WO2022114333A1 - Method for efficient production of 2-[18f]fluoro-4-boronophenylalanine comprising radioisotopes - Google Patents
Method for efficient production of 2-[18f]fluoro-4-boronophenylalanine comprising radioisotopes Download PDFInfo
- Publication number
- WO2022114333A1 WO2022114333A1 PCT/KR2020/017310 KR2020017310W WO2022114333A1 WO 2022114333 A1 WO2022114333 A1 WO 2022114333A1 KR 2020017310 W KR2020017310 W KR 2020017310W WO 2022114333 A1 WO2022114333 A1 WO 2022114333A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- branched
- straight
- halogen
- formula
- chain
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- -1 t-butyloxycarbonyl Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 22
- 230000002285 radioactive effect Effects 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 150000001450 anions Chemical class 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000006242 amine protecting group Chemical group 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GPKUICFDWYEPTK-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=CC=C=C[CH]1 GPKUICFDWYEPTK-UHFFFAOYSA-N 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 4
- JORMZLCKCZMVJM-UHFFFAOYSA-N 4'-(4-fluorophenyl)acetanilide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=CC=C(F)C=C1 JORMZLCKCZMVJM-UHFFFAOYSA-N 0.000 abstract description 62
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 abstract description 62
- 238000006243 chemical reaction Methods 0.000 abstract description 61
- 238000003786 synthesis reaction Methods 0.000 abstract description 41
- 230000015572 biosynthetic process Effects 0.000 abstract description 40
- 239000002243 precursor Substances 0.000 abstract description 19
- GGGVVBGRTWMSPX-IZFLLFDKSA-N (2s)-2-amino-3-(4-borono-2-fluoranylphenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1[18F] GGGVVBGRTWMSPX-IZFLLFDKSA-N 0.000 abstract description 4
- 238000003384 imaging method Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 41
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000011161 development Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000012636 positron electron tomography Methods 0.000 description 8
- 230000002194 synthesizing effect Effects 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000004296 chiral HPLC Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- 125000005619 boric acid group Chemical group 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 230000005251 gamma ray Effects 0.000 description 4
- 230000004153 glucose metabolism Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000010409 thin film Substances 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- IHHHQROJDZQCQH-UHFFFAOYSA-N 4-bromo-1-(bromomethyl)-2-iodobenzene Chemical compound BrCC1=CC=C(Br)C=C1I IHHHQROJDZQCQH-UHFFFAOYSA-N 0.000 description 3
- LRVKMSDCJCZTTB-UHFFFAOYSA-N 4-bromo-2-iodo-1-methylbenzene Chemical compound CC1=CC=C(Br)C=C1I LRVKMSDCJCZTTB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003957 anion exchange resin Substances 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000007336 electrophilic substitution reaction Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 239000012857 radioactive material Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- PAXWQORCRCBOCU-LURJTMIESA-N 6-fluoro-L-dopa Chemical compound OC(=O)[C@@H](N)CC1=CC(O)=C(O)C=C1F PAXWQORCRCBOCU-LURJTMIESA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 239000012630 HPLC buffer Substances 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 238000012879 PET imaging Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- XUBMPLUQNSSFHO-UHFFFAOYSA-M hydrogen carbonate;tetraethylazanium Chemical compound OC([O-])=O.CC[N+](CC)(CC)CC XUBMPLUQNSSFHO-UHFFFAOYSA-M 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 1
- GGGVVBGRTWMSPX-UHFFFAOYSA-N 2-amino-3-(4-borono-2-fluorophenyl)propanoic acid Chemical compound OC(=O)C(N)CC1=CC=C(B(O)O)C=C1F GGGVVBGRTWMSPX-UHFFFAOYSA-N 0.000 description 1
- AOYNUTHNTBLRMT-SLPGGIOYSA-N 2-deoxy-2-fluoro-aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](F)C=O AOYNUTHNTBLRMT-SLPGGIOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-SFIIULIVSA-N 2-hydroxy(211C)ethyl(trimethyl)azanium Chemical compound O[11CH2]C[N+](C)(C)C OEYIOHPDSNJKLS-SFIIULIVSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- XMHNLZXYPAULDF-UHFFFAOYSA-N 4-bromo-1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC(Br)=CC=C1CBr XMHNLZXYPAULDF-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- RXQNKKRGJJRMKD-UHFFFAOYSA-N 5-bromo-2-methylaniline Chemical compound CC1=CC=C(Br)C=C1N RXQNKKRGJJRMKD-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101710178133 Exotoxin type C Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000862969 Stella Species 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-JVVVGQRLSA-N acetic acid Chemical compound [11C](C)(=O)O QTBSBXVTEAMEQO-JVVVGQRLSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000006795 borylation reaction Methods 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 238000001948 isotopic labelling Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- FFEARJCKVFRZRR-JJZBXVGDSA-N methionine c-11 Chemical compound [11CH3]SCC[C@H](N)C(O)=O FFEARJCKVFRZRR-JJZBXVGDSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 229940010733 o-18 water Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003667 tyrosine derivatives Chemical class 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Definitions
- Nuclear medicine imaging technology a molecular imaging technology that can sensitively quantify the presence or progression of a disease by acquiring biochemical changes in the body in real time, is very useful.
- [ 18 F]FDG D-2-deoxy-2-fluoro-glucose
- [ 18 F]FDG D-2-deoxy-2-fluoro-glucose
- a basic limitation of glucose metabolizing PET is that tumors of some organs are indistinguishable from normal cells, which significantly reduces the accuracy of diagnosis.
- tumor cells and normal cells appear almost identical.
- lung cancer, liver cancer, and prostate cancer have very low tumor contrast in glucose metabolism, and many researchers have attempted to develop new PET radiopharmaceuticals to overcome these limitations.
- [ 18 F]FBPA shows a high tumor uptake rate based on amino acid uptake and is known as a derivative of phenylalanine, one of the essential amino acids. It is also a derivative of L-boronophenylalanine (L-BPA) used in boron neutron capture therapy (BNCT) as a structure containing a boric acid functional group.
- L-BPA L-boronophenylalanine
- BNCT boron neutron capture therapy
- L-BPA was first introduced in the 1970s and [ 18 F ] FBPA in the late 1990s, and many researchers conducted preclinical and clinical PET studies. There is a problem in that it is necessary to break away from the conventional synthesis method and introduce a synthesis method using the [ 18 F]F anion.
- the advantage of the electrophilic substitution reaction is that it is easy to obtain a precursor (a reactive material for labeling a radioisotope), and the synthesis process of the reaction is simple.
- the production of [ 18 F]F 2 gas for commercial purposes has disadvantages in that it is difficult to install and operate a facility, has a very low specific radioactivity characteristic, and is difficult to apply to high radioactivity production.
- Another object of the present invention is to provide a method for preparing the precursor.
- step 2 preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2);
- It provides a method for preparing a compound containing a radioactive isotope represented by Formula 1, including; preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3). :
- R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other ego,
- R 6 and R 7 are each independently —H, halogen, unsubstituted or substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,
- the substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-10 aryl ;
- Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight -chain or branched C 1-5 alkoxy ;
- R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
- R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl).
- Another aspect of the present invention provides a compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:
- the method for synthesizing [ 18 F]FBPA uses a nucleophilic substitution reaction using [ 18 F]F anion to overcome the disadvantages of the existing electrophilic substitution reaction to effectively produce [ 18 ] in high yield.
- F]FBPA was synthesized.
- HVI hypervalent iodine ylide
- the method of the present invention enables the mass production of [ 18 F]FBPA using an automatic synthesis device under GMP manufacturing conditions, so it is difficult to diagnose cancer with [ 18 F]FDG, patients who want to predict BNCT treatment, or cancer treatment. It will be very useful when trying to determine the prognosis.
- TEAB tetraethylammonium bicarbonate
- FIG. 5 is a diagram showing the results of measuring the radiochemical purity of the FBPA standard sample and the purified [ 18 F]FBPA solution using HPLC.
- FIG. 6 is a view showing the results of HPLC analysis by mixing the synthesized [ 18 F]FBPA solution and FBPA standard sample.
- FIG. 7 is a view showing a measurement result of specific radioactivity using a quantitative line of a standard sample.
- FIG 8 is a diagram showing an efficient three-step label synthesis process of [ 18 F]FBPA provided in one aspect of the present invention.
- FIG. 10 is a view showing the results of chiral HPLC analysis of Compound A-3 prepared according to step 3 of Example 1 below.
- FIG. 11 is a view showing the results of chiral HPLC analysis of Compound A-4 prepared according to step 4 of Example 1 below.
- FIG. 12 is a view showing the results of chiral HPLC analysis of Compound A-5 prepared according to step 5 of Example 1 below.
- FIG. 13 is a view showing the results of chiral HPLC analysis of Compound A-6 prepared according to step 6 of Example 1 below.
- FIG. 14 is a view showing the results of chiral HPLC analysis of Compound A ([ 18 F]FBPA) prepared according to step 7 of Example 1 below.
- [ 18 F]FBPA is a derivative used in boron neutron capture therapy (BNCT), and studies have shown that the intake of L-BPA administered to patients in BNCT can be predicted with PET. It has been reported, and it has recently attracted attention in that it is a method that can confirm the results of brain tumor diagnosis and treatment earlier than MRI.
- the conventional electrophilic substitution reaction for synthesizing [ 18 F]FBPA has the advantage of being easy to secure a precursor, but has the disadvantages of low specific activity and difficulty in mass production.
- one aspect of the present invention proposes a hypervalent iodine ylide (HVI) leaving group of a precursor as an effective method for synthesizing [ 18 F]FBPA in high yield in order to solve the above problem.
- HVI hypervalent iodine ylide
- the specific activity described in the specification of the present invention refers to the radioactivity per unit mass of a material having a radioactive isotope, and refers to a value obtained by dividing the radioactivity intensity of a specific material by its mass.
- One aspect of the present invention is
- step 2 preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2);
- It provides a method for preparing a compound containing a radioactive isotope represented by Formula 1, including; preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3). :
- R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other ego,
- R 6 and R 7 are each independently —H, halogen, unsubstituted or substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,
- the substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S C 6-10 aryl substituted with one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including;
- Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight-chain or branched C 1-5 alkoxy;
- R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
- R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl).
- a precursor for synthesizing [ 18 F]FBPA having excellent yield and isomeric purity can be prepared using a tert-butyl group for R 3 .
- the cycloalkyl may be a bridged cyclic, a fused cyclic, a spiro cyclic, or a branched cyclic.
- R 4 and R 5 are each independently -H, halogen, unsubstituted or one or more halogen-substituted straight or branched C 1-10 alkyl , straight or branched C 1-3 alkoxy , unsubstituted or substituted C 6-8 aryl, or R 4 and R 5 are linked to each other ego,
- R 6 and R 7 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight-chain or branched C 1-10 alkyl, straight - chain or branched C 1-3 alkoxy , or R 6 and R 7 is a cycloalkyl of 5 to 12 atoms formed by connecting to each other,
- the substituted C 6-8 aryl is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, and one or more heteroatoms selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-8 aryl;
- Y is -H, halogen, -N 2 + , or -NO 2 ;
- R 3 may be hydrogen, straight - chain or branched C 1-10 alkyl.
- X is ego
- R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other
- Y is halogen, or —N 2 + ;
- the R 3 may be a straight - chain or branched C 3-6 alkyl.
- X is ego
- Y may be halogen
- step 1 of Scheme I may be a nucleophilic substitution reaction with a [ 18 F]F anion.
- step 2 of Scheme I may be performed using various Pd catalysts, preferably through Miyaura borylation, and most preferably Pd(dppf)Cl 2 ([1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II)).
- Pd(dppf)Cl 2 [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II)
- step 3 of Scheme I may be performed under an acidic solution.
- Another aspect of the present invention provides a compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:
- X is ego
- R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other
- Y may be halogen
- said X is ego
- Y may be halogen
- X is ego
- R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other
- Y may be halogen
- said X is ego
- Y may be halogen
- any solvent suitable for each experimental condition may be used without limitation, for example, an ether solvent including tetrahydrofuran (THF) dioxane ethyl ether, 1,2-dimethoxyethane, etc.
- an ether solvent including tetrahydrofuran (THF) dioxane ethyl ether, 1,2-dimethoxyethane, etc.
- lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenyl Propionate, Phenylbutyrate, Cycrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate These may be used alone or in combination.
- DMF dimethylformamide
- DCM dichloromethane
- dichloroethane water, acetonazensulfonate, toluene
- the acetonitrile solution in which 5-bromo-2-methylaniline was dissolved was mixed with 30% sulfuric acid aqueous solution, and then the sodium nitrile aqueous solution was slowly added dropwise at 0 °C using a dropping funnel. After reacting the reaction solution at 0° C. for 1 hour, an aqueous sodium iodide solution was further added dropwise and reacted at room temperature for 1 hour. The final reaction solution was extracted three times using ethyl acetate, and the extracted organic solution was treated with brine and MgSO 4 to remove moisture, concentrated, and purified using column chromatography to purify the desired compound 4-bromo-2-io Do-1-methylbenzene ( A-1 ) was obtained in a yield of 60%.
- N-bromosuccinimide and AIBN Azobisisobutyronitrile
- acetonitrile solution in which Compound A-1 prepared in step 1 was dissolved, followed by reflux for 18 hours.
- the reaction solution was passed through celite, the filtrate was concentrated and purified through column chromatography, and the desired compound 4-bromo-1-(bromomethyl)-2-iodobenzene ( A- 2 ) was obtained in a yield of 73%.
- Step 3 Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-((diphenylmethylene)amino)propanoate (A-3)
- N-diphenylmethylene glycine tert-butyl ester and Maruoka catalyst as an asymmetric phase transfer catalyst were added to a mixture of 45% KOH aqueous solution and toluene, and the reaction solution was lowered to 0 ° C., followed by vigorous stirring, Compound A prepared in step 2 -2 toluene solution was slowly added dropwise. The reaction was carried out at 0° C. for 18 hours, and after the reaction was completed, the organic layer extracted with diethyl ether three times was removed from moisture using brine and MgSO 4 , and then concentrated under reduced pressure.
- Step 4 Synthesis of tert -butyl (S)-2-amino-3-(4-bromo-2-iodophenyl)propanoate (A-4)
- Step 5 Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert -butoxycarbonyl)amino)-propanoate (A-5)
- Step 6 Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert -butoxycarbonyl) 2 -amino)propanoate (A-6)
- Boc 2 O and DMAP were added to the acetonitrile solution of Compound A-5 prepared in step 5, and reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the desired compound tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert ) was subjected to column chromatography. -Butoxycarbonyl) 2 amino) propanoate ( A-6 ) was obtained in a yield of 98% and an ee value of 96% (FIG. 13).
- Step 7 ( tert -butyl ( S )-3-(4-bromo-2-((4',6'-dioxospiro[tricyclo[5.3.1.1 3, 9 ]dodecane-10,2'-[1,3] Synthesis of dioxane]-5-'ylidene- ⁇ 3 -iodanyl)phenyl)-2-(( tert -butoxycarbonyl)amino)propanoate (A, precursor)
- Acetic acid was added dropwise to the acetone solution of Compound A-6 prepared in step 6 on an ice bath and stirred for 1 hour, then DMDO prepared in step 7-2 was added dropwise to the reaction solution, the ice bath was removed, and the mixture was cooled to 3 time was stirred. After the reaction is complete, the solvent in the reaction solution is removed by concentration under reduced pressure, and the remaining reactant is added to (1r,3r,5r,7r)-spiro[adamantane-2,2'-[1,3]dioxane]- A solution of 4',6'-dione in 10% Na 2 CO 3 was added dropwise and reacted at room temperature for 2 hours.
