CN114057634A - 一种5-三氟甲硫基烟酸酯系列物的制备方法 - Google Patents
一种5-三氟甲硫基烟酸酯系列物的制备方法 Download PDFInfo
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- trifluoromethylthio
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- -1 nicotinate series compounds Chemical class 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000010949 copper Substances 0.000 claims abstract description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052802 copper Inorganic materials 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 239000007800 oxidant agent Substances 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000000654 additive Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- 239000000758 substrate Substances 0.000 claims abstract description 5
- GZRXLNQFRQGJLU-UHFFFAOYSA-M silver;trifluoromethanethiolate Chemical compound [Ag+].FC(F)(F)[S-] GZRXLNQFRQGJLU-UHFFFAOYSA-M 0.000 claims abstract description 4
- 229910052723 transition metal Inorganic materials 0.000 claims abstract 2
- 150000003624 transition metals Chemical class 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical group CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 15
- 229910002567 K2S2O8 Inorganic materials 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- IDWJREBUVYSPKS-UHFFFAOYSA-N 3,8-dibromo-1,10-phenanthroline Chemical compound BrC1=CN=C2C3=NC=C(Br)C=C3C=CC2=C1 IDWJREBUVYSPKS-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 229910004882 Na2S2O8 Inorganic materials 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
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- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- QSPSCCUUGYIQCI-UHFFFAOYSA-N trifluoromethyl hydrogen carbonate Chemical group OC(=O)OC(F)(F)F QSPSCCUUGYIQCI-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 21
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- 229940079593 drug Drugs 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- PSODNBWECRSMRX-UHFFFAOYSA-N C1(=CC=CC=C1)OC(C=CC#C)=O Chemical compound C1(=CC=CC=C1)OC(C=CC#C)=O PSODNBWECRSMRX-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- CZHXAJUGVVDTNH-UHFFFAOYSA-N 2-(trifluoromethylsulfanyl)pyridine Chemical compound FC(F)(F)SC1=CC=CC=N1 CZHXAJUGVVDTNH-UHFFFAOYSA-N 0.000 description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000005906 Imidacloprid Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- YWTYJOPNNQFBPC-UHFFFAOYSA-N imidacloprid Chemical compound [O-][N+](=O)\N=C1/NCCN1CC1=CC=C(Cl)N=C1 YWTYJOPNNQFBPC-UHFFFAOYSA-N 0.000 description 2
- 229940056881 imidacloprid Drugs 0.000 description 2
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 2
- 229960001785 mirtazapine Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000006636 nicotinic acid Chemical class 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 2
- 229960003226 nikethamide Drugs 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
