CN117865870A - Method for synthesizing 1-trifluoromethyl indole compound by taking 2-alkynyl aryl isothiocyanate as raw material - Google Patents
Method for synthesizing 1-trifluoromethyl indole compound by taking 2-alkynyl aryl isothiocyanate as raw material Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 29
- -1 1-trifluoromethyl indole compound Chemical class 0.000 title claims abstract description 19
- 239000002994 raw material Substances 0.000 title abstract description 8
- 230000002194 synthesizing effect Effects 0.000 title abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 229940096017 silver fluoride Drugs 0.000 claims abstract description 18
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims abstract description 18
- 239000000575 pesticide Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 22
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 12
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 11
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 11
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 11
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 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
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 238000006692 trifluoromethylation reaction Methods 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 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
- 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
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 2
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 abstract description 12
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 10
- 239000011737 fluorine Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- AOWOVTUGHIKKNC-UHFFFAOYSA-N 1-(trifluoromethyl)indole Chemical group C1=CC=C2N(C(F)(F)F)C=CC2=C1 AOWOVTUGHIKKNC-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000010276 construction Methods 0.000 abstract description 2
- 239000008204 material by function Substances 0.000 abstract description 2
- 239000012948 isocyanate Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- FCQRKDSALKMOGU-UHFFFAOYSA-K rhodium(3+);triphenylphosphane;trichloride Chemical compound Cl[Rh](Cl)Cl.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 FCQRKDSALKMOGU-UHFFFAOYSA-K 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000003281 allosteric effect Effects 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000006467 substitution reaction Methods 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
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- CMTKJYPJPSONIT-UHFFFAOYSA-K trichlororuthenium;triphenylphosphane Chemical compound Cl[Ru](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMTKJYPJPSONIT-UHFFFAOYSA-K 0.000 description 2
- VYWWXOJAAXRFDT-UHFFFAOYSA-N 1-(trifluoromethyl)indole-5-carbonitrile Chemical compound N#CC1=CC=C2N(C(F)(F)F)C=CC2=C1 VYWWXOJAAXRFDT-UHFFFAOYSA-N 0.000 description 1
- QWWYRSZFQDJYDL-UHFFFAOYSA-N 1-isothiocyanato-2-(2-phenylethynyl)benzene Chemical compound S=C=NC1=CC=CC=C1C#CC1=CC=CC=C1 QWWYRSZFQDJYDL-UHFFFAOYSA-N 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 241001330002 Bambuseae Species 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000008848 allosteric regulation Effects 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 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
- 238000004334 fluoridation Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000010348 incorporation Methods 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
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005406 washing Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- 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 aryl isothiocyanate as a raw material, belonging to the field of organic chemistry. According to the method, an o-alkynyl thiophenyl isocyanate compound is used as a substrate, green and easily available silver fluoride is used as a fluorine source, and under the action of a catalyst, the construction of a 1-trifluoromethyl indole skeleton can be realized in one step, so that a target compound is obtained. 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 can realize the synthesis of the target product, and the target product can be obtained in a 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 aryl isothiocyanate as a raw material, belonging to the field of organic chemistry.
Background
The introduction of fluorine atoms was found since the 50 s of the 20 th centurySince the incorporation of specific sites of drug molecules can improve their biological activity, a large array of fluorine-containing drugs began to emerge as a spring bamboo shoot after rain. From 1970, only 2% of the pharmaceutical market, up to now about 20%. The U.S. Food and Drug Administration (FDA) approved 35 chemicals in 2019, 14 of which contained fluorine atoms and 7 contained trifluoromethyl groups. In addition, indole drugs account for a large proportion of drugs, and many CF have been explored in the past decades 3 Novel strategies for the introduction of groups into organic molecules. N-trifluoromethylation process studies have attracted considerable attention over the last decade.
Disclosure of Invention
The invention develops a novel method for synthesizing N-trifluoromethyl indole, namely a method for synthesizing polysubstituted-1-trifluoromethyl indole compounds. According to the invention, the 2-alkynyl aryl thioisocyanate compound and silver fluoride are subjected to a serial N-trifluoromethyl/cyclization reaction under the catalysis of a catalyst, so that the polysubstituted-1-trifluoromethyl indole compound is synthesized, and the synthesis of the 1-trifluoromethyl indole derivative is conveniently realized.
