CN105237466A - 一种合成三取代吡啶衍生物的方法 - Google Patents
一种合成三取代吡啶衍生物的方法 Download PDFInfo
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- CN105237466A CN105237466A CN201510699625.6A CN201510699625A CN105237466A CN 105237466 A CN105237466 A CN 105237466A CN 201510699625 A CN201510699625 A CN 201510699625A CN 105237466 A CN105237466 A CN 105237466A
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- tolylpyridine
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- phenyl
- pyridine
- ethyl acetate
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- -1 tri-substituted pyridine Chemical class 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000013329 compounding Methods 0.000 title abstract 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000003222 pyridines Chemical class 0.000 claims abstract description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 132
- 238000006243 chemical reaction Methods 0.000 claims description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
- 238000004440 column chromatography Methods 0.000 claims description 24
- 239000003208 petroleum Substances 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 22
- 238000010791 quenching Methods 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 20
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 14
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims description 10
- FSPSELPMWGWDRY-UHFFFAOYSA-N m-Methylacetophenone Chemical compound CC(=O)C1=CC=CC(C)=C1 FSPSELPMWGWDRY-UHFFFAOYSA-N 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000003944 tolyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 claims description 6
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 claims description 5
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 claims description 5
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 claims description 4
- RGXUCUWVGKLACF-UHFFFAOYSA-N (3-methylphenyl)methanamine Chemical compound CC1=CC=CC(CN)=C1 RGXUCUWVGKLACF-UHFFFAOYSA-N 0.000 claims description 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 4
- XSAYZAUNJMRRIR-UHFFFAOYSA-N 2-acetylnaphthalene Chemical compound C1=CC=CC2=CC(C(=O)C)=CC=C21 XSAYZAUNJMRRIR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- YUTFQTAITWWGFH-UHFFFAOYSA-N 1-(1-benzofuran-2-yl)ethanone Chemical compound C1=CC=C2OC(C(=O)C)=CC2=C1 YUTFQTAITWWGFH-UHFFFAOYSA-N 0.000 claims description 3
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 claims description 3
