JP2021533176A - 18f−bpaの製造方法及び中間体 - Google Patents
18f−bpaの製造方法及び中間体 Download PDFInfo
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- JP2021533176A JP2021533176A JP2021507794A JP2021507794A JP2021533176A JP 2021533176 A JP2021533176 A JP 2021533176A JP 2021507794 A JP2021507794 A JP 2021507794A JP 2021507794 A JP2021507794 A JP 2021507794A JP 2021533176 A JP2021533176 A JP 2021533176A
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- boric acid
- hydrogen
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 25
- 239000000543 intermediate Substances 0.000 title claims description 49
- 125000006239 protecting group Chemical group 0.000 claims description 56
- 125000003277 amino group Chemical group 0.000 claims description 51
- -1 ion compounds Chemical group 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 24
- 229910052796 boron Inorganic materials 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 239000004327 boric acid Substances 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 150000002500 ions Chemical class 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- 125000005619 boric acid group Chemical group 0.000 claims description 13
- 239000010949 copper Substances 0.000 claims description 13
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical group CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 1
- 238000002372 labelling Methods 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 7
- 230000002285 radioactive effect Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
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- 239000002245 particle Substances 0.000 description 5
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- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 229960005190 phenylalanine Drugs 0.000 description 4
- 230000004224 protection Effects 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- IKRDGIFMBIEIKR-AWEZNQCLSA-N tert-butyl (2S)-3-(2,4-dibromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C(C)(C)(C)OC([C@@H](NC(=O)OC(C)(C)C)CC1=C(C=C(C=C1)Br)Br)=O IKRDGIFMBIEIKR-AWEZNQCLSA-N 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- DBOLXXRVIFGDTI-UHFFFAOYSA-N 4-benzylpyridine Chemical group C=1C=NC=CC=1CC1=CC=CC=C1 DBOLXXRVIFGDTI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
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- 230000007062 hydrolysis Effects 0.000 description 2
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- 230000014759 maintenance of location Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 125000006000 trichloroethyl group Chemical group 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [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 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 0 *C(*)Cc1ccc(*)cc1* Chemical compound *C(*)Cc1ccc(*)cc1* 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- WCGLKHFEADTGKN-UHFFFAOYSA-N 2,5-dibromo-5-(bromomethyl)cyclohexa-1,3-diene Chemical compound BrC1(CBr)CC=C(C=C1)Br WCGLKHFEADTGKN-UHFFFAOYSA-N 0.000 description 1
- WYBQOWXCLDXZNR-UHFFFAOYSA-N 2-(1,3,2-benzodioxaborol-2-yl)-1,3,2-benzodioxaborole Chemical compound O1C2=CC=CC=C2OB1B1OC2=CC=CC=C2O1 WYBQOWXCLDXZNR-UHFFFAOYSA-N 0.000 description 1
- MDNDJMCSXOXBFZ-UHFFFAOYSA-N 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane Chemical compound O1CC(C)(C)COB1B1OCC(C)(C)CO1 MDNDJMCSXOXBFZ-UHFFFAOYSA-N 0.000 description 1
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
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- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
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- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical group O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
