JP2007532524A - フッ素化方法 - Google Patents
フッ素化方法 Download PDFInfo
- Publication number
- JP2007532524A JP2007532524A JP2007506837A JP2007506837A JP2007532524A JP 2007532524 A JP2007532524 A JP 2007532524A JP 2007506837 A JP2007506837 A JP 2007506837A JP 2007506837 A JP2007506837 A JP 2007506837A JP 2007532524 A JP2007532524 A JP 2007532524A
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- JP
- Japan
- Prior art keywords
- water
- alkyl
- solvent
- ion
- fluoride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 46
- 238000003682 fluorination reaction Methods 0.000 title claims description 17
- -1 fluorine ions Chemical class 0.000 claims abstract description 33
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000011737 fluorine Substances 0.000 claims abstract description 11
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 39
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 150000002500 ions Chemical class 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000002950 deficient Effects 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical group [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 239000011698 potassium fluoride Substances 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 239000004743 Polypropylene Substances 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000011521 glass Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 229920002223 polystyrene Polymers 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims 2
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 claims 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims 2
- 238000004255 ion exchange chromatography Methods 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 235000013024 sodium fluoride Nutrition 0.000 claims 1
- 239000011775 sodium fluoride Substances 0.000 claims 1
- SBQIJPBUMNWUKN-UHFFFAOYSA-M diphenyliodanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[I+]C1=CC=CC=C1 SBQIJPBUMNWUKN-UHFFFAOYSA-M 0.000 description 19
- 239000000047 product Substances 0.000 description 18
- 238000001035 drying Methods 0.000 description 13
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 8
- 229910052700 potassium Inorganic materials 0.000 description 8
- 239000011591 potassium Substances 0.000 description 8
- 239000002872 contrast media Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 230000009257 reactivity Effects 0.000 description 6
- 230000000269 nucleophilic effect Effects 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002739 cryptand Substances 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- NLMDJJTUQPXZFG-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Chemical compound C1COCCOCCNCCOCCOCCN1 NLMDJJTUQPXZFG-UHFFFAOYSA-N 0.000 description 3
