고 나서는 용매를 날려보내고 남은 반응물에 50mL의 물을 넣고 유기물을 100mL의 에틸아세테이트로 4차례 추출하며 유기 용매들을 모은다. 이 유기용매를 20mL의 브라인(brine)으로 씻어내고 무수 황산나트륨 (Na2SO4)으로 수분을 제거한 후 여과하였다. 여액을 감압 농축한 후 실리카젤의 칼럼을 통과시켜 표제 화합물을 4.6g을 78% 수율로 제조하였다.This solution was stirred for 30 minutes, and then (7.6 g, 21.3 mmol) of N-phenyltrifluoromethanesulfonamide (15.4 g, 43 mmol) was slowly added dropwise over 10 minutes. After the dropwise addition was completed, the reaction solution was stirred at 0°C for 1 hour and then stirred at room temperature for 4 hours. After completing the reaction, the solvent is blown away, 50 mL of water is added to the remaining reactant, the organic matter is extracted four times with 100 mL of ethyl acetate, and the organic solvents are collected. This organic solvent was washed with 20 mL of brine, moisture was removed with anhydrous sodium sulfate (Na2SO4), and then filtered. The filtrate was concentrated under reduced pressure and passed through a silica gel column to produce 4.6 g of the title compound with a yield of 78%.
1H NMR (CDCl3): δ 1H NMR (400 MHz, CDCl3) δ 3.94 (d, J = 5.4 Hz, 2H), 3.82 (s, 6H), 3.44 (dd, J = 6.0, 5.1 Hz, 2H), 2.88 (d, J = 4.6 Hz, 1H), 2.83 (d, J = 4.6 Hz, 1H), 2.40 (s, 6H), 2.18 (dd, J = 6.5, 5.5 Hz, 4H), 2.02 - 1.92 (m, 4H), 1.65 - 1.57 (m, 2H); 13C NMR (CDCl3) δ 163.8, 149.1, 125.2, 118.2 (q, J = 319.8 Hz), 60.0, 57.4, 52.0, 34.8, 33.0, 30.0. 1 H NMR (CDCl 3 ): δ 1 H NMR (400 MHz, CDCl 3 ) δ 3.94 (d, J = 5.4 Hz, 2H), 3.82 (s, 6H), 3.44 (dd, J = 6.0, 5.1 Hz, 2H), 2.88 (d, J = 4.6 Hz, 1H), 2.83 (d, J = 4.6 Hz, 1H), 2.40 (s, 6H), 2.18 (dd, J = 6.5, 5.5 Hz, 4H), 2.02 - 1.92 (m, 4H), 1.65 - 1.57 (m, 2H); 13 C NMR (CDCl 3 ) δ 163.8, 149.1, 125.2, 118.2 (q, J = 319.8 Hz), 60.0, 57.4, 52.0, 34.8, 33.0, 30.0.
실시예 2. (R)-2-카보메톡시-3-페닐-2-트로핀 ((R)-2-carbomethoxy-3-phenyl-2-tropene) (도 1의 4번 참조):Example 2. (R)-2-carbomethoxy-3-phenyl-2-tropene ((R)-2-carbomethoxy-3-phenyl-2-tropene) (see number 4 in Figure 1):
(R)-2-카보메톡시-3-트로피논-3-트리플레이트 (4.0g, 12.1mmol), 페닐보로닉산 (phenyl boronicacid) (1.77g, 14.5mmol), Pd(PPh3)4 (0.42g, 0.36mmol), and 불화세슘 (cesium fluoride) (4.0g, 26.8mmol)을 30mL의 DEM (30mL)에 녹이고 70℃에서 2시간 동안 교반한다. 반응이 끝난 후 반응 용액에 200mL의 디메틸에테르를 넣고 이 용액에 생겨 있는 고체를 여과하여 제거한다. 통과한 유기용매를 10mL의 물로 두 차례 씻어내고 무수 황산나트륨 (Na2SO4)으로 수분을 제거한 후 여과하였다. 여액을 감압 농축한 후 실리카겔의 칼럼을 통과시켜 표제 화합물을 2.7g을 87% 수율로 제조하였다.(R)-2-Carbomethoxy-3-tropinone-3-triflate (4.0g, 12.1mmol), phenyl boronicacid (1.77g, 14.5mmol), Pd(PPh 3 ) 4 ( Dissolve 0.42g, 0.36mmol), and cesium fluoride (4.0g, 26.8mmol) in 30mL of DEM (30mL) and stir at 70°C for 2 hours. After the reaction is over, add 200 mL of dimethyl ether to the reaction solution, and remove the solids formed in this solution by filtration. The passed organic solvent was washed twice with 10 mL of water, moisture was removed with anhydrous sodium sulfate (Na 2 SO 4 ), and then filtered. The filtrate was concentrated under reduced pressure and passed through a silica gel column to produce 2.7 g of the title compound with a yield of 87%.