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- PFFIDZXUXFLSSR-UHFFFAOYSA-N 1-methyl-N-[2-(4-methylpentan-2-yl)-3-thienyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound S1C=CC(NC(=O)C=2C(=NN(C)C=2)C(F)(F)F)=C1C(C)CC(C)C PFFIDZXUXFLSSR-UHFFFAOYSA-N 0.000 description 1
- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical group FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 description 1
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229910014263 BrF3 Inorganic materials 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- YWBVHLJPRPCRSD-UHFFFAOYSA-N Fluridone Chemical compound O=C1C(C=2C=C(C=CC=2)C(F)(F)F)=CN(C)C=C1C1=CC=CC=C1 YWBVHLJPRPCRSD-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 241000370001 Hantavirus Liu Species 0.000 description 1
- 239000005816 Penthiopyrad Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000005926 Pyridalyl Substances 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000037354 amino acid metabolism Effects 0.000 description 1
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- 229960000590 celecoxib Drugs 0.000 description 1
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- 229940121657 clinical drug Drugs 0.000 description 1
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- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- OUIPBCNSMSGISS-UHFFFAOYSA-N pent-2-en-4-ynoic acid Chemical compound OC(=O)C=CC#C OUIPBCNSMSGISS-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- AEHJMNVBLRLZKK-UHFFFAOYSA-N pyridalyl Chemical group N1=CC(C(F)(F)F)=CC=C1OCCCOC1=C(Cl)C=C(OCC=C(Cl)Cl)C=C1Cl AEHJMNVBLRLZKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
- 239000011708 vitamin B3 Substances 0.000 description 1
Classifications
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及烟酸酯系列化合物,公开了一种5‑三氟甲硫基烟酸酯系列物的制备方法,它采用(E)‑2‑(叠氮甲基)‑5‑芳基戊‑2‑烯‑4‑炔酸甲酯作为反应底物,在过渡金属铜催化剂、配体、氧化剂、添加剂等作用下,于有机溶剂中与三氟甲硫基银加热搅拌反应得到5‑三氟甲硫基烟酸酯系列物。本发明的制备方法反应条件温和、成本较低、底物官能团适用范围广。本发明所得的产物经1H NMR,13C NMR,HRMS等表征确认。本发明所提供方法为合成具有潜在生物和药物活性的5‑三氟甲硫基烟酸酯衍生物及其类似化合物提供了新途径,在化工中间体、农药和医药等领域具有潜在的应用前景。
Description
技术领域
本发明涉及烟酸酯系列化合物,具体涉及一种5-三氟甲硫基烟酸酯系列物的制备方法。
背景技术
含氟氮杂环类化合物具有很好的生物活性,在诸多领域如医药、农药、日用化工等表现出广泛的应用前景。(M.Hamzehloo,A.Hosseinian,S.Ebrahimiasl,A.Monfared,E.Vessally,J.Fluor.Chem.2019,224,52.)尤其是在医药、农药方面,含氟氮杂环占据了重要地位。比如,已经上市的抗菌药Norfloxacin、Ofloxacin,抗肿瘤药物Celecoxib,杀虫剂Penthiopyrad、Pyridalyl、Benthiavalicard等。[(a)K.Muller,C.Faeh,F.Diederich.Science,2007,317,1881;(b)S.Purser,P.R.Moore,S.Swallow,V.Gouverneur,Chem.Soc.Rev.2008,37,320;(c)W.K.Hagmann,J.Med.Chem.2008,51,4359;(d)C.J.Zhang,Jin,C.Y.Zhang,J.Org.Chem.2014,34,662;(e)Y.Zhou,J.Wang,Z.Gu,S.Wang,W.Zhu,J.L.Acena,V.A.Soloshonok,K.Lzawa,H.Liu,Chem.Rev.2016,116,422.]
含吡啶骨架的化合物分子也广泛应用在医药和农药领域。比如,含吡啶环的药物分子米氮平(Mirtazapine),是一种抗抑郁药;含吡啶单元的药物分子尼可刹米(Nikethamide),是一种抑制呼吸中毒的药物;硝苯地平(Nifedipine),是治疗心绞痛的临床药物等;氟啶酮(Fluridone)是一种防除玉米田杂草的除草剂,吡虫啉(Imidacloprid)是一类高效、低毒、广谱的杀虫剂。(杜汉权,张勇,含氟吡啶类农药中间体的制备[J].有机氟工业,2012,02,49.)
