CN117865869A - Method for synthesizing 1-trifluoromethyl indole compound by taking 2-alkynyl aromatic amine as raw material - Google Patents
Method for synthesizing 1-trifluoromethyl indole compound by taking 2-alkynyl aromatic amine as raw material Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 34
- -1 1-trifluoromethyl indole compound Chemical class 0.000 title claims abstract description 31
- 239000002994 raw material Substances 0.000 title abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title abstract description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 51
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 229940096017 silver fluoride Drugs 0.000 claims abstract description 16
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000003446 ligand Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- FGXBBVZKCBZAEO-UHFFFAOYSA-N silver;trifluoro(trifluoromethylsulfanyl)methane Chemical compound [Ag].FC(F)(F)SC(F)(F)F FGXBBVZKCBZAEO-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 10
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 229940126027 positive allosteric modulator Drugs 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- AOWOVTUGHIKKNC-UHFFFAOYSA-N 1-(trifluoromethyl)indole Chemical class C1=CC=C2N(C(F)(F)F)C=CC2=C1 AOWOVTUGHIKKNC-UHFFFAOYSA-N 0.000 claims description 4
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 4
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 claims description 4
- 238000006692 trifluoromethylation reaction Methods 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000003905 agrochemical Substances 0.000 claims 1
- 239000011261 inert gas Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000575 pesticide Substances 0.000 abstract description 3
- 229910052709 silver Inorganic materials 0.000 abstract description 3
- 239000004332 silver Substances 0.000 abstract description 3
- 239000008204 material by function Substances 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000003281 allosteric effect Effects 0.000 description 4
- VYWWXOJAAXRFDT-UHFFFAOYSA-N 1-(trifluoromethyl)indole-5-carbonitrile Chemical class N#CC1=CC=C2N(C(F)(F)F)C=CC2=C1 VYWWXOJAAXRFDT-UHFFFAOYSA-N 0.000 description 3
- MWVTWFVJZLCBMC-UHFFFAOYSA-N 4,4'-bipyridine Chemical compound C1=NC=CC(C=2C=CN=CC=2)=C1 MWVTWFVJZLCBMC-UHFFFAOYSA-N 0.000 description 3
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- YGGPWQOKKJZBJU-UHFFFAOYSA-N 2-methyl-1-(trifluoromethyl)indole-5-carbonitrile Chemical compound N#CC1=CC=C2N(C(F)(F)F)C(C)=CC2=C1 YGGPWQOKKJZBJU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000013110 organic ligand Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 229910021610 Silver(III) fluoride Inorganic materials 0.000 description 1
- DXGTUUQHTDOFFQ-UHFFFAOYSA-N [N].C1=CC=C2NC=CC2=C1 Chemical group [N].C1=CC=C2NC=CC2=C1 DXGTUUQHTDOFFQ-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000008848 allosteric regulation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000003009 desulfurizing effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- PGGQSYHSNJQLOQ-UHFFFAOYSA-K silver trifluoride Chemical compound F[Ag](F)F PGGQSYHSNJQLOQ-UHFFFAOYSA-K 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing a 1-trifluoromethyl indole compound by taking 2-alkynyl aromatic amine as a raw material, belonging to the field of organic chemistry. The method takes 2-alkynyl arylamine compounds and silver trifluoromethylthio as raw materials, potassium iodide and silver fluoride are added, and the multi-substituted-1-trifluoromethyl indole compounds can be synthesized by a one-pot method under the action of a catalyst and a ligand. The method has the advantages of wide applicability of the substrate, simple and easily obtained raw materials and low economic cost; in addition, the method of the invention realizes the synthesis of the target product, the target product can be obtained in good yield only by reacting for 3-10 hours, and the target compound has wide application in the fields of medicines, pesticides, functional materials and the like.
Description
Technical Field
The invention particularly relates to a method for synthesizing a 1-trifluoromethyl indole compound by taking 2-alkynyl aromatic amine as a raw material, belonging to the field of organic chemistry.
Background
Trifluoromethyl is the smallest and most important perfluoroalkyl function, and the introduction of trifluoromethyl into an organic molecule tends to enhance the physical, chemical or biological activity of the parent molecule, e.g., organic compounds formed by the introduction of trifluoromethyl onto a heteroatom tend to have better lipophilicity and membrane permeability. In addition, indoles and their derivatives also exhibit broad-spectrum biological activity in anti-inflammatory, insecticidal, bactericidal, anti-tumor, etc. However, the current introduction of CF onto the indole nitrogen atom 3 The method of (2) has been recently reported. Therefore, it is very useful to develop a simple and mild N-trifluoromethylation process. In the field of organic synthesis, research on N-trifluoromethylation methods has also attracted considerable attention.
