CN113683550A - 一种n-(氰基(2-氰基取代苯基)甲基)取代的三级胺的合成方法 - Google Patents
一种n-(氰基(2-氰基取代苯基)甲基)取代的三级胺的合成方法 Download PDFInfo
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 15
- 125000004093 cyano group Chemical group *C#N 0.000 title claims abstract description 14
- 150000003512 tertiary amines Chemical class 0.000 title claims abstract description 6
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- XBHPFCIWRHJDCP-UHFFFAOYSA-N (2-trimethylsilylphenyl) trifluoromethanesulfonate Chemical class C[Si](C)(C)C1=CC=CC=C1OS(=O)(=O)C(F)(F)F XBHPFCIWRHJDCP-UHFFFAOYSA-N 0.000 claims abstract description 46
- -1 tertiary amine compound Chemical class 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- GXDKXRIMUVUELI-UHFFFAOYSA-N 2-aminopropanedinitrile Chemical class N#CC(N)C#N GXDKXRIMUVUELI-UHFFFAOYSA-N 0.000 claims abstract description 8
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical group [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 26
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 235000003270 potassium fluoride Nutrition 0.000 claims description 13
- 239000011698 potassium fluoride Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- MKZHJJQCUIZEDE-UHFFFAOYSA-N 1-[(2-hydroxy-3-naphthalen-1-yloxypropyl)-propan-2-ylamino]-3-naphthalen-1-yloxypropan-2-ol Chemical class C1=CC=C2C(OCC(O)CN(CC(O)COC=3C4=CC=CC=C4C=CC=3)C(C)C)=CC=CC2=C1 MKZHJJQCUIZEDE-UHFFFAOYSA-N 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 46
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 238000001514 detection method Methods 0.000 description 29
- 238000002844 melting Methods 0.000 description 26
- 230000008018 melting Effects 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012046 mixed solvent Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 6
- ZCWWZFXNICWDIB-UHFFFAOYSA-N (2-methyl-6-trimethylsilylphenyl) trifluoromethanesulfonate Chemical compound CC1=CC=CC([Si](C)(C)C)=C1OS(=O)(=O)C(F)(F)F ZCWWZFXNICWDIB-UHFFFAOYSA-N 0.000 description 4
- IPZYLSPWZUDOHB-UHFFFAOYSA-N (4-methoxy-2-trimethylsilylphenyl) trifluoromethanesulfonate Chemical compound COC1=CC=C(OS(=O)(=O)C(F)(F)F)C([Si](C)(C)C)=C1 IPZYLSPWZUDOHB-UHFFFAOYSA-N 0.000 description 4
- JCFDLGDOHBRADK-UHFFFAOYSA-N 2-amino-1-(4-methylphenyl)-4-phenylpyrrole-3-carbonitrile Chemical compound C1=CC(C)=CC=C1N1C(N)=C(C#N)C(C=2C=CC=CC=2)=C1 JCFDLGDOHBRADK-UHFFFAOYSA-N 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- OSZYFPWWHQEAGW-UHFFFAOYSA-N (3-trimethylsilylnaphthalen-2-yl) trifluoromethanesulfonate Chemical compound C1=CC=C2C=C(OS(=O)(=O)C(F)(F)F)C([Si](C)(C)C)=CC2=C1 OSZYFPWWHQEAGW-UHFFFAOYSA-N 0.000 description 2
- DLUVZOFWZNLGTJ-UHFFFAOYSA-N (4,5-dimethoxy-2-trimethylsilylphenyl) trifluoromethanesulfonate Chemical compound COC1=CC(OS(=O)(=O)C(F)(F)F)=C([Si](C)(C)C)C=C1OC DLUVZOFWZNLGTJ-UHFFFAOYSA-N 0.000 description 2
- GQMGFGZDAOMFRJ-UHFFFAOYSA-N 2-(3,4-dihydro-1H-isoquinolin-2-yl)propanedinitrile Chemical compound N#CC(C#N)N1CCc2ccccc2C1 GQMGFGZDAOMFRJ-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- RHHXOVPPWRMLIO-UHFFFAOYSA-N 2-piperidin-1-ylpropanedinitrile Chemical compound N#CC(C#N)N1CCCCC1 RHHXOVPPWRMLIO-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 2
- WGZCUXZFISUUPR-UHFFFAOYSA-N acetonitrile;oxolane Chemical compound CC#N.C1CCOC1 WGZCUXZFISUUPR-UHFFFAOYSA-N 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OLEQLHYSYODKCC-UHFFFAOYSA-N 1,2-dichloroethane;ethanol Chemical compound CCO.ClCCCl OLEQLHYSYODKCC-UHFFFAOYSA-N 0.000 description 1
- PYKJFEPAUKAXNN-UHFFFAOYSA-N 2-(2-methyl-8-phenylmethoxy-3-imidazo[1,2-a]pyridinyl)acetonitrile Chemical compound C=1C=CN2C(CC#N)=C(C)N=C2C=1OCC1=CC=CC=C1 PYKJFEPAUKAXNN-UHFFFAOYSA-N 0.000 description 1