The invention aims to provide a synthesis method of a polysubstituted-N-trifluoromethyl indole compound, which comprises the steps of taking a 2-alkynyl aryl isothiocyanate compound shown in a formula (1) and silver fluoride shown in a formula (2) as reactants, and carrying out 1-trifluoromethyl/cyclization reaction under the catalysis of a catalyst to synthesize the polysubstituted-1-trifluoromethyl indole compound shown in a formula (3);
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, 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 present invention, the organic solvent includes any one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone. Acetonitrile is preferred.
In one embodiment of the invention, the catalyst is any one or more of tris (triphenylphosphine) rhodium chloride, zinc chloride, copper acetate, bis (triphenylphosphine) palladium chloride and ruthenium dichloride. Rhodium tris (triphenylphosphine) chloride is preferred.
In one embodiment of the invention, the temperature of the reaction is from 25 ℃ to 100 ℃. Preferably 35-45 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 feed ratio of the 2-alkynylaryl isothiocyanate compound to silver fluoride is 1 (3.0-4.0); preferably 1:3.2.
In one embodiment of the invention, the molar ratio of 2-alkynylaryl isothiocyanate compound to catalyst is 1 (0.001-0.1); further alternatively 1:0.005-0.01.
In one embodiment of the invention, the reaction concentration of the 2-alkynylaryl isothiocyanate compound is 0.05-5mmol/mL. Specifically, 0.1mmol/mL is preferred.
In one embodiment of the invention, the 1-trifluoromethyl/cyclization reaction is carried out under an inert atmosphere. Such as: and (3) nitrogen atmosphere.
In one embodiment of the invention, the molar ratio of 2-alkynylaryl isothiocyanate to silver fluoride is 1: (2-5); further alternatively 1: (3.0-4.0); specifically, the ratio of the components is 1:3.2.
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, a novel green economical synthesis method comprises the following steps:
taking 2-alkynyl aryl isothiocyanate and silver fluoride as raw materials, adding a catalyst, 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 is performed by flash column chromatography to obtain the final product polysubstituted-1-trifluoromethylindole compound.
In one embodiment of the invention, the method is preferably carried out as follows: adding a 2-alkynyl aryl isothiocyanate compound, silver fluoride and a catalyst into a reaction vessel containing acetonitrile solvent according to the mol ratio of 1:3.2:0.01, stirring for 3-10 hours at 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: desulfur fluorination of 2-alkynylaryl isothiocyanates to silver fluoride to form ArN (CF) 3 ) And under the action of a catalyst, the Ag intermediate and the alkynyl at the ortho position of the aromatic ring undergo nucleophilic addition/cyclization to generate the 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, taking a 2-alkynyl aryl isothiocyanate compound and silver fluoride as reactants, and carrying out 1-trifluoromethyl/cyclization under the catalysis of a catalyst to obtain a polysubstituted-1-trifluoromethyl-5-cyano indole compound;
(2) The obtained polysubstituted-1-trifluoromethyl-5-cyano indole 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 involved in the step (1) are the same as those for the synthesis of the polysubstituted-1-trifluoromethylindole compound.
In one embodiment of the present invention, the hydrogenation reduction of step (2) is carried out by dissolving the polysubstituted-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, under the action of a catalyst, the construction of an N-trifluoromethyl indole skeleton can be realized in one step by taking 2-alkynyl aryl isothiocyanate as a substrate and silver fluoride as a fluoridation reagent in a nitrogen atmosphere, so as to obtain the target compound.
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 aryl isothiocyanate into the corresponding polysubstituted-N-trifluoromethyl indole compound under a simpler condition, realizes the synthesis of the N-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:
2-alkynyl aryl isothiocyanate and silver fluoride are used as raw materials, tris (triphenylphosphine) rhodium chloride is used as a catalyst, acetonitrile is used as a reaction solvent, and the reaction is carried out for 3 to 10 hours at the temperature of 25 to 50 ℃ to obtain the target compound. The reaction expression is shown in figure 1.