- AUFVJZSDSXXFOI-UHFFFAOYSA-N 2.2.2-cryptand Chemical compound C1COCCOCCN2CCOCCOCCN1CCOCCOCC2 AUFVJZSDSXXFOI-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052792 caesium Inorganic materials 0.000 description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 125000005520 diaryliodonium group Chemical group 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000700 radioactive tracer Substances 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LQXCRTMNFBGGST-UHFFFAOYSA-N 1-iodo-4-methoxybenzene trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F.COC1=CC=C(I)C=C1 LQXCRTMNFBGGST-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 150000001501 aryl fluorides Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 229940121896 radiopharmaceutical Drugs 0.000 description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 description 2
- XNAXIKHGGWKCKA-UHFFFAOYSA-N 1-(3-fluoro-2-methoxy-5-methylphenyl)ethanone Chemical compound COC1=C(F)C=C(C)C=C1C(C)=O XNAXIKHGGWKCKA-UHFFFAOYSA-N 0.000 description 1
- 235000006506 Brasenia schreberi Nutrition 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- 241000656145 Thyrsites atun Species 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- OZLBDYMWFAHSOQ-UHFFFAOYSA-N diphenyliodanium Chemical compound C=1C=CC=CC=1[I+]C1=CC=CC=C1 OZLBDYMWFAHSOQ-UHFFFAOYSA-N 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/361—Preparation of halogenated hydrocarbons by reactions involving a decrease in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
【選択図】なし
Description
Aigbirhio et al 1995 J.Fluor.Chem.70 pp 279−87 Moughamir et al 1998 Tett.Letts.39 pp 7305−6 Handbook of Radiopharmaceuticals 2003 Welch & Redvanly eds.ch.6 pp 195−227 1995 J.Chem.Soc.Chem.Comm.pp 2215−6 1998 J.Chem.Soc.,Perkin Trans.1,pp2043−6 1982,J.Fluorine Chem.,21 385−392 Protecting proups in organic synthesis,Theodora W.Greene and peter G.M.Wuts,Published by John Wiley & Sons Inc
R1、R2、R3、R4及びR5は各々独立に水素、−O(C1−10アルキル)又はC1−10アルキルであり、
Y−はトリフルオロメタンスルホン酸イオン(トリフレート)、ペルフルオロC2〜C10アルキルスルホン酸イオン、トリフルオロ酢酸イオン、メタンスルホン酸イオン(メシレート)、トルエンスルホン酸イオン(トシレート)、テトラフェニルホウ酸イオンのような対イオンである。
式中、Qは一般式(I)及び(II)で定義した通りである。
(i)過剰な18F−を例えばイオン交換クラマトグラフィーで除去する段階、及び/又は
(ii)保護基を除去する段階、及び/又は
(iii)有機溶媒を除去する段階、及び/又は
(iv)得られる化合物を水溶液として処方する段階
の1以上の段階を任意の順序でさらに含んでいてもよい。
(i)フッ素イオン源を溶解するための水性溶媒を収容したバイアル、