[α]D20 = -60.5 (c = 1.0, CHCl3) (lit. [α]D
20 = -61.4 (c = 7.25, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.37 - 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, 4.3 Hz, 1H), 2.47 (s, 3H), 2.34 - 2.14 (m, 2H), 2.10 - 1.90 (m, 2H), 1.66 (m, 1H); 13C NMR (CDCl3): δ 168.3, 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.[α]D 20 = -60.5 (c = 1.0, CHCl 3 ) (lit. [α] D 20 = -61.4 (c = 7.25, CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ): δ 7.37 - 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, 4.3 Hz, 1H), 2.47 ( s, 3H), 2.34 - 2.14 (m, 2H), 2.10 - 1.90 (m, 2H), 1.66 (m, 1H); 13 C NMR (CDCl 3 ): δ 168.3, 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.
실시예 3. (1R,5S)-메틸 3-페닐-8-아자바이사이클로[3.2.1]옥트-2-엔-2-다이카복실레이트 ((1R,5S)ㅡmethyl 3-phenyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate) (도 1의 화학식 5 참조):Example 3. (1R,5S)-methyl 3-phenyl-8-azabicyclo[3.2.1]oct-2-en-2-dicarboxylate ((1R,5S)—methyl 3-phenyl-8- azabicyclo[3.2.1]oct-2-ene-2-carboxylate) (see Formula 5 in Figure 1):
질소 환경 아래에서 (R)-2-카보메톡시-3-페닐-2-트로핀 ((R)-2-carbomethoxy-3-phenyl-2-tropene 4 (2.5g, 9.7mmol)를 다이클로로에탄 (dichloroethane) (40mL)에 녹이고 소듐바이카보네이트 (sodium bicarbonate) (1.1g, 13.8mmol)을 넣고 가열 환류 교반 하면서 8.9mL l-클로로에틸 클로로포메이트 (l-chloroethyl chloroformate)를 세번에 나누어 넣고 계속해서 반응물을 48시간 가열 환류한다.(R)-2-carbomethoxy-3-phenyl-2-tropene 4 (2.5 g, 9.7 mmol) was dissolved in dichloroethane under nitrogen environment. Dissolve in dichloroethane (40mL), add sodium bicarbonate (1.1g, 13.8mmol), heat and reflux and stir, and add 8.9mL l-chloroethyl chloroformate in three portions. The reaction was heated to reflux for 48 hours.
반응이 끝난 후 모든 휘발성 물질들을 감압농축기에서 제거하고 여기에 100mL의 메탄올을 넣고 12시간 동안 가열 환류 교반한다. 반응이 끝난 후 반응 용매를 감압 농축한 후 NH4OH와 CH2Cl2로 묽힌다. 그런 후 반응 산물을 CH2Cl2 100mL씩 5회에 걸쳐 추출한다. 이후 유기용매를 50mL의 물로 3회에 걸쳐 씻고 무수 황산나트륨 (Na2SO4)으로 수분을 제거한 후 여과하였다. 여액을 감압 농축한 후 정제 없이 다음 반응에 사용된다.After the reaction is over, all volatile substances are removed in a vacuum concentrator, 100 mL of methanol is added, and the mixture is heated, refluxed, and stirred for 12 hours. After the reaction is over, the reaction solvent is concentrated under reduced pressure and then diluted with NH 4 OH and CH 2 Cl 2 . Then, the reaction product was extracted five times with 100 mL of CH 2 Cl 2 each. Afterwards, the organic solvent was washed three times with 50 mL of water, moisture was removed with anhydrous sodium sulfate (Na 2 SO 4 ), and then filtered. The filtrate is concentrated under reduced pressure and used in the next reaction without purification.
여기에 20mL의 메탄올을 넣고 소듐바이카보네이트 (sodium bicarbonate) (3.0g, 25.9mmol)과 디-터트-부틸 디카보네이트 (di-tert-butyl dicarbonate) (2.6g, 12.3mmol)을 넣고 3시간 동안 상온 교반한다. 반응이 끝난 후 CH2Cl2 60mL로 묽힌 후 브라인 (brine) 과 물로 씻고 CH2Cl2 50mL씩 2회에 걸쳐 추출한다. 무수 황산나트륨 (Na2SO4)으로 수분을 제거한 후 여과하였다. 여액을 감압 농축한 후 실리카젤의 칼럼을 통과시켜 표제 화합물을 2.8g을 85%로 제조하였다.Add 20 mL of methanol, add sodium bicarbonate (3.0 g, 25.9 mmol) and di-tert-butyl dicarbonate (2.6 g, 12.3 mmol), and leave at room temperature for 3 hours. Stir. After the reaction is over, it is diluted with 60 mL of CH 2 Cl 2 , washed with brine and water, and extracted twice with 50 mL of CH 2 Cl 2 each. Moisture was removed with anhydrous sodium sulfate (Na 2 SO 4 ) and then filtered. The filtrate was concentrated under reduced pressure and passed through a silica gel column to prepare 2.8 g of the title compound at 85% concentration.
1H NMR (400 MHz, CDCl3): δ 7.42 - 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). 1 H NMR (400 MHz, CDCl 3 ): δ 7.42 - 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).
