CN116874438A - 一锅法制备多取代1,2,3-三唑类化合物 - Google Patents
一锅法制备多取代1,2,3-三唑类化合物 Download PDFInfo
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- -1 polysubstituted 1,2, 3-triazole compound Chemical class 0.000 title claims abstract description 56
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims abstract description 11
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 7
- NMMMFUQJURZRPE-UHFFFAOYSA-N dimethyl 2-prop-1-ynylpropanedioate Chemical compound COC(=O)C(C#CC)C(=O)OC NMMMFUQJURZRPE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 14
- 229940073608 benzyl chloride Drugs 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 claims description 4
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- QKLWAMMQKBOTCD-UHFFFAOYSA-N butane;diphenylphosphane Chemical compound CCCC.C=1C=CC=CC=1PC1=CC=CC=C1 QKLWAMMQKBOTCD-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 125000001399 1,2,3-triazolyl group Chemical class N1N=NC(=C1)* 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract 1
- 239000007777 multifunctional material Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 2
- MOBRMRJUKNQBMY-UHFFFAOYSA-N 1-(chloromethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CCl MOBRMRJUKNQBMY-UHFFFAOYSA-N 0.000 description 2
- KAYMDMKWWHKHSY-UHFFFAOYSA-N 1-[2-(chloromethyl)phenyl]naphthalene Chemical compound ClCC1=CC=CC=C1C1=CC=CC2=CC=CC=C12 KAYMDMKWWHKHSY-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- FUOHKPSBGLXIRL-UHFFFAOYSA-N 2-(chloromethyl)thiophene Chemical compound ClCC1=CC=CS1 FUOHKPSBGLXIRL-UHFFFAOYSA-N 0.000 description 2
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 2
- VALUMXGSLBMNES-UHFFFAOYSA-N 4,5-dimethyl-2h-triazole Chemical compound CC=1N=NNC=1C VALUMXGSLBMNES-UHFFFAOYSA-N 0.000 description 2
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- TYXWDMWSFQYDKQ-UHFFFAOYSA-N 4-diphenylphosphanylbutan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 TYXWDMWSFQYDKQ-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- 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
- C07D409/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于生物医药中间体及相关化学技术领域,提供了一锅法制备多取代1,2,3‑三唑类化合物,以含苄基卤化物及其衍生物、丁炔二甲酸二甲酯和叠氮三甲基硅烷为原料,在金属催化剂、配体,添加剂的作用下,在无水有机溶剂条件下,在100℃下反应24小时,得到相应的多取代1,2,3‑三唑化合物。本发明的有益效果是该合成方法为一步法反应、操作简便,高收率;所得反应产物可以作为药物分子合成的中间体或应用于其他多功能材料。
Description
技术领域
本发明属于生物医药中间体及相关化学技术领域,提供了一种高效的多取代1,2,3-三唑类化合物的制备方法。
背景技术
1,2,3-三唑化合物因具有独特电子性质,在生物、医药等领域,都有着很重要的应用价值,并广泛存在于已有的药物分子中。而多取代1,2,3-三唑结构的构筑则尤为重要。
已经报道的多取代1,2,3-三唑化合物的合成方法采用NH-1,2,3-三唑衍生物与苄基卤代物反应得到,而NH-1,2,3-三唑衍生物则需叠氮化钠与硝基烯烃和烯酮在碱的催化下发生加成反应得到[Chem.Commun.,2008,(28):3254-3256],反应过程复杂。
近年来,过渡金属催化合成多取代1,2,3-三唑化合物因其具有操作简单,反应效率高,易于制取复杂功能分子等优点被越来越多的人所看好[Org.Chem.Front.,2018,5(16):2463-2467]、[Org.Biomol.Chem.,2019,17(19):4843-4849]、[Catal.Sci.Technol.,2018,8(13):3246-3259]。而如今以过渡金属作为催化剂直接获得N-苄基-4,5-二酯基-1,2,3-三唑化合物的合成方法还未见报道。
发明内容
本发明提供了一锅法制备多取代1,2,3-三唑化合物的具体内容,该制备方法具有反应条件操作简便、底物范围广泛等优点。
本发明的技术方案:
一锅法制备多取代1,2,3-三唑类化合物,以苄基氯代物及其衍生物、叠氮三甲基硅烷(TMSN3)和丁炔二甲酸二甲酯为原料,在钯催化剂、配体和添加剂的共同作用下,在无水有机溶剂中,一锅法制备相应的多取代1,2,3-三唑化合物,合成路线如下:
R1选自萘基、2-甲氧基萘基、2-甲基萘基、2-氟苯基、2-噻吩基和3-苯基-2-噻吩基;
苄基氯代物及其衍生物与丁炔二甲酸二甲酯的摩尔比为1:1~1:2;