- GAHYRGJJMQPDEI-UHFFFAOYSA-N 2-[(4-fluoroanilino)methyl]-1-methylindole-3-carbonitrile Chemical compound N#CC=1C2=CC=CC=C2N(C)C=1CNC1=CC=C(F)C=C1 GAHYRGJJMQPDEI-UHFFFAOYSA-N 0.000 description 1
- YONYPNNXOHWPBZ-UHFFFAOYSA-N 2-methyl-4,6-diphenyl-1,3,5-triazine Chemical compound N=1C(C)=NC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 YONYPNNXOHWPBZ-UHFFFAOYSA-N 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 1
- 229960002049 etravirine Drugs 0.000 description 1
- PUPKPAZSFZOLOR-UHFFFAOYSA-N n,n-dimethylformamide;toluene Chemical compound CN(C)C=O.CC1=CC=CC=C1 PUPKPAZSFZOLOR-UHFFFAOYSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 description 1
- 229960005198 perampanel Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- 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
- C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D405/02—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 two hetero rings
- C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明属于有机合成技术领域,具体涉及一种N‑(氰基(2‑氰基取代苯基)甲基)取代的三级胺的合成方法,其反应通式如下:
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种N-(氰基(2-氰基取代苯基)甲基)取代的三级胺的合成方法。
背景技术
多取代苯腈是一类重要的化学骨架结构,在有机合成化学、药物化学、农药化学中有广泛的应用,比如吡仑帕奈、阿格列汀和依曲韦林等。N-(氰基(2-氰基取代苯基)甲基)取代的三级胺是一类重要的苯腈化合物,由于该类化合物中存在的氨基,芳环取代基,氰基等基团,使得这类多取代苯腈化合物比较容易发生衍生化反应,这进一步拓展多取代苯腈化合物的应用范围。目前针对该类化合物现有的合成文献是先制备卤代芳烃,再与氰化亚铜反应得到产物,其缺点为:反应条件苛刻,操作步骤繁琐以及需要剧毒化合物参与反应(Org.Biomol. Chem.,2012,10,8539)。本发明创造性地将N,N-二取代氨基-丙二腈、取代2-(三甲基硅)苯基三氟甲烷磺酸酯、催化剂,依次加入到有机溶剂中,加热条件下得到N-(氰基(2-氰基取代苯基) 甲基)取代的三级胺类化合物。该合成方法原料易得,操作简单,反应条件温和,底物适用性广,改进了现有制备方法的诸多不足。因此本发明有良好的实用价值和社会经济效率,对同类产品及下游产品的工艺开发具有很好的借鉴意义。
发明内容
本发明的目的在于克服现有制备技术的缺陷,提供一种起始原料简单易得,收率高,操作方便的N-(氰基(2-氰基取代苯基)甲基)取代的三级胺类化合物的合成方法。
本发明的技术方案为:一种N-(氰基(2-氰基取代苯基)甲基)取代的三级胺类化合物的合成方法,其特征为N,N-二取代氨基-丙二腈、取代2-(三甲基硅)苯基三氟甲烷磺酸酯、催化剂,依次加入到有机溶剂中,加热条件下得到N-(氰基(2-氰基取代苯基)甲基)取代的三级胺类化合物,反应式如下:
其中:
(1)R1、R2不在同一个环系上时,R1选自甲基、正丁基、苄基,R2选自甲基、取代苯基、取代苄基;
(2)R1、R2在同一环系上时,R1、R2连同N原子选自哌啶基、吗啉基、二氢吲哚基、1,2,3,4-四氢异喹啉基、1,2,3,4-四氢喹啉基;
(3)R3选自氢,甲基,甲氧基,4,5-二甲氧基,4,5-亚甲二氧基,4,5-环戊基。
(4)所用催化剂选自氟化铯+18-冠醚-6、氟化铯、氟化钾+18-冠醚-6、氟化钾、四丁基氟化铵,优选氟化铯+18-冠醚-6。
(5)所用的溶剂选自乙腈、二氯甲烷、四氢呋喃、乙醚、甲苯、乙醇、1,2-二氯乙烷、N,N-二甲基甲酰胺、1,4-二氧六环的一种或几种,优选四氢呋喃。
(6)所用加热的温度为0℃-70℃,维持时间为1-4小时,优选30℃,维持2小时。
(7)反应中各物质的摩尔量比为:N,N-二取代氨基-丙二腈:取代2-(三甲基硅)苯基三氟甲烷磺酸酯:催化剂=1:1-2:1.5-3,优选N,N-二取代氨基-丙二腈:取代2-(三甲基硅)苯基三氟甲烷磺酸酯:催化剂=1:1.5:2。
具体实施方式
以下通过具体实施例对本发明做进一步的说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例
1.以二氢吲哚基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式1)
氩气保护下,在一个10mL的反应管中将二氢吲哚基氨基-丙二腈(100mg,0.55mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(244mg,0.82mmol),氟化铯(165mg,1.09mmol)和18-冠醚-6(289mg,1.09mmol),依次加入到搅拌的四氢呋喃(2mL)中,在30℃下反应2小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(106mg,75%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.91(d,J=7.6Hz,1H),7.79(d,J=7.6Hz,1H),7.73(t,J=7.6Hz, 1H),7.57(t,J=7.6Hz,1H),7.17(t,J=7.2Hz,2H),6.87(t,J=7.2Hz,1H),6.78(d,J=8.0Hz, 1H),5.97(s,1H),3.44-3.37(m,1H),3.17-3.12(m,1H),3.09-3.02(m,1H),3.00-2.91(m,1H);13C NMR(100MHz,CDCl3)δ148.29,136.49,134.18,133.05,130.40,129.85,128.54,127.56,125.01, 121.06,116.26,114.37,112.71,108.86,53.50,50.40,28.03;HRMS(ESI)calcd for C17H13N3 [M+H]+:260.1182,found 260.1190;熔程:195℃-197℃。
2.以N-苯基-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式2)
氩气保护下,在一个10mL的反应管中将N-苯基-N-甲基氨基-丙二腈(200mg,1.17mmol), 2-(三甲基硅)苯基三氟甲烷磺酸酯(523mg,1.75mmol),氟化铯(532mg,3.50mmol),依次加入到搅拌的四氢呋喃(2mL)中,在40℃下反应2小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(196mg,68%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.85-7.80(m,2H),7.73-7.69(m,1H),7.56(t,J=8.0Hz,1H),7.36 (t,J=8.8Hz,2H),7.25(d,J=8.0Hz,2H),7.07(t,J=7.6Hz,1H),5.93(s,1H),2.70(s,3H);13C NMR(100MHz,CDCl3)δ148.72,136.68,134.48,132.95,129.84,129.41,129.35,123.04,119.05, 116.70,114.54,112.51,59.31,35.16;HRMS(ESI)calcd for C16H13N3[M+H]+:248.1182,found 248.1185;熔程:167℃-169℃。