실시예 4. (1R,2S,3S,5S)-8-tert-부틸-2-메틸-3-페닐-8-아자바이사이클로[3.2.1]옥탄-2,8-다이카복실레이트 ((1R,2S,3S,5S)-8-tert-butyl 2-methyl 3-phenyl-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate) (도 1의 화학식 6 및, 화학식 7과 그 이성질체인 화학식 7' 참조):Example 4. (1R,2S,3S,5S)-8-tert-butyl-2-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate ((1R ,2S,3S,5S)-8-tert-butyl 2-methyl 3-phenyl-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate) (Formula 6 and Formula 7 of Figure 1 and their isomers (see formula 7'):
앞서 만든 (R)-8-tert-부틸-2-메틸-3-페닐-8-아자바이사이클로[3.2.1]옥트-2-엔-2,8-다이카복실레이크 ((1R,5S)-8-tert-butyl-2-methyl 3-phenyl-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate (5) 2.5g (7.2mmol)을 40mL의 CH2Cl2에 녹이고 질소 환경하에서 1시간 동안 교반하여 도 1에서 화학식 6의 화합물을 얻는다. 그런 후 이 화합물을 다음 반응에 적접 사용한다. 용액 상태로 얻어진 화합물에 50% Pd(OH)2/C (1.0g, 7.2mmol)를 첨가하고 그런 후 질소를 제거하고 상압 수소 환경을 만들어 준다.Previously prepared (R)-8-tert-butyl-2-methyl-3-phenyl-8-azabicyclo[3.2.1]oct-2-en-2,8-dicarboxylate ((1R,5S)- Dissolve 2.5 g (7.2 mmol) of 8-tert-butyl-2-methyl 3-phenyl-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate (5) in 40 mL of CH 2 Cl 2 Stir under nitrogen environment for 1 hour to obtain the compound of formula 6 in Figure 1. This compound is then used directly in the next reaction. 50% Pd(OH)2/C (1.0g, 7.2%) is added to the compound obtained in solution. mmol) is added and then nitrogen is removed and an atmospheric pressure hydrogen environment is created.
반응 혼합물을 수소 환경하에서 12시간 교반하면서 반응을 시킨 후 반응의 종결을 확인하고 반응액을 소량의 MeOH을 첨가한다. 반응 산물을 MeOH을 첨가하여 셀라이트를 입힌 여과 필터에서 여과하고 여과되어 나온 용액을 감압하에서 농축한다. 농축된 산물을 실리카젤의 칼럼을 통과시켜 부분입체 이성질체 두 가지를 각각 1.32g(수율 60%)의 무색 액체와 고체 성상의 0.88g(수율 40%)의 양으로 얻는다(dr = 60 : 40). 이때 주산물로 얻어지는 화합물이 표제 화합물이며 이를 다음 반응에 사용한다.The reaction mixture was reacted with stirring in a hydrogen environment for 12 hours. After confirming the completion of the reaction, a small amount of MeOH was added to the reaction solution. The reaction product is filtered through a celite-coated filter with the addition of MeOH, and the filtered solution is concentrated under reduced pressure. The concentrated product is passed through a silica gel column to obtain two diastereomers, 1.32 g (yield 60%) of colorless liquid and 0.88 g (40% yield) of solid, respectively (dr = 60:40). . At this time, the compound obtained as the main product is the title compound and is used in the next reaction.
주산물 이성질체 (화학식 7): 1H NMR (400 MHz, CDCl3): δ 7.40 - 7.13 (m, 5H), 4.68 (m, 1H), 4.55 (m, 1H), 3.46 (s, 3H), 3.29 (dt, J = 12.5, 5.2 Hz, 1H), 2.92 (d, J = 11.4 Hz, 1H), 2.81 (m, 1H), 2.26 - 1.95 (m, 2H), 1.94-1.63 (m, 3H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.3, 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. Main product isomer (Formula 7): 1 H NMR (400 MHz, CDCl 3 ): δ 7.40 - 7.13 (m, 5H), 4.68 (m, 1H), 4.55 (m, 1H), 3.46 (s, 3H), 3.29 (dt, J = 12.5, 5.2 Hz, 1H), 2.92 (d, J = 11.4 Hz, 1H), 2.81 (m, 1H), 2.26 - 1.95 (m, 2H), 1.94-1.63 (m, 3H), 1.47 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.3, 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.
부산물 이성질체 (화학식 7'): 1H NMR (400 MHz, CDCl3) δ 7.36 - 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): By-product isomers (Formula 7'): 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 - 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):
실시예 5. (1R,2S,3S,5S)-메틸 3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 ((1R,2S,3S,5S)-methyl 3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (도 1의 화학식 8 참조):Example 5. (1R,2S,3S,5S)-methyl 3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((1R,2S,3S,5S )-methyl 3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (see Formula 8 in Figure 1):
출발 물질인 (1R,2S,3S,5S)-8-tert-부틸-2-메틸-3-페닐-8-아자바이사이클로[3.2.1]옥탄-2,8-다이카복실레이트 ((1R,2S,3S,5S)-8-tert-butyl 2-methyl 3-phenyl-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate) (1.2g, 3.4mmol)를 10mL의 CH2Cl2에 녹이고 여기에 초산 (acetic acid) (4mL), 아이오딘 (iodine) (2.3g, 9.3mmol), 그리고 트리플로로메탄술폰산은 (silvertrifluoromethanesulfonate) (1.7g, 7.0mmol)을 넣는다.Starting material (1R,2S,3S,5S)-8-tert-butyl-2-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate ((1R, 2S,3S,5S)-8-tert-butyl 2-methyl 3-phenyl-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate) (1.2g, 3.4mmol) in 10mL of CH 2 Cl 2 Dissolve and add acetic acid (4mL), iodine (2.3g, 9.3mmol), and silvertrifluoromethanesulfonate (1.7g, 7.0mmol).