(ii)ヨードニウム塩を収容した反応容器。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これにアセトニトリル中のKryptofix222(11.4mg)及び炭酸カリウム(0.1M溶液0.2ml)を添加した。フッ化物を共沸乾燥によって乾燥させた。乾燥プロセスの完了後、ジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、22.5mg)の無水アセトニトリル(1ml)溶液を、乾燥フッ化物に添加した。混合物を95℃で15分間加熱したのち圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を、Phenomenex Luna3μC18カラム(150×4.6mm)を用いた高速液体クロマトグラフィー(HPLC)で、水中0.1%トリフルオロ酢酸(TFA)に対するアセトニトリル中0.1%TFAの割合を15分かけて5%から95%に変化させる1ml/分の勾配溶出を用いて分析した。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これにアセトニトリル中のKryptofix222(11.4mg)及び炭酸カリウム(0.1M溶液0.2ml)を添加した。フッ化物を共沸乾燥によって乾燥させた。乾燥プロセスの完了後、無水アセトニトリル(0.9ml)と水(0.1ml)の混合物中のジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、23.0mg)の溶液を、乾燥フッ化物に添加した。混合物を100℃で15分間加熱したのち圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.1ml)中の[18F]フッ化物を反応容器に仕込み、これにアセトニトリル(0.9ml)及びジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、21.7mg)中のKryptofix222(11.4mg)及び炭酸カリウム(0.1M溶液0.2ml)を添加した。この混合物を100℃で15分間加熱した後、圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.1ml)中の[18F]フッ化物を反応容器に仕込み、これにアセトニトリル(0.9ml)中の炭酸カリウム(0.1M溶液0.2ml)及びジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、23.2mg)を添加した。この混合物を100℃で15分間加熱した後、圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これにアセトニトリル中の炭酸カリウム(0.1M溶液0.2ml)を添加した。フッ化物を共沸乾燥によって乾燥させた。乾燥プロセスの完了後、無水アセトニトリル(0.9ml)及び水(0.1ml)の混合物中のジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、28.7mg)の溶液を、乾燥フッ化物に添加した。混合物を100℃で15分間加熱したのち圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これに炭酸セシウム(24mg)、水(0.2ml)及びアセトニトリル(1ml)を添加した。フッ化物を共沸乾燥によって乾燥させた。乾燥プロセスの完了後、ジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、22.5mg)の無水アセトニトリル(1ml)溶液を、乾燥フッ化物に添加した。混合物を95℃で15分間加熱したのち圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これに炭酸セシウム(27.7mg)、水(0.2ml)及びアセトニトリル(1ml)を添加した。フッ化物を共沸乾燥によって乾燥させた。乾燥プロセスの完了後、無水アセトニトリル(0.99ml)と水(0.01ml)の混合物中のジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、24.8mg)の溶液を乾燥フッ化物に添加した。混合物を100℃で20分間加熱したのち圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これに炭酸セシウム(27.7mg)、水(0.2ml)及びアセトニトリル(1ml)を添加した。フッ化物を共沸乾燥によって乾燥させた。乾燥プロセスの完了後、無水アセトニトリル(0.9ml)と水(0.1ml)の混合物中のジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、24.9mg)の溶液を、乾燥フッ化物に添加した。混合物を100℃で20分間加熱したのち圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.6ml)中の[18F]フッ化物を反応容器に仕込み、これに炭酸セシウム(〜27mg)、アセトニトリル(0.7ml)及びジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、26.5mg)を添加した。この混合物を100℃で15分間加熱した後、圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
18O濃縮水(〜0.3ml)中の[18F]フッ化物を反応容器に仕込み、これに炭酸セシウム(〜27mg)、アセトニトリル(0.5ml)、水(0.2ml)及びジフェニルヨードニウムトリフレート(Sigma−Aldrich Chemicals社製、25.3mg)を添加した。この混合物を100℃で15分間加熱した後、圧縮気流中で冷却した。生成物を密封式回収バイアルに移し、反応物を実施例1に記載の通りHPLCで分析した。
Claims (28)
- フッ素イオン源でヨードニウム塩をフッ素化することを含む芳香族又は複素環式芳香族フッ素標識化合物の製造方法であって、反応溶媒が水を含むことを特徴とする方法。
- 反応溶媒が100%水である、請求項1記載の方法。
- 反応溶媒が水と水混和性溶媒との混合物である、請求項1記載の方法。
- 水混和性溶媒がアセトニトリル、エタノール、メタノール、テトラヒドロフラン又はジメチルホルムアミドである、請求項3記載の方法。
- 水:水混和性溶媒の体積:体積比が1:99〜1:1である、請求項3又は請求項4記載の方法。
- 水:水混和性溶媒の体積:体積比が10:90〜30:70である、請求項5記載の方法。
- 前記フッ素イオン源がフッ化カリウム、フッ化セシウム又はフッ化ナトリウムである、請求項1乃至請求項6のいずれか1項記載の方法。