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- 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 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000011275 oncology therapy Methods 0.000 description 1
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- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
Description
前記中間体I−1は式I−1の構造を有し、
R3、R4は、それぞれ水素とアミノ基の保護基であるか、又はアミノ基と共にアミノ基を保護するイミノ基を形成し、
R5は、水素又はカルボキシル基の保護基である。
特に定義されない限り、本明細書の全ての科学技術用語の意味は、特許請求の範囲の主題が属する分野の当業者に一般的に理解される意味と同じである。特に明記しない限り、本明細書の全文に引用された全ての特許、特許出願、開示材料は、参照によりその全体が本明細書に組み込まれる。
本発明の前記「中間体」は、L型フェニルアラニン構造とD型フェニルアラニン構造の2種類の構造を有し、いずれも本発明の保護範囲に含まれる。
本発明に記載の18F−BPAの新規な製造方法は、例えば、以下の例により実現することができるが、例示的な方法に限定されない。以下の反応式に用いられるアミノ基及びカルボキシル基の保護基とホウ酸エステル基とは、適切に変更することができ、例示的な方法に限定されない。
N−ジフェニルメチレン−グリシンtert−ブチルエステル(40g、135.42mmol、1 eq)、1,4−ジブロモベンジルブロミド(44.53g、135.42mmol、1 eq)、テトラブチルアンモニウムブロミド(TBAB、436.55mg、1.35mmol、0.01 eq)を300mLのトルエンに溶解させ、80mLの水酸化カリウム(100.00g、1.78mol、13.16 eq)水溶液を添加する。25℃で反応が終了するまで12時間撹拌する。反応混合物を100mLの酢酸エチルで希釈し、400mL(200mL×2)の酢酸エチルで抽出し、有機相を混合すると共に、600mL(300mL×2)の飽和食塩水で洗浄し、Na2SO4で乾燥し、濾過して固形物を得る。粗生成物をカラムクロマトグラフィー(石油エーテル/酢酸エチル=100:1−20:1)により分離して、15gの産物を得る。
N−ジフェニルメチレン−2,4−ジブロモフェニルアラニンtert−ブチルエステル(30g、55.22mmol、1 eq)をTHF(70mL)に溶解させ、クエン酸(31.83g、165.66mmol、31.86mL、3 eq)水溶液を20mL添加し、25℃で12h撹拌する。50mLのNa2CO3(29.26g、276.10mmol、5 eq)の水溶液とBoc2O(13.26g、60.74mmol、13.95mL、1.1 eq)を添加し、継続して4h撹拌する。反応が終了すると、反応混合物を400mL(200mL×2)の酢酸エチルで抽出し、有機相を混合すると共に、400mL(200mL×2)の飽和食塩水で洗浄し、Na2SO4で乾燥し、濾過して固形物を得る。粗生成物をカラムクロマトグラフィー(石油エーテル/酢酸エチル=100:1−10:1)により分離して、19.6gの収率が73.48%で、純度が99.2%の産物を得る。
N−tert−ブトキシカルボニル−2,4−ジブロモ−フェニルアラニンtert−ブチルエステル(7.50g、15.6mmol、1.00 eq)、ピナコールジボロン酸エステル(19.8g、78.2mmol、5.00 eq)、KOAc(6.14g、62.6mmol、4.00 eq)、Pd(dppf)Cl2(1.15g、1.57mmol、0.10 eq)及びジオキサン(75.0mL)を90℃の窒素雰囲気で1h撹拌する。反応が終了すると、濾過し、200mLの水を添加し、反応混合物を300mL(100mL×3)の酢酸エチルで抽出し、有機相を混合すると共に、200mL(100mL×2)の飽和食塩水で洗浄し、Na2SO4で乾燥し、濾過して固形物を得る。粗生成物をHPLCにより精製して、6.5gの純度が96.3%の産物を得る。
O−tert−ブトキシカルボニル−2,4−ジブロモ−フェニルアラニンtert−ブチルエステル(7.00g、14.6mmol、1.00 eq)、ピナコールジボロン酸エステル(18.5g、73.0mmol、5.00 eq)、KOAc(5.73g、58.4mmol、4.00 eq)、Pd(dppf)Cl2(5.73g、58.4mmol、4.00 eq)及びジオキサン(70.0mL)を90℃の窒素雰囲気で3h撹拌する。反応が終了すると、濾過し、200mLの水を添加し、反応混合物を300mL(100mL×3)の酢酸エチルで抽出し、有機相を混合すると共に、200mL(100mL×2)の飽和食塩水で洗浄し、Na2SO4で乾燥し、濾過して固形物を得る。粗生成物をHPLCにより精製して、5.37gの純度が97.35%の産物を得る。
N−tert−ブトキシカルボニル−2,4−ジブロモ−フェニルアラニンtert−ブチルエステル(7.00g、14.6mmol、1.00 eq)、ピナコールジボロン酸エステル(18.5g、73.0mmol、5.00 eq)、KOAc(5.73g、58.4mmol、4.00 eq)、Pd(dppf)Cl2(5.73g、58.4mmol、4.00 eq)及びジオキサン(70.0mL)を90℃の窒素雰囲気で3h撹拌する。反応が終了すると、濾過し、200mLの水を添加し、反応混合物を300mL(100mL×3)の酢酸エチルで抽出し、有機相を混合すると共に、200mL(100mL×2)の飽和食塩水で洗浄し、Na2SO4で乾燥し、濾過して固形物を得る。粗生成物をHPLCにより精製して、5.37gの純度が97.35%の産物を得る。プロトン核磁気共鳴スペクトルについて、図1を参照する。
加速された陽子をH2 18Oに照射し、18O(p,n)反応により18Fイオンを得て、18Fイオンをイオン交換カラムに捕捉し、K2.2.2/K2CO3混合溶液で溶出し、脱水乾燥した後に標識反応に用いる。実施例5で得られた化合物をDMA溶液に18FイオンとCu(OTf)2Py4の存在の下で15min反応させ、反応が終了した後、混合溶液をカチオンカラムにより精製し、乾燥する。HCl溶液で110℃で10min反応させ、NaOH溶液を添加して中和し、加水分解してアミノ基及びカルボキシル基の保護基を除去して粗生成物を得る。粗生成物をHPLCにより精製して、純度が99%より高い18F−BPAを得ることができる。
Claims (15)
- 前記中間体I−2と18Fイオンの反応は、銅触媒の使用をさらに含み、好ましくは、銅触媒がCu(OTf)2Py4又はCu(OTf)2を含む、ことを特徴とする請求項3に記載の方法。
- 前記中間体I−2と18Fイオンの反応温度は20〜150℃であり、好ましくは100〜130℃である、ことを特徴とする請求項3に記載の方法。
- 前記中間体I−2と18Fイオンの反応に用いられる溶媒は、水、メタノール、DMF、DMA、DMSO、アセトニトリル、n−ブタノール、エタノール、ジクロロメタンなど、又はそれらの任意の混合溶媒を含む、ことを特徴とする請求項3に記載の方法。
- 中間体I−1をキラル分離した後、それぞれホウ酸又はホウ酸エステルと反応させることをさらに含む、ことを特徴とする請求項9に記載の方法。
- ホウ酸基に加水分解可能な置換基は、ホウ酸エステル基であり、好ましくは、ボロン酸ピナコールエステル基であり、R3とR4は、アルコキシカルボニル保護基、アシル保護基、アルキル保護基を含み、R5は、置換又は非置換のC1〜C20アルキル基を含み、好ましくは、t−ブチル基である、ことを特徴とする請求項11又は12に記載の中間体I。
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US20210230192A1 (en) | 2021-07-29 |
CN110835352B (zh) | 2022-05-24 |
JP7292375B2 (ja) | 2023-06-16 |
CN110835310A (zh) | 2020-02-25 |
EP3838890A4 (en) | 2021-12-22 |
TWI723496B (zh) | 2021-04-01 |
EP3838890B1 (en) | 2023-10-04 |
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