JP2014509299A - 前駆体化合物に対するプロセス簡略化 - Google Patents
前駆体化合物に対するプロセス簡略化 Download PDFInfo
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- JP2014509299A JP2014509299A JP2013543829A JP2013543829A JP2014509299A JP 2014509299 A JP2014509299 A JP 2014509299A JP 2013543829 A JP2013543829 A JP 2013543829A JP 2013543829 A JP2013543829 A JP 2013543829A JP 2014509299 A JP2014509299 A JP 2014509299A
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- 238000000034 method Methods 0.000 title claims description 67
- 150000001875 compounds Chemical class 0.000 title claims description 60
- 230000008569 process Effects 0.000 title claims description 12
- 239000002243 precursor Substances 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 46
- -1 trimethylstannyl Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 7
- 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 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000002739 cryptand Substances 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
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- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 2
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 claims description 2
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- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 claims description 2
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- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical group N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 claims 1
- 125000005543 phthalimide group Chemical group 0.000 claims 1
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- 238000004519 manufacturing process Methods 0.000 abstract description 8
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- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
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- 238000000746 purification Methods 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
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- 239000000463 material Substances 0.000 description 9
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 229910004298 SiO 2 Inorganic materials 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
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- 229940091173 hydantoin Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- KAOJAYKTZHRBIJ-UHFFFAOYSA-N cyclobutyloxymethylbenzene Chemical compound C=1C=CC=CC=1COC1CCC1 KAOJAYKTZHRBIJ-UHFFFAOYSA-N 0.000 description 5
- 238000006264 debenzylation reaction Methods 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000011148 porous material Substances 0.000 description 5
- 230000002285 radioactive effect Effects 0.000 description 5
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
- QIBHSXMRVAAKPX-UHFFFAOYSA-N 1-azaniumyl-3-phenylmethoxycyclobutane-1-carboxylate Chemical compound C1C(N)(C(O)=O)CC1OCC1=CC=CC=C1 QIBHSXMRVAAKPX-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
