CN110015973A - 一种α-偕二氟叠氮化合物及其制备方法和应用 - Google Patents
一种α-偕二氟叠氮化合物及其制备方法和应用 Download PDFInfo
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- -1 difluoro azido compound Chemical class 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 239000011737 fluorine Substances 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- 229910002651 NO3 Inorganic materials 0.000 claims description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 5
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- QEQBMZQFDDDTPN-UHFFFAOYSA-N (2-methylpropan-2-yl)oxy benzenecarboperoxoate Chemical compound CC(C)(C)OOOC(=O)C1=CC=CC=C1 QEQBMZQFDDDTPN-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 3
- 230000000975 bioactive effect Effects 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 150000004673 fluoride salts Chemical class 0.000 claims description 3
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 3
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 claims description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 3
- 229910001512 metal fluoride Inorganic materials 0.000 claims description 3
- VGGNVBNNVSIGKG-UHFFFAOYSA-N n,n,2-trimethylaziridine-1-carboxamide Chemical compound CC1CN1C(=O)N(C)C VGGNVBNNVSIGKG-UHFFFAOYSA-N 0.000 claims description 3
- 125000005561 phenanthryl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 3
- 235000019394 potassium persulphate Nutrition 0.000 claims description 3
- MCUBENBVGHHVMR-UHFFFAOYSA-N pyridine hydrochloride hydrofluoride Chemical compound Cl.N1=CC=CC=C1.F MCUBENBVGHHVMR-UHFFFAOYSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- ZXKIFUWANBZSKF-UHFFFAOYSA-N [I].CC(O)=O Chemical compound [I].CC(O)=O ZXKIFUWANBZSKF-UHFFFAOYSA-N 0.000 claims description 2
- 235000010338 boric acid Nutrition 0.000 claims description 2
- 125000005619 boric acid group Chemical class 0.000 claims description 2