3.以N-(4-甲基苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式 3)
氩气保护下,在一个50mL的反应瓶将N-(4-甲基苯基)-N-甲基氨基-丙二腈(1000mg,5.40 mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(1611mg,5.40mmol),氟化钾(784mg,13.50mmol) 和18-冠醚-6(3567mg,13.50mmol),依次加入到搅拌的乙腈(10mL)中,在50℃下反应4 小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(861mg,61%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.83-7.80(m,2H),7.72-7.68(m,1H),7.58-7.54(m,1H),7.17(s, 4H),5.85(s,1H),2.67(s,3H),2.32(s,3H);13C NMR(100MHz,CDCl3)δ146.50,136.83,134.41, 132.94,132.89,129.94,129.77,129.36,119.65,116.77,114.58,112.62,59.98,35.51,20.64; HRMS(ESI)calcd for C17H15N3[M+H]+:262.1339,found 262.1342,熔程:116℃-117℃。
4.以N-(2-甲基苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式 4)
氩气保护下,在一个250mL的反应瓶将N-(2-甲基苯基)-N-甲基氨基-丙二腈(10g,53.99
mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(20.222g,67.78mmol),氟化钾(6.273g,107.97 mmol),依次加入到搅拌的甲苯(40mL)中,在70℃下反应4小时完成反应,使用乙酸乙酯(50mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(10.158g,72%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.72(d,J=7.6Hz,1H),7.65-7.57(m,2H),7.53-7.46(m,2H),7.21 (t,J=6.8Hz,1H),7.14-7.06(m,2H),5.55(s,1H),2.75(s,3H),2.15(s,3H);13C NMR(100MHz, CDCl3)δ147.43,136.97,134.94,133.68,132.63,131.26,129.48,129.11,126.70,125.88,122.30, 116.45,116.24,113.00,58.78,39.99,17.63;HRMS(ESI)calcdfor C17H15N3[M+H]+:262.1339, found 262.1343,熔程:94℃-96℃。
5.以N-(4-甲氧基苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式5)
氩气保护下,在一个10mL的反应管将N-(4-甲氧基苯基)-N-甲基氨基-丙二腈(50mg,0.25 mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(134mg,0.45mmol),四丁基氟化铵(118mg,0.45 mmol),依次加入到搅拌的二氯甲烷(2mL)中,在20℃下反应1小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(43g,63%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.82(d,J=7.6Hz,1H),7.76(d,J=7.6Hz,1H),7.68(t,J=7.6Hz, 1H),7.56(t,J=7.6Hz,1H),7.26(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),5.69(s,1H),3.79(s, 3H),2.65(s,3H);13C NMR(100MHz,CDCl3)δ156.41,142.47,136.83,134.32,132.87,129.77, 129.43,122.59,116.92,114.66,114.53,112.77,61.27,55.43,36.43;HRMS(ESI)calcd for C17H15N3O[M+H]+:278.1288,found 278.1293,熔程:89℃-90℃。
6.以N-(4-氟苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式6)
氩气保护下,在一个10mL的反应管中将N-(4-氟苯基)-N-甲基氨基-丙二腈(250mg,1.32
mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(433mg,1.45mmol),氟化铯(442mg,2.91mmol) 和18-冠醚-6(769mg,2.91mmol),依次加入到搅拌的乙醚(2mL)中,在0℃下反应3小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(214mg,61%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.84-7.79(m,2H),7.71(t,J=7.6Hz,1H),7.58(t,J=7.6Hz,1H), 7.29-7.26(m,2H),7.05(t,J=8.8Hz,2H),5.76(s,1H),2.66(s,3H);13C NMR(100MHz,CDCl3) δ159.30(d,J=241.9Hz),145.15(d,J=2.4Hz),136.47,134.42,132.99,129.95,129.41,122.16 (d,J=8.2Hz),116.84,116.07(d,J=22.5Hz),114.37,112.62,60.66,35.98;HRMS(ESI)calcd for C16H12FN3[M+H]+:266.1088,found 266.1093;熔程:92℃-93℃。
7.以N-(4-氯苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式7)
氩气保护下,在一个10mL的反应管将N-(4-氯苯基)-N-甲基氨基-丙二腈(100mg,0.49mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(218mg,0.73mmol),氟化钾(85mg,1.46mmol),依次加入到搅拌的乙醇(2mL)中,在10℃下反应2小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(75mg,55%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.82(t,J=7.2Hz,2H),7.72(t,J=7.6Hz,1H),7.58(t,J=7.2Hz, 1H),7.31(d,J=8.8Hz,2H),7.18(d,J=8.8Hz,2H),5.87(s,1H),2.67(s,3H);13CNMR(100 MHz,CDCl3)δ147.28,136.33,134.49,133.05,130.00,129.40,129.34,128.31,120.45,116.67, 114.29,112.47,59.26,35.33;HRMS(ESI)calcd for C16H12 35ClN3[M+H]+:282.0793,found 282.0802;HRMS(ESI)calcd for C16H12 37ClN3[M+H]+:284.0763,found284.0771,熔程: 108℃-109℃。