- the fluorine-18 anion required for the label synthesis of fluorine-18 was obtained by irradiating a 55uA proton beam to the isotope target (O-18 water) for 5 to 30 minutes using 11 MeV cyclotron (Siemens, USA). , an anion exchange resin column (QMA light Sep-Pak, Waters) was used to remove moisture and secure fluorine-18 anion. Cationic impurities that may remain in the anion exchange resin column were removed by using an appropriate amount of tertiary distilled water, and an organic solvent containing a phase transfer catalyst was flowed to extract the fluorine-18 anion from the column for use in synthesis.
- an anion exchange resin column QMA light Sep-Pak, Waters
- Fluorine-18 anion in the anion exchange resin column was placed in a reaction vessel (7ml borosilicate tube) by flowing tetraethylammoium bicarbonate solution (2.1 mg in MeOH 700 ul, D.W. 300 ul), and argon gas was heated while heating the reaction vessel to 110 ° C. Water and acetonitrile were evaporated by running. In order to sufficiently remove moisture, an additional 300 ul of acetonitrile was added and evaporated to dryness, and the same process was repeated 1-2 times to completely remove the remaining moisture.
- the precursor ( A ) was dissolved in dimethylformamide (300 ul) in a reaction vessel, put into a reaction vessel, and reacted by heating at 120° C. for 10 minutes to synthesize B-1.
- a small amount of the reaction solution was added dropwise to silica TLC, developed with n-Hex/EtOAc (10:1) developing solvent, and radiated using a radioactive TLC scanner (AR-2000, Apanpack). By measuring the chemical purity, it was confirmed that the Rf value of B-1 produced without side reaction was 0.47, and the synthesis yield was 60-70%.
- step 3 To purify [ 18 F]FBPA, the result of step 3, add 1.3 ml of 0.1% TFA aqueous solution to the reaction solution and dilute it, then inject it into HPLC and use 5% acetonitrile aqueous solution (0.1% TFA water) at 4ml/min.
- [ 18 F]FBPA separated and eluted by flowing at a flow rate was collected. The elution time was between 9 and 11 minutes, the UV wavelength was 254 nm, and a gamma ray detector installed in parallel with the UV was used for detection of radioactive compounds.
- the purified [ 18 F]FBPA aliquot was diluted in 30 ml of tertiary distilled water and flowed through a reversed-phase column cartridge (C-18 Sep-Pak, waters) to remove the solvent, and the remaining 10 ml of tertiary distilled water was additionally flowed.
- the solvent was sufficiently removed, and [ 18 F]FBPA was extracted by sequentially flowing 1 ml of ethanol and 9 ml of physiological saline, and the solution was passed through a sterile filter (Millex GV, Waters) and put into a sterile vial.
- the radiochemical yield (non-attenuation correction) of the finally synthesized compound was about 10%, and when the synthesis was started with about 150 mCi of fluorine-18 anion, about 16 mCi of [ 18 F]FBPA could be obtained, The total synthesis time was about 2 hours.
- [ 18 F]FBPA could be prepared with excellent yield and isomeric purity by using the precursor having a carboxyl group substituted with a t-butyl group prepared according to Example 1.
- [ 18 F]FBPA the final product after synthesis and purification, was subjected to quality control such as radiochemical purity and specific activity.
- the glass thin film used was a thin film plate with a size of 1 cm in width and 10 cm in length coated with silica gel, and at each stage, about 1 ul of the stock solution was dripped at the origin of the plate using a glass microtube without separate treatment of the reaction solution, and at each stage. Appropriate development conditions were used for development and analysis.
- the fluorine-18 anion not participating in the first-step reaction remained as it is, and [ 18 F]FBPA, the final product of which hydrolysis occurred, was confirmed at an Rf value of 0.564.
- the reaction mixture in the last step was separated and purified using HPLC, and analyzed by anal-HPLC to obtain final purity and component analysis (confirmation of FBPA components through co-injection).
- FBPA standard material In order to identify the components of [ 18 F]FBPA obtained through fluorine-18 labeling synthesis, a non-radioactive material, FBPA standard material is required. FBPA can be obtained through organic synthesis, and the structure of the compound was identified through NMR analysis. The FBPA standard sample for checking the HPLC component analysis was synthesized as follows, and the overall reaction formula is shown in Scheme 3 below.
- Step 1 Synthesis of test-butyl 3-(4-bromo-2-fluorophenyl)-2-((diphenylmethylene)amino)propanoate (C - 1)
- Step 2 tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-3-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Synthesis of lora-2-yl)phenyl)propanoate (C-2)
- the automatic synthesizer was used to perform the synthesis of [ 18 F]FBPA with high radioactivity (over 100 mCi).
- the automatic synthesis apparatus is an apparatus that performs synthesis according to the programmed sequence except for HPLC separation and purification, and here, Flexlab (iPhase, AUS), a general-purpose F-18 automatic synthesis apparatus, was used.
- Flexlab iPhase, AUS
- the reaction sequence is as follows.
- Step 2 Reagent Preparation: Heat A at 100 °C 3 min and mix A to B
- Vial 15 was loaded with 1 mL HPLC buffer.
- HPLC was used to measure the radiochemical purity, and a small amount (20 ul) of the finally obtained compound was taken and injected into the HPLC.
- the HPLC developing solvent was 5% acetonitrile (0.1% TFA aqueous solution), and it was flowed at a flow rate of 1 ml/min.
- a UV detector was used to detect organic foreign substances, and a gamma ray detector (2x2” Nal) was used to detect radioactive organic substances. scintillation detector) was used alongside the UV detector.
- the column used was a C18 column (4.6x250 mm, Agilent), with a UV detection wavelength of 254 nm and a gamma-ray detection energy band of 100-700 keV.
- the radiochemical purity of [ 18 F]FBPA was 95% or more, and it was suitable for the standard value of radiochemical purity that is generally accepted in PET.
- a standard sample (FBPA) was prepared at concentrations of 500, 250, 50, and 25 ppm, and each absorbance was measured in analytical HPLC to draw a quantitative line.
- the UV absorbance for concentration can be calculated through the quantitative line, and the specific radioactivity of the synthesized [ 18 F]FBPA solution using an automatic synthesis device was found to have a value of at least 10 Ci/umol or more.
- the FBPA peak between 6 and 8 minutes was below the detection limit, so it was confirmed that it had a very high specific radioactivity to the extent that analysis was impossible.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Disclosed is a method for producing of 2-[18F]fluoro-4-boronophenylalanine comprising radioisotopes ([18F]FBPA), the method having a precursor with an effective leaving group and reaction conditions for high-yield synthesis of [18F]FBPA to allow the target compound, [18F]FBPA, to be efficiently synthesized, and same can be mass produced using automated synthesis apparatuses to allow effective use in molecular imaging technology.
Description
방사성 동위원소를 포함하는 2-[
18F]플루오로-4-보로노페닐알라닌의 효과적인 제조방법에 관한 것이다.It relates to an effective method for preparing 2-[ 18 F]fluoro-4-boronophenylalanine containing a radioactive isotope.
체내 생화학적 변화를 실시간으로 얻음으로써 질병의 유무 또는 진행 정도를 민감하게 정량화할 수 있는 분자영상기술인 핵의학 영상 기술은 매우 유용하다.Nuclear medicine imaging technology, a molecular imaging technology that can sensitively quantify the presence or progression of a disease by acquiring biochemical changes in the body in real time, is very useful.
지난 수십 년 동안 암 진단 및 치료 예후 관찰을 위한 포도당 대사 PET 영상을 위해 [
18F]FDG (D-2-deoxy-2-fluoro-glucose)가 널리 사용되어 왔으며, 앞으로도 많이 사용될 전망이다. 그러나, 포도당 대사 PET의 기본적인 한계점은 일부 장기의 종양이 정상세포와 구분이 불가하여 진단의 정확도를 현저히 떨어뜨린다는 것이다. 특히 뇌종양의 경우, 뇌조직 자체의 포도당 대사율이 매우 높기 때문에 종양세포와 정상세포는 거의 동일하게 나타난다. 그 밖에 폐암, 간암, 전립선 암 등이 포도당 대사의 종양 대비도가 매우 낮아, 많은 연구자들이 이러한 한계점을 극복하고자 새로운 PET 방사성의약품을 개발하고자 하였다. 종양 세포의 활발한 증식 작용에 관여하는 여러 인자들(아미노산 섭취율 증가, DNA 합성, 혈관 신생 등)에 대해 이러한 연구들의 성과물들이 잘 알려져 있다. 그 중에서도 아미노산 섭취율 증가에 대한 PET 영상 프로브 개발이 가장 널리 연구되어 왔으며, [
11C]methionine, [
11C]choline, [
11C]acetate, [
18F]Tyrosine-유도체들, [
18F]FDopa, [
18F]FBPA 등이 포도당 대사와 무관한 종양 PET 마커로서 유용함이 입증되었다.[ 18 F]FDG (D-2-deoxy-2-fluoro-glucose) has been widely used for PET imaging of glucose metabolism for cancer diagnosis and treatment prognosis for the past several decades, and is expected to be widely used in the future. However, a basic limitation of glucose metabolizing PET is that tumors of some organs are indistinguishable from normal cells, which significantly reduces the accuracy of diagnosis. In particular, in the case of brain tumors, since the glucose metabolism rate of the brain tissue itself is very high, tumor cells and normal cells appear almost identical. In addition, lung cancer, liver cancer, and prostate cancer have very low tumor contrast in glucose metabolism, and many researchers have attempted to develop new PET radiopharmaceuticals to overcome these limitations. The results of these studies are well known on the factors involved in the active proliferation of tumor cells (increased amino acid uptake, DNA synthesis, angiogenesis, etc.). Among them, the development of a PET imaging probe for increased amino acid uptake has been most widely studied, [ 11 C]methionine, [ 11 C]choline, [ 11 C]acetate, [ 18 F]Tyrosine-derivatives, [ 18 F]FDopa , [ 18 F]FBPA, etc. have been demonstrated to be useful as tumor PET markers independent of glucose metabolism.
이 중에서도 [
18F]FBPA는 아미노산 섭취도에 근거하는 높은 종양 섭취율을 보이며, 필수 아미노산 중 하나인 phenylalanine의 유도체로 알려져 있다. 붕산 기능기가 포함된 구조로서 붕소중성자포획치료(BNCT;boron neutron capture therapy)에서 사용되는 L-boronophenylalanine(L-BPA)의 유도체이기도 하다. 최근 [
18F]FBPA가 주목을 받는 이유는 첫째로, BNCT에서 환자에게 투여되는 L-BPA의 체내 (또는 종양 내) 섭취도가 [
18F]FBPA PET으로 예측 가능하다는 연구와 데이터들이 보고되고 있으며, 둘째로는 뇌종양의 진단과 치료 후의 결과를 MRI보다 일찍 확인할 수 있는 방법이 될 수 있기 때문이다. L-BPA는 1970년대에, [
18F]FBPA는 1990년대 후반에 처음 소개되었으며, 그동안 많은 연구자들이 전임상과 임상 PET 연구를 실시하였으나, 상용화를 앞둔 대량 생산을 위해서는 [
18F]F
2를 이용한 종래의 합성 방법을 탈피하고 [
18F]F 음이온을 이용한 합성 방법을 도입해야 하는 과제를 가지고 있다.Among them, [ 18 F]FBPA shows a high tumor uptake rate based on amino acid uptake and is known as a derivative of phenylalanine, one of the essential amino acids. It is also a derivative of L-boronophenylalanine (L-BPA) used in boron neutron capture therapy (BNCT) as a structure containing a boric acid functional group. The reason why [ 18 F]FBPA has recently received attention is firstly, studies and data have been reported that the in vivo (or intratumoral) intake of L-BPA administered to patients in BNCT can be predicted with [ 18 F]FBPA PET. Second, it is because it can be a method that can confirm the results of brain tumor diagnosis and treatment earlier than MRI. L-BPA was first introduced in the 1970s and [ 18 F ] FBPA in the late 1990s, and many researchers conducted preclinical and clinical PET studies. There is a problem in that it is necessary to break away from the conventional synthesis method and introduce a synthesis method using the [ 18 F]F anion.
상기에서 기술한 바와 같이 기존의 [
18F]FBPA의 합성은 주로 방사성 불소 기체 ([
18F]F
2)를 이용한 친전자성 방향족 치환반응에 의해 실시되었다.As described above, the conventional synthesis of [ 18 F]FBPA was mainly carried out by electrophilic aromatic substitution reaction using radioactive fluorine gas ([ 18 F]F 2 ).
친전자성 치환반응의 장점은 전구체(precursor; 방사성동위원소 표지를 위한 반응 물질)의 확보가 용이하고, 반응의 합성과정이 단순하다는 것이다. 그러나, 상업적 목적에서의 [
18F]F
2 기체의 생산은 시설의 설치 및 운영이 어렵고, 비방사능이 매우 낮은 고유의 특성이 있으며, 고방사능 생산에 적용하기에 어려운 단점을 가지고 있다.The advantage of the electrophilic substitution reaction is that it is easy to obtain a precursor (a reactive material for labeling a radioisotope), and the synthesis process of the reaction is simple. However, the production of [ 18 F]F 2 gas for commercial purposes has disadvantages in that it is difficult to install and operate a facility, has a very low specific radioactivity characteristic, and is difficult to apply to high radioactivity production.
지난 10여년간 이와 유사한 경우로서 [
18F]FDOPA의 경우에도, [
18F]F
2를 사용하는 대신, [
18F]F 음이온을 이용한 합성법 연구에 많은 연구자들이 노력을 하였으며, 결과적으로 현재 친핵성 치환반응을 이용한 [
18F]FDOPA의 고방사능 생산이 가능하게 되었다.In the case of [ 18 F]FDOPA as a similar case for the past 10 years, many researchers have made efforts to study the synthesis method using [ 18 F]F anion instead of [ 18 F]F 2 , and as a result, the current nucleophilicity It became possible to produce [ 18 F]FDOPA with high radioactivity using the substitution reaction.
[
18F]FBPA의 경우는 현재까지 보고된 문헌으로는 일본의 스텔라사의 특허가 있으나(특허문헌 1, US 9,815,855 B2), 실제로 [
18F]FBPA를 합성한 최종 수율이 실시예로 나타나 있지 않다.In the case of [ 18 F] FBPA, there is a patent of Stella Corporation of Japan as a document reported to date (Patent Document 1, US 9,815,855 B2), but the final yield of actually synthesizing [ 18 F] FBPA is not shown as an example. .
[
18F]FBPA 대량생산에 있어서 경제적으로 우수한 전구체의 확보와 방사성동위원소 합성 과정에서 높은 수율, 높은 비방사능, 높은 입체이성질체 순도 등이 중요한 요소로 평가되어야 한다.[ 18 F] In mass production of FBPA, high yield, high specific activity, and high stereoisomeric purity should be evaluated as important factors in securing economically excellent precursors and in the process of radioisotope synthesis.