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- 239000000126 substance Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- ZZSFCRFLCCLRFG-UHFFFAOYSA-N ethyl 1-amino-3-phenylmethoxycyclobutane-1-carboxylate Chemical compound C1C(C(=O)OCC)(N)CC1OCC1=CC=CC=C1 ZZSFCRFLCCLRFG-UHFFFAOYSA-N 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000003682 fluorination reaction Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
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- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 2
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
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- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- DFNJPPOAVCXQQQ-UHFFFAOYSA-N (1,1,1-trichloro-2-methylpropan-2-yl) carbamate Chemical compound ClC(Cl)(Cl)C(C)(C)OC(N)=O DFNJPPOAVCXQQQ-UHFFFAOYSA-N 0.000 description 1
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
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- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
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- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
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- 238000005342 ion exchange Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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-
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- 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
- C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
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- 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
- C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
【選択図】 なし
Description
R1はC1-5直鎖又は枝分れアルキル基を表し、
R2はアミノ保護基を表し、
Xはハロゲン又は−O−SO2−R3基(式中、R3はハロゲン、直鎖又は枝分れC1-10アルキル、直鎖又は枝分れC1-10ハロアルキル又はC6-10アリールである。)から選択される脱離基を表し、
nは0〜4の整数である。)
(a)以下の式Iaの化合物を脱ベンジル化して以下の式Ibの化合物を生成させる段階と、
(b)段階(a)で直接得られる式Ibの化合物を、適当な形態のX(ただし、Xは式Iで定義した通りである。)との反応によって式Iの化合物に転化する段階と
を含む方法に関する。
式Ibの化合物は次式のものである。
当該方法が、本明細書に記載した式Iの化合物を得る方法と、さらに以下の段階:
(c)本明細書で定義する式Iの化合物を好適な[18F]フッ化物源と反応させて式IIaの化合物を得る段階と、
(d)段階(c)で得られる式IIaの化合物を脱保護してR31及びR32を除去する段階と
を含む方法も提供する。
(i)本明細書で定義される式Iの化合物を含有する槽と、
(ii)槽内を本明細書で定義される[18F]フッ化物の好適な供給源によって溶出する手段と、
(iii)過剰な[18F]フッ化物を除去するためのイオン交換カートリッジと、
(iv)式IIaの化合物の脱保護を行い、式IIの化合物を形成するためのカートリッジと
を含む。
例1は5−(3−ベンジルオキシシクロブタン)ヒダントインの合成について述べる。
例において使用する略語一覧
DCM 二塩化メタン
EtOAc 酢酸エチル
Et2O ジエチルエーテル
Et3N トリエチルアミン
g グラム
hr 時間
l リットル
min 分
ml ミリリットル
mol モル
sat.aq 飽和水溶液
TLC 薄層クロマトグラフィー
w/w 重量/重量
1H NMR(500MHz,DMSO−d6)δ(ppm):10.63(s,1H,NH),8.24(s,1H,NH),7.38〜7.27(m,5H,Bz),4.32(s,1H,CH2−Bz),4.06〜3.98(m,1H,CH環),2.68〜2.61(m,2H,CH2環)及び2.24〜2.16(m,2H,CH2環)。
1H NMR(500MHz,D2O)δ(ppm):7.37〜7.28(m,5H,Bz),4.40(s,2H,CH2),4.30〜4.23(m,1H,CH環),2.79〜2.71(m,2H,CH2環)及び2.26〜2.18(m,2H,CH2環)。
1H NMR(500MHz,DMSO−d6)δ(ppm):7.38〜7.27(m,5H,Bz),4.41(s,2H,CH2),4.16(q,2H,CH2),4.07〜4.01(m,1H,CH環),2.77〜2.70(m,2H,CH2環),2.26〜2.19(m,2H,CH2環)及び1.22(t,3H,CH3)。