Disclosure of Invention
The invention develops a novel method for synthesizing 1-trifluoromethyl indole. The 2-alkynyl arylamine compound reacts with silver trifluoromethylthio, potassium iodide and silver fluoride under the catalysis of a catalyst, and is subjected to addition cyclization to obtain the 1-trifluoromethyl indole compound, so that the synthesis of the 1-trifluoromethyl indole derivative is conveniently realized.
The invention aims to provide a synthesis method of a 1-trifluoromethyl indole compound, which comprises the steps of taking a 2-alkynyl arylamine compound shown in a formula (1) and silver trifluormethyl sulfide as reactants in an organic solvent, adding potassium iodide and silver trifluormethyl sulfide, and carrying out cyclization reaction under the catalysis of a catalyst and a ligand to obtain the 1-trifluoromethyl indole compound shown in a formula (2);
wherein R is 1 Selected from H, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, aryl, halogen (F, cl, br), cyano, nitro, C 1 -C 8 Alkoxy, acyl and amido groups and heterocycles; r is R 2 Selected from C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, aryl, C 1 -C 8 Alkoxy, acyl and amido groups, and heterocyclic rings.
In one embodiment of the invention, aryl includes a substituted or unsubstituted benzene ring, naphthalene ring; the substitution may be one to three; the substituted groups being selected from halogen, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, ester, cyano, nitro and heterocycle.
In one embodiment of the invention, the acyl group is-COR a ，R a H, C1 to 8 alkyl groups.
In one embodiment of the present invention, the amide group is-NHCOR b ，R b H, C1 to 8 alkyl groups.
In one embodiment of the invention, the heterocycle is a three to six membered ring containing 1-3 heteroatoms. Heteroatoms include N, O, S.
In one embodiment of the invention, the ester group is-COOR c ，R c Is C1-8 alkyl.
In one embodiment of the present invention, the organic solvent comprises acetonitrile (CH 3 CN), tetrahydrofuran (THF), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), any one or more of. Preferably CH 3 CN。
In one embodiment of the invention, the catalyst is any one or more of cuprous iodide, cuprous chloride, ruthenium dichloride, cupric fluoride, bis (triphenylphosphine) palladium chloride and tris (triphenylphosphine) rhodium chloride. Preferably cuprous iodide.
In one embodiment of the invention, the ligand is any one or more of 2,2 '-bipyridine, 4' -bipyridine, triphenylphosphine, and phenanthroline. 2,2' -bipyridine is preferred.
In one embodiment of the invention, the temperature of the reaction is from 25 ℃ to 100 ℃. Preferably 45-55 deg.c.
In one embodiment of the invention, the reaction time is 3 to 10 hours. Specifically, the time is 5 hours.
In one embodiment of the invention, the molar ratio of the 2-alkynylarylamine compound, silver trifluormethylsulfide, potassium iodide, silver fluoride, catalyst and ligand is 1 (1.0-2.0): (1.0-2.0): (3.0-6.0): (0.05-0.2): (0.05-0.2). Preferably 1:1.5:1.5:5:0.2:0.2.
In one embodiment of the invention, the reaction concentration of the 2-alkynylarylamine compound is 0.05-5mmol/mL. Particularly preferably 0.5mmol/mL.
In one embodiment of the present invention, the structure of the 2-alkynylaryl isothiocyanate is specifically:
wherein R is 1 、R 2 Is defined as above, in particular R 1 Selected from H, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, aryl, halogen (F, cl, br), cyano, nitro, C 1 -C 8 Alkoxy, acyl and amido groups and heterocycles; r is R 2 Selected from C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, aryl, C 1 -C 8 Alkoxy, acyl and amido groups, and heterocyclic rings.
In one embodiment of the invention, the N-trifluoromethylation/cyclization reaction is carried out under an inert atmosphere. Such as: and (3) nitrogen atmosphere.
In one embodiment of the invention, a novel green economical synthesis method comprises the following steps:
taking 2-alkynyl arylamine compounds, silver trifluoromethylsulfide, potassium iodide and silver fluoride as raw materials, adding a catalyst and an organic ligand, stirring and reacting for a period of time at 25-50 ℃ to obtain a crude product of the polysubstituted-1-trifluoromethyl indole compound, and then filtering, washing, reduced pressure distillation and column chromatography separation to obtain the pure polysubstituted-1-trifluoromethyl indole compound.