- ZJCTYYUDFSDIRH-UHFFFAOYSA-N 2,6-bis(4-chlorophenyl)-4-phenylpyridine Chemical compound C1=CC(Cl)=CC=C1C1=CC(C=2C=CC=CC=2)=CC(C=2C=CC(Cl)=CC=2)=N1 ZJCTYYUDFSDIRH-UHFFFAOYSA-N 0.000 claims description 3
- FNLDRAROVORXHU-UHFFFAOYSA-N 2,6-bis(4-methylphenyl)-4-phenylpyridine Chemical compound C1=CC(C)=CC=C1C1=CC(C=2C=CC=CC=2)=CC(C=2C=CC(C)=CC=2)=N1 FNLDRAROVORXHU-UHFFFAOYSA-N 0.000 claims description 3
- KJNZQKYSNAQLEO-UHFFFAOYSA-N 2-(4-methylphenyl)pyridine Chemical compound C1=CC(C)=CC=C1C1=CC=CC=N1 KJNZQKYSNAQLEO-UHFFFAOYSA-N 0.000 claims description 3
- UTODHTFABTZGPE-UHFFFAOYSA-N 4-(3-fluorophenyl)-2,6-diphenylpyridine Chemical compound FC=1C=C(C=CC=1)C1=CC(=NC(=C1)C1=CC=CC=C1)C1=CC=CC=C1 UTODHTFABTZGPE-UHFFFAOYSA-N 0.000 claims description 3
- BQGKESGNZMNTHR-UHFFFAOYSA-N 4-(4-fluorophenyl)-2,6-bis(4-methylphenyl)pyridine Chemical compound C1=CC(C)=CC=C1C1=CC(C=2C=CC(F)=CC=2)=CC(C=2C=CC(C)=CC=2)=N1 BQGKESGNZMNTHR-UHFFFAOYSA-N 0.000 claims description 3
- ZHONNHZXRBFQTC-UHFFFAOYSA-N 4-(4-fluorophenyl)-2,6-diphenylpyridine Chemical compound C1=CC(F)=CC=C1C1=CC(C=2C=CC=CC=2)=NC(C=2C=CC=CC=2)=C1 ZHONNHZXRBFQTC-UHFFFAOYSA-N 0.000 claims description 3
- HWBPBZOOZRTDRV-UHFFFAOYSA-N 4-(4-methylphenyl)-2,6-dinaphthalen-2-ylpyridine Chemical compound C1=CC(C)=CC=C1C1=CC(C=2C=C3C=CC=CC3=CC=2)=NC(C=2C=C3C=CC=CC3=CC=2)=C1 HWBPBZOOZRTDRV-UHFFFAOYSA-N 0.000 claims description 3
- MYIPUBKLAVAYOG-UHFFFAOYSA-N 4-phenyl-2,6-dithiophen-2-ylpyridine Chemical compound C1=CSC(C=2N=C(C=C(C=2)C=2C=CC=CC=2)C=2SC=CC=2)=C1 MYIPUBKLAVAYOG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 239000000047 product Substances 0.000 description 43
- 239000003054 catalyst Substances 0.000 description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 18
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- HZARTZNXFXVMNF-UHFFFAOYSA-N 4-pentyl-2,6-diphenylpyridine Chemical compound C(CCCC)C1=CC(=NC(=C1)C1=CC=CC=C1)C1=CC=CC=C1 HZARTZNXFXVMNF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 1
- 229960003868 paraldehyde Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
- C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
- C07D213/12—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from unsaturated compounds
-
- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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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- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
本发明提供了一种合成三取代吡啶衍生物的方法,属于吡啶衍生物的合成技术领域。一种合成三取代吡啶衍生物的方法,在三氟甲磺酸的存在下,由胺化合物和酮化合物反应合成吡啶衍生物,反应式如下:
Description
技术领域
本发明属于吡啶衍生物的合成技术领域,具体涉及一种合成三取代吡啶衍生物的方法。
背景技术