苄基氯代物及其衍生物与叠氮三甲基硅烷的摩尔比为1:1~1:2;
苄基氯代物及其衍生物与钯催化剂的摩尔比为1:0.01~1:0.05;
苄基氯代物及其衍生物与配体的摩尔比为1:0.1~1:0.5;
苄基氯代物及其衍生物与添加剂的摩尔比为1:0.1~1:0.5;
苄基氯代物及其衍生物在反应体系中的摩尔浓度为0.06mmol/mL;
所述的钯催化剂为三(二亚苄基丙酮)二钯、三(二亚苄基丙酮)二钯-氯仿络合物、四(三苯基膦)钯、三氟乙酸钯、二(三苯基膦)二氯化钯,优选为三(二亚苄基丙酮)二钯和三(二亚苄基丙酮)二钯-氯仿络合物;
所述的配体为1,3-双(二苯膦)丙烷、1,3-双(二苯基膦)乙烷、1,3-双(二苯基膦)丁烷、三环己基膦、三苯基膦,优选为1,3-双(二苯膦)丙烷和三环己基膦;
所述的添加剂为碘化亚铜、氰化亚铜、三氟甲磺酸亚铜,优选为碘化亚铜和三氟甲磺酸亚铜;
所述的无水有机溶剂为甲苯、乙酸乙酯、乙二醇二甲醚、1,4-二氧六环、四氢呋喃,优选为1,4-二氧六环、乙酸乙酯和乙二醇二甲醚;
分离方法为柱层析;
用柱层析方法进行产物分离时,可以使用硅胶或者中性氧化铝作为固定相,展开剂一般为极性与非极性的混合溶剂,如乙酸乙酯-石油醚、乙酸乙酯-正己烷、二氯甲烷-石油醚、甲醇-石油醚。
本发明的有益效果是该方法为一步合成法、反应操作简便,高收率;所得产物可以进行多种官能化,反应产物可以应用于药物分子的合成[Bioorg.Med.Chem.Lett.2006,16,3985–3988]。
附图说明
图1是实施例1中2-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图2是实施例1中2-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图3是实施例1中1-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图4是实施例1中1-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图5是实施例2中2-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图6是实施例2中2-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图7是实施例2中1-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图8是实施例2中1-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图9是实施例3中2-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图10是实施例3中2-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图11是对比例3中1-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图12是对比例3中1-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图13是实施例4中2-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图14是实施例4中2-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图15是实施例4中1-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图16是实施例4中2-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图17是实施例5中2-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图18是实施例5中2-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
图19是实施例5中1-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的1H核磁谱图。
图20是实施例5中1-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的13C核磁谱图。
具体实施方式
本发明所述的多取代1,2,3-三唑类化合物的制备方法,具有反应步骤少、操作简单和反应收率高等优点。
下面结合具体实施例,进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。在本领域内的技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案之内。
实施例1:2-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑和1-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的合成
在氮气保护下,向一干燥的25mL Schlenk反应器中依次加入三(二亚苄基丙酮)二钯(18.3mg,5mol%)、1,3-双(二苯膦)丙烷(13mg,10mol%)、碘化亚铜(3.8mg,10mol%)、萘苄氯(35mg,0.2mmol)和无水1,4-二氧六环(3mL),在室温下搅拌30min后,加入叠氮三甲基硅烷(23mg,0.2mmol)和丁炔二酸二甲酯(28mg,0.2mmol),在100℃下加热回流24小时。反应结束后,冷却至室温,通过TLC点板检测确认萘苄氯消耗完,通过旋蒸除去溶剂,并使用硅胶柱色谱法(硅胶,200-300目;展开剂,石油醚:乙酸乙酯=20:1~石油醚:乙酸乙酯=6:1)将所得油状物进行分离纯化,分别得到2-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑33mg,产率48%和1-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑21mg,产率30%,总产率78%。
2-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色油状液体;1H NMR(400MHz,CDCl3)δ8.12(d,J=9.3Hz,1H),7.85(d,J=8.2Hz,2H),7.58–7.39(m,4H),6.07(s,2H),3.91(s,6H);13C{1H}NMR(100MHz,CDCl3)δ162.0,142.7,135.8,133.8,131.2,130.1,129.1,128.9,128.5,127.2,126.2,125.8,122.9,57.0,52.8;IR(neat):υmax3452,3047,2954,2925,1736,1599,1510,1456,1303,1222,1095,1017,838,783cm-1;HRMS(ESI)m/zcalcd forC16H12N3O4[M+H]+:326.1135,found:326.1134.