이렇게 만들어진 반응물을 상온의 어두운 후드에서 15시간 교반한다. 반응 용기에 생겨 있는 요오드화은 등의 고체들을 여과시켜 제거하고 CH2Cl2 (4 * 30 mL)로 반응 산물을 추출한다. 이렇게 얻어진 유기CH2Cl2 용액을 희석된 NH4OH와 1M Na2SO3와 물 20ml로 씻은 후 무수 황산나트륨 (Na2SO4)으로 수분을 제거한 후 여과하였다. 여액을 감압 농축한 후 실리카젤의 칼럼을 통과시켜 표제 화합물 (1.15g, 90%)을 노란 액체로 얻었다.The reactant thus prepared is stirred for 15 hours in a dark hood at room temperature. Solids such as silver iodide formed in the reaction vessel are removed by filtration, and the reaction product is extracted with CH 2 Cl 2 (4 * 30 mL). The organic CH 2 Cl 2 solution obtained in this way was washed with diluted NH 4 OH, 1M Na 2 SO 3 and 20 ml of water, then the moisture was removed with anhydrous sodium sulfate (Na 2 SO 4 ) and then filtered. The filtrate was concentrated under reduced pressure and passed through a silica gel column to obtain the title compound (1.15 g, 90%) as a yellow liquid.
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.3 Hz, 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, 2.8 Hz, 1H), 2.18 - 1.96 (m, 3H), 1.79 - 1.58 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 173.5, 142.1, 137.2, 129.4, 91.7, 56.3, 53.6, 51.2, 50.9, 35.2, 29.1, 27.7. 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.3 Hz, 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, 2.8 Hz, 1H), 2.18 - 1.96 (m, 3H), 1.79 - 1.58 (m, 3H) ; 13 C NMR (101 MHz, CDCl 3 ) δ 173.5, 142.1, 137.2, 129.4, 91.7, 56.3, 53.6, 51.2, 50.9, 35.2, 29.1, 27.7.
실시예 6. (1R,2S,3S,5S)-메틸 N-(3-하이드록시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 ((1R,2S,3S,5S)-methyl N-(3-hydroxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (도 1의 화학식 9 참조):Example 6. (1R,2S,3S,5S)-methyl N-(3-hydroxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxyl Rate ((1R,2S,3S,5S)-methyl N-(3-hydroxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (see Formula 9 in FIG. 1 ):
톨루엔 20mL에 녹인 (1R,2S,3S,5S)-메틸 3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트((1R,2S,3S,5S)-methyl 3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) 1.0g (2.6mmol)과 3-브로모-1-프로판올 0.86mL (9.4mmol )과 트라이에틸아민 5.6mL (40.4mmol)를 질소 환경하에서 첨가하고 반응 혼합물을 4시간 동안 가열 환류 한다.(1R,2S,3S,5S)-methyl 3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((1R,2S,3S,5S) dissolved in 20mL of toluene )-methyl 3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) 1.0g (2.6mmol) and 3-bromo-1-propanol 0.86mL (9.4mmol) and triethylamine 5.6mL (40.4mmol) was added under nitrogen environment and the reaction mixture was heated to reflux for 4 hours.
반응이 종결된 후 반응 혼합물을 여과하여 고체들을 제거하고서 통과한 유기 용액을 감압 농축하여 원하는 시리카젤 관 크로마토그래피로 정제하여 순수한 표제 화합물 1.0 g을 86% 수율로 얻는다.After the reaction is completed, the reaction mixture is filtered to remove solids, and the passed organic solution is concentrated under reduced pressure and purified by the desired silica gel column chromatography to obtain 1.0 g of the pure title compound in 86% yield.
1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 3.82 - 3.73 (m, 2H), 3.67 - 3.56 (m, 2H), 3.49 (s, 3H), 2.98 (dt, J = 10.8, 5.1 Hz, 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 (101 MHz, CDCl3) δ 172.1, 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. 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 3.82 - 3.73 (m, 2H), 3.67 - 3.56 (m, 2H), 3.49 (s, 3H), 2.98 (dt, J = 10.8, 5.1 Hz, 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); 13 C NMR (101 MHz, CDCl 3 ) δ 172.1, 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.