In one embodiment of the invention, the separation and purification method is to use flash column chromatography to obtain the final product polysubstituted-1-trifluoromethyl indole compound.
In one embodiment of the invention, the method is preferably carried out as follows: adding a 2-alkynyl arylamine compound, silver trifluo-methylthio, potassium iodide, silver fluoride, a catalyst and an organic ligand into a reaction container containing acetonitrile solvent according to the molar ratio of 1:1.5:1.5:5:0.2:0.2, stirring for 3-10 hours at the temperature of 25-50 ℃, and separating and purifying to obtain a target product.
In one embodiment of the invention, the reaction mechanism of the invention is as follows: reacting 2-alkynylarylamine compound with silver trifluormethylsulfide and potassium iodide to generate 2-alkynylaryl isothiocyanate, and then desulfurizing and fluoridating the 2-alkynylaryl isothiocyanate with silver fluoride to form ArN (CF) 3 ) Ag unit is nucleophilic added/cyclized with alkynyl at ortho position of aromatic ring under the action of catalyst to produce polysubstituted-1-trifluoromethyl indole compound.
The target substance-polysubstituted-1-trifluoromethyl indole compound prepared by the method can be used as a synthesis intermediate to prepare a plurality of drug molecules with biological activity, such as positive allosteric modulators of nicotinic acetylcholine receptors and the like reported in patent document WO2012131031A 1.
The invention also provides application of the method in the fields of medicine, pesticide and functional material preparation.
The invention also provides a synthesis method of the important intermediate of the positive allosteric modulator of the nicotinic acetylcholine receptor, wherein the structure of the important intermediate of the positive allosteric modulator of the nicotinic acetylcholine receptor is shown as follows:the reaction route of the method is as follows:
wherein R is 1 、R 2 Is as defined above.
In one embodiment of the invention, R 1 In particular H, R 2 The methyl group is particularly selected.
In one embodiment of the present invention, the method for synthesizing an important intermediate for a positive allosteric modulator of a nicotinic acetylcholine receptor comprises the steps of:
(1) In an organic solvent, 2-alkynyl-4 cyano arylamine compounds and silver trifluoromethylsulfide are used as reactants, potassium iodide and silver trifluoride are added, and cyclization reaction is carried out under the catalysis of a catalyst and a ligand, so that 1-trifluoromethyl-5-cyano indole compounds are synthesized;
(2) The obtained 1-trifluoromethyl-5-cyanoindole compound is subjected to hydrogenation reduction to obtain an important intermediate of the positive allosteric modulator of the nicotinic acetylcholine receptor.
In one embodiment of the present invention, the conditions in the step (1) are the same as those in the method for synthesizing the 1-trifluoromethylindole compound.
In one embodiment of the present invention, the hydrogenation reduction of step (2) is performed by dissolving 1-trifluoromethyl-5-cyanoindole in MeOH NH 3 Then Raney-Ni is added, and the mixture is reacted for a period of time at room temperature in a hydrogen environment.
In one embodiment of the invention, meOH NH 3 Is 5M.
In one embodiment of the invention, raney-Ni is added in an amount of 0.2g/mmol relative to 1-trifluoromethyl-5-cyanoindole.
The beneficial effects are that:
in the method, 2-alkynyl arylamine, silver trifluormethyl sulfide, potassium iodide and silver fluoride are used as reactants in a nitrogen atmosphere, and under the action of a catalyst and a ligand, the construction of a 1-trifluoromethyl indole skeleton is realized by one-pot reaction, so that a target compound is obtained.
The method uses silver fluoride as a fluorine source, has wide substrate applicability, simple and easily obtained raw materials and lower economic cost; in addition, the method can obtain the target product in good yield only by reacting for 3-10 hours, and is rapid and efficient.
The synthesis method of the invention converts the easily obtained 2-alkynyl aromatic amine into the corresponding 1-trifluoromethyl indole compound under a simpler condition, realizes the synthesis of the polysubstituted-1-trifluoromethyl indole derivative in one step, and has wide application in the fields of medicines, pesticides, functional materials and the like.
Drawings
FIG. 1 is a synthetic route diagram of the method of the present invention.
Detailed Description
The following are specific embodiments of the present invention.