烟酸,即维生素B3,是还原/氧化辅酶的一部分,参与能量代谢、氨基酸代谢,以及药物和其他物质的解毒反应,对人体具有非常重要的作用。烟酸酯作为烟酸的衍生物,其生物活性具有潜在的应用价值,非常值得研究和关注。
因此,研究和发展一些简单有效的方法合成含三氟甲硫基吡啶类化合物具有十分重要的科学意义和应用价值。至今合成三氟甲硫基吡啶的方法主要有三种:一是基于吡啶的格氏试剂与三氟甲硫基化试剂Ph-N(CH3)-SCF3之间的反应而制备(Baert,F.;Colomb,J.;Billard,T.Angew.Chem.Int.Ed.2012,51,10382.);第二种方法是通过二芳基二硫化物与碘甲烷反应而制备(Pooput,C.;Jr.,W.R.D.;Médebielle,M.J.Org.Chem.2006,71,3564.);第三种方法是利用杂环溴代烃与三氟甲硫基化试剂(bpy)Cu(SCF3)之间的偶联反应而制备(Zhang,M.;Weng,Z.Adv.Synth.Catal.2016,358,386.)。尽管上述方法的发展为合成三氟甲硫基吡啶衍生物提供了有效方法,但也存在原料制备复杂,反应条件要求严格、成本高等特点。此外,5-三氟甲硫基烟酸酯类化合物并没有找到现成的有效合成方法,因此开发一种有效方法合成5-三氟甲硫基烟酸酯衍生物具有十分重要的理论研究价值和工业生产方面的现实意义。
发明内容
本发明的目的就是要克服现有技术所存在的不足,提供一种反应条件温和的5-三氟甲硫基烟酸酯系列物的制备方法。
为实现上述目的,本发明采用(E)-2-(叠氮甲基)-5-芳基戊-2-烯-4-炔酸甲酯作为反应底物,在10mol%铜催化剂、20mol%配体2-双环己基膦-2',6'-二甲氧基联苯(S-phos)、0.5当量添加剂六甲基磷酰三胺(HMPA)和3.0当量氧化剂过硫酸钾作用下,于有机溶剂中,与1.5当量三氟甲硫基银反应(AgSCF3),反应温度80℃,于氮气氛围中进行反应12h,以中等产率得到5-三氟甲硫基烟酸酯系列物。
具体反应方程式如下:
其中,R为苯基、甲基、甲氧基、三氟甲氧基、甲酸酯基、氟、氯、溴、三氟甲基、氰基、苯基、乙酰基、叔丁基等基团取代的苯基、α-萘基和α-噻吩基中的一种或多种;铜催化剂为CuCl、CuBr、CuI、CuCN、CuF2或Cu(OAc)2;配体为3,8-二溴-1,10-菲啰啉、2,2'-双喹啉或2-双环己基膦-2',6'-二甲氧基联苯(S-phos);氧化剂为K2S2O8和/或Na2S2O8;有机溶剂为乙腈、DMF或DMSO;添加剂为六甲基磷酰三胺(HMPA)。反应温度为80℃,反应时间为12小时,反应在氮气氛围中进行。
优选地,本发明中反应体系所使用的(E)-2-(叠氮甲基)-5-芳基戊-2-烯-4-炔酸甲酯与三氟甲硫基银的摩尔比为1:1.5。
优选地,所述铜催化剂为CuF2。
优选地,所述配体为2-双环己基膦-2',6'-二甲氧基联苯(S-phos)。
优选地,所述氧化剂为K2S2O8。
优选地,所述反应溶剂为乙腈。
优选地,所述5-三氟甲硫基烟酸酯系列物的制备方法的具体步骤为:在20mL反应管中依次加入2-(叠氮基甲基)-5-芳基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,随后在PE:EA=20:1(即石油醚与乙酸乙酯的体积比为20:1)的极性下通过柱层析法进行分离提纯,分离所得产物即为5-三氟甲硫基烟酸酯系列化合物。
本发明的有益效果在于:本发明的制备方法反应条件温和、成本较低、底物官能团适用范围广。本发明所得的产物经1H NMR,13C NMR,HRMS等表征确认。本发明所提供方法为合成具有潜在生物和药物活性的5-三氟甲硫基烟酸酯衍生物及其类似化合物提供了新途径。在化工中间体、农药和医药等领域具有潜在的应用前景。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点,以下结合具体实施例对本发明作进一步的详细说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是,本发明还可以采用其他不同于在此描述的其他方式来实施,因此,本发明并不限于下面公开的具体实施例的限制。
实例1
在20mL反应管中依次加入2-(叠氮基甲基)-5-苯基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到白色固体产物,即6-苯基-5-三氟甲硫基烟酸甲酯(式a),产率60%。
mp 102-104℃.(Rf=0.3),PE:EA=10:1.1H NMR(400MHz,CDCl3)δ9.32(d,J=1.8Hz,1H),8.70(s,1H),7.59–7.57(m,2H),7.50–7.49(m,3H),4.01(s,3H).13C NMR(100MHz,CDCl3)δ166.6,164.6,151.6,145.5,138.1,129.6,128.9(q,1JCF=307.9Hz),128.2,125.2,120.9,52.8.19F NMR(376MHz,CDCl3)δ-41.47(s).HRMS(ESI):m/z[M+H]+calcd for C14H11F3NO2S+:314.0458;found:314.0457.