吡啶类衍生物是一种重要的精细化工中间体,广泛应用于农药、医药橡胶助剂、表面活性剂、粘结剂和日用化工领域,随着人类社会的不断进步以及应用研究不断深入,对吡啶衍生物的需求量也急剧增加。因此,研究其新的、简单利于工业化的合成方法也十分必要,也必将产生较好的经济效益。
目前吡啶衍生物的合成方法尽管很多,然而,这些方法主要有气相法和液相法,却存在很大的局限性。例如,气相法是采用醋酸酸化乙醛,使乙醛聚合为三聚乙醛,然后同醋酸经过高压泵与氨水混合,反应需要高温(220~280℃)、高压(10~20MPa)。如果采用三氧化二铝为催化剂,反应需要的温度更高,达到500℃。目前气相法采用的其它催化剂产率,底物的适应性,反应条件很难同时满足社会需求。液相法包括醛酮-烯腈法、苄胺路线法和环戊二烯路线合成法等。但是这些方法也存在很多缺点:反应条件苛刻,反应温度高,有的需要高温高压,分离困难,反应的底物限制性较强,因此,利用一种方法合成吡啶衍生物很有限。另外,利用金属催化过程中,催化剂的活性有限,这些缺点造成制备过程的操作难度增加,危害操作人员健康,环境污染严重。然而,现有合成吡啶衍生物的方法普遍存在:需要活泼的反应底物、反应收率低、反应时间较长、副产物多难处理及反应的形式过于单一(导致所合成的产物有很大的局限性)以及反应过程需要大量的溶剂或金属催化剂等缺点。鉴于此,研发新颖、绿色环保的吡啶衍生物的制备方法显得尤为重要。
发明内容
本发明所要解决的技术问题是,针对现有技术的不足,提供一种操作简单,产率高,产物单一,便于分离和提纯的利用胺、酮衍生物合成吡啶衍生物的方法。
为解决上述技术问题,本发明所采用的技术方案是:
一种合成三取代吡啶衍生物的方法,在三氟甲磺酸(HOTf)的存在下,由式Ⅰ所示的胺化合物和式Ⅱ所示的酮化合物反应合成式Ⅲ所示的吡啶衍生物,
式Ⅰ:;式Ⅱ:;式Ⅲ:;
其中,
R1选自苯基、甲苯基、噻吩基、苯甲基、C1-C7烷基中的一种,其中,R1取代基中的苯基、甲苯基、噻吩基、苯甲基、C1-C7烷基中的任何CH、CH2或CH3基团任选在所述CH、CH2或CH3基团上带有1、2或3个可相同或不同的以下的取代基:卤素或硝基;
R2选自苯基、甲苯基、噻吩基、苯并呋喃基、萘基中的一种,其中,R2取代基中的苯基、甲苯基、噻吩基、苯并呋喃基、萘基中的任何CH、CH2或CH3基团任选在所述CH、CH2或CH3基团上带有1、2或3个可相同或不同的以下的取代基:卤素或硝基;
卤素为氟、氯、溴或碘的取代基。
合成三取代吡啶衍生物的反应通式如下:
。
优选的,所述式Ⅰ所示的胺化合物为苄胺、对甲基苄胺、对氟苄胺、间甲基苄胺、间氟苄胺、2-噻吩甲胺、2-苯基乙胺或正己胺。
优选的,所述式Ⅱ所示的酮化合物为苯乙酮、对甲基苯乙酮、间甲基苯乙酮、2-乙酰基噻吩、2-乙酰基苯并呋喃、2-萘乙酮或对氯苯乙酮。
优选的,所述式Ⅲ所示的吡啶衍生物为2,6-二苯基-4-对甲基吡啶、4-(4-氟苯基)-2,6-二苯基吡啶、2,6-二苯基-4-间甲基吡啶、4-(3-氟苯基)-2,6-二苯基吡啶、2,6-苯基-4-(2-噻吩基)吡啶、4-苄基-2,6-二苯基吡啶、4-戊基-2,6-二苯基吡啶、4-戊基-2,6-二对甲苯基吡啶、4-戊基-2,6-二间甲苯基吡啶、4-苯基-2,6-二-(2-噻吩基)吡啶、2,6-二-(2-苯并呋喃)-4-苯基吡啶、2,6-二-(2-萘基)-4-对甲苯基吡啶、4-(4-氟苯基)-2,6-二-(2-萘基)吡啶、2,6-二-(4-氯苯基)-4-苯基吡啶、4-苯基-2,6-二对甲苯基吡啶、2,4,6-对甲苯基吡啶、4-(4-氟苯基)-2,6-二对甲苯基吡啶、2,4,6-三间甲基吡啶或4-(间氟苯基)-2,6-二间甲苯基吡啶。
优选的,所述合成三取代吡啶衍生物的方法,具体步骤如下:在反应容器中依次加入摩尔比为4:3的式Ⅰ所示的酮化合物和式Ⅱ所示的胺化合物,接着加入催化剂三氟甲磺酸,所述催化剂的加入量为0.05mmol/mmol酮化合物,在115~125℃油浴中反应18~24小时,冷却至室温,加水淬灭反应,萃取,减压浓缩,经柱层析纯化,得到三取代吡啶衍生物产品。
优选的,所述柱层析纯化的条件为:洗脱剂为石油醚和乙酸乙酯的混合物,石油醚和乙酸乙酯的体积比为50:1。
与现有技术相比,本发明的有益效果如下:本发明提供了一种利用胺、酮化合物在三氟甲磺酸的催化作用下合成吡啶衍生物的方法,该方法的反应底物易得,反应条件温和,无需高温高压处理,操作简便、安全,可高效地制备吡啶类化合物。本发明方法不仅能够适用于大量的官能团,而且操作简单、安全,产物的产率高、结构单一,便于分离和提纯,污染小。
具体实施方式
为了更好地理解本发明,下面结合实施例进一步清楚阐述本发明的内容,但本发明的保护内容不仅仅局限于下面的实施例。在下文的描述中,给出了大量具体的细节以便提供对本发明更为彻底的理解。然而,对于本领域技术人员来说显而易见的是,本发明可以无需一个或多个这些细节而得以实施。在其他的例子中,为了避免与本发明发生混淆,对于本领域公知的一些技术特征未进行描述。
下述实施例中,HOTf表示三氟甲磺酸,为其英文缩写。
实施例1
2,6-二苯基-4-对甲基吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),对甲基苄胺0.75mmol(91.6mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率92%,纯度为99.9%。1HNMR(400MHz,DMSO-d 6)δppm:δ8.33(d,J=7.2Hz,4H),8.18(s,2H),7.96(d,J=8.4Hz,2H),7.49-7.58(m,6H),7.38(d,J=8.0Hz,2H);13CNMR(100MHz,DMSO-d 6)δppm:δ156.4,149.9,139.5,139.3,135.2,130.2,129.7,129.2,127.6,127.4,116.7,21.3;HRMS(EI)Calcd.forC24H19N:[M+],321.1517.Found:m/z321.1521.