The synthetic route diagram of the embodiment of the invention is shown in fig. 1:
o-alkynyl aniline, silver trifluo-methylthio, potassium iodide and silver fluoride are used as raw materials, cuprous iodide is used as a catalyst, 2' -bipyridine is used as a ligand, acetonitrile is used as a reaction solvent, and the target compound can be obtained after 3-10 hours of reaction at 25-50 ℃. The reaction expression is shown in figure 1.
Example 1: synthesis of 2-phenyl-1-trifluoromethylindole
P-2-phenylethynyl aniline (97 mg,0.5 mmol), silver trifluormethylsulfide (157 mg,0.75 mmol), potassium iodide (125 mg,0.75 mmol), silver fluoride (317 mg,2.5 mmol), cuprous iodide (19 mg,0.1 mmol), 2' -bipyridine (16 mg,0.1 mmol) and acetonitrile (5 mL) were added to a 25mL reaction tube equipped with a stirrer, respectively, and reacted at 50℃for 8 hours under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the residue was washed with ethyl acetate, concentrated in vacuo to remove the solvent, and the target product was purified by column chromatography to give 93mg of the product in 88% yield (yield: 71%).
1 H NMR(400MHz,CDCl 3 )δ7.79-7.69(m,1H),7.69-7.62(m,1H),7.57(dd,J＝6.5,2.8Hz,2H),7.52-7.44(m,3H),7.43-7.30(m,2H),6.69-6.61(m,1H). 19 F NMR(376MHz,CDCl 3 )δ-49.82(s,3F). 13 C NMR(101MHz,CDCl 3 )δ139.4(s),136.0(s),132.4(s),129.6(s),129.3(s),128.8(s),128.2(s),124.4(s),123.0(s),121.1(s),120.7(q,J＝263.2Hz),113.2(q,J＝4.3Hz),109.8(s).HRMS(ESI)m/z calculated for C 15 H 11 F 3 N[M+H] + :262.0844,found:262.0838.
Example 2: synthesis of 2-p-cyanophenyl-1-trifluoromethylindole
2-Cyanophenylethynyl aniline (109 mg,0.5 mmol), silver trifluormethyl sulfide (157 mg,0.75 mmol), potassium iodide (125 mg,0.75 mmol), silver fluoride (317 mg,2.5 mmol), cuprous iodide (19 mg,0.1 mmol), 2' -bipyridine (16 mg,0.1 mmol) and acetonitrile (5 mL) were each added to a 25mL reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 50℃for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the residue was washed with ethyl acetate, concentrated in vacuo to remove the solvent, and the target product was purified by column chromatography to give 109mg of the product with a fluorine spectrum yield of 83% (yield: 76%).
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝8.5Hz,2H),7.69-7.66(m,1H),7.63(t,J＝7.4Hz,3H),7.42-7.37(m,1H),7.35-7.29(m,1H),6.69(s,1H). 19 F NMR(376MHz,CDCl 3 )δ-49.90(s,3F). 13 C NMR(101MHz,CDCl 3 )δ137.1(s),136.9(s),136.4(s),132.1(s),130.1-129.8(m),129.0(s),125.3(s),123.5(s),121.5(s),120.5(q,J＝262.1Hz),118.6(s),113.3(q,J＝4.2Hz),112.5(s),111.4(s).HRMS(ESI)m/z calcd.for C 16 H 10 F 3 N 2 (M+H) + :287.0796；found:287.0791.
Example 3: synthesis of 2-biphenyl-1-trifluoromethylindole
2-Biphenylethynylaniline (125 mg,0.5 mmol), silver trifluormethylsulfide (157 mg,0.75 mmol), potassium iodide (125 mg,0.75 mmol), silver fluoride (317 mg,2.5 mmol), cuprous iodide (19 mg,0.1 mmol), 2' -bipyridine (16 mg,0.1 mmol) and acetonitrile (5 mL) were each added to a 25mL reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 50℃for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the residue was washed with ethyl acetate, concentrated in vacuo to remove the solvent, and the target product was purified by column chromatography to give 68mg of the product with a fluorine spectrum yield of 49% (yield 40%).
1 H NMR(400MHz,CDCl 3 )δ7.66(dt,J＝5.6,3.5Hz,5H),7.63-7.56(m,3H),7.47(t,J＝7.6Hz,2H),7.41-7.26(m,3H),6.64(s,1H). 19 F NMR(376MHz,CDCl 3 )δ-49.27(s,3F). 13 CNMR(101MHz,CDCl 3 )δ140.94(d,J＝108.1Hz),138.98(s),135.99(s),131.14(s),129.85-129.66(m),129.17(s),128.87(s),127.64(s),126.94(d,J＝36.8Hz),124.27(s),122.93(s),120.97(s),δ120.60(q,J＝263.2Hz),113.08(q,J＝4.3Hz),109.82(s).HRMS(AP)m/zcalculated for C 21 H 15 F 3 N[M+H] + :338.1142,found:338.1157.