2-(萘-1-基甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色油状液体;1H NMR(400MHz,CDCl3)δ8.09(d,J=8.1Hz,1H),7.86(dd,J=8.4,8.4Hz,2H),7.60–7.48(m,2H),7.40(dd,J=7.7,7.7Hz,1H),7.18(d,J=7.1Hz,1H),6.25(s,2H),3.93(s,3H),3.74(s,3H);13C{1H}NMR(100MHz,CDCl3)δ160.3,159.2,139.6,133.8,130.9,130.9,129.9,129.2,128.9,127.3,127.1,126.4,125.0,122.7,53.4,52.7,52.1;IR(neat):υmax 3047,2954,2925,1736,1599,1510,1456,1303,1222,1095,1017,838,783cm-1;HRMS(ESI)m/zcalcd forC16H12N3O4[M+H]+:326.1135,found:326.1135.
实施例2:2-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑和1-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的合成
在氮气保护下,向一干燥的25mL Schlenk反应器中依次加入三(二亚苄基丙酮)二钯-氯仿络合物(19mg,5mol%)、1,3-双(二苯膦)丁烷(16mg,10mol%)、氰化亚铜(2mg,10mol%)、2-甲氧基萘苄氯(41mg,0.2mmol)和无水乙二醇二甲醚(3mL),在室温下搅拌30min后,加入叠氮三甲基硅烷(35mg,0.3mmol)和丁炔二酸二甲酯(43mg,0.3mmol),在100℃下加热回流24小时。反应结束后,冷却至室温,通过TLC点板检测确认2-甲氧基萘苄氯消耗完,通过旋蒸除去溶剂,并使用硅胶柱色谱法(硅胶,200-300目;洗脱剂:石油醚/乙酸乙酯=5:1)将所得油状物进行分离纯化,得到2-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑30mg,产率43%和1-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑32mg,产率45%,总产率88%。2-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色固体,熔点111–113℃;1H NMR(400MHz,CDCl3)δ8.02(d,J=8.6Hz,1H),7.87(d,J=9.1Hz,1H),7.78(d,J=8.2Hz,1H),7.54–7.46(m,1H),7.32(dd,J=22.6,8.4Hz,2H),6.17(s,2H),3.99(s,3H),3.90(s,6H);13C{1H}NMR(100MHz,CDCl3)δ161.2,159.5,139.3,137.31,132,5,132.2,131.5,130.1,129.0,128.8,127.4,125.3,125.0,122.4,53.2.51.5,47.8,19.6;IR(KBr):υmax 2955,2927,1737,1583,1511,1460,1394,1303,1224,1094,825,795,768,738cm-1;HRMS(ESI)m/zcalcd forC18H17N3O5[M+H]+:356.1241,found:356.1238.
1-((2-甲氧基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色固体,熔点111–113℃;1H NMR(400MHz,CDCl3)δ8.08(d,J=8.6Hz,1H),7.89(d,J=9.1Hz,1H),7.79(d,J=8.2Hz,1H),7.55–7.50(m,1H),7.37(dd,J=7.5,7.5Hz,1H),7.24(d,J=9.1Hz,1H),6.17(s,2H),3.90(d,J=2.3Hz,6H),3.76(s,3H);13C{1H}NMR(100MHz,CDCl3)δ160.5,159.5,156.0,138.4,132.8,132.0,131.9,128.9,128.7,127.9,123.9,122.4,113.5,112.3,56.3,53.2,52.5,44.8;IR(KBr):υmax 2955,2927,1737,1583,1511,1460,1394,1303,1224,1094,825,795,768,738cm-1;HRMS(ESI)m/zcalcd forC18H17N3O5[M+H]+:356.1241,found:356.1238.