1H NMR(500MHz,DMSO−d6)δ(ppm):7.73(1H,NH),7.38〜7.26(m,5H,Bz),4.37(s,2H; CH2),4.15〜3.95(m,2H,CH2及びm,1H,CH環),2.80〜2.71(m,2H,CH2環),2.10〜2.02(m,2H,CH2環),1.37(s,9H,CH3,BOC),1.22〜1.11(m,CH3).少量の立体配座異性体についてはNMRスペクトル中に記載しない。
1H NMR(500MHz,DMSO−d6)δ(ppm):7.64(1H,NH),5.15(1H,OH),4.12〜3.99(m,1H,CH環及びm,2H,CH2),2.75〜2.66(m,2H,CH2環),2.02〜1.93(m,2H,CH2環),1.37(s,9H,BOC)及び1.22〜1.12(m,3H,CH3)。
化合物1a(8.5g、24.3mmol)を仕込んだ反応フラスコにエタノール(155ml)及び酢酸(2.13ml、37.2mmol)を添加し、N2雰囲気とし、反応フラスコをH2供給源にも接続した。湿らせた炭素担持Pd(2.13g、10%w/w)を混合物に添加し、反応混合物にH2ガスを供給した。反応混合物を室温にて2.25日間撹拌して完全に転化させた(TLCにより反応の進行状況を監視)。反応混合物をガラス焼結フィルターにより濾過し、濾過ケークをエタノール(40ml)で洗浄し、減圧下、40℃未満の温度で濾液から溶媒を留去し、化合物1bの粗生成物(6.21g)を得た。得られた物質を、さらに如何なる精製も行うことなく、次の反応段階に使用した。
1H NMR(500MHz,DMSO−d6)δ(ppm):5.44〜4.95(m,1H,CH環及びs,br,1H,NH),4.26(q,2H,CH2),3.15〜2.68(m,4H,2×CH2環),1.45(s,9H,BOC)及び1.31(t,3H,CH3)
例8:粗製化合物1bを用いた化合物1の合成(本発明の方法)
この反応に使用した物質は従来技術の操作方法に基づく精製を行わなかった。出発物質である化合物1bに対して唯一行った精製は、ガラス焼結ロートを用いた濾過とそれに続く乾燥のための減圧下での留去であった。
Claims (19)
- 次の式Iの化合物を得る方法であって、
R1はC1-5直鎖又は枝分れアルキル基を表し、
R2はアミノ保護基を表し、
Xはハロゲン又は−O−SO2−R3基(式中、R3はハロゲン、直鎖又は枝分れC1-10アルキル、直鎖又は枝分れC1-10ハロアルキル又はC6-10アリールである。)から選択される脱離基を表し、
nは0〜4の整数である。)
(a)以下の式Iaの化合物を脱ベンジル化して以下の式Ibの化合物を生成させる段階と、
(b)段階(a)で直接得られる式Ibの化合物を、式Iで定義した適当な形態のXとの反応によって式Iの化合物に転化する段階と
を含む方法。 - Xが−O−SO2−R3基で表される基である、請求項1記載の方法。
- R3がトルエンスルホン酸、ニトロベンゼンスルホン酸、ベンゼンスルホン酸、トリフルオロメタンスルホン酸、フルオロスルホン酸、パーフルオロアルキルスルホン酸、トリメチルスタニル及びトリエチルスタニルからなる群から選択される、請求項2記載の方法。
- R3がトリフルオロメタンスルホン酸である、請求項3記載の方法。
- Xがハロゲンである、請求項1記載の方法。
- ハロゲンがブロモ又はクロロである、請求項5記載の方法。
- R1がエチルである、請求項1乃至請求項6のいずれか1項記載の方法。
- R2がt−ブトキシカルボニル基、アリルオキシカルボニル基、フタルイミド基及びN−ベンジリデンアミン置換基からなる群から選択される、請求項1乃至請求項7のいずれか1項記載の方法。
- nが0又は1である、請求項1乃至請求項8のいずれか1項記載の方法。
- 式Iの化合物が次式のものであり、
- 次の式IIの化合物を得る方法であって、
請求項1記載の方法と、さらに以下の段階:
(c)請求項1記載の式Iの化合物と好適な[18F]フッ化物源との反応によって式IIaの化合物を得る段階と、
(d)段階(c)で得られる式IIaの化合物を脱保護して、R31及びR32を除去する段階と
を含む方法。 - [18F]フッ化物源が、ルビジウム、セシウム、クリプタンドと錯形成したカリウム又はテトラアルキルアンモニウム塩から選択される対イオン存在下の[18F]フッ化物である、請求項11記載の方法。
- 脱保護が、R31を除去した後にR32を除去することを含む、請求項11又は請求項12記載の方法。
- xとyとが等しく、0又は1である、請求項11乃至請求項13のいずれか1項記載の方法。
- R31がエチルである、請求項11乃至請求項14のいずれか1項記載の方法。
- R32がt−ブトキシカルボニル基である、請求項11乃至請求項15のいずれか1項記載の方法。
- 式IIの化合物が次式のものであり、
- 脱保護する段階が、塩基性加水分解によるEtの除去及び酸性加水分解によるBocの除去を含む、請求項17記載の方法。
- 段階(c)及び(d)を自動合成装置上で行う、請求項11乃至請求項18のいずれか1項記載の方法。
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KR20130133248A (ko) | 2013-12-06 |
CN103261152A (zh) | 2013-08-21 |
US9238596B2 (en) | 2016-01-19 |
BR112013015002A2 (pt) | 2016-08-09 |
US20130274507A1 (en) | 2013-10-17 |
RU2013126497A (ru) | 2015-01-27 |
MX2013007188A (es) | 2013-07-12 |
AU2011347636A1 (en) | 2014-09-25 |
JP6047100B2 (ja) | 2016-12-21 |
WO2012084794A1 (en) | 2012-06-28 |
GB201021523D0 (en) | 2011-02-02 |
MX340407B (es) | 2016-07-06 |
RU2593372C2 (ru) | 2016-08-10 |
CA2819088A1 (en) | 2012-06-28 |
EP2655320A1 (en) | 2013-10-30 |
AU2011347636B2 (en) | 2017-02-09 |
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