实施例2
4-(4-氟苯基)-2,6-二苯基吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),对氟苄胺0.75mmol(93.8mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率78%,纯度为99.8%1HNMR(400MHz,DMSO-d 6)δppm:δ8.36(d,J=7.6Hz,4H),8.21(s,2H),8.15(q,2H),7.49-7.60(m,6H),7.43(t,2H);13CNMR(100MHz,DMSO-d 6)δppm:δ164.7,162.2,157.0,148.9,139.2,134.6,130.1,129.7,129.2,127.4,116.5;HRMS(EI)Calcd.forC23H16NF:[M+],325.1267.Found:m/z325.1268.
实施例3
2,6-二苯基-4-间甲基吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),间甲基苄胺0.75mmol(91.6mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率91%,纯度为99.9%。1HNMR(400MHz,CDCl3)δppm:δ8.22(d,J=7.6Hz,4H),7.87(q,2H),7.41-7.55(m,9H),7.29(s,1H);13CNMR(100MHz,CDCl3)δppm:δ157.5,150.4,139.7,139.1,138.9,129.8,129.1,128.8,128.0,127.2,127.2,124.4,117.2,21.6;HRMS(EI)Calcd.forC24H19N:[M+],321.1517.Found:m/z321.1519.
实施例4
4-(3-氟苯基)-2,6-二苯基吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),间氟苄胺0.75mmol(93.8mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率87%,纯度为99.5%。1HNMR(400MHz,DMSO-d 6)δppm:δ8.35(d,J=7.6Hz,4H),8.24(s,2H),7.91-8.00(m,2H),7.47-7.58(m,8H);13CNMR(100MHz,DMSO-d 6)δppm:δ164.5,162.0,157.1,148.6,139.1,131.5,129.8,129.2,129.1,128.4,128.1,127.5,117.1;HRMS(EI)Calcd.forC23H16NF:[M+],325.1267.Found:m/z325.1270.
实施例5
2,6-苯基-4-(2-噻吩基)吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),2-噻吩甲胺0.75mmol(84.9mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率89%,纯度为99.7%。1HNMR(400MHz,DMSO-d 6)δppm:δ8.29(d,J=7.2Hz,4H),8.12(s,2H),8.09-8.11(q,1H),7.91-8.00(m,2H),7.78–7.80(m,2H),7.48-7.58(m,6H),7.28-7.30(m,1H),13CNMR(100MHz,DMSO-d 6)δppm:δ157.2,143.5,141.2,138.9,129.9,129.3,129.3,128.8,127.6,127.3,115.1;HRMS(EI)Calcd.forC21H15NS:[M+],313.0925.Found:m/z313.0926.