8.以N-(2-氯苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式8)
氩气保护下,在一个10mL的反应管将N-(2-氯苯基)-N-甲基氨基-丙二腈(10mg,0.049mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(29mg,0.097mmol),氟化铯(15mg,0.097mmol),依次加入到搅拌的1,2-二氯乙烷(1mL)中,在60℃下反应1小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(10mg,71%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.76-7.73(m,2H),7.65(t,J=7.6Hz,1H),7.52(t,J=7.6Hz,1H), 7.45-7.37(m,2H),7.29(t,J=7.6Hz,1H),7.12(t,J=7.6Hz,1H),5.73(s,1H),2.83(s,3H);13C NMR(100MHz,CDCl3)δ145.75,136.09,134.04,132.72,130.93,130.82,129.70,129.03,127.72, 126.58,123.68,116.29,115.79,113.03,58.19,38.46;HRMS(ESI)calcdfor C16H12 35ClN3[M+H]+: 282.0793,found 282.0799;HRMS(ESI)calcd for C16H12 37ClN3[M+H]+:284.0763,found 284.0768,熔程:79℃-80℃。
9.以N-(4-溴苯基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式9)
氩气保护下,在一个10mL的反应管将N-(4-溴苯基)-N-甲基氨基-丙二腈(300mg,1.20mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(430mg,1.44mmol),氟化铯(401mg,2.64mmol)和18-冠醚-6(698mg,2.64mmol),依次加入到搅拌的N,N-二甲基甲酰胺(2mL)中,在70℃下反应2小时完成反应,使用乙酸乙酯(10mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(235mg,60%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.82(t,J=8.8Hz,2H),7.72(t,J=7.6Hz,1H),7.57(t,J=7.2Hz, 1H),7.45(d,J=8.8Hz,2H),7.11(d,J=8.8Hz,2H),5.88(s,1H),2.67(s,3H);13CNMR(100 MHz,CDCl3)δ147.70,136.29,134.49,133.05,132.31,130.00,129.31,120.59,116.63,115.73, 114.26,112.42,58.94,35.22;HRMS(ESI)calcd for C16H12 79BrN3[M+H]+:326.0287,found 326.0298,HRMS(ESI)calcd for C16H12 81BrN3[M+H]+:328.0267,found328.0276,熔程: 90℃-91℃。
10.以2-(3,4-二氢喹啉-1(2H)-基)丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式1 0)
氩气保护下,在一个100mL的反应瓶将2-(3,4-二氢喹啉-1(2H)-基)丙二腈(5g,25.35mmol), 2-(三甲基硅)苯基三氟甲烷磺酸酯(7.563g,25.35mmol),氟化钾(2.209g,38.02mmol)和 18-冠醚-6(10.049g,38.02mmol),依次加入到搅拌的1,4-二氧六环(15mL)中,在50℃下反应4小时完成反应,使用乙酸乙酯(30mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(3.811g,55%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.94(d,J=8.0Hz,1H),7.78(d,J=7.6Hz,1H),7.73(t,J=7.6Hz, 1H),7.55(t,J=7.2Hz,1H),7.15(t,J=7.2Hz,1H),7.07(d,J=7.2Hz,1H),6.98(d,J=8.4Hz, 1H),6.84(t,J=7.2Hz,1H),6.14(s,1H),3.20-3.14(m,1H),2.95-2.81(m,2H),2.78-2.71(m,1H), 2.06-1.89(m,2H);13C NMR(100MHz,CDCl3)δ142.96,137.03,134.61,132.98,129.74,129.63, 129.22,127.14,126.29,120.22,116.36,115.21,113.28,112.19,54.96,45.78,27.45,21.98;HRMS (ESI)calcd for C18H15N3[M+H]+:274.1339,found 274.1348,熔程:177℃-179℃。
11.以2-(3,4-二氢异喹啉-2(1H)-基)丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式 11)
氩气保护下,在一个25mL的反应瓶将2-(3,4-二氢异喹啉-2(1H)-基)丙二腈(300mg,1.52 mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(907mg,3.04mmol),四丁基氟化铵(1192mg, 4.56mmol),依次加入到搅拌的四氢呋喃:二氯甲烷:1,2-二氯乙烷=1:1:1(6mL)的混合溶剂中,在15℃下反应3小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(333mg, 80%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.84(d,J=7.6Hz,1H),7.77-7.69(m,2H),7.54(t,J=7.2Hz,1H), 7.16-7.09(m,3H),6.97(d,J=8.0Hz,1H),5.29(s,1H),3.91(d,J=14.4Hz,1H),3.63(d,J= 14.4Hz,1H),3.11-3.00(m,2H),2.92-2.81(m,2H);13C NMR(100MHz,CDCl3)δ136.78,134.09, 133.51,132.88,132.61,129.62,128.71,128.65,126.44,126.38,125.79,116.46,113.88,113.35, 60.77,51.34,48.09,29.02;HRMS(ESI)calcd forC18H15N3[M+H]+:274.1339,found 274.1348, 熔程:110℃-112℃。
12.以N-丁基-N-苯基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式12)