Example 4: synthesis of 1-trifluoromethyl-2-methyl-5-cyano-indole
2-propynyl-4-cyanoaniline (0.5 mmol), silver trifluormethylsulfide (157 mg,0.75 mmol), potassium iodide (125 mg,0.75 mmol), silver fluoride (317 mg,2.5 mmol), cuprous iodide (19 mg,0.1 mmol), 2' -bipyridine (16 mg,0.1 mmol) and acetonitrile (5 mL) were each added to a 25mL reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 50℃for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through celite, and the residue was washed with ethyl acetate, concentrated in vacuo to remove the solvent, and the target product was purified by column chromatography to give 38mg of the product with a fluorine spectrum yield of 40% (yield 34.2%).
1 H NMR(400MHz,CDCl 3 )δ7.96-7.72(m,1H),7.62(d,J＝6.6Hz,1H),7.56-7.43(m,1H),6.45(s,1H),2.54(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-51.75(s,3F). 13 C NMR(101MHz,CDCl 3 )δ137.67(s),137.04(s),129.10(s),126.45(s),δ124.65-115.35(m),125.07(s),119.53(s),112.99(q,J＝4.9Hz),107.27-107.13(m),106.11(s),14.12(q,J＝3.6Hz).
The 2-propynyl-4-cyanoaniline is replaced by other substitution conditions to prepare more corresponding multi-substituted-1-trifluoromethyl indole.
Example 5: influence of different catalysts on the Synthesis of 2-phenyl-1-trifluoromethylindole
With reference to example 1, the catalyst was replaced by cuprous iodide, ruthenium dichloride, cupric fluoride, bis (triphenylphosphine) palladium chloride, tris (triphenylphosphine) rhodium chloride, respectively, without adding any ligand, and a set of experiments without adding any catalyst were added, and the other conditions were unchanged, so as to synthesize 2-phenyl-1-trifluoromethyl indole. Specific yield results are shown in table 1.
TABLE 1 influence of different catalysts on the Synthesis of 2-phenyl-1-trifluoromethylindole
The result shows that: the product yields obtained were all worse than in example 1 without catalyst and with copper chloride, copper acetate, copper chloride, ruthenium dichloride, copper fluoride, bis (triphenylphosphine) palladium chloride, tris (triphenylphosphine) rhodium chloride instead of copper iodide as the catalyst in example 1.
Example 6: effect of different ligands on 2-phenyl-1-trifluoromethylindole Synthesis
Referring to example 1, 2-phenyl-1-trifluoromethyl indole was synthesized by replacing the catalyst with 4,4' -bipyridine, triphenylphosphine, and phenanthroline, respectively, under the same conditions. Specific yield results are shown in table 2.
TABLE 2 influence of different ligands on the synthesis of 2-phenyl-1-trifluoromethylindole
| Catalyst | Fluorine spectrum yield (%) |
| 2,2’-Bipyridine | 88 |
| 4,4’-Bipyridine | 24 |
| PPh 3 | 50 |
| 1,10-Phen | 40 |
The result shows that: the yields of the products obtained were all worse than in example 1 using 4,4 '-bipyridine, triphenylphosphine, and 2,2' -bipyridine from phenanthroline in example 1 as ligands.
Example 7: influence of different solvents on the Synthesis of 2-phenyl-1-trifluoromethylindole
Referring to example 1, 2-phenyl-1-trifluoromethylindole was synthesized by replacing the solvent with tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, and water, respectively, under the same conditions. Specific yield results are shown in Table 3.
TABLE 3 influence of different solvents on the Synthesis of 2-phenyl-1-trifluoromethylindole
| Solvent(s) | Fluorine spectrum yield (%) |
| CH 3 CN | 88 |
| THF | Trace |
| DMF | Trace |
| DMSO | Trace |
| H 2 O | 0 |
| o-DCB | 0 |
The result shows that: the acetonitrile in example 1 was replaced with tetrahydrofuran, N-dimethylformamide, dimethylsulfoxide, water, 1, 2-dichlorobenzene as a solvent to obtain the product in a yield inferior to that of example 1.