실시예 7. (1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (도 1의 화학식 1 참조):Example 7. (1R,2S,3S,5S)-methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2 -Carboxylate ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (Formula 1 in Figure 1 reference):
N-(3-하이드록시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 (0.9g, 2.0mmol)을 10mL의 무수 CH2Cl2에 녹인 용액에 (10mL) 무수 메탄설폰네이트 (0.8g, 4.6mmol)와 다이아이소프로필아민 (0.4mL, 2.3mmol)을 상온 질소 환경하에서 첨가하고 저어 준다. 3시간 교반 후 반응 혼합물을 감압하에서 농축하고 산물을 얻은 후 실리카겔 관 크로마토그래피로 정제하여 순수한 표지 화합물 0.92g을 86% 수율로 무색 오일 형태로 얻는다.N-(3-hydroxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (0.9 g, 2.0 mmol) was dissolved in 10 mL of anhydrous CH 2 Cl. 2 Add (10mL) anhydrous methanesulfonate (0.8g, 4.6mmol) and diisopropylamine (0.4mL, 2.3mmol) to the solution dissolved in 2 at room temperature in a nitrogen environment and stir. After stirring for 3 hours, the reaction mixture was concentrated under reduced pressure, and the product was purified by silica gel column chromatography to obtain 0.92 g of the pure labeled compound in the form of a colorless oil in 86% yield.
1H NMR (400 MHz, CDCl3): δ 1.60-1.88 (m, 5H), 1.94-2.15 (m, 2H), 2.30-2.42 (m, 2H), 2.50 (td, 1H, J = 12.4, 2.8 Hz ), 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 = 8.4 Hz), 7.58 (d, 2H, J = 8.4 Hz).13C NMR (100 MHz, CDCl3) δ 25.9, 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. 1 H NMR (400 MHz, CDCl 3 ): δ 1.60-1.88 (m, 5H), 1.94-2.15 (m, 2H), 2.30-2.42 (m, 2H), 2.50 (td, 1H, J = 12.4, 2.8 Hz ), 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 = 8.4 Hz), 7.58 (d, 2H, J = 8.4 Hz). 13 C NMR (100 MHz, CDCl 3 ) δ 25.9, 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.
도 2는 화학식 1의 물질로부터 화학식 2의 물질을 얻어내는 과정을 나타내는 도면이다. Figure 2 is a diagram showing the process of obtaining a material of Chemical Formula 2 from a material of Chemical Formula 1.
실시예 8. (1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 메탄술포닉안하이드라이드 염 ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate methanesulfonic anhydride salt: (X = CH3SO3-, Y = SO2CH3)Example 8. (1R,2S,3S,5S)-methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2 -Carboxylate methanesulfonic anhydride salt ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate methanesulfonic anhydride salt: (X = CH3SO3-, Y = SO2CH3)
도 2를 참조하면, (1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 150mg을 2mL의 핵산과 CH2Cl2 10:1 혼합 용매에 녹이고 여기에 메탄술포닐안하이드라이드 48mg을 넣고 10분간 저어준다. 이때 감압 증류로 용매를 날려 보내고 핵산으로 씻어낸 고체를 표제화합물 염을 190mg 얻는다.Referring to Figure 2, (1R,2S,3S,5S)-methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane Dissolve 150 mg of -2-carboxylate in 2 mL of nucleic acid and CH 2 Cl 2 10:1 mixed solvent, add 48 mg of methanesulfonyl anhydride, and stir for 10 minutes. At this time, the solvent is blown away through reduced pressure distillation, and the solid washed with nucleic acid yields 190 mg of the title compound salt.
1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 6.9 Hz, 2H), 6.96 (d, J = 7.2 Hz, 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 = 14.3 Hz, 1H), 2.88 (s, 3H), 2.62 (m, 1H), 2.55 - 1.90 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5, 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. 1H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 6.9 Hz, 2H), 6.96 (d, J = 7.2 Hz, 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 = 14.3 Hz, 1H), 2.88 (s, 3H), 2.62 (m, 1H), 2.55 - 1.90 (m, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.5, 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, 2 4.7, 23.6.
한편, 화학식 1-1의 물질로부터 화학식 2의 물질을 얻어내는 과정은 화학식 1의 물질로부터 화학식 2의 물질을 얻어내는 과정과 실질적으로 동일하다고 할 수 있다.Meanwhile, the process of obtaining a substance of Formula 2 from a substance of Formula 1-1 can be said to be substantially the same as the process of obtaining a substance of Formula 2 from a substance of Formula 1.
실시예 9. (1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 노나플루오로부탄술포닉안하이드라이드 염 ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate nonafluorobutanesulfonic anhydride salt: (X = n-C4F9SO3-, Y = n-C4F9SO2)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-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2 -carboxylate nonafluorobutanesulfonic anhydride salt: (X = n-C4F9SO3-, Y = n-C4F9SO2)
도 2를 참조하면, (1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트에 실시예 9와 같이 모든 몰 조건과 용매 등을 같이 하면서 메탄술포닐안하이드라이드 대신 노나플루오로부탄술포닉안하이드라이드를 넣고 저어준다. 이때 감압 증류로 용매를 날려 보내고 표제화합물 염을 얻는다.Referring to Figure 2, (1R,2S,3S,5S)-methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane -2-Carboxylate was stirred by adding nonafluorobutanesulfonic anhydride instead of methanesulfonylanhydride while maintaining all molar conditions and solvents as in Example 9. At this time, the solvent is blown away through reduced pressure distillation and the salt of the title compound is obtained.