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 claims description 2
- 229930014626 natural product Natural products 0.000 claims description 2
- XBZSSTBCJNNUND-UHFFFAOYSA-N C1=CC=CC=C1.[I].[F] Chemical class C1=CC=CC=C1.[I].[F] XBZSSTBCJNNUND-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 4
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical group [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 238000001228 spectrum Methods 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- OSNIIMCBVLBNGS-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)propan-1-one Chemical compound CN(C)C(C)C(=O)C1=CC=C2OCOC2=C1 OSNIIMCBVLBNGS-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241000801593 Pida Species 0.000 description 1
- OSYLPIYJUCCMTQ-UHFFFAOYSA-N [O-][N+]([O-])=O.N.[Ce+3] Chemical compound [O-][N+]([O-])=O.N.[Ce+3] OSYLPIYJUCCMTQ-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000008424 iodobenzenes Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物中间体技术领域,尤其涉及一种α‑偕二氟叠氮化合物及其制备方法和应用。本发明提供的α‑偕二氟叠氮化合物可作为α‑偕二氟氨基化合物的潜在前体,由于叠氮官能团的高反应活性,此类结构同样可以作为潜在的偕二氟基团的载体。本发明还提供了所述α‑偕二氟叠氮化合物的制备方法,所述制备方法所用原料简便易得,操作简单、反应高效,可实现工业化合成。
Description
技术领域
本发明涉及药物中间体技术领域,尤其涉及一种α-偕二氟叠氮化合物及其制备方法和应用。
背景技术
众所周知,氟化基团的引入通常在药物改性和功能材料制备中具有重要的作用。其中,偕二氟基团由于具有特殊的空间效应和电子效应,可以作为醇、硫醇和其他极性官能团的生物电子排布,可以用来调节分子的亲脂性,提高生物利用度和改善结合亲和力。
目前,人们已经发展了众多含有偕二氟官能团的有机分子,然而对于含有叠氮官能团的偕二氟化合物,尤其是α-偕二氟叠氮类化合物确未见报道。
发明内容
本发明的目的在于提供一种α-偕二氟叠氮化合物及其制备方法和应用。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种α-偕二氟叠氮化合物,具有式Ⅰ所示结构:
式Ⅰ中,R1~R3各自独立的为取代或未取代的芳基或H;
所述芳基为苯基、C5~C15杂芳基或C10~C20稠芳基;
所述芳基中的取代基团为-O-、-NR2、-NHR、-NH2、-OH、-OR、-NHCOR、-OCOR、-R、-CH2COOH、-SH、-Br、-Cl、-F、-COR和-COOR中的一种或几种;
所述R为烷基;
当所述芳基中的取代基团中含有-Br、-Cl或-F时,-Br、-Cl或-F的个数为1。
优选的,当所述取代或未取代的芳基为取代或未取代的C5~C15杂芳基时,所述C5~C15杂芳基中的杂原子为O、S和N中的一种或几种;
所述杂原子的个数为1~3。
优选的,当所述取代或未取代的芳基为取代或未取代的C10~C20稠芳基时,所述稠芳基为萘基、菲基或蒽基。
优选的,所述α-偕二氟叠氮化合物为:
本发明还提供了所述α-偕二氟叠氮化合物的制备方法,包括以下步骤:
将具有式Ⅱ所示结构的烯基叠氮类化合物、氧化剂、氟源和溶剂混合,进行反应,得到α-偕二氟叠氮化合物;
