CN106083713B - 一种喹(喔)啉-2-甲醛类化合物的化学合成方法 - Google Patents
一种喹(喔)啉-2-甲醛类化合物的化学合成方法 Download PDFInfo
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- -1 quinoline -2- benzaldehyde compound Chemical class 0.000 title claims abstract description 32
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract description 56
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract description 18
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 238000012805 post-processing Methods 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000007832 Na2SO4 Substances 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WPYJKGWLDJECQD-UHFFFAOYSA-N quinoline-2-carbaldehyde Chemical class C1=CC=CC2=NC(C=O)=CC=C21 WPYJKGWLDJECQD-UHFFFAOYSA-N 0.000 claims description 8
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229910002554 Fe(NO3)3·9H2O Inorganic materials 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 150000002505 iron Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical group [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 238000013517 stratification Methods 0.000 claims description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 229940113088 dimethylacetamide Drugs 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 6
- FBOFHVFMPNNIKN-UHFFFAOYSA-N 2,3-dimethylquinoline Chemical compound C1=CC=C2N=C(C)C(C)=CC2=C1 FBOFHVFMPNNIKN-UHFFFAOYSA-N 0.000 description 4
- JJPSZKIOGBRMHK-UHFFFAOYSA-N 2,3-dimethylquinoline Natural products N1=C(C)C=CC2=CC(C)=CC=C21 JJPSZKIOGBRMHK-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 2
- BELFSAVWJLQIBB-UHFFFAOYSA-N 2,8-dimethylquinoline Chemical compound C1=CC=C(C)C2=NC(C)=CC=C21 BELFSAVWJLQIBB-UHFFFAOYSA-N 0.000 description 2
- ALHUXMDEZNLFTA-UHFFFAOYSA-N 2-methylquinoxaline Chemical compound C1=CC=CC2=NC(C)=CN=C21 ALHUXMDEZNLFTA-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DXDPHHQJZWWAEH-UHFFFAOYSA-N 2-methyl-6-nitroquinoline Chemical compound C1=C([N+]([O-])=O)C=CC2=NC(C)=CC=C21 DXDPHHQJZWWAEH-UHFFFAOYSA-N 0.000 description 1
- PJEIWNDQRUDUBL-UHFFFAOYSA-N 3-methylquinoline-2-carbaldehyde Chemical compound C1=CC=C2N=C(C=O)C(C)=CC2=C1 PJEIWNDQRUDUBL-UHFFFAOYSA-N 0.000 description 1