실시예 10. (1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (도 1의 화학식 1 참조):Example 10. (1R,2S,3S,5S)-methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2 -Carboxylate ((1R,2S,3S,5S)-methyl N-(3-methansulfonyloxypropyl-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate) (Formula 1 in Figure 1 reference):
(1R,2S,3S,5S)-메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트 메탄술포닐안하이드라이드 염 (화학식 2로 나타내는 모든 염) 200mg을 5mL의 CH2Cl2 용매에 녹이고 NaHCO3 포화용액을 두어 방울 적하한 후 교반한다. 그런 후 전체 용액을 작은 실리카겔 관을 10mL의 CH2Cl2를 더해서 통과시킨다. 이때 얻어진 CH2Cl2 용액을 감압 증류하여 날려 보내면 염이 아닌 표제 화합물을 정량적으로 얻는다.(1R,2S,3S,5S)-methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate methane Dissolve 200 mg of sulfonyl anhydride salt (all salts represented by Formula 2) in 5 mL of CH 2 Cl 2 solvent, add two drops of saturated NaHCO 3 solution, and stir. The entire solution is then passed through a small silica gel tube to which 10 mL of CH 2 Cl 2 is added. When the CH 2 Cl 2 solution obtained at this time is distilled under reduced pressure and blown away, the title compound, not a salt, is quantitatively obtained.
도 3은 화학식 2의 물질로부터 화학식 1의 물질을 얻어내는 과정을 나타내는 도면이고, 도 4는 화학식 2의 물질로부터 친핵성 플루오르화 반응을 통해 [18F]FP-CIT를 얻어내는 과정을 나타내는 도면이다.Figure 3 is a diagram showing the process of obtaining a material of Chemical Formula 1 from a material of Chemical Formula 2, and Figure 4 is a diagram showing the process of obtaining [18F]FP-CIT from a material of Chemical Formula 2 through a nucleophilic fluorination reaction. .
<실험예><Experimental example>
DATA SET 1 DATA SET 1
1-1. Precursor Information1-1. Precursor Information
- Date of Manufacturing : 28-Feb-22- Date of Manufacturing: 28-Feb-22
- Weight : 8mg- Weight: 8mg
- Physical State : white syrup- Physical State: white syrup
1-2. Test Result (표 1 및 도 5 참조)1-2. Test Result (see Table 1 and Figure 5)
- Date of Test : 28-Mar-22- Date of Test: 28-Mar-22
- Site : Duchembiochil-gokkyungbuk RP center- Site: Duchembiochil-gokkyungbuk RP center
- Synthesis condition : AIO + AMA + 8mg (impurity를 개선한 8mg 전구체를 사용)- Synthesis condition: AIO + AMA + 8mg (8mg precursor with improved impurity is used)
| Batch no.Batch no. | FP-CIT 22032801-DC05FP-CIT 22032801-DC05 |
| mCimCi | |
| Starting activityStarting activity | 48904890 |
| Product activityProduct activity | 12141214 |
| Yield (n.d.c)Yield (n.d.c) | 24.82%24.82% |
도 6 및 도 7을 참조하면, 정제 chromatogram의 경우 impurity 개선 전의 전구체에서 관찰되었던 unknown peak가 관찰되지 않았다.Referring to Figures 6 and 7, in the case of the purified chromatogram, the unknown peak observed in the precursor before impurity improvement was not observed.
DATA SET 2DATA SET 2
2-1. Precursor Information2-1. Precursor Information
- Date of Manufacturing : 28-Feb-22- Date of Manufacturing: 28-Feb-22
- Weight : 8mg- Weight: 8mg
- Physical State : white syrup- Physical State: white syrup
2-2. Test Result (표 2 및 도 8 참조)2-2. Test Result (see Table 2 and Figure 8)
- Date of Test : 11-Apr-22- Date of Test: 11-Apr-22
- Site : Duchembiochil-gokkyungbuk RP center- Site: Duchembiochil-gokkyungbuk RP center
- Synthesis condition : AIO + AMA + 8mg (impurity를 개선한 8mg 전구체를 사용)- Synthesis condition: AIO + AMA + 8mg (8mg precursor with improved impurity is used)
| Batch no.Batch no. | FP-CIT 22041101-DC05FP-CIT 22041101-DC05 |
| mCimCi | |
| Starting activityStarting activity | 44304430 |
| Product activityProduct activity | 11441144 |
| Yield (n.d.c)Yield (n.d.c) | 25.82%25.82% |
도 9 및 도 10을 참조하면,정제 chromatogram의 경우 impurity 개선 전의 전구체에서 관찰되었던 unknown peak가 관찰되지 않았다.Referring to Figures 9 and 10, in the case of the purified chromatogram, the unknown peak observed in the precursor before impurity improvement was not observed.