实施例3:2-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑和1-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的合成
在氮气保护下,向一干燥的25mL Schlenk反应器中依次加入三氟乙酸钯(4mg,5mol%)、三环己基膦(5.6mg,10mol%)、三氟甲磺酸亚铜(4.3mg,10mol%)、2-甲基萘苄氯(38mg,0.2mmol)和无水四氢呋喃(3mL),在室温下搅拌30min后,加入叠氮三甲基硅烷(46mg,0.4mmol)和丁炔二酸二甲酯(56.8mg,0.4mmol),在100℃下加热回流24小时。反应结束后,冷却至室温,通过TLC点板检测确认2-甲基萘苄氯消耗完,通过旋蒸除去溶剂,并使用硅胶柱色谱法(硅胶,200-300目;洗脱剂:石油醚/乙酸乙酯=6:1)将所得油状物进行分离纯化,得到2-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑36mg,产率52%和1-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑28mg,产率41%,总产率93%。
2-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色固体,熔点94–96℃;1H NMR(400MHz,CDCl3)δ8.22(d,J=8.6Hz,1H),7.92–7.71(m,2H),7.56–7.52(m,1H),7.48–7.41(m,1H),7.37(d,J=8.4Hz,1H),6.12(s,2H),3.91(s,6H),2.75(s,3H);13C{1H}NMR(100MHz,CDCl3)δ160.5,139.7,137.1,132.5,132.4,129.9,129.2,128.7,127.3,125.8,125.2,123.0,53.2,52.8,20.6;IR(KBr):υmax 2954,2926,1737,1625,1458,1302,1222,1178,1095,1012,837,800,739cm-1;HRMS(ESI)m/zcalcd forC18H17N3O4[M+H]+:340.1292,found:340.1289.
1-((2-甲基萘-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色固体,熔点95–97℃;1H NMR(400MHz,CDCl3)δ7.94–7.70(m,3H),7.48–7.44(m,2H),7.35(d,J=8.4Hz,1H),6.18(s,2H),3.89(s,3H),3.56(s,3H),2.55(s,3H);13C{1H}NMR(100MHz,CDCl3)δ161.2,159.5,139.3,137.31,132,5,132.2,131.5,130.1,129.0,128.8,127.4,125.3,125.0,122.4,53.2.51.5,47.8,19.6;IR(KBr):υmax 2954,2926,1737,1625,1458,1302,1222,1178,1095,1012,837,800,739cm-1;HRMS(ESI)m/zcalcd forC18H17N3O4[M+H]+:340.1292,found:340.1289.
实施例4:2-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑和1-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的合成
在氮气保护下,向一干燥的25mL Schlenk反应器中依次加入二(三苯基膦)二氯化钯(14mg,5mol%)、三苯基膦(6mg,10mol%)、碘化亚铜(3.8mg,10mol%)、2-氟苄氯(29mg,0.2mmol)和无水乙酸乙酯(3mL),在室温下搅拌30min后,加入叠氮三甲基硅烷(46mg,0.4mmol)和丁炔二酸二甲酯(56.8mg,0.4mmol),在100℃下加热回流24小时。反应结束后,冷却至室温,通过TLC点板检测确认2-氟苄氯消耗完,通过旋蒸除去溶剂,并使用硅胶柱色谱法(硅胶,200-300目;洗脱剂:石油醚/乙酸乙酯=6:1)将所得油状物进行分离纯化,得到2-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑29.3mg,产率50%和1-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑23mg,产率39%,总产率89%。
2-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色油状液体;1H NMR(400MHz,CDCl3)δ7.35(q,J=7.6Hz,1H),7.27(d,J=3.7Hz,1H),7.18–7.06(m,2H),5.74(s,2H),3.96(s,6H);13C{1H}NMR(100MHz,CDCl3)δ160.2,140.2,131.0(d,J=8.2Hz),130.4(d,J=3.0Hz),124.6(d,J=3.7Hz),120.7(d,J=147Hz),115.9(d,J=21.0Hz),53.4(d,J=4.6Hz),52.8;19FNMR(376MHz,CDCl3)δ-117.43;IR(neat):υmax 2954,2925,2852,1735,1618,1493,1457,1377,1303,1222,1177,1093,1016,971,834,789,755cm-1;HRMS(ESI)m/zcalcd forC13H12FN3O4[M+Na]+:316.0705,found:316.0702.
1-((2-氟苯-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色油状液体;1H NMR(400MHz,CDCl3)δ7.39–7.31(m,1H),7.25–7.00(m,3H),5.88(s,2H),3.98(s,3H),3.93(s,3H);13C{1H}NMR(100MHz,CDCl3)δ159.6(d,J=168.7Hz),140.1,131.0(d,J=8.2Hz),130.5,129.9(d,J=3.0Hz),124.8(d,J=3.8Hz),121.4(d,J=14.4Hz),115.9(d,J=21.1Hz),53.6,52.8,47.7(d,J=4.5Hz);19FNMR(376MHz,CDCl3)δ-117.9;IR(neat):υmax2954,2925,2852,1735,1618,1493,1457,1377,1303,1222,1177,1093,1016,971,834,789,755cm-1;HRMS(ESI)m/zcalcd forC13H12FN3O4[M+Na]+:316.0705,found:316.0702.