氩气保护下,在一个50mL的反应管将N-丁基-N-苯基氨基-丙二腈(2g,9.38mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(3.076g,10.31mmol),氟化铯(4.273g,28.13mmol),依次加入到搅拌的甲苯:N,N-二甲基甲酰胺:1,2-二氯乙烷:1,4-二氧六环=1:1:1:2(10mL)的混合溶剂中,在70℃下反应1.5小时完成反应,使用乙酸乙酯(20mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(1.764g,65%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.79(d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.63(t,J=7.6Hz, 1H),7.52(t,J=7.6Hz,1H),7.32(t,J=8.4Hz,2H),7.24(d,J=7.6Hz,2H),7.10(t,J=7.2Hz, 1H),5.70(s,1H),3.30-3.23(m,1H),2.99-2.91(m,1H),1.47-1.31(m,2H),1.28-1.11(m,2H),0.73 (t,J=7.6Hz,3H);13C NMR(100MHz,CDCl3)δ146.58,137.19,134.31,132.77,129.63,129.51, 129.27,124.33,122.56,116.88,115.62,112.80,59.62,49.14,29.23,19.91,13.54;HRMS(ESI) calcd for C19H19N3[M+H]+:290.1652,found290.1659,熔程:65℃-66℃。
13.以N-苄基-N-苯基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式13)
氩气保护下,在一个10mL的反应管将N-苄基-N-苯基氨基-丙二腈(50mg,0.20mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(90mg,0.30mmol),氟化铯(77mg,0.51mmol)和18-冠醚-6(135mg,0.51mmol),依次加入到搅拌的乙腈:四氢呋喃=1:4(2.5mL)的混合溶剂中,在35℃下反应2小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(40.5mg,62%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.70(t,J=8.0Hz,2H),7.54(t,J=7.6Hz,1H),7.41(t,J=7.2Hz, 1H),7.25-7.22(m,6H),7.18(t,J=7.2Hz,2H),7.11(t,J=7.2Hz,1H),7.04-6.99(m,1H),5.86(s, 1H),4.44(d,J=14.8Hz,1H),4.23(d,J=14.8Hz,1H);13C NMR(100MHz,CDCl3)δ146.75, 136.60,136.45,134.25,132.77,129.67,129.62,129.15,128.27,127.93,127.17,124.10,121.91, 116.91,115.19,112.65,58.98,53.82;HRMS(ESI)calcdfor C22H17N3[M+H]+:324.1495,found 324.1504,熔程:117℃-118℃。
14.以N-苄基-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式14)
氩气保护下,在一个10mL的反应管将N-苄基-N-甲基氨基-丙二腈(100mg,0.54mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(322mg,1.08mmol),氟化钾(78mg,1.35mmol)和18-冠醚-6(357mg,1.35mmol),依次加入到搅拌的二氯甲烷:乙醚:乙醇=1:3:1(2mL)的混合溶剂中,在0℃下反应2.5小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(92mg,65%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.79(d,J=8.0Hz,2H),7.65(t,J=7.6Hz,1H),7.51(t,J=7.6Hz, 1H),7.40(d,J=6.8Hz,2H),7.32(t,J=7.2Hz,2H),7.27(t,J=6.8Hz,1H),5.23(s,1H),3.75(d, J=12.8Hz,1H),3.66(d,J=12.8Hz,1H),2.17(s,3H);13C NMR(100MHz,CDCl3)δ137.12, 136.59,134.20,132.51,129.41,128.98,128.82,128.33,127.57,116.76,113.66,112.89,60.44, 59.14,37.30;HRMS(ESI)calcd for C17H15N3[M+H]+:262.1339,found 262.1342,熔程: 82℃-84℃。
15.以N-(4-氟苄基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式1 5)
氩气保护下,在一个25mL的反应瓶将N-(4-氟苄基)-N-甲基氨基-丙二腈(500mg,2.46mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(955mg,3.20mmol),氟化钾(314mg,5.41mmol)和18-冠醚-6(1430mg,5.41mmol),依次加入到搅拌的四氢呋喃:1,2-二氯乙烷=1:3(5mL)的混合溶剂中,在10℃下反应4小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得黄色油状液体(481mg,70%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.78(d,J=8.4Hz,2H),7.66(t,J=7.6Hz,1H),7.51(t,J=7.6Hz, 1H),7.37(t,J=8.4Hz,2H),7.00(t,J=8.4Hz,2H),5.22(s,1H),3.74(d,J=12.8Hz,1H),3.63 (d,J=12.8Hz,1H),2.13(s,3H);13C NMR(100MHz,CDCl3)δ162.27(d,J=244.4Hz),137.11, 134.28,132.62,132.38(d,J=2.9Hz),130.69(d,J=8.2Hz),129.53,128.90,116.83,115.24(d,J =21.2Hz),113.60,112.93,60.42,58.65,37.11;HRMS(ESI)calcd for C17H14FN3[M+H]+: 280.1245,found 280.1251。
16.以N-(4-氯苄基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式1 6)
氩气保护下,在一个25mL的反应瓶将N-(4-氯苄基)-N-甲基氨基-丙二腈(400mg,1.82
mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(979mg,3.28mmol),氟化铯(719mg,4.73mmol) 和18-冠醚-6(1250mg,4.73mmol),依次加入到搅拌的甲苯:1,2-二氯乙烷:1,4-二氧六环:二氯甲烷:四氢呋喃=1:3:1:2:5(4.8mL)的混合溶剂中,在55℃下反应1.5小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得黄色固体(377mg,70%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.80-7.77(m,2H),7.66(t,J=7.6Hz,1H),7.52(t,J=7.6Hz,1H), 7.36-7.27(m,4H),5.23(s,1H),3.74(d,J=12.8Hz,1H),3.62(d,J=12.8Hz,1H),2.14(s,3H);13C NMR(100MHz,CDCl3)δ137.02,135.19,134.28,133.40,132.63,130.36,129.56,128.88, 128.55,116.82,113.56,112.92,60.51,58.61 37.23;HRMS(ESI)calcdfor C17H14 35ClN3[M+H]+: 296.0949,found 296.0959;HRMS(ESI)calcd for C17H14 37ClN3[M+H]+:298.0920,found 298.0925,熔程:101℃-103℃。