Example 1: synthesis of 2-phenyl-1-trifluoromethylindole
2-phenylethynyl phenyl isothiocyanate (80 mg,0.5 mmol), silver fluoride (202 mg,1.6 mmol), rhodium tris (triphenylphosphine) chloride (5 mg,0.005 mmol) and acetonitrile (5 mL) were each added to a 25mL reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 45℃for 8 hours. After the reaction was completed, cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution, respectively, the solvent was removed by vacuum concentration, and the target product was purified by column chromatography to give 104mg of the product in 80% yield (fluorine spectrum yield 90%).
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 )δ138.18,134.81,131.18,128.37,128.07,127.59,126.99,123.16,121.83,119.90,119.52(q,J＝263.2Hz),111.97(q,J＝4.3Hz),108.62.HRMS(AP)m/z calcd.for C 15 H 11 F 3 N[M+H] + :262.0844；found:262.0838.
Example 2: synthesis of 2-cyclohexyl-1-trifluoromethylindole
2-Cyclohexynylphenylisothiocyanate (121 mg,0.5 mmol), silver fluoride (202 mg,1.6 mmol), rhodium tris (triphenylphosphine) chloride (5 mg,0.005 mmol) and acetonitrile (5 ml) were each added to a 25ml reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 45℃for 8 hours. After the reaction was completed, cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution, respectively, the solvent was removed by vacuum concentration, and the target product was purified by column chromatography to give 104mg of the product in 78% (fluorine spectrum yield 90%).
1 H NMR(400MHz,CDCl 3 )δ7.64-7.57(m,1H),7.56-7.50(m,1H),7.31-7.18(m,2H),6.45(s,1H),2.85(s,1H),2.11(t,J＝9.7Hz,2H),1.89(dd,J＝5.3,2.5Hz,2H),1.81(ddt,J＝11.1,3.0,1.4Hz,1H),1.45(p,J＝11.7Hz,5H). 19 F NMR(376MHz,CDCl 3 )δ-51.35(s,3F). 13 C NMR(101MHz,CDCl 3 )δ146.03,135.16,129.26,123.29,122.35,121.02(q,J＝260.2Hz),120.37,112.57(q,J＝5.1Hz),104.50,36.95(q,J＝2.9Hz),34.18,26.66,26.16.HRMS(AP)m/z calcd.for C 15 H 16 F 3 N[M] + :267.1235；found:267.1235.
Example 3: synthesis of 6-chloro-2-phenyl-1-trifluoromethylindole
5-chloro-2-phenylethynyl phenylisothiocyanate (135 mg,0.5 mmol), silver fluoride (202 mg,1.6 mmol), rhodium tris (triphenylphosphine) chloride (5 mg,0.005 mmol) and acetonitrile (5 ml) were each added to a 25ml reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 45℃for 8 hours. After the reaction was completed, cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution, respectively, the solvent was removed by vacuum concentration, and the target product was purified by column chromatography to give 96mg of the product in a yield of 65% (fluorine spectrum yield 76%).
1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.55-7.48(m,3H),7.48-7.42(m,3H),7.28(dd,J＝8.4,1.8Hz,1H),6.58(s,1H). 19 F NMR(376MHz,CDCl 3 )δ-49.97(s,3F). 13 C NMR(101MHz,CDCl 3 )δ140.0(s),136.2(s),131.8(s),130.2(s),129.5(s),129.1(s),128.3(s),127.7(s),123.7(s),121.8(s),120.4(q,J＝263.9Hz),113.4(q,J＝4.7Hz),109.4(s).HRMS(ESI)m/z calcd.for C 15 H 10 ClF 3 N(M+H) + :296.0454；found:296.0448.
Example 4: synthesis of 1-trifluoromethyl-2-methyl-5-cyano-indole
2-propynyl-4-cyanobenzenesulfocyanate (99.1 mg,0.5 mmol), silver fluoride (202 mg,1.6 mmol), rhodium tris (triphenylphosphine) chloride (5 mg,0.005 mmol) and acetonitrile (5 ml) were each added to a 25ml reaction tube equipped with a stirrer under nitrogen atmosphere, and reacted at 45℃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 50.4mg of the product with a fluorine spectrum yield of 52% (yield 45.0%).