EXAMPLE 8 Synthesis of 2-phenyl-1-trifluoromethylindole at different reaction temperatures
Referring to example 1, 2-phenyl-1-trifluoromethylindole was synthesized by replacing the reaction temperature from 50℃to 30℃and 70℃and 90℃respectively, with the other conditions unchanged.
Specific yield results are shown in Table 3.
TABLE 3 different reaction temperatures for the synthesis of 2-phenyl-1-trifluoromethylindole
The result shows that: the product yield obtained by substituting 30℃at 70℃at 90℃for 50℃in example 2 was not much different from that obtained in example 1, the temperature reached 90℃and the yield was much lower.
Comparative example 1
Referring to example 1, potassium iodide was not added, and others were unchanged.
The result shows that: potassium iodide was not added and the yield was reduced to zero.
Comparative example 2
With reference to example 1, no silver fluoride was added, the others being unchanged.
The result shows that: no silver fluoride was added and the yield was reduced to zero.
EXAMPLE 9 Synthesis of an important intermediate for Positive allosteric modulators of nicotinic acetylcholine receptors
An important intermediate of Positive Allosteric Modulators (PAMs) of nicotinic acetylcholine receptors(WO 2012131031A1, china discloses a synthesis method of an intermediate M18):
1-trifluoromethyl-2-methyl-5-cyano-indole (0.5 mmol) in MeOH. NH 3 Raney-Ni (100 mg) was added to (10 mL, 5M) at room temperature, and the reaction mixture was stirred at H 2 The reaction was stirred for 2h (60 psi), filtered after completion and the filtrate evaporated to dryness. The crude compound was washed with pentane to give intermediate M18 (70.4 mg, 40% yield).
1 H NMR(400MHz,CDCl 3 )δ7.56-7.37(m,2H),7.17(d,J＝8.5Hz,1H),6.32(s,1H),3.87(br s,2H),2.48(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-52.32(s,3F).
Further, the method comprises the steps of,can also be used for R 1 、R 2 More substitution expansion is performed to obtain more analogues, so as to excavate more positive allosteric regulation of nicotinic acetylcholine receptorReactive small molecules provide corresponding synthetic methods.
Furthermore, positive Allosteric Modulators (PAMs) of nicotinic acetylcholine receptors can be prepared by reference to compounds 83-85 of WO2012131031A 1.
Claims (10)
1. The method comprises the steps of taking 2-alkynyl aromatic amine compounds shown in a formula (1) and silver trifluormethyl sulfide as reactants in an organic solvent, adding potassium iodide and silver trifluormethyl sulfide, and carrying out cyclization reaction under the catalysis of a catalyst and a ligand to obtain the 1-trifluoromethyl indole compounds shown in a formula (2);
wherein R is 1 Selected from H, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, aryl, halogen, cyano, nitro, C 1 -C 8 Alkoxy, acyl and amido groups and heterocycles; r is R 2 Selected from C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, aryl, C 1 -C 8 Alkoxy, acyl and amido groups, and heterocyclic rings.
2. The method according to claim 1, wherein the organic solvent comprises any one or more of acetonitrile, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide.
3. The method according to claim 1, wherein the catalyst is any one or more of cuprous iodide, cuprous chloride, ruthenium dichloride, bis (triphenylphosphine) palladium chloride, and tris (triphenylphosphine) rhodium chloride.
4. The method according to claim 1, wherein the ligand is any one or more of 2,2 '-bipyridine, 4' -bipyridine, triphenylphosphine, and phenanthroline.
5. The method of claim 1, wherein the temperature of the reaction is from 25 ℃ to 100 ℃.
6. The method according to claim 1, wherein the molar ratio of the 2-alkynylarylamine compound, silver trifluormethylsulfide, potassium iodide, silver fluoride, catalyst and ligand is 1 (1.0-2.0): (1.0-2.0): (3.0-6.0): (0.05-0.2): (0.05-0.2).
7. The method according to claim 1, wherein the reaction concentration of the 2-alkynylarylamine compound is 0.05-5mmol/mL.
8. The process according to claim 1, wherein the N-trifluoromethylation/cyclization reaction is carried out under an inert gas atmosphere.
9. Use of the method according to any one of claims 1-8 in the field of pharmaceutical, agrochemical and functional material preparation.
10. A synthesis method of an important intermediate of a positive allosteric modulator of a nicotinic acetylcholine receptor is characterized in that the important intermediate of the positive allosteric modulator of the nicotinic acetylcholine receptor has the structure as followsThe reaction route of the method is as follows:
wherein R is 1 、R 2 Is as defined in claim 1.
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