优选的,所述氧化剂为双氧水、叔丁基过氧化氢、2,3-二氯-5,6-二氰对苯醌、硝酸铈铵、过氧苯甲酸叔丁酯、间氯过氧苯甲酸、双叔丁基过氧化物、碘苯二乙酸、乙酸碘、亚碘酰苯、高价碘试剂、过硫酸钾、高锰酸钾、硝酸盐、次氯酸钾和高氯酸钾中的一种或几种。
优选的,所述氟源为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)、N-氟代双苯磺酰胺、1-氟-3,3-二甲基-1,2-苯并碘氧杂戊环、三乙胺三氢氟酸盐、氟化氢吡啶盐酸盐、N,N-二甲基丙脲氟化氢络合物、二氟化碘苯、二氟化碘苯衍生物、三氟化硼乙醚和氟化金属盐中的一种或几种。
优选的,所述溶剂为乙酸乙酯、四氢呋喃、甲苯、二氯甲烷、二氯乙烷、二甲基亚砜、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或几种。
优选的,所述烯基叠氮类化合物、氧化剂和氟源的摩尔比为1:(1~2):(5~7);
所述反应的温度为-20~80℃,所述反应的时间为1~180min。
本发明还提供了上述技术方案所述的α-偕二氟叠氮化合物或由权利要求5~9任一项所述的制备方法制备得到的α-偕二氟叠氮化合物作为合成药物、生物活性分子和天然产物前驱体的应用。
本发明提供了具有式Ⅰ所示结构的α-偕二氟叠氮化合物,可作为α-偕二氟氨基化合物的潜在前体,由于叠氮官能团的高反应活性,此类结构同样可以作为潜在的偕二氟基团的载体。本发明还提供了所述α-偕二氟叠氮化合物的制备方法,所述制备方法所用原料简便易得,操作简单、反应高效,可实现工业化合成。
附图说明
图1为2a的1H-NMR的核磁共振谱;
图2为2a的13C-NMR的核磁共振谱;
图3为2a的19F-NMR的核磁共振谱;
图4为2b的1H-NMR的核磁共振谱;
图5为2b的13C-NMR的核磁共振谱;
图6为2b的19F-NMR的核磁共振谱;
图7为2c的1H-NMR的核磁共振谱;
图8为2c的13C-NMR的核磁共振谱;
图9为2c的19F-NMR的核磁共振谱;
图10为2d的1H-NMR的核磁共振谱;
图11为2d的13C-NMR的核磁共振谱;
图12为2d的19F-NMR的核磁共振谱;
图13为2e的1H-NMR的核磁共振谱;
图14为2e的13C-NMR的核磁共振谱;
图15为2e的19F-NMR的核磁共振谱;
图16为2f的1H-NMR的核磁共振谱;
图17为2f的13C-NMR的核磁共振谱;
图18为2f的19F-NMR的核磁共振谱;
图19为2g的1H-NMR的核磁共振谱;
图20为2g的13C-NMR的核磁共振谱;
图21为2g的19F-NMR的核磁共振谱。
具体实施方式
本发明提供了一种α-偕二氟叠氮化合物,具有式Ⅰ所示结构:
式Ⅰ中,R1~R3各自独立的为取代或未取代的芳基或H;
所述芳基为苯基、C5~C15杂芳基或C10~C20稠芳基;
所述芳基中的取代基团为-O-、-NR2、-NHR、-NH2、-OH、-OR、-NHCOR、-OCOR、-R、-CH2COOH、-SH、-Br、-Cl、-F、-COR和-COOR中的一种或几种;
所述R为烷基;
当所述芳基中的取代基团中含有-Br、-Cl或-F时,-Br、-Cl或-F的个数为1。
在本发明中,当所述芳基为C5~C15杂芳基时,即R1~R3各自独立的为为取代或未取代的C5~C15杂芳基时,所述C5~C15杂芳基中的杂原子为O、S和N中的一种或几种;所述杂原子的个数优选为1~3,更优选为1~2。当所述杂原子个数为1,所述杂原子为N原子时,所述C5~C15杂芳基优选为当所述杂原子个数为1,所述杂原子为O原子时,所述杂芳基优选为当所述杂原子个数为1,所述杂原子为S时,所述C5~C15杂芳基优选为当所述杂原子个数为2时,所述杂原子为O和N、S和N,所述C5~C15杂芳基优选为
在本发明中,当所述R1~R3各自独立的为取代C5~C15杂芳基时,所述取代C5~C15杂芳基的取代基团优选为-O-、-NR2、-NHR、-NH2、-OH、-OR、-NHCOR、-OCOR、-R、-CH2COOH、-SH、-Br、-Cl、-F、-COR和-COOR中的一种或几种;所述R为烷基。当所述C5~C15杂芳基中的取代基团中含有-Br、-Cl或-F时,-Br、-Cl或-F的个数优选为1;本发明对所述C5~C15杂芳基中的取代基的总个数没有特殊的限定;本发明对所述-Br、-Cl或-F的取代位点优选为4号位取代或3号取代位。当所述芳基中的取代基团中不含-Br、-Cl或-F时,本发明对所述芳基中的取代基的个数或取代位点没有任何特殊的限定。