현재까지는 수치화된 기록으로서 [
18F]F 음이온을 이용한 [
18F]FBPA 합성의 사례가 보고된 바 없으며, 본 발명에서 그 방법을 제시하고자 한다.So far, as a numerical record, there has been no case of synthesis of [ 18 F]FBPA using [ 18 F ]F anion, and the present invention intends to present the method.
본 발명의 일 측면에서의 목적은, 방사성 동위원소를 포함하는 2-[
18F]플루오로-4-보로노페닐알라닌의 효과적인 제조방법을 제공하는 것이다.It is an object of one aspect of the present invention to provide an effective method for preparing 2-[ 18 F]fluoro-4-boronophenylalanine containing a radioactive isotope.
본 발명의 다른 측면에서의 목적은, 상기 방사성 동위원소를 포함하는 2-[
18F]플루오로-4-보로노페닐알라닌을 제조하기 위한 전구체를 제공하는 것이다.It is an object of another aspect of the present invention to provide a precursor for preparing 2-[ 18 F]fluoro-4-boronophenylalanine containing the radioactive isotope.
본 발명의 또 다른 측면에서의 목적은, 상기 전구체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the precursor.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명의 일 측면은 하기 반응식 Ⅰ에서 나타난 바와 같이,One aspect of the present invention is as shown in the following Scheme I,
화학식 2로 표시되는 화합물로부터 화학식 3으로 표시되는 화합물을 제조하는 단계(단계 1);preparing a compound represented by Formula 3 from the compound represented by Formula 2 (Step 1);
상기 단계 1에서 제조한 화학식 3으로 표시되는 화합물로부터 화학식 4로 표시되는 화합물을 제조하는 단계(단계 2); 및preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2); and
상기 단계 2에서 제조한 화학식 4로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계(단계 3);를 포함하는, 화학식 1로 표시되는 방사성 동위원소를 포함하는 화합물의 제조방법을 제공한다:It provides a method for preparing a compound containing a radioactive isotope represented by Formula 1, including; preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3). :
<반응식 Ⅰ><Scheme I>
(상기 반응식 Ⅰ에서,(In Scheme I,
상기 X는
이고,wherein X is ego,
상기 R
4 및 R
5는 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C
1-
20알킬, 직쇄 또는 분지쇄의 C
1-
5알콕시, 비치환 또는 치환된 C
6-
10아릴, 또는 R
4과 R
5가 서로 연결되어 형성된
이고,Wherein R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other ego,
상기 R
6 및 R
7은 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C
1-
20알킬, 직쇄 또는 분지쇄의 C
1-
5알콕시, 또는 R
6 및 R
7가 서로 연결되어 형성된 3 내지 15원자의 사이클로알킬이고,R 6 and R 7 are each independently —H, halogen, unsubstituted or substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,
상기 치환된 C
6-
10아릴은 C
1-5의 직쇄 또는 분지쇄 알킬, C
1-5의 직쇄 또는 분지쇄 알킬카보닐, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C
6-
10아릴이고; The substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-10 aryl ;
상기 Y는 -H, 할로겐, -N
2
+, -NO
2, -CN, 직쇄 또는 분지쇄의 C
1-
5알콕시이고;Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight -chain or branched C 1-5 alkoxy ;
상기 R
1 및 R
2는 각각 독립적으로 -H, 또는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이고;wherein R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
상기 R
3은 수소, 직쇄 또는 분지쇄의 C
1-
10알킬, 또는 직쇄 또는 분지쇄의 C
1-10알킬이 치환된 페닐이다).wherein R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl).
본 발명의 다른 일 측면은 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체, 수화물, 또는 이의 약학적으로 허용 가능한 염을 제공한다:Another aspect of the present invention provides a compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:
<화학식 2><Formula 2>
(상기 화학식 2에서,(In Formula 2,
X, Y, R
1, R
2, 및 R
3는 상기 반응식 Ⅰ에서 정의한 바와 같다).X, Y, R 1 , R 2 , and R 3 are as defined in Scheme I above).
본 발명의 또 다른 일 측면은 하기 반응식 Ⅱ에서 나타난 바와 같이,Another aspect of the present invention is as shown in Scheme II below,
화학식 5로 표시되는 화합물로부터 화학식 2로 표시되는 화합물을 제조하는 단계를 포함하는, 하기 화학식 2로 표시되는 화합물의 제조방법을 제공한다:It provides a method for preparing a compound represented by the following formula (2), comprising the step of preparing a compound represented by formula (2) from a compound represented by formula (5):
<반응식 Ⅱ><Scheme II>
(상기 반응식 Ⅱ에서,(In Scheme II,
X, Y, R
1, R
2, 및 R
3는 상기 반응식 Ⅰ에서 정의한 바와 같다).X, Y, R 1 , R 2 , and R 3 are as defined in Scheme I above).
본 발명의 일 측면에서 제공하는 [
18F]FBPA의 합성방법은 기존의 친전자성 치환반응의 단점을 극복하고자 [
18F]F 음이온을 이용한 친핵성 치환반응을 이용하여 효과적으로 높은 수율의 [
18F]FBPA를 합성하고자 하였다. F-18 표지가 가장 용이한 초원자가 아이오딘 일리드(hypervalent iodine ylide, HVI)를 선택성 있게 합성하는 조건을 활용하였으며, 붕산기를 높은 수율로 도입하여 목적화합물인 [
18F]FBPA를 효율적으로 높은 수율로 합성할 수 있었다. 또한 PET 종양영상을 위하여 높은 입체화학적 순도를 유지할 수 있음을 확인하였다. 본 발명의 방법으로 GMP 제조 조건에서 자동합성장치를 이용한 [
18F]FBPA의 대량 생산이 가능하게 되어 [
18F]FDG로 암진단이 어려운 환자나, BNCT 치료를 예측하고자 하는 환자 또는 암치료의 예후를 판단하려는 경우에 매우 유용하게 사용될 것이다.The method for synthesizing [ 18 F]FBPA provided in one aspect of the present invention uses a nucleophilic substitution reaction using [ 18 F]F anion to overcome the disadvantages of the existing electrophilic substitution reaction to effectively produce [ 18 ] in high yield. F]FBPA was synthesized. The conditions for selectively synthesizing hypervalent iodine ylide (HVI), which are the easiest to label F-18, were utilized, and the target compound [ 18 F]FBPA was efficiently increased by introducing a boric acid group in high yield. It could be synthesized in yield. In addition, it was confirmed that high stereochemical purity can be maintained for PET tumor imaging. The method of the present invention enables the mass production of [ 18 F]FBPA using an automatic synthesis device under GMP manufacturing conditions, so it is difficult to diagnose cancer with [ 18 F]FDG, patients who want to predict BNCT treatment, or cancer treatment. It will be very useful when trying to determine the prognosis.
도 1은 TEAB(tetraethylammonium bicarbonate)를 이용하여
18F를 도입한 1단계 반응의 radio-TLC 결과 (n-Hex:EtOAc=10:1)를 나타내는 도면이다.1 is a diagram showing a radio-TLC result (n-Hex:EtOAc=10:1) of a one-step reaction in which 18 F was introduced using TEAB (tetraethylammonium bicarbonate).
도 2는 팔라듐 촉매와 (BPin)
2를 이용하여 붕산기를 도입한 2단계 반응의 radio-TLC 결과 (n-Hex:EtOAc=10:1)를 나타내는 도면이다.2 is a view showing the radio-TLC result (n-Hex:EtOAc=10:1) of a two-step reaction in which a boric acid group was introduced using a palladium catalyst and (BPin) 2 .
도 3은 염산을 이용하여 보호기를 가수분해한 3단계 반응의 radio-TLC 결과 (n-Hex:EtOAc=10:1)를 나타내는 도면이다.3 is a diagram showing the radio-TLC result (n-Hex:EtOAc=10:1) of a three-step reaction in which a protecting group is hydrolyzed using hydrochloric acid.
도 4는 염산을 이용하여 보호기를 가수분해한 3단계 반응의 radio-TLC 결과 (nBuOH:DW:AcOH=12:3:5)를 나타내는 도면이다.4 is a diagram showing the radio-TLC result (nBuOH:DW:AcOH=12:3:5) of a three-step reaction in which a protecting group is hydrolyzed using hydrochloric acid.
도 5는 FBPA 표준 시료와 정제된 [
18F]FBPA 용액의 방사화학적 순도를 HPLC를 이용하여 측정한 결과를 나타내는 도면이다.5 is a diagram showing the results of measuring the radiochemical purity of the FBPA standard sample and the purified [ 18 F]FBPA solution using HPLC.
도 6은 합성된 [
18F]FBPA 용액과 FBPA 표준 시료를 혼합하여 HPLC 분석한 결과를 나타내는 도면이다.6 is a view showing the results of HPLC analysis by mixing the synthesized [ 18 F]FBPA solution and FBPA standard sample.
도 7은 표준 시료의 정량선을 이용한 비방사능의 측정 결과를 나타내는 도면이다.7 is a view showing a measurement result of specific radioactivity using a quantitative line of a standard sample.
도 8은 본 발명의 일 측면에서 제공하는 [
18F]FBPA의 효율적인 3 단계 표지 합성과정을 나타내는 도면이다.8 is a diagram showing an efficient three-step label synthesis process of [ 18 F]FBPA provided in one aspect of the present invention.
도 9는 하기 실시예 2의 단계 3에 따라 제조한 [
18F]FBPA의 카이랄 HPLC 분석 결과를 나타낸 도면이다.9 is a view showing the results of chiral HPLC analysis of [ 18 F]FBPA prepared according to step 3 of Example 2 below.
도 10은 하기 실시예 1의 단계 3에 따라 제조한 화합물 A-3의 카이랄 HPLC 분석 결과를 나타낸 도면이다.10 is a view showing the results of chiral HPLC analysis of Compound A-3 prepared according to step 3 of Example 1 below.
도 11은 하기 실시예 1의 단계 4에 따라 제조한 화합물 A-4의 카이랄 HPLC 분석 결과를 나타낸 도면이다.11 is a view showing the results of chiral HPLC analysis of Compound A-4 prepared according to step 4 of Example 1 below.
도 12는 하기 실시예 1의 단계 5에 따라 제조한 화합물 A-5의 카이랄 HPLC 분석 결과를 나타낸 도면이다.12 is a view showing the results of chiral HPLC analysis of Compound A-5 prepared according to step 5 of Example 1 below.
도 13은 하기 실시예 1의 단계 6에 따라 제조한 화합물 A-6의 카이랄 HPLC 분석 결과를 나타낸 도면이다.13 is a view showing the results of chiral HPLC analysis of Compound A-6 prepared according to step 6 of Example 1 below.
도 14는 하기 실시예 1의 단계 7에 따라 제조한 화합물 A([
18F]FBPA)의 카이랄 HPLC 분석 결과를 나타낸 도면이다.14 is a view showing the results of chiral HPLC analysis of Compound A ([ 18 F]FBPA) prepared according to step 7 of Example 1 below.
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
한편, 본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Meanwhile, the embodiment of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiment described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, in the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless specifically stated otherwise.
전술한 바와 같이, [
18F]FBPA는 붕소중성자포획치료(BNCT;boron neutron capture therapy)에서 사용되는 유도체로, BNCT에서 환자에게 투여되는 L-BPA의 체내 섭취도를 PET로 예측가능하다는 연구가 보고되어 있고, 뇌종양의 진단과 치료 후의 결과를 MRI보다 일찍 확인할 수 있는 방법이라는 점에서 최근 주목받고 있다. 그러나, [
18F]FBPA를 합성하기 위한 종래의 친전자성 치환반응은 전구체 확보가 용이하다는 장점이 있으나, 비방사능이 낮고 대량생산이 어렵다는 단점이 있다. 이에, 본 발명의 일 측면은 상기 문제를 해결하기 위하여 [
18F]FBPA를 높은 수율로 합성하기 위한 효과적인 방법으로 전구체의 hypervalent iodine ylide(HVI) 이탈기를 제안한다. 이를 통해 [
18F]FBPA의 대량생산에 있어서 경제적으로 우수한 전구체 확보 및 높은 수율, 높은 비방사능(specific activity), 높은 입체이성질체 순도를 확보할 수 있는 방법을 제시한다. 본 발명의 명세서에 기재된 비방사능(specific activity)은 방사성 동위원소를 갖고 있는 물질의 단위질량당 방사능을 의미하며, 특정 물질의 방사능 강도를 그 질량으로 나눈 값을 의미한다.As described above, [ 18 F]FBPA is a derivative used in boron neutron capture therapy (BNCT), and studies have shown that the intake of L-BPA administered to patients in BNCT can be predicted with PET. It has been reported, and it has recently attracted attention in that it is a method that can confirm the results of brain tumor diagnosis and treatment earlier than MRI. However, the conventional electrophilic substitution reaction for synthesizing [ 18 F]FBPA has the advantage of being easy to secure a precursor, but has the disadvantages of low specific activity and difficulty in mass production. Accordingly, one aspect of the present invention proposes a hypervalent iodine ylide (HVI) leaving group of a precursor as an effective method for synthesizing [ 18 F]FBPA in high yield in order to solve the above problem. Through this, we propose a method for securing economically excellent precursors, high yield, high specific activity, and high stereoisomeric purity in the mass production of [ 18 F]FBPA. The specific activity described in the specification of the present invention refers to the radioactivity per unit mass of a material having a radioactive isotope, and refers to a value obtained by dividing the radioactivity intensity of a specific material by its mass.
본 발명의 일 측면은,One aspect of the present invention is
하기 반응식 Ⅰ에서 나타난 바와 같이,As shown in Scheme I below,
화학식 2로 표시되는 화합물로부터 화학식 3으로 표시되는 화합물을 제조하는 단계(단계 1);preparing a compound represented by Formula 3 from the compound represented by Formula 2 (Step 1);
상기 단계 1에서 제조한 화학식 3으로 표시되는 화합물로부터 화학식 4로 표시되는 화합물을 제조하는 단계(단계 2); 및preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2); and
상기 단계 2에서 제조한 화학식 4로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계(단계 3);를 포함하는, 화학식 1로 표시되는 방사성 동위원소를 포함하는 화합물의 제조방법을 제공한다:It provides a method for preparing a compound containing a radioactive isotope represented by Formula 1, including; preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3). :
<반응식 Ⅰ><Scheme I>
(상기 반응식 Ⅰ에서,(In Scheme I,
상기 X는
이고,wherein X is ego,
상기 R
4 및 R
5는 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C
1-
20알킬, 직쇄 또는 분지쇄의 C
1-
5알콕시, 비치환 또는 치환된 C
6-
10아릴, 또는 R
4과 R
5가 서로 연결되어 형성된
이고,Wherein R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other ego,
상기 R
6 및 R
7은 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C
1-
20알킬, 직쇄 또는 분지쇄의 C
1-
5알콕시, 또는 R
6 및 R
7가 서로 연결되어 형성된 3 내지 15원자의 사이클로알킬이고,R 6 and R 7 are each independently —H, halogen, unsubstituted or substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,
상기 치환된 C
6-
10아릴은 C
1-5의 직쇄 또는 분지쇄 알킬, C
1-5의 직쇄 또는 분지쇄 알킬카보닐, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C
6-10아릴이고; The substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S C 6-10 aryl substituted with one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including;
상기 Y는 -H, 할로겐, -N
2
+, -NO
2, -CN, 직쇄 또는 분지쇄의 C
1-5알콕시이고;Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight-chain or branched C 1-5 alkoxy;
상기 R
1 및 R
2는 각각 독립적으로 -H, 또는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이고;wherein R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);
상기 R
3은 수소, 직쇄 또는 분지쇄의 C
1-
10알킬, 또는 직쇄 또는 분지쇄의 C
1-10알킬이 치환된 페닐이다).wherein R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl).