实施例6
4-苄基-2,6-二苯基吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),2-苯基乙胺0.75mmol(90.9mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率84%,纯度为99.6%。1HNMR(400MHz,CDCl3)δppm:δ8.09(d,J=7.2Hz,4H),7.42-7.48(m,6H),7.35-7.39(m,2H),7.19-7.31(m,5H),4.01(s,2H);13CNMR(100MHz,CDCl3)δppm:δ157.2,151.4,139.3,139.3,129.2,129.1,128.9,128.8,127.2,126.8,119.5,41.8;HRMS(EI)Calcd.forC24H19N:[M+],321.1517.Found:m/z321.1519.
实施例7
4-戊基-2,6-二苯基吡啶的制备:在反应容器中加入苯乙酮1mmol(120mg),正己胺0.75mmol(75.9mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率87%,纯度为99.7%。1HNMR(400MHz,CDCl3)δppm:δ8.14(d,J=7.2Hz,4H),7.39-7.51(m,8H),2.69-2.73(q,2H),1.68-1.73(m,2H),1.32-1.37(m,4H),0.89-0.92(q,3H);13CNMR(100MHz,CDCl3)δppm:δ156.9,153.2,139.8,128.8,128.7,127.1,119.1,35.8,31.5,30.3,22.6,14.1;HRMS(EI)Calcd.forC22H23N:[M+],301.1830.Found:m/z301.1833.
实施例8
4-戊基-2,6-二对甲苯基吡啶的制备:在反应容器中加入对甲基苯乙酮1mmol(134.2mg),正己胺0.75mmol(75.9mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率90%,纯度为99.9%。1HNMR(400MHz,CDCl3)δppm:δ7.96(d,J=8.0Hz,4H),7.78(s,2H),7.20(d,J=8.0Hz,4H),2.59-2.63(q,2H),2.33(s,6H),1.61-1.65(m,2H),1.28-1.29(m,4H),0.81-0.84(q,3H);13CNMR(100MHz,CDCl3)δppm:δ156.8,153.0,138.7,137.1,129.3,126.9,118.5,35.8,31.5,30.3,22.6,21.3,14.0;HRMS(EI)Calcd.forC24H27N:[M+],329.2143.Found:m/z329.2145.
实施例9
4-戊基-2,6-二间甲苯基吡啶的制备:在反应容器中加入间甲基苯乙酮1mmol(134.2mg),正己胺0.75mmol(75.9mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率88%,纯度为99.7%。(3j):1HNMR(400MHz,CDCl3)δppm:δ7.72-7.93(m,4H),7.39(s,2H),7.26-7.33(m,2H),7.13(d,J=6.8Hz,2H),2.59-2.63(q,2H),2.37(s,6H),1.61-1.64(m,2H),1.27-1.33(m,4H),0.81-0.85(q,3H);13CNMR(100MHz,CDCl3)δppm:δ157.1,153.1,139.9,138.2,129.6,128.6,127.8,124.3,119.2,35.8,31.6,30.4,22.6,21.7,14.1;HRMS(EI)Calcd.forC24H27N:[M+],329.2143.Found:m/z329.2144.
实施例10
4-苯基-2,6-二-(2-噻吩基)吡啶的制备:在反应容器中加入2-乙酰基噻吩1mmol(126.2mg),苄胺0.75mmol(80.4mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率77%,纯度为99.5%。1HNMR(400MHz,CDCl3)δppm:δ7.62-7.66(m,6H),7.38-7.49(m,5H),7.08-7.11(t,2H),;13CNMR(100MHz,CDCl3)δppm:152.7,150.2,144.9,138.6,129.2,129.2,128.0,127.9,127.1,124.9,115.1;HRMS(EI)Calcd.forC19H13NS2:[M+],319.0489.Found:m/z319.0484.