17.以N-(4-甲基苄基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式 17)
氩气保护下,在一个250mL的反应瓶将N-(4-甲基苄基)-N-甲基氨基-丙二腈(5g,25.09mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(11.230g,37.64mmol),四丁基氟化铵(13.123g,50.19mmol),依次加入到搅拌的乙腈:N,N-二甲基甲酰胺=4:1(50mL)的混合溶剂中,在60℃下反应3小时完成反应,使用乙酸乙酯(60mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得黄色固体(4.906g,71%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.78(d,J=7.6Hz,2H),7.65(t,J=7.6Hz,1H),7.51(t,J=7.6Hz, 1H),7.30(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),5.22(s,1H),3.72(d,J=12.8Hz,1H),3.65 (d,J=12.8Hz,1H),2.33(s,3H),2.16(s,3H);13C NMR(100MHz,CDCl3)δ137.32,134.27, 133.56,132.52,129.41,129.08,129.07,128.93,116.79,113.73,113.04,60.42,59.05,37.30,21.03; HRMS(ESI)calcd for C18H17N3[M+H]+:276.1495,found 276.1502,熔程:112℃-113℃。
18.以N-(4-甲氧基苄基)-N-甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式18)
氩气保护下,在一个10mL的反应管将N-(4-甲氧基苄基)-N-甲基氨基-丙二腈(10mg,0.046 mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(21mg,0.070mmol),四丁基氟化铵(37mg,0.14 mmol),依次加入到搅拌的二氯甲烷:四氢呋喃:乙醚=1:4:1(1.2mL)的混合溶剂中,在15℃下反应1小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得黄色固体(10mg,72%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.77(d,J=8.0Hz,2H),7.64(t,J=7.6Hz,1H),7.50(t,J=7.6Hz, 1H),7.33(d,J=8.8Hz,2H),6.86(d,J=8.8Hz,2H),5.21(s,1H),3.78(s,3H),3.70(d,J=12.8 Hz,1H),3.62(d,J=12.8Hz,1H),2.13(s,3H);13C NMR(100MHz,CDCl3)δ159.15,137.33, 134.30,132.56,130.37,129.42,128.93,128.65,116.86,113.78,113.73,112.96,60.31,58.89,55.16, 37.09;HRMS(ESI)calcd for C18H17N3O[M+H]+:292.1444,found 292.1453,熔程:91℃-93℃。
19.以N,N-二甲基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式19)
氩气保护下,在一个10mL的反应管将N,N-二甲基氨基-丙二腈(100mg,0.92mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(274mg,0.92mmol),氟化铯(208mg,1.37mmol)和18-冠醚-6(362mg,1.37mmol),依次加入到搅拌的甲苯:1,2-二氯乙烷:乙醚=1:1:1(2.4mL)的混合溶剂中,在25℃下反应2.5小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得黄色油状液体(47.5mg,28%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.74(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.65(t,J=8.0Hz, 1H),7.50(t,J=8.0Hz,1H),5.06(s,1H),2.33(s,6H);13C NMR(100MHz,CDCl3)δ137.31, 133.93,132.56,129.44,128.51,116.53,113.52,113.09,61.38,41.49;HRMS(ESI)calcd for C11H11N3[M+H]+:186.1026,found 186.1023。
20.以2-(哌啶-1-基)丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式20)
氩气保护下,在一个10mL的反应管将2-(哌啶-1-基)丙二腈(100mg,0.67mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(319mg,1.07mmol),氟化钾(78mg,1.34mmol)和18-冠醚-6(354mg,1.34mmol),依次加入到搅拌的1,4-二氧六环(2mL)中,在70℃下反应2.5小时完成反应,使用乙酸乙酯(8mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得黄色固体(68mg,45%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.72(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),7.62(t,J=8.0Hz, 1H),7.48(t,J=8.0Hz,1H),5.00(s,1H),2.60-2.57(m,2H),2.46-2.40(m,2H),1.65-1.57(m,2H), 1.55-1.40(m,4H);13C NMR(100MHz,CDCl3)δ137.27,133.96,132.26,129.17,128.52,116.47, 113.88,113.02,61.34,50.59,25.30,23.61;HRMS(ESI)calcdfor C14H15N3[M+H]+:226.1339, found 226.1335,熔程:65℃-67℃。
21.以吗啉基氨基-丙二腈和2-(三甲基硅)苯基三氟甲烷磺酸酯为原料(反应式21)
氩气保护下,在一个10mL的反应管中将吗啉基氨基-丙二腈(100mg,0.64mmol),2-(三甲基硅)苯基三氟甲烷磺酸酯(285mg,0.96mmol),氟化铯(192mg,1.27mmol)和18-冠醚-6(336mg,1.27mmol),依次加入到搅拌的四氢呋喃(2mL)中,在30℃下反应2小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得淡黄色油状液体(93mg,64%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.74(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),7.63(t,J=8.0Hz, 1H),7.50(t,J=8.0Hz,1H),5.03(s,1H),3.71-3.66(m,2H),3.64-3.59(m,2H),2.67-2.62(m,2H), 2.49-2.45(m,2H);13C NMR(100MHz,CDCl3)δ136.13,133.99,132.45,129.50,128.60,116.35, 113.44,112.97,66.10,60.62,49.47;HRMS(ESI)calcd forC13H13N3O[M+H]+:228.1131,found 228.1128.