이때, 가장 바람직하게는 R
3를 tert-butyl기를 사용하여 우수한 수율 및 이성질체 순도를 갖는 [
18F]FBPA 합성을 위한 전구체를 제조할 수 있다.In this case, most preferably, a precursor for synthesizing [ 18 F]FBPA having excellent yield and isomeric purity can be prepared using a tert-butyl group for R 3 .
상기 사이클로알킬은 다리걸친 고리형, 접합된 고리형, 스파이로 고리형, 또는 곁가지를 가진 고리형일 수 있다.The cycloalkyl may be a bridged cyclic, a fused cyclic, a spiro cyclic, or a branched cyclic.
다른 측면에서,On the other hand,
상기 X는
이고,wherein X is ego,
상기 R
4 및 R
5는 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C
1-
10알킬, 직쇄 또는 분지쇄의 C
1-
3알콕시, 비치환 또는 치환된 C
6-
8아릴, 또는 R
4과 R
5가 서로 연결되어 형성된
이고,R 4 and R 5 are each independently -H, halogen, unsubstituted or one or more halogen-substituted straight or branched C 1-10 alkyl , straight or branched C 1-3 alkoxy , unsubstituted or substituted C 6-8 aryl, or R 4 and R 5 are linked to each other ego,
상기 R
6 및 R
7은 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C
1-
10알킬, 직쇄 또는 분지쇄의 C
1-
3알콕시, 또는 R
6 및 R
7가 서로 연결되어 형성된 5내지 12원자의 사이클로알킬이고,R 6 and R 7 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight-chain or branched C 1-10 alkyl, straight - chain or branched C 1-3 alkoxy , or R 6 and R 7 is a cycloalkyl of 5 to 12 atoms formed by connecting to each other,
상기 치환된 C
6-
8아릴은 C
1-3의 직쇄 또는 분지쇄 알킬, C
1-3의 직쇄 또는 분지쇄 알킬카보닐, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C
6-
8아릴이고; The substituted C 6-8 aryl is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, and one or more heteroatoms selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-8 aryl;
상기 Y는 -H, 할로겐, -N
2
+, 또는 -NO
2이고;wherein Y is -H, halogen, -N 2 + , or -NO 2 ;
상기 R
3은 수소, 직쇄 또는 분지쇄의 C
1-
10알킬일 수 있다.R 3 may be hydrogen, straight - chain or branched C 1-10 alkyl.
또 다른 측면에서, 상기 X는
이고,In another aspect, X is ego,
상기 R
6 및 R
7은 서로 연결되어 형성된 8 내지 11원자의 사이클로알킬이고,wherein R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other,
상기 Y는 할로겐, 또는 -N
2
+이고;Y is halogen, or —N 2 + ;
상기 R
3은 직쇄 또는 분지쇄의 C
3-
6알킬일 수 있다.The R 3 may be a straight - chain or branched C 3-6 alkyl.
가장 바람직하게는, 상기 X는
이고;Most preferably, X is ego;
상기 Y는 할로겐일 수 있다.Y may be halogen.
다른 측면에서, 상기 반응식 Ⅰ의 단계 1은 [
18F]F 음이온에 의한 친핵성 치환반응인 것일 수 있다.In another aspect, step 1 of Scheme I may be a nucleophilic substitution reaction with a [ 18 F]F anion.
또한, 상기 반응식 Ⅰ의 단계 2는 다양한 Pd 촉매를 이용하여 수행될 수 있으며, 바람직하게는 Miyaura borylation을 통해 수행될 수 있고, 가장 바람직하게는 Pd(dppf)Cl
2([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II))를 이용하여 수행될 수 있다.In addition, step 2 of Scheme I may be performed using various Pd catalysts, preferably through Miyaura borylation, and most preferably Pd(dppf)Cl 2 ([1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium(II)).
또한, 상기 반응식 Ⅰ의 단계 3은 산성용액 하에서 수행될 수 있다.In addition, step 3 of Scheme I may be performed under an acidic solution.
본 발명의 다른 일 측면은, 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체, 수화물, 또는 이의 약학적으로 허용 가능한 염을 제공한다:Another aspect of the present invention provides a compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:
<화학식 2><Formula 2>
(상기 화학식 2에서,(In Formula 2,
X, Y, R
1, R
2, 및 R
3는 상기의 반응식 Ⅰ에서 정의한 바와 같다).X, Y, R 1 , R 2 , and R 3 are as defined in Scheme I above).
바람직하게는, 상기 X는
이고,Preferably, X is ego,
상기 R
6 및 R
7은 서로 연결되어 형성된 8 내지 11원자의 사이클로알킬이고,wherein R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other,
상기 Y는 할로겐일 수 있고,Y may be halogen,
가장 바람직하게는 상기 X는
이고;Most preferably, said X is ego;
상기 Y는 할로겐일 수 있다.Y may be halogen.
본 발명의 또 다른 일 측면은, 하기 반응식 Ⅱ에서 나타난 바와 같이,Another aspect of the present invention, as shown in the following Scheme II,
화학식 5로 표시되는 화합물로부터 화학식 2로 표시되는 화합물을 제조하는 단계를 포함하는, 하기 화학식 2로 표시되는 화합물의 제조방법을 제공한다:It provides a method for preparing a compound represented by the following formula (2), comprising the step of preparing a compound represented by formula (2) from a compound represented by formula (5):
<반응식 Ⅱ><Scheme II>
(상기 반응식 Ⅱ에서,(In Scheme II,
X, Y, R
1, R
2, 및 R
3는 상기 반응식 Ⅰ에서 정의한 바와 같다).X, Y, R 1 , R 2 , and R 3 are as defined in Scheme I above).
바람직하게는, 상기 X는
이고,Preferably, X is ego,
상기 R
6 및 R
7은 서로 연결되어 형성된 8 내지 11원자의 사이클로알킬이고,wherein R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other,
상기 Y는 할로겐일 수 있고,Y may be halogen,
가장 바람직하게는 상기 X는
이고;Most preferably, said X is ego;
상기 Y는 할로겐일 수 있다.Y may be halogen.
본 발명에 따른 화합물의 제조방법은 각 실험 조건에 맞는 용매라면 제한없이 사용될 수 있으며, 예를 들면 테트라하이드로퓨란(THF) 디옥산 에틸에테르, 1,2-다이메톡시에탄 등을 포함하는 에테르용매, 메탄올, 에탄올, 프로판올 및 부탄올을 포함하는 저급 알코올; 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 디클로로메탄(DCM), 디클로로에탄, 물, 아세토나젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 에틸아세테이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시크레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 단독 또는 혼합하여 사용할 수 있다.In the method for preparing the compound according to the present invention, any solvent suitable for each experimental condition may be used without limitation, for example, an ether solvent including tetrahydrofuran (THF) dioxane ethyl ether, 1,2-dimethoxyethane, etc. , lower alcohols including methanol, ethanol, propanol and butanol; Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, acetonazensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenyl Propionate, Phenylbutyrate, Cycrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate These may be used alone or in combination.
이하, 본 발명의 실시예 및 실험예를 하기에 구체적으로 예시하여 설명한다. 다만, 후술하는 실시예 및 실험예는 본 발명의 일부를 예시하는 것일 뿐, 본 발명에 이에 한정되는 것은 아니다.Hereinafter, Examples and Experimental Examples of the present invention will be specifically illustrated and described below. However, the Examples and Experimental Examples to be described below are only illustrative of a part of the present invention, and are not limited thereto.
<실시예 1> [
18F]FBPA 합성을 위한 전구체(A) 합성<Example 1> [ 18 F] Synthesis of precursor (A) for FBPA synthesis
[
18F]FBPA 합성을 위한 전구체의 합성을 아래와 같이 실시하였다. 전체 반응식은 하기 반응식 1과 같다.[ 18 F] The synthesis of a precursor for FBPA synthesis was performed as follows. The overall reaction scheme is as in Scheme 1 below.
<반응식 1><Scheme 1>
단계 1: 4-브로모-2-아이오도-1-메틸벤젠(A-1)의 합성Step 1: Synthesis of 4-bromo-2-iodo-1-methylbenzene (A-1)
5-브로모-2-메틸아닐린을 녹인 아세토나이트릴 용액을 30% 황산 수용액과 섞은 후, 0 ℃에서 드로핑 깔대기(dropping funnel)을 이용하여 소듐 나이트릴 수용액을 천천히 적가하였다. 반응액을 0 ℃에서 1시간 반응한 후, 소듐 아이오다이드 수용액을 추가로 적가하여 상온에서 1시간 동안 반응시켰다. 최종 반응액을 에틸 아세테이트를 이용하여 3회 추출하고, 추출한 유기용액에 브라인과 MgSO
4를 처리하여 수분을 제거하고 농축시킨 후 컬럼 크로마토그래피를 이용하여 정제하여 원하는 화합물 4-브로모-2-아이오도-1-메틸벤젠(
A-1)을 60%의 수율로 얻었다.The acetonitrile solution in which 5-bromo-2-methylaniline was dissolved was mixed with 30% sulfuric acid aqueous solution, and then the sodium nitrile aqueous solution was slowly added dropwise at 0 °C using a dropping funnel. After reacting the reaction solution at 0° C. for 1 hour, an aqueous sodium iodide solution was further added dropwise and reacted at room temperature for 1 hour. The final reaction solution was extracted three times using ethyl acetate, and the extracted organic solution was treated with brine and MgSO 4 to remove moisture, concentrated, and purified using column chromatography to purify the desired compound 4-bromo-2-io Do-1-methylbenzene ( A-1 ) was obtained in a yield of 60%.
1H-NMR (CDCl
3); 7.87 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 2.36 (s, 3H). 1 H-NMR (CDCl 3 ); 7.87 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 2.36 (s, 3H).
단계 2: 4-브로모-1-(브로모메틸)-2-아이오도벤젠(A-2)의 합성Step 2: Synthesis of 4-bromo-1-(bromomethyl)-2-iodobenzene (A-2)
상기 단계 1에서 제조한 화합물
A-1을 녹인 아세토나이트릴 용액에 N-브로모석신이미드와 AIBN(Azobisisobutyronitrile)을 적가한 후 18시간 동안 환류하였다. 반응이 완료된 후 반응액을 셀라이트(celite)를 통과시켜 여과액을 농축하여 컬럼 크로마토그래피를 통해 정제하여 원하는 화합물 4-브로모-1-(브로모메틸)-2-아이오도벤젠(
A-2)를 73%의 수율로 얻었다. N-bromosuccinimide and AIBN (Azobisisobutyronitrile) were added dropwise to an acetonitrile solution in which Compound A-1 prepared in step 1 was dissolved, followed by reflux for 18 hours. After the reaction was completed, the reaction solution was passed through celite, the filtrate was concentrated and purified through column chromatography, and the desired compound 4-bromo-1-(bromomethyl)-2-iodobenzene ( A- 2 ) was obtained in a yield of 73%.
1H-NMR (CDCl
3); 8.01 (d, 1H), 7.47 (dd, 1H), 7.34 (d, 1H), 4.54 (s, 2H) 1 H-NMR (CDCl 3 ); 8.01 (d, 1H), 7.47 (dd, 1H), 7.34 (d, 1H), 4.54 (s, 2H)
단계 3:
tert-뷰틸 (
S)-3-(4-브로모-2-아이오도페닐)-2-((다이페닐메틸렌)아미노) 프로파노에이트(A-3)의 합성Step 3: Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-((diphenylmethylene)amino)propanoate (A-3)
N-다이페닐메틸렌 글라이신 tert-뷰틸 에스테르와 비대칭 상전이 촉매인 Maruoka 촉매를 45% KOH 수용액과 톨루엔 혼합물에 첨가하고, 반응액을 0 ℃로 낮춘 후, 격렬하게 교반하면서 상기 단계 2에서 제조한 화합물
A-2의 톨루엔 용액을 천천히 적가하였다. 반응은 0 ℃에서 18시간 동안 진행하였으며, 반응이 완료된 후 반응액을 디에틸에테르로 총 3회 추출한 유기 층을 브라인과 MgSO
4를 이용하여 수분을 제거한 후, 감압농축하였다. 컬럼 크로마토그래피를 통해 정제하여 원하는 화합물
tert-뷰틸 (
S)-3-(4-브로모-2-아이오도페닐)-2-((다이페닐메틸렌)아미노)- 프로파노에이트(
A-3)를 약 74%의 수율, 94% ee값 (도 10)으로 얻었다.N-diphenylmethylene glycine tert-butyl ester and Maruoka catalyst as an asymmetric phase transfer catalyst were added to a mixture of 45% KOH aqueous solution and toluene, and the reaction solution was lowered to 0 ° C., followed by vigorous stirring, Compound A prepared in step 2 -2 toluene solution was slowly added dropwise. The reaction was carried out at 0° C. for 18 hours, and after the reaction was completed, the organic layer extracted with diethyl ether three times was removed from moisture using brine and MgSO 4 , and then concentrated under reduced pressure. Purification by column chromatography to the desired compound tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-((diphenylmethylene)amino)-propanoate ( A-3 ) was obtained with a yield of about 74%, 94% ee value (FIG. 10).
1H-NMR (DMSO); 7.89 (t, 1H), 7.39 (m, 9H), 7.07 (dd, 1H), 6.52 (s, 2H), 4.15 (m, 1H), 3.17 (m, 2H), 1.36 (s, 9H). 1 H-NMR (DMSO); 7.89 (t, 1H), 7.39 (m, 9H), 7.07 (dd, 1H), 6.52 (s, 2H), 4.15 (m, 1H), 3.17 (m, 2H), 1.36 (s, 9H).
단계 4:
tert-뷰틸 (S)-2-아미노-3-(4-브로모-2-아이오도페닐)프로파노- 에이트(A-4)의 합성Step 4: Synthesis of tert -butyl (S)-2-amino-3-(4-bromo-2-iodophenyl)propanoate (A-4)
상기 단계 3에서 제조한 화합물
A-3의 THF 용액에 30% 시트르산 수용액을 적가하고 상온에서 4시간 동안 반응하였다. 반응 완료 후 반응액을 디에틸에테르로 유기 층을 제거하고, NaHCO
3수용액을 이용하여 물 층의 pH를 중성으로 맞춘 후, 에틸아세테이트를 이용하여 원하는 화합물
tert-뷰틸 (S)-2-아미노-3- (4-브로모-2-아이오도페닐)프로파노에이트(
A-4)를 추출하였다 (3회). 추출한 유기 층을 MgSO
4를 이용하여 수분을 제거하고, 농축한 후 컬럼 크로마토그래피를 통해 원하는 화합물
tert-뷰틸 (S)-2-아미노-3-(4-브로모-2-아이오도페닐)프로파노에이트 (
A-
4)를 32%의 수율, 91%의 ee값 (도 11)으로 얻었다.30% aqueous citric acid solution was added dropwise to the THF solution of Compound A-3 prepared in step 3, and reacted at room temperature for 4 hours. After completion of the reaction, the organic layer of the reaction solution was removed with diethyl ether, the pH of the water layer was adjusted to neutral using an aqueous NaHCO 3 solution, and then the desired compound tert -butyl (S)-2-amino- using ethyl acetate 3- (4-bromo-2-iodophenyl) propanoate ( A-4 ) was extracted (3 times). The extracted organic layer was dried using MgSO 4 , and after concentration, the desired compound tert -butyl (S)-2-amino-3-(4-bromo-2-iodophenyl)prop through column chromatography. Panoate ( A- 4 ) was obtained with a yield of 32% and an ee value of 91% (FIG. 11).