在本发明中,当所述芳基为稠芳基时,即R1~R3各自独立的为取代或未取代的芳基为取代或未取代的稠芳基时,所述稠芳基优选为萘基、菲基或蒽基。
在本发明中,当所述R1~R3各自独立的为取代的C10~C20稠芳基时,所述C10~C20稠芳基的取代基团优选为-O-、-NR2、-NHR、-NH2、-OH、-OR、-NHCOR、-OCOR、-R、-CH2COOH、-SH、-Br、-Cl、-F、-COR和-COOR中的一种或几种;所述R为烷基;当所述C10~C20稠芳基中的取代基团中含有-Br、-Cl或-F时,-Br、-Cl或-F的个数优选为1;本发明对所述C10~C20稠芳基中的取代基的总个数没有特殊的限定;本发明所述-Br、-Cl或-F的取代位点优选为4号位取代。当所述C10~C20稠芳基中的取代基团中不含-Br、-Cl或-F时,本发明对所述C10~C20稠芳基中的取代基的个数或取代位点没有任何特殊的限定。
在本发明中,所述α-偕二氟叠氮化合物优选为:
本发明还提供了所述的α-偕二氟叠氮化合物的制备方法,包括以下步骤:
将具有式Ⅱ所示结构的烯基叠氮类化合物、氧化剂、氟源和溶剂混合,进行反应,得到α-偕二氟叠氮化合物;
在本发明中,所述氧化剂优选为双氧水、叔丁基过氧化氢、2,3-二氯-5,6-二氰对苯醌、硝酸铈铵、过氧苯甲酸叔丁酯、间氯过氧苯甲酸、双叔丁基过氧化物、碘苯二乙酸、乙酸碘、亚碘酰苯、高价碘试剂、过硫酸钾、高锰酸钾、硝酸盐、次氯酸钾和高氯酸钾中的一种或几种;当所述氧化剂为上述具体选择中的两种以上时,本发明对所述具体物质的配比没有任何特殊的限定。所述氟源优选为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)、N-氟代双苯磺酰胺、1-氟-3,3-二甲基-1,2-苯并碘氧杂戊环、三乙胺三氢氟酸盐、氟化氢吡啶盐酸盐,N,N-二甲基丙脲氟化氢络合物,二氟化碘苯、二氟化碘苯其衍生物、三氟化硼乙醚和氟化金属盐中的一种或几种;当所述氟源为上述具体选择中的两种以上时,本发明对所述具体物质的配比没有任何特殊的限定。所述溶剂优选为乙酸乙酯、四氢呋喃、甲苯、二氯甲烷、二氯乙烷、二甲基亚砜、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或几种;当所述溶剂为上述具体选择中的两种以上时,本发明对所述具体物质的配比没有任何特殊的限定。
在本发明中,所述具有式Ⅱ所示结构的烯基叠氮类化合物、氧化剂和氟源的摩尔比优选为1:(1~2):(5~7),更优选为1:(1.2~1.8):(5.5~6.5)最优选为1:(1.4~1.6):(5.8~6.2)。在本发明中,所述具有式Ⅱ所示结构的烯基叠氮类化合物在反应液中的浓度优选为0.1~0.5mol/L,更优选为0.2~0.4mol/L,最优选为0.3mol/L。
在本发明中,所述混合优选在搅拌的条件下进行,本发明对所述搅拌没有任何特殊的限定,采用本领域技术人员熟知的搅拌过程并达到混合均匀的目的即可。本发明对所述混合的顺序没有任何特殊的限定,在本发明的具体实施例中,可以具体选择为先将氟源、氧化剂和溶剂混合后,再与具有式Ⅱ所示结构的烯基叠氮类化合物混合。
在本发明中,所述反应的温度优选为-20~80℃,更优选为20~30℃;所述反应的时间优选为1~180min。在本发明中,所述反应的时间优选通过TLC检测反应底物的含量来确定。
在本发明中,所述反应优选在油浴锅或杜瓦瓶中进行。
反应完成后,本发明优选对产物体系进行后处理;当所述芳基中的取代基团为-O-、-NR2、-NHR、-NH2、-OH、-OR、-NHCOR、-OCOR、-R、-CH2COOH、-SH、-Br、-Cl和-F中的一种或几种,且-Cl的取代位点为4号位碳原子时,所述后处理为对得到的产物体系进行减压蒸馏去除溶剂后,采用硅胶柱进行层析,得到α-偕二氟叠氮化合物;
当所述芳基中的取代基团为-COR、-COOR和-Cl中的一种或几种,且-Cl的取代位点为3号碳原子时;所述后处理为萃取后干燥、减压蒸馏和柱层析;本发明对所述萃取、干燥、减压蒸馏和柱层析均没有任何特殊的限定。
本发明还提供了所述α-偕二氟叠氮化合物或由上述制备方法制备得到的α-偕二氟叠氮化合物作为合成多种药物、生物活性分子和天然产物前驱体的应用。
下面结合实施例对本发明提供的α-偕二氟叠氮化合物及其制备方法和应用进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