- OCCIBGIEIBQGAJ-UHFFFAOYSA-N 6-chloro-2-methylquinoline Chemical compound C1=C(Cl)C=CC2=NC(C)=CC=C21 OCCIBGIEIBQGAJ-UHFFFAOYSA-N 0.000 description 1
- NAGJQQFMJKMXJQ-UHFFFAOYSA-N 6-methoxy-2-methylquinoline Chemical compound N1=C(C)C=CC2=CC(OC)=CC=C21 NAGJQQFMJKMXJQ-UHFFFAOYSA-N 0.000 description 1
- QEVADHKTNBIYSD-UHFFFAOYSA-N 7-methoxy-2-methylquinoline Chemical compound C1=CC(C)=NC2=CC(OC)=CC=C21 QEVADHKTNBIYSD-UHFFFAOYSA-N 0.000 description 1
- VVLYDFPOGMTMFJ-UHFFFAOYSA-N 8-chloro-2-methylquinoline Chemical compound C1=CC=C(Cl)C2=NC(C)=CC=C21 VVLYDFPOGMTMFJ-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960001951 montelukast sodium Drugs 0.000 description 1
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
本发明涉及一种喹(喔)啉‑2‑甲醛类化合物的制备方法:将式(Ⅱ)所示的2‑甲基喹(喔)啉溶于有机溶剂中,加入铁盐,在微波辅助下,于100~180℃条件下反应完全,反应液后处理,得式(Ⅰ)所示的喹(喔)啉‑2‑甲醛类化合物,所述铁盐与2‑甲基喹(喔)啉类化合物的投料物质的量比为0.5~3.5:1。式(Ⅰ)、式(Ⅱ)中的R同时为氢,或氢被C1‑C8的烷基、C1‑C8的烷氧基、硝基或卤素单取代或多取代,取代基个数为n,式(Ⅰ)、式(Ⅱ)中的X同时为碳或氮。本发明反应时间短,反应温度低,反应适用范围广,反应选择性好,所用催化剂廉价无毒,操作简便,符合绿色化学的要求。
Description
技术领域
本发明涉及一种喹(喔)啉-2-甲醛类化合物的化学合成方法,具体地说,涉及式(Ⅰ)所示的喹(喔)啉-2-甲醛类化合物的制备方法,属于有机合成领域。
背景技术
喹(喔)啉-2-甲醛及其衍生物,作为一类重要的喹(喔)啉类化合物,在药物、材料等多个领域内都有广泛应用。第一个上市治疗艾滋病的蛋白酶抑制剂沙奎那韦、哮喘药孟鲁司特钠、多种具有抗肿瘤、抗疟疾、抗结核、抗癫痫等活性的化合物均可以喹(喔)啉-2-甲醛作为中间体合成。此外,喹(喔)啉醛衍生物及其配合物具有独特的共轭结构,可用于制备优良的发光材料及荧光探针。
因喹(喔)啉环上氮原子的吸电子效应,降低了喹(喔)啉环的亲电反应活性,且该氮原子易质子化不易溶于有机溶剂,导致在喹(喔)啉环上更难发生亲电取代反应。喹(喔)啉-2-甲醛的合成难度较大,主要通过直接氧化法、间接氧化法、自由基反应等方法制备。
很多文献报道了喹啉-2-甲醛类衍生物的合成方法,如1972年Muth等人以2-甲基喹啉为起始原料,先与乙酸酐发生缩合反应,然后水解、氧化缩合制得喹啉-2-甲醛(J.Hex.Chem.,1972,9: 1299-1304),该反应使用了双氧水作为氧化剂,绿色环保,产物易于分离,但步骤繁琐,总收率不高。1986年Giordanoh等人报道了以喹啉和三聚甲醛为原料,在叔丁醇过氧化氢(TBHP)与Fe2+的作用下,发生自由基缩合反应得到三聚甲醛衍生物,继续在酸性条件下水解得到喹啉-2-甲醛(J.Org.Chem.,1986,51(4):536-537),该氧化方法选择性差,在喹啉的2位及4位均会发生反应。1996年Achremowicz等人通过二氧化硒氧化2-甲基喹啉一步制得喹啉-2-甲醛(Synthetic Commun.,1996,26(9):1681-1684),该方法选择性不好,当喹啉环的2~7位任意位置有甲基时,均可不同程度地被氧化为相应的醛。此外,二氧化硒为剧毒物质,环境污染严重,应用受到限制。还有很多其他的方法,但大部分方法的反应条件都比较苛刻,使用试剂价格昂贵。因此,有必要开发一条反应时间短、选择性好、环境友好的新颖合成路线。本发明提出了一种高效合成喹(喔)啉-2-甲醛类化合物的新方法,具有选择性高、催化剂易得价廉、操作简便等优点。
发明内容
本发明的目的在于提供一种简便高效制备喹(喔)啉-2-甲醛类化合物的新方法。
本发明合成路线如下:
为实现上述目的,本发明采用如下技术方案:
一种喹(喔)啉-2-甲醛类化合物的化学合成方法,所述化学合成方法按如下步骤进行:
将式(Ⅱ)所示的2-甲基喹(喔)啉溶于有机溶剂中,加入铁盐,在微波辅助下,于100~180℃条件下反应完全,TLC跟踪检测,反应完毕后反应液后处理,得式(Ⅰ)所示的喹(喔)啉-2-甲醛类化合物,所述铁盐与2-甲基喹(喔)啉类化合物的投料物质的量比为0.5~3.5:1;式(Ⅰ)、式(Ⅱ)中的R同时为氢,或氢被C1-C8的烷基、C1-C8的烷氧基、硝基或卤素单取代或多取代,取代基个数为n,n为1或2,式(Ⅰ)、式(Ⅱ)中的X同时为碳或氮。
式(Ⅰ)、式(Ⅱ)中的X同时优选为碳。
所述式(Ⅰ)、式(Ⅱ)中的R优选为氢,或氢被甲基、甲氧基、硝基或卤素单取代。
本发明所述的铁盐为FeSO4、FeCl2、FeCl3、FeCl3·6H2O、Fe(NO3)3或Fe(NO3)3·9H2O,优选为三价铁盐如FeCl3、FeCl3·6H2O和Fe(NO3)3·9H2O等,特别优选三价铁盐为FeCl3。
进一步,本发明所述的铁盐与2-甲基喹(喔)啉类化合物的投料物质的量比优选为1.0~2.5:1。
再进一步,本发明所述的有机溶剂为二甲基亚砜、甲苯、二氧六 环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或丙酮,优选为二甲基亚砜。
更进一步,本发明所述的有机溶剂的体积用量以所述的式(Ⅱ)所示的2-甲基喹(喔)啉的物质的量计为5~30mL/mmol,优选为10~15mL/mmol。
本发明所述的微波功率为150W。
本发明所述的反应,反应时间为:3~40min。
本发明所述的反应推荐在130~150℃条件下反应5~20min。
本发明所述的喹(喔)啉-2-甲醛类化合物的化学合成方法,特别推荐所述的喹(喔)啉-2-甲醛类化合物为下列之一:
具体的,本发明所述的反应液后处理方法为:反应完毕后,将反应液过滤,收集滤液倒入饱和NaHCO3水溶液中,混匀静置分层,所得水层用乙酸乙酯多次萃取,合并有机层,取乙酸乙酯层,用无水Na2SO4干燥,浓缩后得浓缩物经正己烷重结晶,得式(Ⅰ)所示的喹(喔)啉-2-甲醛类化合物。通常所述乙酸乙酯的用量与水相的体积比 为1:2,所述的无水Na2SO4的质量与乙酸乙酯的体积比为1:10(g/mL),重结晶时,所述正己烷的加入量要使浓缩物在回流温度下充分溶解,如在正已烷回流状态下浓缩物还没完全溶解,可在加热过程中继续加入正已烷直至所述的浓缩物全部溶解。
本发明所得化合物的结构经1H NMR、13C NMR等表征并得以确认。
本发明技术效果体现在反应时间大大缩短,反应温度降低,反应适用范围广,尤其是反应选择性非常好,比如起始原料是2,3-二甲基喹啉时,只有2-位甲基被氧化,专一性地生成产物3-甲基喹啉-2-甲醛,无3-位氧化产物生成。所用催化剂廉价无毒、操作简便,选择性好,反应迅速,避免使用二氧化硒有毒物质,符合绿色化学的要求。
具体实施方式
下面以具体的实施例对本发明的技术方案做进一步的说明,但本发明的保护范围不限于此。
实施例1
在80mL微波管中加入2-甲基喹啉(0.572g,4mmol)、Fe(NO3)3·9H2O(1.616g,4mmol)和DMSO(40mL),于CEM Discover微波反应器中于150W下,加热至150℃反应20min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×30mL) 萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(30mL)重结晶,得白色目标产物0.49g,收率78%。
熔点:68-69℃((文献70-72℃).1H NMR(400MHz,CDCl3)δ=10.21(s,1H),8.29(d,J=8.4Hz,1H),8.23(d,J=8.4Hz,1H),8.01(d,J=8.4Hz,1H),7.88(d,J=8.0Hz,1H),7.83~7.79(m,1H),7.69~7.66(m,1H);13C NMR(100MHz,CDCl3)δ192.6,151.9,147.2,136.8,130.0,129.9,129.5,128.7,127.4,116.9.
实施例2
在80mL微波管中加入2-甲基-6-甲氧基喹啉(0.346g,2mmol)、Fe(NO3)3(0.726g,3mmol)和丙酮(40mL),于CEM Discover微波反应器中于150W下,加热至160℃反应10min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×10mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(8mL)重结晶,得黄色目标产物0.12g,收率60%。
熔点:101-102℃(文献105℃),yield:60%.1H NMR(400MHz,CDCl3)δ=10.16(s,1H),8.15(d,J=8.4Hz,1H),8.11(d,J=9.2Hz,1H),7.98(d,J=8.4Hz,1H),7.45(dd,J=9.2Hz,2.8Hz,1H),7.11(d,J=2.8Hz,1H),3.97(s,3H);13C NMR(100MHz,CDCl3)δ192.4,159.2,149.9,143.3,135.2,131.4,131.2,123.2,117.5,104.8,55.9.