实施例11
2,6-二-(2-苯并呋喃)-4-苯基吡啶的制备:在反应容器中加入2-乙酰基苯并呋喃1mmol(160.2mg),苄胺0.75mmol(80.4mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率84%,纯度为99.6%。1HNMR(400MHz,CDCl3)δppm:δ8.08(s,2H),7.84(d,J=7.2Hz,2H),7.69(d,J=7.6Hz,2H),7.64(s,2H),7.48-7.60(m,5H),7.34(t,2H),7.29(t,2H);13CNMR(100MHz,CDCl3)δppm:δ155.4,155.2,150.1,149.9,138.1,129.4,129.2,128.9,127.2,125.3,123.3,121.8,116.8,111.6,105.5;HRMS(EI)Calcd.forC27H17NO2:[M+],387.1259.Found:m/z387.1265.
实施例12
2,6-二-(2-萘基)-4-对甲苯基吡啶的制备:在反应容器中加入2-萘乙酮1mmol(170mg),对甲基苄胺0.75mmol(91.6mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=40:1(v/v),得到白色固体产品,产率82%,纯度为99.9%。1HNMR(400MHz,CDCl3)δppm:δ8.64(s,2H),8.37(d,J=8.4Hz,2H),7.95-7.98(m,6H),7.87(d,J=8.4Hz,2H),7.66(d,J=7.6Hz,2H),7.50(m,4H),7.31(d,J=7.6Hz,2H),2.41(s,3H);13CNMR(100MHz,CDCl3)δppm:δ157.5,150.2,139.2,137.1,136.1,133.9,133.6,129.9,128.9,128.5,127.8,127.1,126.6,126.3,125.1,117.3,21.4;HRMS(EI)Calcd.forC32H23N:[M+],421.1830.Found:m/z421.1832.
实施例13
4-(4-氟苯基)-2,6-二-(2-萘基)吡啶的制备:在反应容器中加入2-萘乙酮1mmol(170mg),对氟苄胺0.75mmol(93.8mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=40:1(v/v),得到白色固体产品,产率78%,纯度为99.7%。1HNMR(400MHz,DMSO-d 6)δppm:δ8.96(s,2H),8.59(dd,J=8.4,0.8Hz,2H),8.41(s,2H),8.20-8.22(m,2H),8.10-8.15(m,4H),8.00-8.02(m,2H),7.57-7.63(m,4H),7.44-7.57(t,2H);13CNMR(100MHz,DMSO-d 6)δppm:δ150.7,149.1,136.6,134.6,133.9,133.6,130.2,130.1,129.2,128.7,128.1,127.3,127.0,126.8,125.3,116.4;HRMS(EI)Calcd.forC31H20NF:[M+],425.1580.Found:m/z425.1583.
实施例14:2,6-二-(4-氯苯基)-4-苯基吡啶的制备:在反应容器中加入对氯苯乙酮1mmol(154.6mg),苄胺0.75mmol(80.4mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率87%,纯度为99.7%。1HNMR(400MHz,DMSO-d 6)δppm:δ8.16(d,J=7.6Hz,4H),7.90(s,2H),7.76(d,J=6.4Hz,2H),7.47-7.55(m,7H);13CNMR(100MHz,DMSO-d 6)δppm:δ160.9,155.3,143.2,142.5,139.8,134.0,134.0,133.6,133.1,131.9,121.8;HRMS(EI)Calcd.forC23H15NCl2:[M+],375.0582.Found:m/z375.0786.
实施例15
4-苯基-2,6-二对甲苯基吡啶的制备:在反应容器中加入对甲基苯乙酮1mmol(134.2mg),苄胺0.75mmol(80.4mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率91%,纯度为99.9%。1HNMR(400MHz,CDCl3)δppm:δ8.08(d,J=8.0Hz,4H),7.81(s,2H),7.71(d,J=7.2Hz,2H),7.44-7.51(m,3H),7.29(d,J=8.0Hz,4H),2.40(s,6H);13CNMR(100MHz,CDCl3)δppm:δ152.7,145.3,134.6,134.2,132.2,124.7,124.4,124.1,122.5,122.3,111.8,16.6;HRMS(EI)Calcd.forC25H21N:[M+],335.1674.Found:m/z335.1679.