1H-NMR (DMSO); 7.97 (t, 1H), 7.49 (dt, 1H), 7.22 (dd, 1H), 3.41 (ddd, 1H), 2.90 (ddd, 1H), 2.71 (m, 1H), 1.30 (s, 9H). 1 H-NMR (DMSO); 7.97 (t, 1H), 7.49 (dt, 1H), 7.22 (dd, 1H), 3.41 (ddd, 1H), 2.90 (ddd, 1H), 2.71 (m, 1H), 1.30 (s, 9H).
단계 5:
tert-뷰틸 (
S)-3-(4-브로모-2-아이오도페닐)-2-((
tert-뷰톡시카보닐)아미노)- 프로파노에이트(A-5)의 합성Step 5: Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert -butoxycarbonyl)amino)-propanoate (A-5)
상기 단계 4에서 제조한 화합물
A-4의 THF 용액에 Boc
2O와 sat. NaHCO
3 수용액을 첨가하고 상온에서 3시간 반응하였다. 반응이 완결된 후, 반응액을 감압 농축하여 용매를 제거하고, 컬럼 크로마토그래피를 통하여 원하는 화합물
tert-뷰틸 (
S)-3-(4-브로모-2-아이오도페닐)-2-((
tert-뷰톡시카보닐)아미노)프로파노에이트(
A-5)를 61%의 수율, 98%의 ee값 (도 12)으로 얻었다.In the THF solution of compound A-4 prepared in step 4, Boc 2 O and sat. NaHCO 3 aqueous solution was added and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the desired compound tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-((( tert -butoxycarbonyl)amino)propanoate ( A-5 ) was obtained in a yield of 61% and an ee value of 98% (FIG. 12).
1H-NMR (DMSO); 8.01(s, 1H), 7.56(d, 1H), 7.25(d, 1H), 7.22(d, 1H), 4.10 (m, 1H), 3.12(dd, 1H), 2.98(dd, 1H), 1.45(s, 9H), 1.37(s, 9H). 1 H-NMR (DMSO); 8.01(s, 1H), 7.56(d, 1H), 7.25(d, 1H), 7.22(d, 1H), 4.10 (m, 1H), 3.12(dd, 1H), 2.98(dd, 1H), 1.45 (s, 9H), 1.37 (s, 9H).
단계 6:
tert-뷰틸 (
S)-3-(4-브로모-2-아이오도페닐)-2-((
tert-뷰톡시카보닐)
2- 아미노)프로파노에이트(A-6)의 합성Step 6: Synthesis of tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert -butoxycarbonyl) 2 -amino)propanoate (A-6)
상기 단계 5에서 제조한 화합물
A-5의 아세토니트릴 용액에 Boc
2O와 DMAP을 첨가하고 상온에서 5시간 동안 반응하였다. 반응이 완결된 후, 반응액을 감압 농축하여 용매를 제거하고 컬럼 크로마토그래피를 통하여 원하는 화합물
tert-뷰틸 (
S)-3-(4-브로모-2-아이오도페닐)-2-((
tert-뷰톡시카보닐)
2아미노)프로파노에이트(
A-6)를 98%의 수율, 96%의 ee값 (도 13)으로 얻었다.Boc 2 O and DMAP were added to the acetonitrile solution of Compound A-5 prepared in step 5, and reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the desired compound tert -butyl ( S )-3-(4-bromo-2-iodophenyl)-2-(( tert ) was subjected to column chromatography. -Butoxycarbonyl) 2 amino) propanoate ( A-6 ) was obtained in a yield of 98% and an ee value of 96% (FIG. 13).
1H-NMR(DMSO); 8.01(s, 1H), 7.56(d, 1H), 7.02(d, 1H), 5.02(d, 2H), 3.25(dd, 1H), 1.47 (s, 9H), 1.36 (s, 18H). 1 H-NMR (DMSO); 8.01(s, 1H), 7.56(d, 1H), 7.02(d, 1H), 5.02(d, 2H), 3.25(dd, 1H), 1.47 (s, 9H), 1.36 (s, 18H).
단계 7: (
tert-뷰틸
(
S)-3-(4-브로모-2-((4',6'-다이옥소스파이로[트라이사이클로 [5.3.1.1
3,
9]도데케인-10,2'-[1,3]다이옥세인]-5-'일리덴-λ
3-아이오단일)페닐)-2-((
tert-뷰톡시카보닐)아미노)프로파노에이트(A, 전구체)의 합성Step 7: ( tert -butyl ( S )-3-(4-bromo-2-((4',6'-dioxospiro[tricyclo[5.3.1.1 3, 9 ]dodecane-10,2'-[1,3] Synthesis of dioxane]-5-'ylidene-λ 3 -iodanyl)phenyl)-2-(( tert -butoxycarbonyl)amino)propanoate (A, precursor)
상기 단계 6에서 제조한 화합물
A-6의 아세톤 용액에 아세트산을 얼음 욕조 상에서 적가하고 1시간 교반한 후, 상기 단계 7-2에서 제조한 DMDO를 반응액에 적가하고 얼음 욕조를 제거하고 상온에서 3시간 교반하였다. 반응이 완료된 후 반응액 중 용매를 감암 농축하여 제거하고, 남은 반응물을 에탄올에 녹인 용액에 (1r,3r,5r,7r)-spiro[adamantane-2,2'-[1,3]dioxane]-4',6'-dione을 10% Na
2CO
3에 녹인 용액을 적가하고 상온에서 2시간 반응하였다. 두번째 반응이 완료된 후 반응액에 물을 추가하고 메틸렌 클로라이드를 이용하여 전구체를 추출하였다. 추출한 유기층을 브라인과 MgSO
4를 이용하여 건조시킨 후 감압 농축하고, 농축된 반응물을 컬럼 크로마토그래피를 통하여 정제하여 원하는 화합물 (
tert-뷰틸
(
S)-3-(4-브로모-2-((4',6'-다이옥소스파이로[트라이사이클로[5.3.1.1
3,9]도데케인-10,2'-[1,3]다이옥세인]-5-'일리덴-λ
3-아이오단일)페닐)-2-((
tert-뷰톡시카보닐)아미노)프로파노에이트(tert-butyl (S)-3-(4-bromo-2-((4',6'-dioxospiro[tricyclo[5.3.1.13,9]dodecane-10,2'- [1,3]dioxan]-5'-ylidene)-l3-iodanyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate)(
A)를 60%의 수율, 91%의 ee값 (도 14)으로 합성하였다.Acetic acid was added dropwise to the acetone solution of Compound A-6 prepared in step 6 on an ice bath and stirred for 1 hour, then DMDO prepared in step 7-2 was added dropwise to the reaction solution, the ice bath was removed, and the mixture was cooled to 3 time was stirred. After the reaction is complete, the solvent in the reaction solution is removed by concentration under reduced pressure, and the remaining reactant is added to (1r,3r,5r,7r)-spiro[adamantane-2,2'-[1,3]dioxane]- A solution of 4',6'-dione in 10% Na 2 CO 3 was added dropwise and reacted at room temperature for 2 hours. After the second reaction was completed, water was added to the reaction solution, and the precursor was extracted using methylene chloride. The extracted organic layer was dried using brine and MgSO 4 , concentrated under reduced pressure, and the concentrated reaction product was purified through column chromatography to obtain the desired compound ( tert -butyl ( S )-3-(4-bromo-2-((4',6'-dioxospiro[tricyclo[5.3.1.1 3,9 ]dodecane-10,2'-[1,3] dioxane]-5-'ylidene-λ 3 -iodanyl)phenyl)-2-(( tert -butoxycarbonyl)amino)propanoate (tert-butyl (S)-3-(4-bromo-) 2-((4',6'-dioxospiro[tricyclo[5.3.1.13,9]dodecane-10,2'-[1,3]dioxan]-5'-ylidene)-l3-iodanyl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoate)( A ) was synthesized with a yield of 60% and an ee value of 91% (FIG. 14).
1H-NMR (CDCl3); 8.03 (d, 1H), 7.55 (dd, 1H), 7.28 (d, 1H), 4.89 (dd, 1H), 3.80 (dd, 1H), 3.16 (dd, 1H), 2.44 (m, 2H), 2.18 (m, 5H), 1.85 (m, 2H), 1.71 (m, 5H), 1.51 (s, 18H), 1.42 (s, 9H). 1 H-NMR (CDCl3); 8.03 (d, 1H), 7.55 (dd, 1H), 7.28 (d, 1H), 4.89 (dd, 1H), 3.80 (dd, 1H), 3.16 (dd, 1H), 2.44 (m, 2H), 2.18 (m, 5H), 1.85 (m, 2H), 1.71 (m, 5H), 1.51 (s, 18H), 1.42 (s, 9H).
<실시예 2> [
18F]FBPA의 합성<Example 2> Synthesis of [ 18 F]FBPA
[
18F]FBPA 합성을 위한 동위원소 표지 및 붕소 치환반응을 아래와 같이 실시하였다. 전체 3단계의 반응은 one-pot으로 진행되었으며, 전체 반응식은 하기 반응식 2와 같다.[ 18 F] Isotope labeling and boron substitution reaction for the synthesis of FBPA were performed as follows. The reaction of all three steps was carried out in one-pot, and the overall reaction formula is as shown in Reaction Scheme 2 below.
<반응식 2><Scheme 2>
표지합성을 위한 for label synthesis
방사성동위원소([F-18]플루오린 음이온)의of radioisotope ([F-18]fluorine anion)
생산 및 전처리 Production and pretreatment
플루오린-18의 표지 합성을 위하여 필요한 플루오린-18 음이온은 11 MeV 싸이클로트론 (지멘스, 미국)을 이용하여 55uA의 양성자빔을 동위원소 표적 (O-18 water)에 5~30분간 조사하여 얻었으며, 수분을 제거하고 플루오린-18 음이온을 확보하기 위하여 음이온 교환 수지 컬럼 (QMA light Sep-Pak, Waters)을 이용하였다. 음이온 교환 수지 컬럼에 잔존할 수 있는 양이온성 불순물들은 적당량의 3차 증류수를 이용하여 제거하였고, 합성에 이용하기 위하여 상전이 촉매를 포함하는 유기용매를 흘려서 컬럼으로부터 플루오린-18 음이온을 추출하였다.The fluorine-18 anion required for the label synthesis of fluorine-18 was obtained by irradiating a 55uA proton beam to the isotope target (O-18 water) for 5 to 30 minutes using 11 MeV cyclotron (Siemens, USA). , an anion exchange resin column (QMA light Sep-Pak, Waters) was used to remove moisture and secure fluorine-18 anion. Cationic impurities that may remain in the anion exchange resin column were removed by using an appropriate amount of tertiary distilled water, and an organic solvent containing a phase transfer catalyst was flowed to extract the fluorine-18 anion from the column for use in synthesis.
[
18F]FBPA
(2-아미노-3-(4-보로노-2-(플루오로-
18F)페닐)프로피온산(B))의 합성[ 18F] FBPA Synthesis of (2-amino-3-(4-borono-2-(fluoro- 18 F)phenyl)propionic acid (B))
음이온 교환수지 컬럼에서 플루오린-18 음이온은 tetraethylammoium bicarbonate 용액 (2.1 mg in MeOH 700 ul, D.W. 300 ul)을 흘려서 반응 용기(7ml borosilicated tube)에 담았으며, 반응 용기를 110 ℃로 가열하면서 아르곤 가스를 흘려서 물과 아세토니트릴을 증발시켰다. 수분이 충분히 제거되기 위하여 추가로 아세토니트릴 300 ul를 추가하여 건조될 때까지 증발시키고, 같은 과정을 1~2회 반복하여 잔존 수분을 완전히 제거하였다.Fluorine-18 anion in the anion exchange resin column was placed in a reaction vessel (7ml borosilicate tube) by flowing tetraethylammoium bicarbonate solution (2.1 mg in MeOH 700 ul, D.W. 300 ul), and argon gas was heated while heating the reaction vessel to 110 ° C. Water and acetonitrile were evaporated by running. In order to sufficiently remove moisture, an additional 300 ul of acetonitrile was added and evaporated to dryness, and the same process was repeated 1-2 times to completely remove the remaining moisture.
반응용기에 전구체(
A)를 dimethylformamide (300 ul)에 녹여서 반응 용기에 넣은 후, 120 ℃에서 10분간 가열하여 반응하여 B-1을 합성하였다. 1단계 반응의 합성 수율을 확인하기 위하여 반응용액의 소량을 실리카 TLC에 점적가여 n-Hex/EtOAc (10:1) 전개용매로 전개하였고, 방사능 TLC 스캐너 (AR-2000, Apanpack)를 이용하여 방사화학적 순도를 측정하여 부반응이 없이 생성된
B-1의 Rf값이 0.47였으며, 합성수율이 60~70%임을 확인하였다.The precursor ( A ) was dissolved in dimethylformamide (300 ul) in a reaction vessel, put into a reaction vessel, and reacted by heating at 120° C. for 10 minutes to synthesize B-1. In order to confirm the synthesis yield of the first-step reaction, a small amount of the reaction solution was added dropwise to silica TLC, developed with n-Hex/EtOAc (10:1) developing solvent, and radiated using a radioactive TLC scanner (AR-2000, Apanpack). By measuring the chemical purity, it was confirmed that the Rf value of B-1 produced without side reaction was 0.47, and the synthesis yield was 60-70%.
2단계 반응을 위하여, 팔라듐 촉매(Tris(dibenzylideneacetone)dipalladium) 0.64 mg과 P(Cy)3(Tricyclohexylphosphine) 0.39 mg을 DMF 200 ul에 녹이고 열을 가하여 충분히 녹인 뒤에, (Bpin)
2 (4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2- dioxaborolane) 5.9 mg과 potassium acetate 3.65 mg을 DMF 200ul에 녹여서 함께 섞은 뒤에 반응용기에 추가하고, 120℃에서 20분간 가열하여 반응하여
B-2를 합성하였다.For the two-step reaction, 0.64 mg of a palladium catalyst (Tris(dibenzylideneacetone)dipalladium) and 0.39 mg of P(Cy)3(Tricyclohexylphosphine) were dissolved in 200 ul of DMF and sufficiently dissolved by heating, (Bpin) 2 (4,4, 4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane) 5.9 mg and potassium acetate 3.65 mg were dissolved in 200ul of DMF and mixed together, followed by a reaction vessel was added and reacted by heating at 120° C. for 20 minutes to synthesize B-2 .