α-偕二氟叠氮化合物2a的制备:
在搅拌的条件下,将2.5mmol氟化氢吡啶盐酸盐(Py·HF)、0.6mmol碘苯二乙酸(PIDA)和5mL二氯甲烷混合后,加入0.5mmol烯基叠氮化合物1a,在25℃下反应1min,减压蒸馏去除溶剂后,采用硅胶柱进行层析得到2a(无色液体),产率为79%;
1H NMR(600MHz,CDCl3)δ7.47(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),3.18(t,J=12.6Hz,2H);13C NMR(150MHz,CDCl3)δ132.1 131.7,130.0(t,J=3.0Hz),122.6(t,J=264.0Hz),122.2,41.6(t,J=27.0Hz).19F NMR(564MHz,CDCl3)-72.58(t,J=12.6Hz).IR(KBr,cm-1)2107。
实施例2
α-偕二氟叠氮化合物2b的制备
制备过程与实施例1相同,区别仅在于将1a替换为1b,产率为75%;
1H NMR(600MHz,CDCl3)δ7.25(t,J=8.4Hz,2H),7.03(t,J=8.4Hz,2H),3.20(t,J=12.6Hz,2H);13C NMR(150MHz,CDCl3)δ162.6(d,J=246.0Hz),132.0(d,J=7.5Hz),126.8(q,J=3.5Hz),122.8(t,J=267.0Hz),115.5(d,J=21.0Hz),41.4(t,J=28.5Hz).19F NMR(564MHz,CDCl3)-72.90(t,J=12.6Hz,),(-114.22)-(-114.38)(m).IR(KBr,cm-1)2108。
实施例3
α-偕二氟叠氮化合物2c的制备
制备过程与实施例1相同,区别仅在于将1c替换为1f,产率为90%;
1H NMR(600MHz,CDCl3)δ7.21-7.11(m,4H),3.19(t,J=12.6Hz,2H),2.35(s,3H);13C NMR(150MHz,CDCl3)δ137.7,130.3,129.2,128.0(t,J=3.5Hz),123.0(t,J=265.5Hz),41.8(t,J=27.0Hz),21.1.19F NMR(564MHz,CDCl3)-72.44(t,J=12.6Hz).IR(KBr,cm-1)2109。
实施例4
α-偕二氟叠氮化合物2d的制备
制备过程与实施例1相同,区别仅在于将1a替换为1d,产率为82%;
1H NMR(600MHz,CDCl3)δ7.13(d,J=8.4Hz,2H),6.81(d,J=8.4Hz,2H),3.73(s,3H),3.10(t,J=12.6Hz,2H);13C NMR(150MHz,CDCl3)δ159.4,131.5,123.0(t,J=265.0Hz),123.0(t,J=3.0Hz),114.0,55.2,41.4(t,J=27.0Hz).19FNMR(564MHz,CDCl3)-73.00(t,J=12.6Hz).IR(KBr,cm-1)2109。
实施例5
α-偕二氟叠氮化合物2e的制备
制备过程与实施例1相同,区别仅在于将1a替换为1e,产率为95%;
1H NMR(600MHz,CDCl3)δ7.36(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),3.20(t,J=12.6Hz,2H),1.32(s,9H);13C NMR(150MHz,CDCl3)δ150.9,130.1,128.0(t,J=3.5Hz),125.5,123.0(t,J=265.5Hz),41.7(t,J=27.0Hz),34.5,31.3.19F NMR(564MHz,CDCl3)-72.38(t,J=12.6Hz).IR(KBr,cm-1)2108。
实施例6
α-偕二氟叠氮化合物2f的制备
制备过程与实施例1相同,区别仅在于将1a替换为1f,产率为82%;
1H NMR(600MHz,CDCl3)δ7.86-7.80(m,3H),7.74(s,1H),7.51-7.45(m,2H),7.39(d,J=8.4Hz,1H),3.39(t,J=12.6Hz,2H);13C NMR(150MHz,CDCl3)δ133.2,132.8,129.7,128.5(t,J=3.0Hz),128.2,128.0,127.8,127.7,126.3,126.2,123.1(t,J=265.5Hz),42.4(t,J=27.0Hz).19F NMR(564MHz,CDCl3)-71.77(t,J=12.6Hz).IR(KBr,cm-1)2109。