DATA SET 3DATA SET 3
3-1. Precursor Information3-1. Precursor Information
- Date of Manufacturing : 28-Feb-22- Date of Manufacturing: 28-Feb-22
- Weight : 8mg- Weight: 8mg
- Physical State : white syrup- Physical State: white syrup
3-2. Test Result (표 3 및 도 11 참조)3-2. Test Result (see Table 3 and Figure 11)
- Date of Test : 25-Arp-22- Date of Test: 25-Arp-22
- Site : Duchembiochil-gokkyungbuk RP center- Site: Duchembiochil-gokkyungbuk RP center
- Synthesis condition : AIO + AMA + 8mg (impurity를 개선한 8mg 전구체를 사용)- Synthesis condition: AIO + AMA + 8mg (8mg precursor with improved impurity is used)
| Batch no.Batch no. | FP-CIT 22042501-DC05FP-CIT 22042501-DC05 |
| mCimCi | |
| Starting activityStarting activity | 42604260 |
| Product activityProduct activity | 10551055 |
| Yield (n.d.c)Yield (n.d.c) | 24.77%24.77% |
도 12 및 도 13을 참조하면,정제 chromatogram의 경우 impurity 개선 전의 전구체에서 관찰되었던 unknown peak가 관찰되지 않았다.Referring to Figures 12 and 13, in the case of the purified chromatogram, the unknown peak observed in the precursor before impurity improvement was not observed.
이상, 본 발명은 한정된 실시예들과 첨부된 도면에 의해 설명되었으나, 본 발명은 전술한 실시예들에 한정되는 것이 아니고, 본 발명의 사상 및 범위를 벗어나지 않고 다양하게 수정 및 변형할 수 있음은 이 기술의 분야에서 통상의 지식을 가진 자에게 자명하다. 따라서 그러한 수정예 또는 변형예들은 본 발명의 청구범위에 속한다 하여야 할 것이다.Above, the present invention has been described with reference to limited embodiments and the accompanying drawings, but the present invention is not limited to the above-described embodiments, and various modifications and variations can be made without departing from the spirit and scope of the present invention. This is obvious to those skilled in the art. Accordingly, such modifications or variations should be considered to fall within the scope of the claims of the present invention.
본 발명은 FP-CIT 전구체의 제조방법 및 이에 의해 제조된 FP-CIT 전구체를 이용한 [18F]FP-CIT의 제조방법에 이용될 수 있다.The present invention can be used in a method for producing an FP-CIT precursor and a method for producing [18F]FP-CIT using the FP-CIT precursor produced thereby.
Claims (14)
- 화학식 1의 화합물을 순수 유기합성을 통해 트로피논(tropinone)으로부터 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that the compound of Formula 1 is obtained from tropinone through pure organic synthesis.<화학식 1><Formula 1>
상기 화학식 1로 표시되는 메틸 N-(3-메탄술포닐옥시프로필)-3-(4-아이오도페닐)-8-아자바이사이클로[3.2.1]옥탄-2-카복실레이트에서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있으며 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있음.In methyl N-(3-methanesulfonyloxypropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate represented by Formula 1, R is C1 -6 alkyl group or C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group may be substituted with at least one of C1-3 alkyl, halogen, and nitro. - 제1항에 있어서,According to paragraph 1,상기 화학식 1의 화합물로부터 화학식 1-1의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining a compound of Formula 1-1 from the compound of Formula 1.<화학식 1-1><Formula 1-1>
상기 화학식 1-1로 표시되는 (1'R,2'S,3'S,5'S)-3'-(4-아이오도페닐)-2'-(메톡시카보닐)스파이로[아제티딘-1,8'-바이사이클로[3.2.1]옥탄]-1-'메탄설포네이트에서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있으며 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있음.(1'R,2'S,3'S,5'S)-3'-(4-iodophenyl)-2'-(methoxycarbonyl)spiro[azetidine-1,8' represented by the formula 1-1 -Bicyclo[3.2.1]octane]-1-' In methanesulfonate, R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, and the aryl group is C1-3 alkyl, May be substituted with at least one of halogen or nitro. - 제1항에 있어서,According to paragraph 1,상기 화학식 1의 화합물로부터 그 염에 해당하는 화학식 2의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining a compound of Formula 2 corresponding to its salt from the compound of Formula 1.<화학식 2><Formula 2>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐으로 치환될 수 있고, 상기 아릴기는 C1-3 알킬, 할로겐, 나이트로 중 적어도 하나로 치환될 수 있으며, X는 아민의 질소와 4차염을 만들 수 있는 치환체로서 알킬 아릴 술폰 음이온이나 다른 안정한 음이온을 포함하고, Y는 알킬 아릴 술폰 이외 4차 아민을 만들 수 있는 작용기 모두를 포함함.Here, R is a C1-6 alkyl group or a C6-12 aryl group, the alkyl group may be substituted with halogen, the aryl group may be substituted with at least one of C1-3 alkyl, halogen, and nitro, and Substituents that can make nitrogen and quaternary salts include alkyl aryl sulfone anions or other stable anions, and Y includes all functional groups that can make quaternary amines other than alkyl aryl sulfone. - 제3항에 있어서,According to paragraph 3,상기 화학식 2의 화합물로부터 상기 화학식 1의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining the compound of Formula 1 from the compound of Formula 2.