实施例16
2,4,6-对甲苯基吡啶的制备:在反应容器中加入对甲基苯乙酮1mmol(134.2mg),对甲基苄胺0.75mmol(91.6mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率95%,纯度为99.8%。1HNMR(400MHz,CDCl3)δppm:δ8.09(d,J=7.6Hz,4H),7.81(s,2H),7.63(d,J=7.2Hz,2H),7.30(d,J=6.4Hz,6H),2.42(s,6H);13CNMR(100MHz,CDCl3)δppm:δ157.4,149.9,138.9,137.0,129.8,129.4,127.0,116.3,21.3;HRMS(EI)Calcd.forC26H23N:[M+],349.1834.Found:m/z349.1830.
实施例17
4-(4-氟苯基)-2,6-二对甲苯基吡啶的制备:在反应容器中加入对甲基苯乙酮1mmol(134.2mg),对氟苄胺0.75mmol(93.8mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率87%,纯度为99.5%。1HNMR(400MHz,CDCl3)δppm:δ8.08(d,J=8.0Hz,4H),7.78(s,2H),7.69-7.73(t,2H),7.31(d,J=8.0Hz,2H),7.19-7.25(m,4H),2.43(s,6H);13CNMR(100MHz,CDCl3)δppm:δ164.6,162.1,157.5,149.0,139.1,136.8,129.4,129.0,128.9,127.0,116.0,21.4;HRMS(EI)Calcd.forC25H20NF:[M+],353.1580.Found:m/z353.1582.
实施例18
2,4,6-三间甲基吡啶的制备:在反应容器中加入间甲基苯乙酮1mmol(134.2mg),间甲基苄胺0.75mmol(91.6mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率89%,纯度为99.7%。1HNMR(400MHz,CDCl3)δppm:δ7.79–8.01(m,4H),7.85(s,2H),7.56(s,2H),7.39-7.43(m,3H),7.25-7.29(m,3H),2.48(s,9H);13CNMR(100MHz,CDCl3)δppm:δ157.7,150.2,139.7,139.1,138.8,138.3,129.8,129.7,129.0,128.6,127.9,127.9,124.4,117.3,21.7,21.6;HRMS(EI)Calcd.forC26H23N:[M+],349.1830.Found:m/z349.1833.
实施例19
4-(间氟苯基)-2,6-二间甲苯基吡啶的制备:在反应容器中加入间甲基苯乙酮1mmol(134.2mg),间氟苄胺0.75mmol(93.8mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率85%,纯度为99.9%。1HNMR(400MHz,CDCl3)δppm:δ7.97(m,4H),7.80(s,2H),7.38=7.52(m,5H),7.26(d,J=7.6Hz,2H),7.13-7.17(t,1H),2.47(s,6H);13CNMR(100MHz,CDCl3)δppm:δ164.5,162.1,157.9,148.8,139.4,138.4,130.7,130.0,128.7,127.9,124.4,122.9,116.6,21.7;HRMS(EI)Calcd.forC25H20NF:[M+],353.1580.Found:m/z353.1581.