[
18F]FBPA를 합성하기 위한 최종단계인 3단계 반응을 위하여, 진한 염산 100 ul를 DMF 200 ul에 혼합하여 반응용기에 추가하고 120 ℃에서 10분간 가열하여 가수분해 반응을 하였고, 가수분해 전환율을 확인하기 위하여 반응용액의 일부를 취하여 실리카 TLC에 점적가고 nBuOH/DW/AcOH (12:3:5) 혼합용액으로 전개하여 Rf값이 0.434인 [
18F]FBPA가 대부분 생성되었음을 확인하였다.[ 18 F] For the three-step reaction, which is the final step for synthesizing FBPA, 100 ul of concentrated hydrochloric acid was mixed with 200 ul of DMF, added to the reaction vessel, and heated at 120 ° C. for 10 minutes for hydrolysis reaction, hydrolysis conversion rate To confirm , a portion of the reaction solution was taken and dropped onto silica TLC, and developed with a mixed solution of nBuOH/DW/AcOH (12:3:5). It was confirmed that most of [ 18 F]FBPA with an Rf value of 0.434 was produced.
3단계 결과물인 [
18F]FBPA를 정제하기 위하여, 반응용액에 0.1% TFA 수용액 1.3 ml을 추가하여 희석한 후, HPLC에 주입하고 5% 아세토니트릴 수용액 (0.1% TFA water)으로 4ml/min의 유속으로 흘려서 분리되어 용출되는 [18F]FBPA를 분취하였다. 용출시간은 9~11분 사이였으며, UV 파장은 254nm를 사용하였고, 방사성화합물의 검출은 UV와 나란히 설치된 감마선검출기를 이용하였다. 정제된 [
18F]FBPA 분취액은 3차 증류수 30 ml에 희석하여 역상 컬럼 카트리지(C-18 Sep-Pak, waters)에 흘려주어 용매를 제거하였으며, 3차 증류수 10 ml을 추가로 흘려주어 잔존 용매를 충분히 제거하였고, 에탄올 1 ml과 생리식염수 9 ml을 순차적으로 흘려서 [
18F]FBPA를 추출하고, 무균필터 (Millex GV, Waters)에 용액을 통과시켜서 무균바이알에 담았다.To purify [ 18 F]FBPA, the result of step 3, add 1.3 ml of 0.1% TFA aqueous solution to the reaction solution and dilute it, then inject it into HPLC and use 5% acetonitrile aqueous solution (0.1% TFA water) at 4ml/min. [ 18 F]FBPA separated and eluted by flowing at a flow rate was collected. The elution time was between 9 and 11 minutes, the UV wavelength was 254 nm, and a gamma ray detector installed in parallel with the UV was used for detection of radioactive compounds. The purified [ 18 F]FBPA aliquot was diluted in 30 ml of tertiary distilled water and flowed through a reversed-phase column cartridge (C-18 Sep-Pak, waters) to remove the solvent, and the remaining 10 ml of tertiary distilled water was additionally flowed. The solvent was sufficiently removed, and [ 18 F]FBPA was extracted by sequentially flowing 1 ml of ethanol and 9 ml of physiological saline, and the solution was passed through a sterile filter (Millex GV, Waters) and put into a sterile vial.
최종적으로 합성이 완료된 화합물의 방사화학적 수율(비감쇠보정)은 약 10% 였으며, 약 150 mCi의 플루오린-18 음이온으로 합성을 시작할 경우, 약 16 mCi의 [
18F]FBPA를 얻을 수 있었으며, 전체 합성시간은 약 2시간이었다.The radiochemical yield (non-attenuation correction) of the finally synthesized compound was about 10%, and when the synthesis was started with about 150 mCi of fluorine-18 anion, about 16 mCi of [ 18 F]FBPA could be obtained, The total synthesis time was about 2 hours.
이를 통해 상기 실시예 1에 따라 제조한 t-butyl기가 치환된 카복실기를 갖는 전구체를 이용함으로써, 우수한 수율 및 이성질체 순도로 [
18F]FBPA를 제조할 수 있음을 확인하였다.Through this, it was confirmed that [ 18 F]FBPA could be prepared with excellent yield and isomeric purity by using the precursor having a carboxyl group substituted with a t-butyl group prepared according to Example 1.
합성 및 정제를 마친 최종 결과물인 [
18F]FBPA는 방사화학적 순도, 비방사능 등의 품질관리를 실시하였다.[ 18 F]FBPA, the final product after synthesis and purification, was subjected to quality control such as radiochemical purity and specific activity.
<실험예 1> 전구체를 이용한 3 단계 플루오린-18 표지반응<Experimental Example 1> 3-step fluorine-18 labeling reaction using a precursor
플루오린-18을 표지하여 최종적으로 [
18F]FBPA를 합성하는 과정은 총 3단계로 이루어졌으며, 각 단계마다 방사능 박막크로마토그래피 (radio-TLC)를 이용하여 방사화학적 변환율 (단계수율)을 측정하였다. 일반 TLC와 거의 유사한 방법으로 분석이 이루어지며, 방사능 물질의 성분 분석이므로, 유리박막에 분포하는 방사성물질들을 분석하는 radio-TLC scanner (AR2000, Bioscan)을 이용하였다. 사용된 유리 박막은 실리카겔이 도포된 가로 1cm, 세로 10cm 크기의 박막 플레이트를 사용하였고, 각 단계마다 반응용액을 별도의 처리없이 원액 약 1 ul를 유리 미세관을 이용하여 플레이트 원점에 점적하고 단계마다 적합한 전개 조건을 사용하여 전개 및 분석하였다.The process of finally synthesizing [ 18 F]FBPA by labeling fluorine-18 consisted of a total of three steps, and radiochemical conversion rate (step yield) was measured using radioactive thin film chromatography (radio-TLC) at each step. did Analysis is performed in a method almost similar to general TLC, and since it is a component analysis of radioactive materials, a radio-TLC scanner (AR2000, Bioscan) that analyzes radioactive materials distributed in the glass thin film was used. The glass thin film used was a thin film plate with a size of 1 cm in width and 10 cm in length coated with silica gel, and at each stage, about 1 ul of the stock solution was dripped at the origin of the plate using a glass microtube without separate treatment of the reaction solution, and at each stage. Appropriate development conditions were used for development and analysis.
먼저, TEAB(tetraethylammonium bicarbonate)를 이용하여
18F를 도입한 상기 실시예 2의 1 단계 반응의 radio-TLC(전개조건; n-Hex:EtOAc=10:1)를 이용하여 분석한 결과를 도 1에 나타내었다. 측정 결과, 원점(60 mm)에 해당하는 성분은 전개조건에서 전개되지 않는(Rf = 0) 플루오린-18 음이온이고, 반응결과물은 약 70%가 생성됨을 확인하였다.First, using TEAB (tetraethylammonium bicarbonate) to introduce 18 F using radio-TLC (development conditions; n-Hex:EtOAc = 10:1) of the first-step reaction of Example 2, the result of analysis is shown in Figure 1 shown in As a result of the measurement, it was confirmed that the component corresponding to the origin (60 mm) was a fluorine-18 anion that did not develop under the developing conditions (Rf = 0), and about 70% of the reaction product was generated.
다음으로, Pd
2(dba)
3 (Tris(dibenzylideneacetone)dipalladium(0))와 (BPin)
2 (Bis(pinacolato)diboron)를 이용하여 붕산기를 도입한 상기 실시예 2의 2 단계 반응의 radio-TLC(전개조건; n-Hex:EtOAc=10:1)를 이용하여 분석한 결과를 도 2에 나타내었다. 측정 결과, 같은 전개 조건에서 Rf값이 0.4인 1단계 결과물이 모두 사라지고, 두번째 결과물이 생성되었음을 확인하였다. 방사화학적 변환율은 TLC결과에 근거하여 90%이상의 고효율임을 확인하였다.Next, Pd 2 (dba) 3 (Tris (dibenzylideneacetone) dipalladium (0)) and (BPin) 2 (Bis (pinacolato) diboron) using a boric acid group was introduced using the radio-TLC of the two-step reaction of Example 2 (Development condition; n-Hex:EtOAc=10:1) The results of the analysis are shown in FIG. 2 . As a result of the measurement, it was confirmed that all of the first-stage results with an Rf value of 0.4 disappeared under the same development conditions, and a second result was generated. It was confirmed that the radiochemical conversion rate was more than 90% high efficiency based on the TLC result.
다음으로, 염산을 이용하여 보호기를 가수분해한 상기 실시예 2의 3 단계 반응의 radio-TLC(전개조건 1; n-Hex:EtOAc=10:1)를 이용하여 분석한 결과를 도 3에 나타내었다. 3단계 반응의 전개 결과, 1,2단계 반응에서 사용한 전개 조건에서 1,2단계 결과물이 모두 다 사라진 것을 확인하였다 (즉, 가수분해 반응의 방사화학적 변환율은 100%에 가깝다). 동일 전개 조건에서는 화합물이 원점에 포함되어 플루오린-18과 구분이 안되므로, 별도의 전개 조건에서 분석이 필요하다.Next, FIG. 3 shows the results of analysis using radio-TLC (development condition 1; n-Hex:EtOAc=10:1) of the three-step reaction of Example 2 in which the protecting group was hydrolyzed using hydrochloric acid. it was As a result of the development of the three-step reaction, it was confirmed that all the products of the first and second steps disappeared under the development conditions used in the first and second steps (that is, the radiochemical conversion rate of the hydrolysis reaction is close to 100%). Under the same development conditions, the compound is included at the origin and cannot be distinguished from fluorine-18, so analysis is required under separate development conditions.
다음으로, 염산을 이용하여 보호기를 가수분해한 상기 실시예 2의 3 단계 반응의 radio-TLC(전개조건 2; nBuOH:DW:AcOH=12:3:5)를 이용하여 분석한 결과를 도 4에 나타내었다. 두번째 전개조건으로 분석한 결과, 1 단계 반응에서 참여하지 않은 플루오린-18 음이온이 그대로 남아있는 것을 확인하였고, 가수분해가 일어난 최종결과물인 [
18F]FBPA가 Rf값 0.564에서 확인되었다. 마지막 단계의 반응 혼합물은 HPLC를 이용하여 분리 정제를 하고, anal-HPLC에서 분석하여 최종 순도 및 성분 분석 (co-injection을 통한 FBPA 성분 확인)이 이루어졌다.Next, FIG. 4 shows the results of analysis using radio-TLC (development condition 2; nBuOH:DW:AcOH=12:3:5) of the three-step reaction of Example 2 in which the protecting group was hydrolyzed using hydrochloric acid. shown in As a result of the second development condition, it was confirmed that the fluorine-18 anion not participating in the first-step reaction remained as it is, and [ 18 F]FBPA, the final product of which hydrolysis occurred, was confirmed at an Rf value of 0.564. The reaction mixture in the last step was separated and purified using HPLC, and analyzed by anal-HPLC to obtain final purity and component analysis (confirmation of FBPA components through co-injection).
다음으로, 염산을 이용하여 보호기를 가수분해한 상기 실시예 2의 3단계 반응의 카이랄(chiral) HPLC (CrownPak® CR(+), 60% aq. HClO4 : DW = 1:250)를 이용하여 분석한 결과를 도 9에 나타내었다. 본 분석조건을 통하여 최종결과물인 [18F]FBPA의 입체화학순도가 89% (L-FBPA : D-FBPA의 비율이 약 16:1)임을 확인하였다.Next, using chiral HPLC (CrownPak® CR(+), 60% aq. HClO4: DW = 1:250) of the three-step reaction of Example 2 in which the protecting group was hydrolyzed using hydrochloric acid The results of the analysis are shown in FIG. 9 . Through this analysis condition, it was confirmed that the stereochemical purity of the final product, [18F]FBPA, was 89% (L-FBPA : D-FBPA ratio of about 16:1).
<실험예 2> FBPA 표준 시료 합성<Experimental Example 2> FBPA standard sample synthesis
플루오린-18 표지합성을 통해 얻어진 [
18F]FBPA의 성분 확인을 위해서는 비방사성물질인 FBPA 표준물질이 필요하다. FBPA는 유기합성을 통해 얻을 수 있으며, NMR 분석을 통해 화합물의 구조를 규명하였다. HPLC 성분 분석 확인을 위한 FBPA 표준시료는 아래와 같이 합성하였으며, 전체 반응식은 하기 반응식 3과 같다.In order to identify the components of [ 18 F]FBPA obtained through fluorine-18 labeling synthesis, a non-radioactive material, FBPA standard material is required. FBPA can be obtained through organic synthesis, and the structure of the compound was identified through NMR analysis. The FBPA standard sample for checking the HPLC component analysis was synthesized as follows, and the overall reaction formula is shown in Scheme 3 below.
<반응식 3><Scheme 3>
단계 1: test-부틸 3-(4-브로모-2-플루오로페닐)-2-((다이페닐메틸렌)아미노) 프로파노에이트(C
-1)의 합성Step 1: Synthesis of test-butyl 3-(4-bromo-2-fluorophenyl)-2-((diphenylmethylene)amino)propanoate (C - 1)
둥근 바닥 플라스크에 N-다이페닐메틸렌 글라이신 tert-부틸 에스테르, 상전이 촉매인 테트라부틸암모늄 브로마이드, 포타슘 하이드록사이드를 넣고 톨루엔에 녹인 후, 상온에서 2-플루오로-4-브로모벤질브로마이드를 천천히 적가하였다. 반응액을 상온에서 16시간 반응한 후, 최종반응액을 에틸 아세테이트로 희석하고 물로 과량의 반응물과 부산물을 제거한 후, 남은 유기용액에 브라인과 MgSO
4를 처리하여 수분을 제거하고 농축시킨 후 컬럼 크로마토그래피를 이용하여 정제하여 원하는 화합물 test-부틸 3-(4-브로모-2-플루오로페닐)-2-((다이페닐메틸렌) 아미노)프로파노에이트(C
-1)를 96%의 수율로 얻었다. In a round bottom flask, put N-diphenylmethylene glycine tert-butyl ester, tetrabutylammonium bromide, a phase transfer catalyst, and potassium hydroxide, dissolved in toluene, and then slowly added 2-fluoro-4-bromobenzyl bromide dropwise at room temperature. did After the reaction solution was reacted at room temperature for 16 hours, the final reaction solution was diluted with ethyl acetate, excess reactants and by-products were removed with water, and the remaining organic solution was treated with brine and MgSO 4 to remove moisture and concentrated, followed by column chromatography. The desired compound test-butyl 3-(4-bromo-2-fluorophenyl)-2-((diphenylmethylene)amino)propanoate (C - 1) was purified using a graph in a yield of 96% got it
1H-NMR (DMSO); 7.39 (m, 9H), 7.26 (m, 1H), 7.12 (dd, 1H), 6.70 (d, 2H), 4.02 (dd, 1H), 3.11 (dd, 1H), 3.00 (m, 1H), 1.32 (s, 9H). 1 H-NMR (DMSO); 7.39 (m, 9H), 7.26 (m, 1H), 7.12 (dd, 1H), 6.70 (d, 2H), 4.02 (dd, 1H), 3.11 (dd, 1H), 3.00 (m, 1H), 1.32 (s, 9H).