- 제1항에 있어서,According to paragraph 1,트로피논(tropinone)으로부터 화학식 3의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that the compound of Formula 3 is obtained from tropinone.<화학식 3><Formula 3>
여기서, R은 C1-6 알킬기 아릴기 또는 치환된 알킬기를 포함함.Here, R includes a C1-6 alkyl group, an aryl group, or a substituted alkyl group. - 제5항에 있어서,According to clause 5,상기 화학식 3의 화합물로부터 화학식 4의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining the compound of Formula 4 from the compound of Formula 3.<화학식 4><Formula 4>
- 제6항에 있어서,According to clause 6,상기 화학식 4의 화합물로부터 화학식 5의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining a compound of Formula 5 from the compound of Formula 4.<화학식 5><Formula 5>
- 제7항에 있어서,In clause 7,상기 화학식 5의 화합물로부터 화학식 6의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining a compound of Formula 6 from the compound of Formula 5.<화학식 6><Formula 6>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐이나 치환된 알코올올 케톤을 포함하는 작용기로 치환될 수 있음.Here, R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone. - 제8항에 있어서,According to clause 8,상기 화학식 6의 화합물로부터 화학식 7의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining a compound of Formula 7 from the compound of Formula 6.<화학식 7><Formula 7>
여기서, R은 C1-6 알킬기 또는 C6-12 아릴기이고, 상기 알킬기는 할로겐이나 치환된 알코올올 케톤을 포함하는 작용기로 치환될 수 있음.Here, R is a C1-6 alkyl group or a C6-12 aryl group, and the alkyl group may be substituted with a functional group including halogen or a substituted alcohol ketone. - 제9항에 있어서,According to clause 9,상기 화학식 7의 화합물로부터 화학식 8의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining a compound of Formula 8 from the compound of Formula 7.<화학식 8><Formula 8>
- 제10항에 있어서,According to clause 10,상기 화학식 8의 화합물로부터 상기 화학식 1의 화합물을 얻어내는 것을 특징으로 하는 FP-CIT 전구체의 제조방법.A method for producing an FP-CIT precursor, characterized in that obtaining the compound of Formula 1 from the compound of Formula 8.
- 제1항 내지 제11항 중 어느 한 항의 제조방법에 의한 FP-CIT 전구체로부터 불소 치환 반응을 통해 [18F]FP-CIT를 제조하는 것을 특징으로 하는 [18F]FP-CIT의 제조방법.A method for producing [18F]FP-CIT, characterized in that [18F]FP-CIT is produced through a fluorine substitution reaction from the FP-CIT precursor according to the production method of any one of claims 1 to 11.
- 제12항에 있어서,According to clause 12,상기 불소 치환 반응에 사용되는 유기 용매는 아세토니트릴, DMF, DMSO 및 알코올로 이루어진 군으로부터 선택되는 1종인 것을 특징으로 하는 [18F]FP-CIT의 제조방법.A method for producing [18F]FP-CIT, wherein the organic solvent used in the fluorine substitution reaction is one selected from the group consisting of acetonitrile, DMF, DMSO, and alcohol.
- 제13항에 있어서,According to clause 13,테트라-n-부틸암모늄 또는 포타슘 메질레이트를 이용한 용리 방법을 활용하여 18F 플루오르화물을 용리하는 것을 특징으로 하는 [18F]FP-CIT의 제조방법.A method for producing [18F]FP-CIT, characterized in that 18F fluoride is eluted using an elution method using tetra-n-butylammonium or potassium mezylate.
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| KR20120038156A (en) * | 2010-10-13 | 2012-04-23 | (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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| 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 |
| KR20120038156A (en) * | 2010-10-13 | 2012-04-23 | (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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| Title |
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| JOHN L. NEUMEYER, GILLES TAMAGNAN, SHAOYIN WANG, YIGONG GAO, RICHARD A. MILIUS, NORA S. KULA, AND ROSS J. BALDESSARINI: "N-SUBSTITUTED ANALOGS OF 2BETA-CARBOMETHOXY-3BETA-(4'-IODOPHENYL) TROPANE ( BETA-CIT) WITH SELECTIVE AFFINITY TO DOPAMINE OR SEROTONIN TRANSPORTERS IN RAT FOREBRAIN", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 39, 1 January 1996 (1996-01-01), US , pages 543 - 548, XP001051290, ISSN: 0022-2623, DOI: 10.1021/jm9505324 * |
| LEE, S.J. OH, S.J. CHI, D.Y. KANG, S.H. KIL, H.S. KIM, J.S. MOON, D.H.: "One-step high-radiochemical-yield synthesis of [^1^8F]FP-CIT using a protic solvent system", NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER, NY., US, vol. 34, no. 4, 1 May 2007 (2007-05-01), US , pages 345 - 351, XP022097721, ISSN: 0969-8051, DOI: 10.1016/j.nucmedbio.2007.02.007 * |
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