22.以二氢吲哚基氨基-丙二腈和2-甲基-6-(三甲基甲硅烷基)苯基三氟甲磺酸酯为原料(反应式22)
氩气保护下,在一个100mL的反应瓶将二氢吲哚基氨基-丙二腈(1.5g,8.82mmol),2-甲基 -6-(三甲基甲硅烷基)苯基三氟甲磺酸酯(2.755g,8.82mmol),四丁基氟化铵(3.211g,12.28 mmol),依次加入到搅拌的四氢呋喃:二氯甲烷=1:1(2mL)的混合溶剂中,在20℃下反应2 小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(559mg,25%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.65(d,J=7.6Hz,1H),7.53(d,J=6.8Hz,1H),7.45(t,J=7.6Hz, 1H),7.17-7.10(m,2H),6.86(t,J=7.6Hz,1H),6.64(d,J=7.6Hz,1H),5.80(s,1H),3.51-3.41 (m,2H),3.07-2.94(m,2H),2.66(s,3H);13C NMR(100MHz,CDCl3)δ149.08,139.23,136.30, 133.89,132.52,130.56,129.78,127.61,124.99,120.78,117.04,115.25,113.48,108.33,51.98, 51.04,28.21,19.97;HRMS(ESI)calcd for C18H15N3[M+H]+:274.1339,found 274.1347,熔程: 189℃-191℃。
23.以二氢吲哚基氨基-丙二腈和2-甲基-6-(三甲基甲硅烷基)苯基三氟甲磺酸酯为原料(反应式23)
氩气保护下,在一个10mL的反应管将二氢吲哚基氨基-丙二腈(100mg,0.55mmol),2-甲基-6-(三甲基甲硅烷基)苯基三氟甲磺酸酯(256mg,0.82mmol),氟化钾(63mg,1.09mmol)和18-冠醚-6(288mg,1.09mmol),依次加入到搅拌的甲苯:N,N-二甲基甲酰胺:1,4-二氧六环=8:1:1(2mL)的混合溶剂中,在55℃下反应2小时完成反应,使用乙酸乙酯(8mL)萃取3次并干燥,过滤所得有机相在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(79mg,53%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.72(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H),7.42(t,J=8.0Hz, 1H),7.18-7.14(m,2H),6.86(t,J=7.2Hz,1H),6.80(d,J=7.6Hz,1H),5.95(s,1H),3.44-3.37 (m,1H),3.17-3.12(m,1H),3.08-3.01(m,1H),2.99-2.91(m,1H),2.61(s,3H);13C NMR(100 MHz,CDCl3)δ148.42,144.18,136.69,132.40,131.10,130.42,127.56,125.86,124.96,120.97, 115.41,114.58,112.95,108.93,53.70,50.43,28.04,20.79;HRMS(ESI)calcd for C18H15N3 [M+H]+:274.1339,found 274.1347,熔程:117℃-119℃。
24.以二氢吲哚基氨基-丙二腈和4-甲氧基-2-(三甲基甲硅烷基)苯基三氟甲磺酸酯为原料(反应式24)
氩气保护下,在一个10mL的反应管将二氢吲哚基氨基-丙二腈(200mg,1.09mmol),4-甲氧基-2-(三甲基甲硅烷基)苯基三氟甲磺酸酯(539mg,1.64mmol),氟化铯(497mg,3.27mmol),依次加入到搅拌的乙腈:四氢呋喃=1:1(2mL)的混合溶剂中,在15℃下反应1小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(73mg,23%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.71(d,J=8.8Hz,1H),7.39(d,J=2.4Hz,1H),7.18-7.14(m,2H), 7.00(d,J=8.4Hz,1H),6.86(t,J=7.6Hz,1H),6.77(d,J=8.0Hz,1H),5.92(s,1H),3.93(s,3H), 3.43-3.36(m,1H),3.21-3.16(m,1H),3.09-2.92(m,2H);13C NMR(100MHz,CDCl3)δ162.91, 148.31,138.50,135.94,130.39,127.56,124.99,121.00,116.66,115.32,114.39,114.32,108.86, 103.93,55.89,53.54,50.42,28.05;HRMS(ESI)calcdfor C18H15N3O[M+H]+:290.1288,found 290.1299,熔程:168℃-169℃。
25.以二氢吲哚基氨基-丙二腈和4-甲氧基-2-(三甲基甲硅烷基)苯基三氟甲磺酸酯为原料(反应式25)
氩气保护下,在一个10mL的反应管将二氢吲哚基氨基-丙二腈(200mg,1.09mmol),4-甲氧基-2-(三甲基甲硅烷基)苯基三氟甲磺酸酯(539mg,1.64mmol),氟化铯(497mg,3.27mmol),依次加入到搅拌的乙腈:四氢呋喃=1:1(2mL)的混合溶剂中,在15℃下反应1小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(148mg,47%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.77(d,J=8.4Hz,1H),7.26(d,J=2.8Hz,1H),7.20-7.13(m,3H), 6.85(t,J=7.6Hz,1H),6.76(d,J=8.4Hz,1H),5.90(s,1H),3.86(s,3H),3.40-3.33(m,1H), 3.16-3.11(m,1H),3.07-2.89(m,2H);13C NMR(100MHz,CDCl3)δ160.03,148.36,130.43, 129.92,128.18,127.51,124.95,120.89,119.43,118.39,116.14,114.66,113.56,108.83,55.80, 52.80,50.25,27.99;HRMS(ESI)calcd for C18H15N3O[M+H]+:290.1288,found 290.1299,熔程: 134℃-136℃。
26.以二氢吲哚基氨基-丙二腈和4,5-二甲氧基-2-(三甲基甲硅烷基)苯基三氟甲磺酸酯为原料 (反应式26)
氩气保护下,在一个10mL的反应管将二氢吲哚基氨基-丙二腈(20mg,0.109mmol),4,5-二甲氧基-2-(三甲基甲硅烷基)苯基三氟甲磺酸酯(59mg,0.164mmol),氟化铯(50mg,0.327mmol)和18-冠醚-6(86mg,0.327mmol),依次加入到搅拌的乙醚(1mL)中,在0℃下反应4小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(22mg,64%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.27(s,1H),7.17-7.13(m,3H),6.85(t,J=7.2Hz,1H),6.76(d,J= 8.0Hz,1H),5.91(s,1H),4.00(s,3H),3.91(s,3H),3.41-3.34(m,1H),3.21-3.16(m,1H), 3.08-2.91(m,2H);13C NMR(100MHz,CDCl3)δ152.50,149.39,148.30,130.38,130.32,127.49, 124.92,120.87,116.58,115.45,114.76,111.09,108.78,103.91,56.38,56.31,53.15,50.36,27.99; HRMS(ESI)calcd for C19H17N3 O2[M+H]+:320.1394,found320.1404,熔程:183℃-185℃。