实施例5:2-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑和1-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑的合成
在氮气保护下,向一干燥的25mL Schlenk反应器中依次加入四(三苯基膦)钯(12mg,5mol%)、1,3-双(二苯膦)乙烷(11mg,10mol%)、碘化亚铜(3.8mg,10mol%)、2-(氯甲基)噻吩(26mg,0.2mmol)和无水甲苯(3mL),在室温下搅拌30min后,加入叠氮三甲基硅烷(46mg,0.4mmol)和丁炔二酸二甲酯(56.8mg,0.4mmol),在100℃下加热回流24小时。反应结束后,冷却至室温,通过TLC点板检测确认2-(氯甲基)噻吩消耗完,通过旋蒸除去溶剂,并使用硅胶柱色谱法(硅胶,200-300目;洗脱剂:石油醚/乙酸乙酯=6:1)将所得油状物进行分离纯化,得到2-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑35mg,产率62%和1-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑16mg,产率27%,总产率89%。
2-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色油状液体;1H NMR(400MHz,CDCl3)δ7.35–7.30(m,1H),7.20(d,J=3.2Hz,1H),7.01–6.96(m,1H),5.83(s,2H),3.97(s,6H);13C{1H}NMR(100MHz,CDCl3)δ160.1,140.2,134.4,128.9,127.5,127.2,54.3,52.9;IR(neat):υmax 2955,2924,2353,1739,1628,1509,1459,1430,1305,1265,1224,1096,1013,834,799,737cm-1;HRMS(ESI)m/zcalcdforC11H11N3O4S[M+H]+:282.0544,found:282.0543.
1-((2-噻吩-1-基)甲基)-4,5-二羧酸二甲酯-1,2,3-三唑黄色油状液体;1H NMR(400MHz,CDCl3)δ7.29(dd,J=5.2,1.3Hz,1H),7.13(d,J=3.6 Hz,1H),6.98–6.94(m,1H),6.00(s,2H),3.98(s,3H),3.96(s,3H);13C{1H}NMR(100 MHz,CDCl3)δ160.4,158.8,140.3,135.4,129.2,128.7,127.4,127.2,53.5,52.7,48.5;IR(neat):υmax2955,2924,2353,1739,1628,1509,1459,1430,1305,1265,1224,1096,1013,834,799,737cm-1;HRMS(ESI)m/zcalcdforC11H11N3O4S[M+H]+:282.0544,found:282.0543.
Claims (5)
1.一锅法制备多取代1,2,3-三唑类化合物,其特征在于,以苄基氯代物及其衍生物、叠氮三甲基硅烷和丁炔二甲酸二甲酯为原料,在钯催化剂、配体和添加剂的共同作用下,在无水有机溶剂中,一锅法制备相应的多取代1,2,3-三唑化合物,合成路线如下:
R1选自萘基、2-甲氧基萘基、2-甲基萘基、2-氟苯基、2-噻吩基和3-苯基-2-噻吩基;
苄基氯代物及其衍生物与丁炔二甲酸二甲酯的摩尔比为1:1~1:2;
苄基氯代物及其衍生物与叠氮三甲基硅烷的摩尔比为1:1~1:2;
苄基氯代物及其衍生物与钯催化剂的摩尔比为1:0.01~1:0.05;
苄基氯代物及其衍生物与配体的摩尔比为1:0.1~1:0.5;
苄基氯代物及其衍生物与添加剂的摩尔比为1:0.1~1:0.5;
苄基氯代物及其衍生物在反应体系中的摩尔浓度为0.06mmol/mL。
2.根据权利要求1所述的一锅法制备多取代1,2,3-三唑类化合物,其特征在于,所述的钯催化剂为三(二亚苄基丙酮)二钯、三(二亚苄基丙酮)二钯-氯仿络合物、四(三苯基膦)钯、三氟乙酸钯、二(三苯基膦)二氯化钯。
3.根据权利要求1所述的一锅法制备多取代1,2,3-三唑类化合物,其特征在于,所述的配体为1,3-双(二苯膦)丙烷、1,3-双(二苯基膦)乙烷、1,3-双(二苯基膦)丁烷、三环己基膦、三苯基膦。
4.根据权利要求1所述的一锅法制备多取代1,2,3-三唑类化合物,其特征在于,所述的添加剂为碘化亚铜、氰化亚铜、三氟甲磺酸亚铜。
5.根据权利要求1所述的一锅法制备多取代1,2,3-三唑类化合物,其特征在于,所述的无水有机溶剂为甲苯、乙酸乙酯、乙二醇二甲醚、1,4-二氧六环、四氢呋喃。
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