实例2
在20mL反应管中依次加入2-(叠氮基甲基)-5-(4-甲基)苯基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到白色固体产物,即6-(对甲苯基)-5-三氟甲硫基烟酸甲酯(式b),产率40%。
mp 102-104℃.(Rf=0.3),PE:EA=20:1.1H NMR(400MHz,CDCl3)δ9.30(d,J=0.8Hz,1H),8.69(s,1H),7.38–7.29(m,4H),4.00(s,3H),2.43(s,3H).13C NMR(100MHz,CDCl3)δ166.6,164.6,151.5,145.1,138.1,130.4,130.1,129.0(q,JCF=307.8Hz),128.0,126.7,125.1,121.0,52.7,21.4.19F NMR(376MHz,CDCl3)δ-41.41(s).HRMS(ESI):m/z[M+H]+calcd for C15H13F3NO2S+:328.0614;found:328.0612.
实例3
在20mL反应管中依次加入2-(叠氮基甲基)-5-(4-三氟甲氧基)苯基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到白色固体产物,即6-(4-三氟甲氧基苯基)-5-三氟甲硫基烟酸甲酯(式c),产率36%。
mp 58-61℃.(Rf=0.3),PE:EA=10:1.1H NMR(400MHz,CDCl3)δ9.32(d,J=1.9Hz,1H),8.71(d,J=0.9Hz,1H),7.65(d,J=8.8Hz,2H),7.34(d,J=8.1Hz,2H),4.02(s,3H).13CNMR(100MHz,CDCl3)δ165.3,164.4,151.9,150.2,146.1,136.6,131.4,130.4(q,1JCF=307.9Hz),125.5,120.7,120.4(q,1JCF=256.5Hz),120.4,52.9.19F NMR(376MHz,CDCl3)δ-41.48(s),-57.71(s).HRMS(ESI):m/z[M+H]+calcd for C15H10F6NO3S+:398.0280;found:398.0280.
实例4
在20mL反应管中依次加入2-(叠氮基甲基)-5-(3-氟苯基)戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到白色固体产物,即6-(3-氟苯基)-5-三氟甲硫基烟酸甲酯(式d),产率34%。
mp 52-55℃.(Rf=0.3),PE:EA=20:1.1H NMR(400MHz,CDCl3)δ9.32(d,J=1.2Hz,1H),8.71(s,1H),7.49–7.44(m,1H),7.36(d,J=7.8Hz,1H),7.32(dt,J=9.6,2.0Hz,1H),7.20(dt,J=2.0,8.4Hz,1H),4.02(s,3H).13C NMR(100MHz,CDCl3)δ165.2,164.4,162.4(d,J=245.6Hz),151.8,145.9,140.1(d,J=7.7Hz),129.8(d,J=8.1Hz),128.9(q,1JCF=308.0Hz),125.6,125.5(d,J=3.0Hz),120.9,116.8(d,J=23.1Hz),116.6(t,J=23.1Hz),52.8.19F NMR(376MHz,CDCl3)δ-41.43,-112.52.HRMS(ESI):m/z[M+H]+calcd forC14H10F4NO2S+:332.0363;found:332.0367.