实施例3
在80mL微波管中加入2-甲基-7-甲氧基喹啉(0.173g,1mmol)、Fe(NO3)3·9H2O(1.41g,3.5mmol)和DMAc(30mL),于CEM Discover微波反应器中于150W下,加热至140℃反应40min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×15mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(8mL)重结晶,得黄色目标产物0.12g,收率64%。
熔点:103-105℃.1H NMR(400MHz,CDCl3)δ=10.15(s,1H),8.15~8.08(m,2H),7.98~7.94(m,1H),7.45~7.42(m,1H),7.10(s,1H),3.96(s,3H);13C NMR(100MHz,CDCl3)δ193.2,159.7,150.4,143.8,135.4,131.7,131.4,123.4,117.7,104.9,55.7.
实施例4
在80mL微波管中加入2,3-二甲基喹啉(0.314g,2mmol)、FeCl3·6H2O(1.02g,5mmol)和DMSO(50mL),于CEM Discover微波反应器中于150W下,加热至180℃反应35min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×15mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(15 mL)重结晶,得黄色目标产物0.18g,收率54%。
熔点:111-112℃(文献115-116℃).54%.1H NMR(400MHz,CDCl3)δ10.30(s,1H),8.17(d,J=8.4Hz,1H),7.99(s,1H),7.78(d,J=8.4Hz,1H),7.75~7.71(m,1H),7.65~7.61(m,1H),2.78(s,3H);13C NMR(100MHz,CDCl3)δ195.0,150.6,146.2,138.0,130.8,129.7,129.2,129.0,126.6,19.2.
实施例5
在80mL微波管中加入2,6-二甲基喹啉(0.417g,3mmol)、Fe(NO3)3·9H2O(1.818g,4.5mmol)和DMSO(45mL),于CEM Discover微波反应器中于150W下,加热至170℃反应30min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×25mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(25mL)重结晶,得黄色目标产物0.318g,收率63%。
熔点105-106℃(文献105-106℃).1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.18(d,J=8.4Hz,1H),8.11(d,J=8.8Hz,1H),7.97(d,J=8.4Hz,1H),7.64~7.63(m,2H),2.58(s,3H);13C NMR(100MHz,CDCl3)δ192.6,151.2,145.9,139.1,136.0,132.3,129.7,129.5,126.2,117.1,22.3.
实施例6
在80mL微波管中加入2,8-二甲基喹啉(0.314g,2mmol)、FeCl3(0.650g,4mmol)和DMF(40mL),于CEM Discover微波反应器中于150W下,加热至150℃反应25min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×15mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(15mL)重结晶,得黄色目标产物0.323g,收率48%。
熔点78-79℃(文献81℃).1HNMR(400MHz,CDCl3)δ10.21(s,1H),8.23(d,J=8.4Hz,1H),7.98(d,J=8.4Hz,1H),7.70(d,J=8.8Hz,1H),7.64~7.62(m,1H),7.56~7.52(m,1H),2.88(s,3H);13C NMR(100MHz,CDCl3):193.9,151.4,146.8,138.7,137.2,130.2,130.0,128.8,125.6,116.8,17.9.
实施例7
在80mL微波管中加入2-甲基-8-氯喹啉(0.888g,5mmol)、Fe(NO3)3(2.02g,5mmol)和DMSO(50mL),于CEM Discover微波反应器中于150W下,加热至130℃反应15min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×40mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(35 mL)重结晶,得黄色目标产物0.498g,收率52%。
熔点:143-145℃(文献129-131℃).1H NMR(400MHz,CDCl3):10.28(s,1H),8.33(d,J=8.4Hz,1H),8.08(d,J=8.4Hz,1H),7.92(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),7.59(t,J=8.0,Hz,1H);13C NMR(100MHz,CDCl3):192.3,152.2,143.7,137.4,134.4,130.9,130.1,128.6,126.4,117.7.
实施例8
在80mL微波管中加入2-甲基-6-硝基喹啉(0.752g,4mmol)、Fe(NO3)3·9H2O(1.616g,4mmol)和甲苯(40mL),于CEM Discover微波反应器中于150W下,加热至130℃反应10min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×30mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(30mL)重结晶,得黄色目标产物0.654g,收率81%。
熔点:136-137oC(文献170-171℃);1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.22~8.16(m,2H),8.03(d,J=8.4Hz,1H),7.78(s,1H),7.74(d,J=8.8Hz,1H);13C NMR(100MHz,CDCl3)δ192.2,152.1,145.7,135.9,134.7,131.5,131.0,130.1,126.1,117.9.