단계 2: tert-부틸 2-(비스(tert-부톡시카보닐)아미노)-3-2-플루오로-4-(4,4,5,5- 테트라메틸-1,3,2-다이옥사보로라-2-닐)페닐)프로파노에이트(C-2)의 합성Step 2: tert-Butyl 2-(bis(tert-butoxycarbonyl)amino)-3-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Synthesis of lora-2-yl)phenyl)propanoate (C-2)
둥근 바닥 플라스크에 상기 단계 1에서 제조한 화합물
C-1과 팔라듐 금속 촉매 (Pd(dppf)Cl
2)와 포타슘 아세테이트와 비스(피나콜라도)다이보론을 넣고 아르곤 기체 하에서 DMSO를 적가하였다. 반응액을 섭씨 100도에서 24시간 반응한 후, 최종반응액을 에틸 아세테이트로 희석하고 물로 과량의 반응물과 부산물을 제거한 후, 남은 유기용액에 브라인과 MgSO
4를 처리하여 수분을 제거하고 농축시킨 후 컬럼 크로마토그래피를 이용하여 정제하여 원하는 화합물 tert-부틸 2-(비스(tert-부톡시카보닐)아미노)-3-2-플루오로-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사-보로라-2-닐)페닐)프로파노에이트(C-2)를 54%의 수율로 얻었다. Compound C-1 prepared in step 1, palladium metal catalyst (Pd(dppf)Cl 2 ), potassium acetate, and bis(pinacolado)diboron were placed in a round bottom flask, and DMSO was added dropwise under argon gas. After the reaction solution was reacted at 100 degrees Celsius for 24 hours, the final reaction solution was diluted with ethyl acetate, excess reactants and by-products were removed with water, and the remaining organic solution was treated with brine and MgSO 4 to remove moisture and concentrated. Purification using column chromatography to tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-3-2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxa-borola-2-yl)phenyl)propanoate (C-2) was obtained in a yield of 54%.
1H-NMR (DMSO); 7.36 (m, 9H), 7.16 (m, 2H), 6.64 (d, 2H), 4.04 (t, 1H), 3.17 (d, 1H), 3.03 (m, 1H), 1.32 (s, 9H), 1.25 (s, 12H). 1 H-NMR (DMSO); 7.36 (m, 9H), 7.16 (m, 2H), 6.64 (d, 2H), 4.04 (t, 1H), 3.17 (d, 1H), 3.03 (m, 1H), 1.32 (s, 9H), 1.25 (s, 12H).
단계 3: 2-아미노-3-(4-보로노-2-플루오로페닐)프로피온산(DL-FBPA)의 합성Step 3: Synthesis of 2-amino-3-(4-borono-2-fluorophenyl)propionic acid (DL-FBPA)
상기 단계 2에서 제조한 화합물 C-2를 에탄올에 녹인 후, 3M 염산 수용액을 추가하고 12시간 동안 환류 반응을 수행하였다. 반응이 완결된 후 반응액을 감압 농축하여 과량의 용액과 부산물을 제거하였다. 얻어진 반응물을 상온에서 이소-프로판올에 녹이고 프로필렌옥사이드를 적가하여 2시간 교반하였으며, 이를 통해 얻어진 흰색 고체를 에틸에테르를 이용하여 여과하여 원하는 최종화합물 DL-FBPA를 약 80%의 수율로 얻었다.After dissolving the compound C-2 prepared in step 2 in ethanol, 3M aqueous hydrochloric acid was added thereto, and a reflux reaction was performed for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove excess solution and by-products. The obtained reactant was dissolved in iso-propanol at room temperature, propylene oxide was added dropwise, and stirred for 2 hours. The white solid thus obtained was filtered using ethyl ether to obtain the desired final compound DL-FBPA in a yield of about 80%.
1H-NMR (D
2O); 7.39 (d, 1H), 7.33 (d, 1H), 7.22 (dd, 1H), 4.09 (dd, 1H), 3.27 (dd, 1H), 3.10 (dd, 1H). 1 H-NMR (D 2 O); 7.39 (d, 1H), 7.33 (d, 1H), 7.22 (dd, 1H), 4.09 (dd, 1H), 3.27 (dd, 1H), 3.10 (dd, 1H).
<실험예 3> 자동합성장치를 이용한 [
18F]FBPA의 합성<Experimental Example 3> Synthesis of [ 18 F]FBPA using an automatic synthesizer
높은 방사능(100 mCi 이상)의 [
18F]FBPA 합성을 실시하기 위하여 자동합성장치를 이용하였다. 자동합성장치는 HPLC 분리 정제를 제외한 모든 과정이 프로그램된 순서에 따라 합성을 수행하는 장치이며, 여기서는 범용성 F-18 자동합성장치인 Flexlab (iPhase, AUS)을 사용하였다. 반응 순서는 아래와 같다.An automatic synthesizer was used to perform the synthesis of [ 18 F]FBPA with high radioactivity (over 100 mCi). The automatic synthesis apparatus is an apparatus that performs synthesis according to the programmed sequence except for HPLC separation and purification, and here, Flexlab (iPhase, AUS), a general-purpose F-18 automatic synthesis apparatus, was used. The reaction sequence is as follows.
1. 반응기 1에 Ar 가스를 가압함. Ar가스가 압력 테스트 수행1. Pressurized Ar gas in Reactor 1. Ar gas pressure test
2. 반응기 1의 라인은 차단함. 압력 누출 테스트 수행2. Shut off the line in Reactor 1. Perform a pressure leak test
3. 반응기 1에 Ar 가스를 가압함. 3. Pressurized Ar gas in Reactor 1.
4. 바이알1에 1.1mL TEAB (25ul), MeOH(0.8mL), H2O(0.5mL)로드함 4. Load vial 1 with 1.1mL TEAB (25ul), MeOH (0.8mL), HO (0.5mL)
5. 0.6mL DMF의 4mg 전구체를 바이알 2에 넣음.5. Add 4mg precursor of 0.6mL DMF to vial 2.
6. 바이알 3에 0.8mL ACN을 넣음. 6. Add 0.8mL ACN to vial 3.
7. 바이알 4에 0.8mL ACN을 넣음. 7. Add 0.8mL ACN to vial 4.
8. 바이알 5에 1mL 2N HCl 로드함.8. Load vial 5 with 1 mL 2N HCl.
9. 2 단계 시약 준비 : 100 °C 3 분에서 A를 가열하고 A에서 B로 혼합9. Step 2 Reagent Preparation: Heat A at 100 °C 3 min and mix A to B
10. A : Pd2dba3_2.62mg + PCy3_400ul (8.1mg / DMF2ml)10. A: Pd2dba3_2.62mg + PCy3_400ul (8.1mg/DMF2ml)
11. B : BPin2_23.6mg + AcOK_100ul (9.82g / 50mlDW)11. B: BPin2_23.6mg + AcOK_100ul (9.82g / 50mlDW)
12. 바이알 2에 전구체가 포함 된 DMF 0.6mL을 로드함12. Load 0.6 mL of DMF with precursor into vial 2.
13. 중간 바이알1에 1.8mL HPLC 버퍼를 로드함13. Load 1.8 mL HPLC buffer into intermediate vial 1.
14. 바이알15에 1mL HPLC 버퍼로드함14. Vial 15 was loaded with 1 mL HPLC buffer.
15. EtOH 및 D.W로 HPLC 플라스크 2를 세척함.15. Wash HPLC flask 2 with EtOH and D.W.
16. Sep-pak없이 SPE-A를 설치함.16. Install SPE-A without Sep-pak.
17. Sep-pak없이 SPE-C를 설치함.17. Install SPE-C without Sep-pak.
18. NaHCO
3로 전처리된 QMA 카트리지 설치함.18. Installed QMA cartridge pretreated with NaHCO 3 .
19. HPLC 용리액 A 확인함 = 식염수 1L (1 % EtOH, 0.01 % AcOH)19. Check HPLC Eluent A = 1L saline (1 % EtOH, 0.01 % AcOH)
20. 최종 화합물 수집 바이알 연결함20. Connect the final compound collection vial
21. 시약이 든 바이알을 가압함.21. Pressurize the vial containing the reagent.
22. 시약이 든 바이알에서 압력 누출을 학인함 22. Check for pressure leaks from vials containing reagents
23. 압력 테스트 시약 약병 사이클로트론에서 F- 준비함. 23. F-prepared in the pressure test reagent vial cyclotron.
24. F- 전송시 NEXT를 누름.24. Press NEXT for F-transmission.
25. F-를 QMA에 흡착함.25. Adsorption of F- to QMA.
26. 반응기 1 로 QMA의 F-를 용리함.26. Elution F- of QMA into reactor 1.
27. F- 건조 (가스 + 진공) 함.27. F- Dry (gas + vacuum).
28. F- 건조 (진공 만 해당) 함.28. F-Dry (vacuum only).
29. 반응기 1에 0.8mL ACN을 (바이알 3)의 첨가.29. Addition of 0.8mL ACN (vial 3) to Reactor 1.
30. F- 건조 (가스 + 진공) 함.30. F-dry (gas + vacuum).
31. 불소 건조 (진공 만 해당)함. 31. Fluoride dry (vacuum only).
32. 반응기 1에 0.8mL ACN을 (바이알 4)의 첨가함.32. Add 0.8mL ACN (vial 4) to reactor 1.
33. 불화 건조 (가스 + 진공)33. Fluoride drying (gas + vacuum)
34. 불소 건조 (진공 만 해당)34. Fluoride Drying (Vacuum Only)
35. 반응기 1 냉각함35. Reactor 1 Cooling Box
36. 반응기 1에 0.6mL DMF의 4mg 전구체(바이알 2)의 첨가36. Addition of 4 mg precursor (vial 2) in 0.6 mL DMF to Reactor 1
37. 라벨링 반응 137. Labeling Reaction 1
38. 반응기 1 냉각함38. Reactor 1 Cooling Box
39. 반응기 1에 2 단계 시약 (바이알 17) 추가39. Add Step 2 Reagent (Vial 17) to Reactor 1
40. 붕소화 반응 240. Boronation 2
41. 반응기 1 냉각함41. Reactor 1 Cooling Box
42. 반응기 1에 1mL 2N HCl (바이알 5) 첨가함42. Add 1mL 2N HCl (vial 5) to Reactor 1
43. 가수 분해 반응함43. Hydrolytic reaction
44. DMF 건조 (가스 + 진공) 함44. DMF drying (gas + vacuum)
45. DMF 건조 (진공만) 함45. DMF dry (vacuum only)
46. 반응기 1 냉각함 46. Reactor 1 Cooling Box
47. 반응기 1에 HPLC 용매 1ml (바이알 15) 추가함47. Add 1ml HPLC solvent (vial 15) to reactor 1
48. 반응기 1에서 중간 바이알 1로 옮김. 48. Transfer from Reactor 1 to Intermediate Vial 1.
49. HPLC 루프에 주입-유체 검출기 대기 1 켬.49. Inject-Fluid Detector Standby 1 on HPLC Loop.
50. HPLC 루프에 주입-유체 검출기 대기 1 끔.50. Inject into HPLC loop - turn off fluid detector standby 1
51. HPLC 컬럼 1에 반응화합물 주입51. Injection of reaction compound into HPLC column 1
52. 플라스크 2에 HPLC 피크를 수집함. 사용자 수동 조작.52. Collect HPLC peak in flask 2. User manual operation.
-피크 수집을 중지.-Stop collecting peaks.
53. 멸균 바이알에 화합물 넣기53. Putting Compounds into Sterile Vials
54. 최종 멸균 바이알에 전송하기54. Transfer to terminal sterile vials
55. HPLC 중지55. Stop HPLC
56. 합성 종료56. End of Compositing
<실험예 4> [
18F]FBPA 용액의 방사화학적 순도 측정 및 성분 확인<Experimental Example 4> [ 18 F] Measurement of radiochemical purity of FBPA solution and confirmation of components
4-1. 분석 HPLC 결과4-1. Analytical HPLC results
방사화학적 순도를 측정하기 위하여 HPLC를 이용하였으며, 최종적으로 얻어진 화합물 소량(20 ul)을 취하여 HPLC에 주입하였다. HPLC 전개용매는 5% 아세토니트릴 (0.1% TFA 수용액)이었고, 1 ml/min의 유속으로 흘려주었으며, 유기 이물질을 검출하기 위하여 UV 검출기를 사용하고, 방사성 유기물을 검출하기 위하여 감마선 검출기(2x2” Nal scintillation detector)를 UV 검출기와 나란히 사용하였다. 사용된 컬럼은 C18 컬럼 (4.6x250 mm, Agilent)을 사용하였으려, UV 검출 파장은 254 nm, 감마선 검출 에너지 대역은 100~700 keV였다. 시료를 분석한 결과 [
18F]FBPA의 방사화학적 순도는 95퍼센트 이상이었으며, 통상적으로 PET에서 허용되는 방사화학적 순도의 기준치에 적합하였다.HPLC was used to measure the radiochemical purity, and a small amount (20 ul) of the finally obtained compound was taken and injected into the HPLC. The HPLC developing solvent was 5% acetonitrile (0.1% TFA aqueous solution), and it was flowed at a flow rate of 1 ml/min. A UV detector was used to detect organic foreign substances, and a gamma ray detector (2x2” Nal) was used to detect radioactive organic substances. scintillation detector) was used alongside the UV detector. The column used was a C18 column (4.6x250 mm, Agilent), with a UV detection wavelength of 254 nm and a gamma-ray detection energy band of 100-700 keV. As a result of analyzing the sample, the radiochemical purity of [ 18 F]FBPA was 95% or more, and it was suitable for the standard value of radiochemical purity that is generally accepted in PET.
4-2. 표준시료와의 co-injection을 진행한 분석 HPLC 결과4-2. Analytical HPLC result of co-injection with standard sample
최종 결과물이 FBPA 표준 시료와 일치하는지 여부를 확인하기 위하여, 합성된 결과물의 용액과 표준시료 용액 (1 mg/1ml)을 혼합하여 HPLC 분석을 하였으며, UV에서 검출되는 [
19F]FBPA(비방사능 물질) 피크와 감마선 검출기에서 검출되는 [
18F]FBPA 피크가 거의 동일한 용출 시간에 나타나는 것을 확인하였다. 그 결과를 도 5 및 도 6에 나타내었다.In order to check whether the final product is consistent with the FBPA standard sample, the solution of the synthesized product and the standard sample solution (1 mg/1ml) were mixed for HPLC analysis, and [ 19 F]FBPA (non-radioactive) detected in UV It was confirmed that the [ 18 F]FBPA peak detected by the material) peak and the gamma-ray detector appeared at almost the same elution time. The results are shown in FIGS. 5 and 6 .
4-3. 표준 시료의 정량선을 이용한 비방사능의 측정 결과4-3. Measurement result of specific radioactivity using quantitative line of standard sample
표준 시료 (FBPA)를 500, 250, 50, 25ppm의 농도로 준비하여 분석 HPLC에서 각각의 흡광도를 측정하여 정량선을 그렸다. 정량선을 통해 농도에 대한 UV 흡광도를 계산할 수 있으며, 자동합성장치를 이용하여 합성된 [
18F]FBPA 용액의 비방사능을 구한 결과 최소 10 Ci/umol 이상의 값을 가지는 것으로 확인하였다. 최종 화합물의 분석 HPLC 데이터에서 6~8분 사이의 FBPA 피크는 검출한계치 이하이므로, 분석이 불가능할 정도로 매우 높은 비방사능을 가짐을 확인하였다.A standard sample (FBPA) was prepared at concentrations of 500, 250, 50, and 25 ppm, and each absorbance was measured in analytical HPLC to draw a quantitative line. The UV absorbance for concentration can be calculated through the quantitative line, and the specific radioactivity of the synthesized [ 18 F]FBPA solution using an automatic synthesis device was found to have a value of at least 10 Ci/umol or more. In the analysis HPLC data of the final compound, the FBPA peak between 6 and 8 minutes was below the detection limit, so it was confirmed that it had a very high specific radioactivity to the extent that analysis was impossible.