实例5
在20mL反应管中依次加入2-(叠氮基甲基)-5-(3-溴苯基)戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到白色固体产物,即6-(3-溴苯基)-5-三氟甲硫基烟酸甲酯(式e),产率45%。
mp 98-99℃.(Rf=0.3),PE:EA=20:1.1H NMR(400MHz,CDCl3)δ9.32(d,J=1.9Hz,1H),8.71(d,J=0.8Hz,1H),7.75(s,1H),7.63(d,J=8.0Hz,1H),7.51(d,J=7.8Hz,1H),7.37(t,J=7.8Hz 1H),4.02(s,3H).13C NMR(100MHz,CDCl3)δ165.0 164.4,151.8,145.9140.0,132.6,129.7,128.8(q,1JCF=308.0Hz),128.3,125.7,122.3,120.9,52.9.19F NMR(376MHz,CDCl3)δ-41.40.HRMS(ESI):m/z[M+H]+calcd for C14H10BrF3NO2S+:391.9562;found:391.9563.
实例6
在20mL反应管中依次加入2-(叠氮基甲基)-5-(3-苯基)苯基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到白色固体产物,即6-(3-苯基)苯基-5-三氟甲硫基烟酸甲酯(式f),产率45%。
mp 149-150℃.(Rf=0.3),PE:EA=20:1.1H NMR(400MHz,CDCl3)δ9.33(d,J=1.9Hz,1H),8.71(s,1H),7.73-7.65(m,6H),7.47(t,J=7.5Hz,2H),7.38(t,J=7.3Hz,1H),4.01(s,3H).13C NMR(100MHz,CDCl3)δ166.2,164.6,151.7,145.6,142.5,140.3,137.0,130.2,129.0(q,1JCF=308.0Hz),128.9,127.8,127.2,126.9,125.1,120.8,52.8.19F NMR(376MHz,CDCl3)δ-41.39(s).HRMS(ESI):m/z[M+H]+calcd for C20H15F3NO2S+:390.0770;found:390.0768.
实例7
在20mL反应管中依次加入2-(叠氮基甲基)-5-(2-三氟甲基)苯基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到黄色油状物,即6-(2-三氟甲基)苯基-5-三氟甲硫基烟酸甲酯(式g),产率40%。
(Rf=0.3),PE:EA=20:1.1H NMR(400MHz,CDCl3)δ9.31(d,J=1.9Hz,1H),8.71(s,1H),7.80(d,J=7.5Hz,1H),7.68–7.59(m,2H),7.33(d,J=7.4Hz,1H),4.03(s,3H).13C NMR(100MHz,CDCl3)δ165.5,164.3,151.2,144.9,137.0,131.6,130.3,129.4,128.7(q,1JCF=307.7Hz),128.5(q,2JCF=30.7Hz),126.5(q,3JCF=4.8Hz),126.3,123.7(q,1JCF=272.3Hz),122.5,52.9.19F NMR(376MHz,CDCl3)δ-41.18,-58.33.HRMS(ESI):m/z[M+H]+calcd for C15H10F6NO2S+:382.0331;found:382.0330.
实例8
在20mL反应管中依次加入2-(叠氮基甲基)-5-(α-萘基)戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到黄色油状物,即6-(α-萘基)-5-三氟甲硫基烟酸甲酯(式h),产率58%。
(Rf=0.3),PE:EA=10:1.1H NMR(400MHz,CDCl3)δ9.40(d,J=2.0Hz,1H),8.78(d,J=0.9Hz,1H),7.99(d,J=8.3Hz,1H),7.94(d,J=8.1Hz,1H),7.58(t,J=7.1Hz,1H),7.52(t,J=7.6Hz,1H),7.46-7.41(m,2H),7.30(d,J=8.4Hz,1H),4.04(s,3H).13C NMR(100MHz,CDCl3)δ166.4,164.6,151.5,144.3,135.8,133.5,131.2,129.8,128.8(q,1JCF=307.8Hz),128.6,127.4,127.0,126.3,125.8,124.9,124.6,123.6,52.9.19F NMR(376MHz,CDCl3)δ-41.30(s).HRMS(ESI):m/z[M+H]+calcd for C18H13F3NO2S+:364.0614;found:364.0612.