实施例20
在反应容器中加入苯乙酮1mmol(120mg),苄胺0.75mmol(80.4mg),催化剂HOTf0.05mmol(7.5mg)。在120℃油浴中反应24小时,冷却至室温,加水淬灭反应,用乙酸乙酯洗涤三次,分液,合并有机层,活性炭脱色,过滤,无水硫酸钠干燥,减压浓缩,产品经过柱层析纯化,洗脱剂为石油醚:乙酸乙酯=50:1(v/v),得到白色固体产品,产率87%,纯度为99.7%。1HNMR(500MHz,CDCl3)ppm:8.43(d,J=8.0Hz,1H),8.34(d,J=8.0Hz,2H),8.00(d,J=8.5Hz,1H),7.92(s,1H),7.80(t,1H),7.51-7.64(m,9H);13CNMR(500MHz,CDCl3):156.90,149.23,149.05,139.77,138.56,130.35,129.70,129.60,129.50,128.96,128.72,128.52,127.75,126.47,125.92,125.75,119.39;HRMS(EI)Calcd.forC21H15N:[M+],281.1207;Found:281.1204。
Claims (6)
1.一种合成三取代吡啶衍生物的方法,在三氟甲磺酸的存在下,其特征在于:由式Ⅰ所示的胺化合物和式Ⅱ所示的酮化合物反应合成式Ⅲ所示的吡啶衍生物,
式Ⅰ:;式Ⅱ:;式Ⅲ:;
其中,
R1选自苯基、甲苯基、噻吩基、苯甲基、C1-C7烷基中的一种,其中,R1取代基中的苯基、甲苯基、噻吩基、苯甲基、C1-C7烷基中的任何CH、CH2或CH3基团任选在所述CH、CH2或CH3基团上带有1、2或3个可相同或不同的以下的取代基:卤素或硝基;
R2选自苯基、甲苯基、噻吩基、苯并呋喃基、萘基中的一种,其中,R2取代基中的苯基、甲苯基、噻吩基、苯并呋喃基、萘基中的任何CH、CH2或CH3基团任选在所述CH、CH2或CH3基团上带有1、2或3个可相同或不同的以下的取代基:卤素或硝基;
卤素为氟、氯、溴或碘的取代基。
2.如权利要求1所述的合成三取代吡啶衍生物的方法,其特征在于:所述式Ⅰ所示的胺化合物为苄胺、对甲基苄胺、对氟苄胺、间甲基苄胺、间氟苄胺、2-噻吩甲胺、2-苯基乙胺或正己胺。
3.如权利要求1所述的合成三取代吡啶衍生物的方法,其特征在于:所述式Ⅱ所示的酮化合物为苯乙酮、对甲基苯乙酮、间甲基苯乙酮、2-乙酰基噻吩、2-乙酰基苯并呋喃、2-萘乙酮或对氯苯乙酮。
4.如权利要求1所述的合成三取代吡啶衍生物的方法,其特征在于:所述式Ⅲ所示的吡啶衍生物为2,6-二苯基-4-对甲基吡啶、4-(4-氟苯基)-2,6-二苯基吡啶、2,6-二苯基-4-间甲基吡啶、4-(3-氟苯基)-2,6-二苯基吡啶、2,6-苯基-4-(2-噻吩基)吡啶、4-苄基-2,6-二苯基吡啶、4-戊基-2,6-二苯基吡啶、4-戊基-2,6-二对甲苯基吡啶、4-戊基-2,6-二间甲苯基吡啶、4-苯基-2,6-二-(2-噻吩基)吡啶、2,6-二-(2-苯并呋喃)-4-苯基吡啶、2,6-二-(2-萘基)-4-对甲苯基吡啶、4-(4-氟苯基)-2,6-二-(2-萘基)吡啶、2,6-二-(4-氯苯基)-4-苯基吡啶、4-苯基-2,6-二对甲苯基吡啶、2,4,6-对甲苯基吡啶、4-(4-氟苯基)-2,6-二对甲苯基吡啶、2,4,6-三间甲基吡啶或4-(间氟苯基)-2,6-二间甲苯基吡啶。
5.如权利要求1所述的合成三取代吡啶衍生物的方法,其特征在于,所述合成三取代吡啶衍生物的方法,具体步骤如下:在反应容器中依次加入摩尔比为4:3的式Ⅰ所示的酮化合物和式Ⅱ所示的胺化合物,接着加入催化剂三氟甲磺酸,所述催化剂的加入量为0.05mmol/mmol酮化合物,在115~125℃油浴中反应18~24小时,冷却至室温,加水淬灭反应,萃取,减压浓缩,经柱层析纯化,得到三取代吡啶衍生物产品。
6.如权利要求5所述的合成三取代吡啶衍生物的方法,其特征在于,所述柱层析纯化的条件为:洗脱剂为石油醚和乙酸乙酯的混合物,石油醚和乙酸乙酯的体积比为50:1。
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CN106336375A (zh) * | 2016-08-02 | 2017-01-18 | 四川大学 | 一种吡啶类化合物双碳氢活化芳基化的方法 |
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