27.以二氢吲哚基氨基-丙二腈和3-(三甲基甲硅烷基)-2-萘基三氟甲磺酸酯为原料(反应式27)
氩气保护下,在一个25mL的反应瓶将二氢吲哚基氨基-丙二腈(500mg,2.73mmol),3-(三甲基甲硅烷基)-2-萘基三氟甲磺酸酯(1902mg,5.46mmol),氟化钾(476mg,8.19mmol)和18-冠醚-6(2159mg,8.169mmol),依次加入到搅拌的乙醇:1,2-二氯乙烷=1:1(6mL)的混合溶剂中,在45℃下反应1.5小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得白色固体(599mg,71%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ8.34(d,J=12.0Hz,2H),8.01(d,J=8.0Hz,1H),7.95(d,J=8.0 Hz,1H),7.78-7.69(m,2H),7.19-7.15(m,2H),6.89-6.83(m,2H),6.08(s,1H),3.48-3.41(m,1H), 3.16-3.11(m,1H),3.08-3.02(m,1H),3.00-2.91(m,1H);13C NMR(100MHz,CDCl3)δ148.41, 136.66,133.93,132.14,130.57,130.47,130.13,128.81,128.52,128.43,128.29,127.62,125.06, 121.10,116.78,114.65,109.30,109.03,53.77,50.36,28.05;HRMS(ESI)calcd for C21H15N3 [M+H]+:310.1339,found 310.1349,熔程:241℃-242℃。
28.以二氢吲哚基氨基-丙二腈和6-(三甲基甲硅烷基)-2,3-二氢-1H-茚满-三氟甲磺酸酯为原料 (反应式28)
氩气保护下,在一个10mL的反应管中将二氢吲哚基氨基-丙二腈(100mg,0.55mmol),6-(三甲基甲硅烷基)-2,3-二氢-1H-茚满-三氟甲磺酸酯(277mg,0.82mmol),氟化铯(165mg,1.09 mmol)和18-冠醚-6(289mg,1.09mmol),依次加入到搅拌的四氢呋喃(2mL)中,在30℃下反应2小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得淡黄色固体(124mg,76%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.59(s,1H),7.16(t,J=8.0Hz,2H),6.87-6.81(m, 2H),5.97(s,1H),3.43-3.36(m,1H),3.20-3.14(m,1H),3.08-2.90(m,6H),2.21-2.14(m,2H);13C NMR(100MHz,CDCl3)δ150.62,148.36,146.28,134.34,130.26,129.59,127.36,124.76,124.56, 120.65,116.90,114.68,109.93,108.69,53.20,50.12,33.10,32.17,27.86,24.94;HRMS(ESI) calcd for C20H17N3[M+H]+:300.1495,found 300.1491;熔程:156℃-158℃。
29.以二氢吲哚基氨基-丙二腈和6-(三甲基甲硅烷基)苯并[d][1,3]二氧-5-甲基三氟甲磺酸酯为原料(反应式29)
氩气保护下,在一个300mL的反应瓶中将二氢吲哚基氨基-丙二腈(10g,54.58mmol),6-(三甲基甲硅烷基)苯并[d][1,3]二氧-5-甲基三氟甲磺酸酯(18.686g,54.58mmol),四丁基氟化铵 (21.406g,81.87mmol),依次加入到搅拌的二氯甲烷(60mL)中,在10℃下反应1小时完成反应,在旋转蒸发仪上抽干溶剂,经柱层析得黄色固体(11.589g,70%yield)。
产物检测数据如下:
1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.18-7.12(m,3H),6.86(t,J=8.0Hz,1H),6.78(d,J= 8.0Hz,1H),6.13(s,2H),5.90(s,1H),3.42-3.35(m,1H),3.25-3.19(m,1H),3.09-2.91(m,2H);13C NMR(100MHz,CDCl3)δ151.66,148.39,148.25,132.67,130.29,127.49,124.92,120.90, 116.29,114.53,112.68,109.19,108.77,105.30,103.06,53.10,50.31,27.98;HRMS(ESI)calcd for C18H13N3O2[M+H]+:304.1081,found 304.1077,熔程:169℃-171℃。
Claims (1)
1.一种N-(氰基(2-氰基取代苯基)甲基)取代的三级胺的合成方法,其特征为N,N-二取代氨基-丙二腈、取代2-(三甲基硅)苯基三氟甲烷磺酸酯、催化剂,依次加入到有机溶剂中,加热条件下得到N-(氰基(2-氰基取代苯基)甲基)取代的三级胺类化合物,反应式如下:
其中:
(1)R1、R2不在同一个环系上时,R1选自甲基、正丁基、苄基,R2选自甲基、取代苯基、取代苄基;
(2)R1、R2在同一环系上时,R1、R2连同N原子选自哌啶基、吗啉基、二氢吲哚基、1,2,3,4-四氢异喹啉基、1,2,3,4-四氢喹啉基;
(3)R3选自氢,甲基,甲氧基,4,5-二甲氧基,4,5-亚甲二氧基,4,5-环戊基;
(4)所用催化剂选自氟化铯+18-冠醚-6、氟化铯、氟化钾+18-冠醚-6、氟化钾、四丁基氟化铵,优选氟化铯+18-冠醚-6;
(5)所用的溶剂选自乙腈、二氯甲烷、四氢呋喃、乙醚、甲苯、乙醇、1,2-二氯乙烷、N,N-二甲基甲酰胺、1,4-二氧六环的一种或几种,优选四氢呋喃;
(6)所用加热的温度为0℃-70℃,维持时间为1-4小时,优选30℃,维持2小时;
(7)反应中各物质的摩尔量比为:N,N-二取代氨基-丙二腈:取代2-(三甲基硅)苯基三氟甲烷磺酸盐:催化剂=1:1-2:1.5-3,优选N,N-二取代氨基-丙二腈:取代2-(三甲基硅)苯基三氟甲烷磺酸盐:催化剂=1:1.5:2。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS5290630A (en) * | 1976-01-21 | 1977-07-30 | Sumitomo Chem Co Ltd | Algicide |
CN107635974A (zh) * | 2015-06-05 | 2018-01-26 | 杜邦公司 | 作为除草剂的2‑(苯氧基或苯硫基)嘧啶衍生物 |
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Publication number | Priority date | Publication date | Assignee | Title |
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JPS5290630A (en) * | 1976-01-21 | 1977-07-30 | Sumitomo Chem Co Ltd | Algicide |
CN107635974A (zh) * | 2015-06-05 | 2018-01-26 | 杜邦公司 | 作为除草剂的2‑(苯氧基或苯硫基)嘧啶衍生物 |
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