实施例9
在80mL微波管中加入2-甲基-6-氟喹啉(0.644g,4mmol)、FeSO4(0.608g,4mmol)和1,4-二氧六环(50mL),于CEM Discover微波反应器中于150W下,加热至100℃反应5min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×30mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(30mL)重结晶,得黄色目标产物0.511g,收率73%。
熔点116-117℃(文献122-124℃).1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.26~8.23(m,2H),8.03(d,J=8.8Hz,1H),7.61~7.56(m,1H),7.51(dd,J=8.4Hz,2.8Hz,1H);13CNMR(100MHz,CDCl3)δ192.3,161.2(d,1JCF=249.4Hz),151.5,144.4,136.1(d,4JCF=5.4Hz),132.6(d,3JCF=9.3Hz),130.5(d,3JCF=10.5Hz),120.6(d,2JCF=25.7Hz),117.7,110.6(d,2JCF=21.8Hz).
实施例10
在80mL微波管中加入2-甲基-6-氯喹啉(0.355g,2mmol)、FeCl2(0.254g,2mmol)和DMSO(30mL),于CEM Discover微波反应器中于150W下,加热至115℃反应10min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×15mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(15mL)重 结晶,得黄色目标产物0.257g,收率67%。
熔点:136-137oC(文献170-171℃).1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.22~8.16(m,2H),8.03(d,J=8.4Hz,1H),7.78(s,1H),7.74(d,J=8.8Hz,1H);13C NMR(100MHz,CDCl3)δ192.2,152.1,145.7,135.9,134.7,131.5,131.0,130.1,126.1,117.9.
实施例11
在80mL微波管中加入2-甲基喹喔啉(0.576g,4mmol)、Fe(NO3)3·9H2O(0.808g,2mmol)和DMSO(50mL),于CEM Discover微波反应器中于150W下,加热至135℃反应3min。反应结束后冷却至室温,过滤,滤液倒入饱和NaHCO3水溶液中,乙酸乙酯(3×30mL)萃取,合并有机层,经无水Na2SO4干燥后,减压浓缩,经正己烷(35mL)重结晶,得黄色目标产物0.506g,收率80%。
熔点:97-98℃(文献107-108℃),yield:%.1H NMR(400MHz,CDCl3):10.20(s,1H),9.35(s,1H),8.20~8.11(m,2H),7.92-7.82(m,2H);13C NMR(100MHz,CDCl3):191.6,145.0,141.9,132.8,132.4,131.4,130.7,130.0,129.2。
Claims (10)
1.一种喹啉-2-甲醛类化合物或喹喔啉-2-甲醛类化合物的制备方法,其特征在于所述制备方法按如下步骤进行:
将式(Ⅱ)所示的2-甲基喹啉类化合物或2-甲基喹喔啉类化合物溶于有机溶剂中,加入铁盐,在微波辅助下,于100~180℃条件下反应完全,反应完毕后反应液后处理,分别得式(Ⅰ)所示的喹啉-2-甲醛类化合物或喹喔啉-2-甲醛类化合物,所述铁盐与2-甲基喹啉类化合物或2-甲基喹喔啉类化合物的投料物质的量比为0.5~3.5:1;
式(Ⅰ)、式(Ⅱ)中的R同时为氢,或氢被C1-C8的烷基、C1-C8的烷氧基、硝基或卤素单取代或多取代,取代基个数为n,n为1或2,式(Ⅰ)、式(Ⅱ)中的X同时为CH或氮,
2.如权利要求1所述的制备方法,其特征在于,所述的铁盐为FeSO4、FeCl2、FeCl3、FeCl3·6H2O、Fe(NO3)3或Fe(NO3)3·9H2O。
3.如权利要求1所述的制备方法,其特征在于,所述的铁盐为三价铁盐。
4.如权利要求1所述的制备方法,其特征在于,所述的铁盐与2-甲基喹啉类化合物或2-甲基喹喔啉类化合物的投料物质的量比为1.0~2.5:1。
5.如权利要求1所述的制备方法,其特征在于所述的有机溶剂为二甲基亚砜、甲苯、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或丙酮。
6.如权利要求1所述的制备方法,其特征在于所述的有机溶剂的体积用量以所述的式(Ⅱ)所示的2-甲基喹啉类化合物或2-甲基喹喔啉类化合物的物质的量计为5~30mL/mmol。
7.如权利要求1所述的制备方法,其特征在于所述的微波功率为150W。
8.如权利要求1所述的制备方法,其特征在于所述的反应,反应时间为:3~40min。
9.如权利要求1所述的制备方法,其特征在于所述的喹啉-2-甲醛类化合物或喹喔啉-2-甲醛类化合物为:
10.如权利要求1所述的制备方法,所述的反应液后处理方法为:反应完毕后,取反应液过滤,收集滤液倒入饱和NaHCO3水溶液中,混匀静置分层,所得水层用乙酸乙酯萃取,取乙酸乙酯层,用无水Na2SO4干燥,浓缩后经正己烷重结晶,得式(Ⅰ)所示的喹啉-2-甲醛类化合物或喹喔啉-2-甲醛类化合物。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1560060A (zh) * | 2004-03-01 | 2005-01-05 | 南开大学 | 二胺桥联邻菲罗啉合镧(ⅲ)配合物的合成及抗癌活性 |
CN101801461A (zh) * | 2007-06-11 | 2010-08-11 | 诺西拉有限公司 | 用于治疗神经组织退化或血液学疾病的[1,10]-菲罗啉衍生物 |
CN102603964A (zh) * | 2012-01-15 | 2012-07-25 | 浙江工商大学 | 水溶性聚合物铁螯合剂及其制备方法和用途 |
CN102898388A (zh) * | 2012-09-26 | 2013-01-30 | 浙江工业大学 | 一种合成取代苯并[α]吩嗪类化合物的方法 |
CN102977040A (zh) * | 2012-11-20 | 2013-03-20 | 浙江工业大学 | 一种2-喹喔啉基二甲缩醛和2-喹喔啉基甲醛的合成方法 |
CN104072495A (zh) * | 2014-07-08 | 2014-10-01 | 河北工业大学 | 天然产物生物碱Aaptamine的制备方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2811525B2 (ja) * | 1993-03-01 | 1998-10-15 | 四国化成工業株式会社 | 2−ブチル−4−クロロ−5−フォルミルイミダゾールの合成方法 |
-
2016
- 2016-07-15 CN CN201610575035.7A patent/CN106083713B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1560060A (zh) * | 2004-03-01 | 2005-01-05 | 南开大学 | 二胺桥联邻菲罗啉合镧(ⅲ)配合物的合成及抗癌活性 |
CN101801461A (zh) * | 2007-06-11 | 2010-08-11 | 诺西拉有限公司 | 用于治疗神经组织退化或血液学疾病的[1,10]-菲罗啉衍生物 |
CN102603964A (zh) * | 2012-01-15 | 2012-07-25 | 浙江工商大学 | 水溶性聚合物铁螯合剂及其制备方法和用途 |
CN102898388A (zh) * | 2012-09-26 | 2013-01-30 | 浙江工业大学 | 一种合成取代苯并[α]吩嗪类化合物的方法 |
CN102977040A (zh) * | 2012-11-20 | 2013-03-20 | 浙江工业大学 | 一种2-喹喔啉基二甲缩醛和2-喹喔啉基甲醛的合成方法 |
CN104072495A (zh) * | 2014-07-08 | 2014-10-01 | 河北工业大学 | 天然产物生物碱Aaptamine的制备方法 |
Non-Patent Citations (4)
Title |
---|
Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen;Hans Sterckx,等;《Beilstein Journal of Organic Chemistry》;20160127;第12卷;第144-153页尤其是第151页表5 |
Iron-Catalyzed C–H Bond Functionalization for the Exclusive Synthesis of Pyrido[1,2-a]indoles or Triarylmethanols;Iyyanar Karthikeyan,等;《European Journal of Organic Chemistry》;20141117;第2014卷(第36期);第8055-8063页以及SUPPORTING INFORMATION尤其是第8页 |
Nanomolar colorimetric quantitative detection of Fe3+ and PPi with high selectivity;Zhanxian Li,等;《Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy》;20160206;第159卷;第249-253页尤其是第250页方案1和实验部分2.4 |
Synthesis and Characterization of Iron(II) Quinaldate Complexes;Dylan T. Houghton,等;《Inorganic Chemistry》;20091223;第49卷(第3期);第879-887页尤其是第880页 |
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