- 以下の式(I)又は(II)のヨードニウム塩のフッ素化によって下記の一般式(III)の生成物を得るための請求項1乃至請求項7のいずれか1項記載の方法。
R1、R2、R3、R4及びR5は各々独立に水素、−O(C1−10アルキル)又はC1−10アルキルであり、
Y−はトリフルオロメタンスルホン酸イオン(トリフレート)、ペルフルオロC2−C10アルキルスルホン酸イオン、トリフルオロ酢酸イオン、メタンスルホン酸イオン(メシレート)、トルエンスルホン酸イオン(トシレート)、テトラフェニルホウ酸イオンのような対イオンである。
Q−F (III)
式中、Qは一般式(I)及び(II)で定義した通りである。 - R1〜R5が各々独立に水素、C1〜3アルキル及び−O−(C1〜C3アルキル)から選択される、請求項8記載の方法。
- 式IIの化合物において、前記「固体担体」がポリスチレン、ポリアクリルアミド、ポリプロピレン、又はこれらのポリマーでコートされたガラス又はシリコンである、請求項8又は請求項9記載の方法。
- 前記固体担体が、小さい離散粒子の形態、又は反応容器の内面のコーティングである、請求項8乃至請求項10のいずれか1項記載の方法。
- 式IIの化合物において、前記「リンカー」が、アミドエーテル又はスルホンアミド結合で樹脂に結合したC1−20アルキル、C1−20アルコキシ、或いはポリエチレングリコール(PEG)リンカーである、請求項8乃至請求項11のいずれか1項記載の方法。
- 前記芳香族基Qが、C1−10アルキル、−O(C1−10アルキル)、−C(=O)C1−10アルキル、−C(=O)NR6(C1−10アルキル)、−(C1〜C6アルキル)−O−(C1〜C6アルキル)、C5−14アリール、−O(C5−14アリール)、−C(=O)C5−14アリール、−C(=O)NR6(C5−14アリール)、C5−14ヘテロアリール、−O(C5−14ヘテロアリール)、−C(=O)C5−14ヘテロアリール、−C(=O)NR6(C5−14ヘテロアリール)、C3−10シクロアルキル、−O(C3−10シクロアルキル)、−C(=O)(C3−10シクロアルキル)、−C(=O)NR6(C3−10シクロアルキル)、C3−10ヘテロシクリル、−O(C3−10ヘテロシクリル)、−C(=O)(C3−10ヘテロシクリル)、−C(=O)NR6(C5−14ヘテロシクリル)(式中、R6はH、C1〜C6アルキル、C3〜C10シクロアルキル、C3〜C10ヘテロシクリル、C4〜C10アリール又はC4〜C10ヘテロアリールである。)から選択される1以上の置換基で置換され、これらの置換基はいずれも適宜OH、NHR6、COOH又はこれらのいずれかの基の保護形で置換されていてもよいし、或いは2つの隣接した置換基が四乃至六員炭素環又は複素環を形成してもよく、該四乃至六員炭素環又は複素環適宜追加の芳香族環、複素環式芳香族環、炭素環又は複素環と縮合していてもよい、請求項8乃至請求項12のいずれか1項記載の方法。
- 芳香族部分Qが、OH、NHR6又はハロゲンから選択される追加の置換基を有する、請求項13記載の方法。
- Q基が以下のいずれかである、請求項8乃至請求項14のいずれか1項記載の方法。
- 前記フッ素標識化合物が[18F]標識化合物であり、前記フッ素イオン源が18F−源である、請求項1乃至請求項18のいずれか1項記載の方法。
- 前記F標識化合物が以下のものから選択される、請求項15又は請求項16記載の方法。
- 過剰な18F−を例えばイオン交換クラマトグラフィーで除去する段階、及び/又は
(i)保護基を除去する段階、及び/又は
(ii)有機溶媒を除去する段階、及び/又は
(iii)得られる化合物を水溶液として処方する、段階
の1以上の段階を任意の順序でさらに含む、請求項1乃至請求項17のいずれか1項記載の方法。 - 芳香族フッ素標識化合物の製造用キットであって、
(i)フッ素イオン源を溶解するための水性溶媒を収容したバイアル、及び
(ii)ヨードニウム塩を収容した反応容器
を備えるキット。 - 前記溶媒が100%水である、請求項19記載のキット。
- 前記溶媒が水と水混和性溶媒との混合物である、請求項19記載のキット。
- 前記水混和性溶媒が、アセトニトリル、エタノール、メタノール、テトラヒドロフラン又はジメチルホルムアミドである、請求項21記載のキット。
- 水−水混和性溶媒の体積:体積比が1:99〜1:1である、請求項21又は請求項22記載のキット。
- 水−水混和性溶媒の体積:体積比が10:90〜30:70である、請求項23記載のキット。
- 前記ヨードニウム塩が請求項8乃至請求項15のいずれか1項で定義した一般式(I)又は(II)の化合物である、請求項19乃至請求項24のいずれか1項記載のキット。
- 前記ヨードニウム塩が請求項8乃至請求項15のいずれか1項で定義した一般式(II)の化合物であり、前記固体担体が反応容器の表面のコーティングを有する、請求項20記載のキット。
- 前記反応容器が、カートリッジ又は微細加工容器である、請求項19乃至請求項26のいずれか1項記載のキット。
- フッ素イオン源をさらに含む、請求項19乃至請求項27のいずれか1項記載のキット。
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Also Published As
Publication number | Publication date |
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EP1732865A1 (en) | 2006-12-20 |
CN1938244A (zh) | 2007-03-28 |
GB0407952D0 (en) | 2004-05-12 |
US20110196149A1 (en) | 2011-08-11 |
US20070092441A1 (en) | 2007-04-26 |
US7935852B2 (en) | 2011-05-03 |
CN1938244B (zh) | 2013-03-13 |
WO2005097713A1 (en) | 2005-10-20 |
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