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 Effect of different catalysts on 2-phenyl-1-trifluoromethylindole Synthesis
With reference to example 1, the catalyst was changed from tris (triphenylphosphine) rhodium chloride to zinc chloride, copper acetate, bis (triphenylphosphine) palladium chloride, and triphenylphosphine ruthenium chloride, respectively, and a set of experiments without any catalyst was added thereto, and the other conditions were unchanged, so as to synthesize 2-phenyl-1-trifluoromethylindole. Specific yield results are shown in table 1.
TABLE 1 Synthesis of different catalystsInfluence of 2-hydrocarbyl-1-trifluoromethylindole a
| Catalyst | Yield (%) |
| Without adding | 55 |
| ZnCl 2 | 50 |
| Cu(OAc) 2 | 66 |
| RuCl 2 (Ph 3 P) 4 | 67 |
| PdCl 2 (Ph 3 P) 2 | 50 |
| RhCl(Ph 3 P) 3 | 90 |
a. The yield was fluorine spectrum yield.
The result shows that: the yields of the products obtained without catalyst and with zinc chloride, copper acetate, bis (triphenylphosphine) palladium chloride, triphenylphosphine ruthenium chloride instead of tris (triphenylphosphine) rhodium chloride from example 2 were all worse than example 2, no more than 70%.
EXAMPLE 6 Effect 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 dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, NMP, and water, respectively, under the same conditions.
Specific yield results are shown in Table 2.
TABLE 2 influence of different solvents on the Synthesis of 2-phenyl-1-trifluoromethylindole a
| Solvent(s) | Yield (%) |
| DMSO | 60 |
| CH 3 CN | 90 |
| DMAc | 40 |
| DMF | 31 |
| NMP | 20 |
| H 2 O | 0 |
a. The yield was fluorine spectrum yield.
The result shows that: the acetonitrile in example 1 was replaced with dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, NMP, and water as a solvent to obtain a product having a yield inferior to that of example 1 by not more than 60%.
EXAMPLE 7 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 with 25℃and 65℃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 a
| Temperature (. Degree. C.) | Yield (%) |
| 25 | 88 |
| 45 | 90 |
| 65 | 87 |
| 90 | 80 |
a. The yield was fluorine spectrum yield.
The result shows that: the product yield obtained by substituting 25℃at 65℃at 90℃for 45℃in example 2 was not much different from that obtained in example 1, the temperature reached 90℃and the yield was much lower.
EXAMPLE 8 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, and a corresponding synthesis method is provided for excavating more small molecules with positive allosteric regulation activity of the nicotinic acetylcholine receptor.
Furthermore, positive Allosteric Modulators (PAMs) of nicotinic acetylcholine receptors can be prepared by reference to compounds 83-85 of WO2012131031A 1.
Claims (10)
1. A synthesis method of a 1-trifluoromethyl indole compound is characterized in that in an organic solvent, a 2-alkynyl aryl isothiocyanate compound shown in a formula (1) and silver fluoride shown in a formula (2) are used as reactants, and N-trifluoromethyl/cyclization reaction is carried out under the action of a catalyst, so that a polysubstituted-1-trifluoromethyl indole compound shown in a formula (3) is synthesized.
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 amide groups, 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 amide groups, heterocycles.
2. The method according to claim 1, wherein the organic solvent comprises any one or more of acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone.
3. The method according to claim 1, wherein the catalyst is any one or more of tris (triphenylphosphine) rhodium chloride, zinc chloride, copper acetate, bis (triphenylphosphine) palladium chloride, and ruthenium dichloride.
4. The method of claim 1, wherein the temperature of the reaction is from 25 ℃ to 100 ℃.
5. The method of claim 1, wherein the molar ratio of 2-alkynylaryl isothiocyanate compound to silver fluoride is 1 (2.0-5.0).
6. The method of claim 1, wherein the molar ratio of 2-alkynylaryl isothiocyanate compound to catalyst is 1 (0.001-0.1).
7. The method of claim 1, wherein the reaction concentration of the 2-alkynylaryl isothiocyanate compound is 0.05-5mmol/mL.
8. The process according to any one of claims 1 to 7, 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 fields of pharmaceutical preparation, pesticide preparation 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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