이상, 본 발명을 바람직한 제조예, 실시예 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특성 실시예에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.As mentioned above, although the present invention has been described in detail through preferred preparation examples, examples and experimental examples, the scope of the present invention is not limited to the characteristic examples, and should be interpreted by the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.
Claims (9)
- 하기 반응식 Ⅰ에서 나타난 바와 같이,As shown in Scheme I below,화학식 2로 표시되는 화합물로부터 화학식 3으로 표시되는 화합물을 제조하는 단계(단계 1);preparing a compound represented by Formula 3 from the compound represented by Formula 2 (Step 1);상기 단계 1에서 제조한 화학식 3으로 표시되는 화합물로부터 화학식 4로 표시되는 화합물을 제조하는 단계(단계 2); 및preparing a compound represented by formula 4 from the compound represented by formula 3 prepared in step 1 (step 2); and상기 단계 2에서 제조한 화학식 4로 표시되는 화합물로부터 화학식 1로 표시되는 화합물을 제조하는 단계(단계 3);를 포함하는, 화학식 1로 표시되는 방사성 동위원소를 포함하는 화합물의 제조방법:Preparing a compound represented by Formula 1 from the compound represented by Formula 4 prepared in Step 2 (step 3); Method for producing a compound containing a radioactive isotope represented by Formula 1, including:<반응식 Ⅰ><Scheme I>
(상기 반응식 1에서,(In Scheme 1,상기 X는이고,wherein X is
ego,상기 R 4 및 R 5는 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C 1- 20알킬, 직쇄 또는 분지쇄의 C 1- 5알콕시, 비치환 또는 치환된 C 6- 10아릴, 또는 R 4과 R 5가 서로 연결되어 형성된이고,R 4 and R 5 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight - chain or branched C 1-20 alkyl, straight - chain or branched C 1-5 alkoxy, unsubstituted or substituted C 6-10 aryl, or R 4 and R 5 are linked to each other
ego,상기 R 6 및 R 7은 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C 1- 20알킬, 직쇄 또는 분지쇄의 C 1- 5알콕시, 또는 R 6 및 R 7가 서로 연결되어 형성된 3 내지 15원자의 사이클로알킬이고,wherein R 6 and R 7 are each independently —H, halogen, unsubstituted or one or more halogen - substituted straight or branched C 1-20 alkyl , straight or branched C 1-5 alkoxy, or R 6 and R 7 is a 3 to 15 membered cycloalkyl formed by connecting to each other,상기 치환된 C 6- 10아릴은 C 1-5의 직쇄 또는 분지쇄 알킬, C 1-5의 직쇄 또는 분지쇄 알킬카보닐, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C 6- 10아릴이고; The substituted C 6-10 aryl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, and at least one heteroatom selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-10 aryl ;상기 Y는 -H, 할로겐, -N 2 +, -NO 2, -CN, 직쇄 또는 분지쇄의 C 1- 5알콕시이고;Y is -H, halogen, -N 2 + , -NO 2 , -CN, straight -chain or branched C 1-5 alkoxy ;상기 R 1 및 R 2는 각각 독립적으로 -H, 또는 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이고;wherein R 1 and R 2 are each independently —H, or t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- an amine protecting group selected from the group consisting of trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc);상기 R 3은 수소, 직쇄 또는 분지쇄의 C 1- 10알킬, 또는 직쇄 또는 분지쇄의 C 1-10알킬이 치환된 페닐이다).wherein R 3 is hydrogen, a linear or branched C 1-10 alkyl , or a phenyl substituted with a straight or branched C 1-10 alkyl). - 제1항에 있어서,According to claim 1,상기 X는이고,wherein X is
ego,상기 R 4 및 R 5는 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C 1- 10알킬, 직쇄 또는 분지쇄의 C 1- 3알콕시, 비치환 또는 치환된 C 6- 8아릴, 또는 R 4과 R 5가 서로 연결되어 형성된이고,R 4 and R 5 are each independently -H, halogen, unsubstituted or one or more halogen-substituted straight-chain or branched C 1-10 alkyl, straight - chain or branched C 1-3 alkoxy , unsubstituted or substituted C 6-8 aryl, or R 4 and R 5 are linked to each other
ego,상기 R 6 및 R 7은 각각 독립적으로 -H, 할로겐, 비치환 또는 하나 이상의 할로겐이 치환된 직쇄 또는 분지쇄의 C 1- 10알킬, 직쇄 또는 분지쇄의 C 1- 3알콕시, 또는 R 6 및 R 7가 서로 연결되어 형성된 5내지 12원자의 사이클로알킬이고,R 6 and R 7 are each independently —H, halogen, unsubstituted or one or more halogen-substituted straight-chain or branched C 1-10 alkyl, straight - chain or branched C 1-3 alkoxy , or R 6 and R 7 is 5 to 12 membered cycloalkyl formed by connecting to each other,상기 치환된 C 6- 8아릴은 C 1-3의 직쇄 또는 분지쇄 알킬, C 1-3의 직쇄 또는 분지쇄 알킬카보닐, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C 6-8아릴이고; The substituted C 6-8 aryl is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, and one or more heteroatoms selected from the group consisting of N, O and S one or more substituents selected from the group consisting of 5 to 6 membered heteroaryl including substituted C 6-8 aryl;상기 Y는 -H, 할로겐, -N 2 +, 또는 -NO 2이고;wherein Y is -H, halogen, -N 2 + , or -NO 2 ;상기 R 3은 수소, 직쇄 또는 분지쇄의 C 1- 10알킬인, 방사성 동위원소를 포함하는 화합물의 제조방법.Wherein R 3 is hydrogen, a straight - chain or branched C 1-10 alkyl, a method for producing a compound containing a radioactive isotope. - 제1항에 있어서,According to claim 1,상기 X는이고,wherein X is
ego,상기 R 6 및 R 7은 서로 연결되어 형성된 8 내지 11원자의 사이클로알킬이고,wherein R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other,상기 Y는 할로겐, 또는 -N 2 +이고;Y is halogen, or —N 2 + ;상기 R 3은 직쇄 또는 분지쇄의 C 3- 6알킬인, 방사성 동위원소를 포함하는 화합물의 제조방법.Wherein R 3 is a straight - chain or branched C 3-6 alkyl, a method for producing a compound containing a radioactive isotope. - 제1항에 있어서,According to claim 1,상기 X는이고;wherein X is
ego;상기 Y는 할로겐인, 방사성 동위원소를 포함하는 화합물의 제조방법.Wherein Y is halogen, a method for producing a compound containing a radioactive isotope. - 제1항에 있어서,According to claim 1,상기 단계 1은 18F 음이온에 의한 친핵성 치환반응인 것인, 방사성 동위원소를 포함하는 화합물의 제조방법.The step 1 is a nucleophilic substitution reaction by 18 F anion, the method for producing a compound containing a radioactive isotope.
- 하기 화학식 2로 표시되는 화합물, 이의 입체 이성질체, 수화물, 또는 이의 약학적으로 허용 가능한 염:A compound represented by the following formula (2), a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof:<화학식 2><Formula 2>
(상기 화학식 2에서,(In Formula 2,X, Y, R 1, R 2, 및 R 3는 제1항의 반응식 Ⅰ에서 정의한 바와 같다).X, Y, R 1 , R 2 , and R 3 are as defined in Scheme I of claim 1). - 제6항에 있어서,7. The method of claim 6,상기 X는이고,wherein X is
ego,상기 R 6 및 R 7은 서로 연결되어 형성된 8 내지 11원자의 사이클로알킬이고,wherein R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other,상기 Y는 할로겐인, 화합물.wherein Y is halogen. - 하기 반응식 Ⅱ에서 나타난 바와 같이,As shown in Scheme II below,화학식 5로 표시되는 화합물로부터 화학식 2로 표시되는 화합물을 제조하는 단계를 포함하는, 하기 화학식 2로 표시되는 화합물의 제조방법:A method for preparing a compound represented by the following formula (2), comprising preparing a compound represented by formula (2) from a compound represented by formula (5):<반응식 Ⅱ><Scheme II>
(상기 반응식 Ⅱ에서,(In Scheme II,X, Y, R 1, R 2, 및 R 3는 제1항의 반응식 Ⅰ에서 정의한 바와 같다).X, Y, R 1 , R 2 , and R 3 are as defined in Scheme I of claim 1). - 제8항에 있어서,9. The method of claim 8,상기 X는이고,wherein X is
ego,상기 R 6 및 R 7은 서로 연결되어 형성된 8 내지 11원자의 사이클로알킬이고,wherein R 6 and R 7 are 8 to 11 membered cycloalkyl formed by connecting to each other,상기 Y는 할로겐인, 제조방법.wherein Y is halogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2020/017310 WO2022114333A1 (en) | 2020-11-30 | 2020-11-30 | Method for efficient production of 2-[18f]fluoro-4-boronophenylalanine comprising radioisotopes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2020/017310 WO2022114333A1 (en) | 2020-11-30 | 2020-11-30 | Method for efficient production of 2-[18f]fluoro-4-boronophenylalanine comprising radioisotopes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022114333A1 true WO2022114333A1 (en) | 2022-06-02 |
Family
ID=81755101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2020/017310 WO2022114333A1 (en) | 2020-11-30 | 2020-11-30 | Method for efficient production of 2-[18f]fluoro-4-boronophenylalanine comprising radioisotopes |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2022114333A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120123120A1 (en) * | 2009-04-08 | 2012-05-17 | The Regents Of The University Of California | No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds |
| JP2016204314A (en) * | 2015-04-23 | 2016-12-08 | 国立研究開発法人理化学研究所 | Compound and method for producing 4-boronophenylalanine derivative |
| US9815855B2 (en) * | 2014-02-28 | 2017-11-14 | Stella Pharma Corporation | Method for producing 4-borono-L-phenylalanine having 18F atom introduced thereinto, and precursor of 4-borono-L-phenylalanine having 18F atom introduced thereinto |
| CN109384806A (en) * | 2017-08-03 | 2019-02-26 | 王璐 | A kind of [18F] FBPA novel processing step |
-
2020
- 2020-11-30 WO PCT/KR2020/017310 patent/WO2022114333A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120123120A1 (en) * | 2009-04-08 | 2012-05-17 | The Regents Of The University Of California | No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds |
| US9815855B2 (en) * | 2014-02-28 | 2017-11-14 | Stella Pharma Corporation | Method for producing 4-borono-L-phenylalanine having 18F atom introduced thereinto, and precursor of 4-borono-L-phenylalanine having 18F atom introduced thereinto |
| JP2016204314A (en) * | 2015-04-23 | 2016-12-08 | 国立研究開発法人理化学研究所 | Compound and method for producing 4-boronophenylalanine derivative |
| CN109384806A (en) * | 2017-08-03 | 2019-02-26 | 王璐 | A kind of [18F] FBPA novel processing step |
Non-Patent Citations (1)
| Title |
|---|
| PETERSEN I. N., VILLADSEN J., HANSEN H. D., MADSEN J., JENSEN A. A., GILLINGS N., LEHEL S., HERTH M. M., KNUDSEN G. M., KRISTENSEN: "18 F-Labelling of electron rich iodonium ylides: application to the radiosynthesis of potential 5-HT 2A receptor PET ligands", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 15, no. 20, 1 January 2017 (2017-01-01), pages 4351 - 4358, XP055934325, ISSN: 1477-0520, DOI: 10.1039/C7OB00628D * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013176522A1 (en) | Method for synthesizing radiopharmaceuticals using a cartridge | |
| WO2012081880A2 (en) | Precursor compound connected to solid support for manufacturing 18f radiopharmaceutical, method for manufacturing same, and application thereof | |
| WO2016064082A2 (en) | Novel aminoalkyl benzothiazepine derivative and use thereof | |
| WO2011052888A2 (en) | (3-fluoro-2-hydroxy)propyl-functionalized aryl derivatives or pharmaceutically acceptable salts thereof, method for preparing same, and pharmaceutical composition containing same as active ingredients for the diagnosis or treatment of neurodegenerative brain diseases | |
| WO2018111012A1 (en) | Novel phenyl propionic acid derivatives and uses thereof | |
| WO2021137646A1 (en) | Pyrrolobenzodiazepine derivative and ligand-linker conjugate thereof | |
| WO2022114333A1 (en) | Method for efficient production of 2-[18f]fluoro-4-boronophenylalanine comprising radioisotopes | |
| WO2019143016A1 (en) | Positron emission tomography radiotracer for diseases associated with translocator protein overexpression, translocator protein-targeting ligand for fluorescence imaging diagnosis and photodynamic therapy, and preparation method therefor | |
| WO2012157900A2 (en) | 18f-labeled precursor of pet radioactive medical supplies, and preparation method thereof | |
| WO2015030440A1 (en) | Thermal dehydroboration of hydroxy arene boronic acid compound, and method for preparing hydroxy arene compound in which functional group is introduced to ortho or meta position of phenolic compound, using thermal dehydroboration | |
| WO2012033374A2 (en) | Sulphonate precursor having a 1,2,3-triazolium salt, a production method therefor and an intramolecular nucleophilic fluorination reaction using the same | |
| WO2019235824A1 (en) | Composition for diagnosing diseases associated with cox2 overexpression and screening method therefor | |
| WO2016072801A1 (en) | Method for preparing organic fluoride-aliphatic compound and method for purifying organic fluoride-aliphatic compound | |
| WO2011014009A2 (en) | Novel di-substituted phenoxyacetyl-based compound or pharmaceutically acceptable salt thereof, production method for same and pharmaceutical composition for suppressing multiple drug resistance comprising same as an active ingredient | |
| WO2016163727A2 (en) | Radioactive probe for detecting hydrogen sulfide | |
| WO2020036382A1 (en) | Method for producing intermediate useful for synethesis of sglt inhibitor | |
| WO2021194228A1 (en) | Pharmaceutical composition for prevention or treatment of cancer | |
| WO2022220610A1 (en) | Method for preparing intermediate for synthesis of sphingosine-1-phosphate receptor agonist | |
| WO2021133033A1 (en) | Method for producing pna oligomer in solution process | |
| WO2021150049A1 (en) | Novel gadolinium-based compound, method for producing same, and mri contrast agent containing same | |
| WO2021149900A1 (en) | Disubstituted adamantyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for suppressing cancer growth comprising same as active ingredient | |
| WO2015064786A1 (en) | Cyanine dye for labeling biomolecules and method for preparing same | |
| WO2021246781A1 (en) | Pyridine derivatives as immunomodulators | |
| WO2020139044A1 (en) | Novel compound and pharmaceutical composition comprising same for enhancing anticancer activity | |
| WO2018236115A1 (en) | 18f-labelled compound for prostate cancer diagnosis, and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20963727 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 20963727 Country of ref document: EP Kind code of ref document: A1 |