实例9
在20mL反应管中依次加入2-(叠氮基甲基)-5-(α-噻吩基)苯基戊-2-烯-4-炔酸甲酯(0.1mmol,24.1mg),CuF2(0.2equiv,1.0mg),K2S2O8(3.0equiv,81.1mg),AgSCF3(1.5equiv,31.3mg),密封后插氮气球抽排三次。在氮气保护下,注射器注入HMPA(0.5equiv)和溶剂乙腈(1.5mL),然后将反应搅拌升温至80℃,反应12h。检测反应,至反应完全后,将反应液冷却至室温,加入10mL乙酸乙酯后通过硅胶短柱过滤除掉催化剂,转移到50mL圆底烧瓶中,加入少量硅胶、旋干,随后在PE:EA(体积比)=20:1的极性下通过柱层析法进行分离提纯,分离得到浅黄色固体产物,即6-(α-噻吩基)-5-三氟甲硫基烟酸甲酯(式i),产率43%。
mp 80-83℃,(Rf=0.3),PE:EA=10:1.1H NMR(400 MHz,CDCl3)δ9.20(d,J=2.4Hz,1H),8.59(d,J=1.0 Hz,1H),8.27(d,J=4.0 Hz,1H),7.58(d,J=5.1 Hz,1H),7.17(dd,J=5.1,4.0 Hz,1H),3.98(s,3H).13C NMR(100 MHz,CDCl3)δ164.4,158.8,152.0,148.1,142.0,131.9,131.6,129.0(q,1JCF=308.4 Hz),128.2,123.9,116.8,52.7.19F NMR(376 MHz,CDCl3)δ-41.55.HRMS(ESI):m/z[M+H]+calcd for C12H9F3NO2S2 +:320.0021;found:320.0021.
Claims (6)
1.一种5-三氟甲硫基烟酸酯系列物的制备方法,其特征在于,采用(E)-2-(叠氮甲基)-5-芳基戊-2-烯-4-炔酸甲酯作为反应底物,在过渡金属铜催化剂、配体、氧化剂、添加剂等作用下,于有机溶剂中与三氟甲硫基银加热搅拌反应得到5-三氟甲硫基烟酸酯系列物;
反应方程式如下:
其中,R为苯基、甲基、甲氧基、三氟甲氧基、甲酸酯基、氟、氯、溴、三氟甲基、氰基、苯基、乙酰基、叔丁基等基团取代的苯基、α-萘基和α-噻吩基中的一种或多种;铜催化剂为CuCl、CuBr、CuI、CuCN、CuF2或Cu(OAc)2;配体为3,8-二溴-1,10-菲啰啉、2,2'-双喹啉或2-双环己基膦-2',6'-二甲氧基联苯;氧化剂为K2S2O8和/或Na2S2O8;添加剂为六甲基磷酰三胺;有机溶剂为DMSO、DMF和乙腈;反应温度为80℃,反应时间为12小时。
2.根据权利要求1所述的5-三氟甲硫基烟酸酯系列物的制备方法,其特征在于:反应体系所使用的(E)-2-(叠氮甲基)-5-芳基戊-2-烯-4-炔酸甲酯与三氟甲硫基银的摩尔比为1:1.5~1:2。
3.根据权利要求1所述的5-三氟甲硫基烟酸酯系列物的制备方法,其特征在于:反应所使用的铜催化剂为CuF2。
4.根据权利要求1所述的5-三氟甲硫基烟酸酯系列物的制备方法,其特征在于:反应所使用的配体为2-双环己基膦-2',6'-二甲氧基联苯。
5.根据权利要求1所述的5-三氟甲硫基烟酸酯系列物的制备方法,其特征在于:反应所使用的氧化剂为K2S2O8。
6.根据权利要求1所述的5-三氟甲硫基烟酸酯系列物的制备方法,其特征在于:反应体系所使用的有机溶剂为乙腈。
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