实施例7
α-偕二氟叠氮化合物2g的制备
制备过程与实施例1相同,区别仅在于将1a替换为1g,产率为75%;
1H NMR(600MHz,CDCl3)δ7.32-7.29(m,1H),7.19(s,1H),7.03(d,J=4.8Hz,1H),3.29(t,J=12.6Hz,2H);13C NMR(150MHz,CDCl3)δ130.9(t,J=3.0Hz),128.9,125.9,124.9,122.6(t,J=264.0Hz),36.86(t,J=25.5Hz).19F NMR(564MHz,CDCl3)-72.77(t,J=12.6Hz).IR(KBr,cm-1)2105。
由以上实施例可知,本发明提供的具有式Ⅰ所示结构的α-偕二氟叠氮化合物的制备方法所用原料简便易得,操作简单、反应高效,可实现工业化合成。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种α-偕二氟叠氮化合物,具有式Ⅰ所示结构:
式Ⅰ中,R1~R3各自独立的为取代或未取代的芳基或H;
所述芳基为苯基、C5~C15杂芳基或C10~C20稠芳基;
所述芳基中的取代基团为-O-、-NR2、-NHR、-NH2、-OH、-OR、-NHCOR、-OCOR、-R、-CH2COOH、-SH、-Br、-Cl、-F、-COR和-COOR中的一种或几种;
所述R为烷基;
当所述芳基中的取代基团中含有-Br、-Cl或-F时,-Br、-Cl或-F的个数为1。
2.如权利要求1所述的α-偕二氟叠氮化合物,其特征在于,当所述芳基为C5~C15杂芳基时,所述C5~C15杂芳基中的杂原子为O、S和N中的一种或几种;
所述杂原子的个数为1~3。
3.如权利要求1所述的α-偕二氟叠氮化合物,其特征在于,当所述芳基为C10~C20稠芳基时,所述稠芳基为萘基、菲基或蒽基。
4.如权利要求1所述的α-偕二氟叠氮化合物,其特征在于,所述α-偕二氟叠氮化合物为:
5.权利要求1~4任一项所述的α-偕二氟叠氮化合物的制备方法,包括以下步骤:
将具有式Ⅱ所示结构的烯基叠氮类化合物、氧化剂、氟源和溶剂混合,进行反应,得到α-偕二氟叠氮化合物;
6.如权利要求5所述的制备方法,其特征在于,所述氧化剂为双氧水、叔丁基过氧化氢、2,3-二氯-5,6-二氰对苯醌、硝酸铈铵、过氧苯甲酸叔丁酯、间氯过氧苯甲酸、双叔丁基过氧化物、碘苯二乙酸、乙酸碘、亚碘酰苯、高价碘试剂、过硫酸钾、高锰酸钾、硝酸盐、次氯酸钾和高氯酸钾中的一种或几种。
7.如权利要求5所述的制备方法,其特征在于,所述氟源为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)、N-氟代双苯磺酰胺、1-氟-3,3-二甲基-1,2-苯并碘氧杂戊环、三乙胺三氢氟酸盐、氟化氢吡啶盐酸盐、N,N-二甲基丙脲氟化氢络合物、二氟化碘苯、二氟化碘苯衍生物、三氟化硼乙醚和氟化金属盐中的一种或几种。
8.如权利要求5所述的制备方法,其特征在于,所述溶剂为乙酸乙酯、四氢呋喃、甲苯、二氯甲烷、二氯乙烷、二甲基亚砜、N-甲基吡咯烷酮和N,N-二甲基甲酰胺中的一种或几种。
9.如权利要求5所述的制备方法,其特征在于,所述烯基叠氮类化合物、氧化剂和氟源的摩尔比为1:(1~2):(5~7);
所述反应的温度为-20~80℃,所述反应的时间为1~180min。
10.权利要求1~4任一项所述的α-偕二氟叠氮化合物或由权利要求5~9任一项所述的制备方法制备得到的α-偕二氟叠氮化合物作为合成药物、生物活性分子和天然产物前驱体的应用。
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SVATAVA VOLTROVÁ等: "Synthesis of tetrafluoroethylene- and tetrafluoroethyl-containing azides and their 1,3-dipolar cycloaddition as synthetic application", 《ORG.BIOMOL.CHEM.》 * |
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