CN117185952A - Alpha-arylamine compound and preparation method and application thereof - Google Patents
Alpha-arylamine compound and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000000758 substrate Substances 0.000 claims abstract description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000003446 ligand Substances 0.000 claims abstract description 15
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims abstract description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 12
- STTGYIUESPWXOW-UHFFFAOYSA-N 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline Chemical compound C=12C=CC3=C(C=4C=CC=CC=4)C=C(C)N=C3C2=NC(C)=CC=1C1=CC=CC=C1 STTGYIUESPWXOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 claims abstract description 10
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 claims abstract description 10
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 claims abstract description 9
- 229960002297 fenofibrate Drugs 0.000 claims abstract description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 9
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims abstract description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 8
- 229960001031 glucose Drugs 0.000 claims abstract description 8
- 239000008103 glucose Substances 0.000 claims abstract description 8
- 229960000905 indomethacin Drugs 0.000 claims abstract description 8
- 229960005256 sulbactam Drugs 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000012986 modification Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 16
- 239000003480 eluent Substances 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000000203 mixture Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- -1 alkenyl amine Chemical class 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 11
- 125000000524 functional group Chemical group 0.000 abstract description 8
- 230000004048 modification Effects 0.000 abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 150000001503 aryl iodides Chemical class 0.000 abstract 1
- 239000007810 chemical reaction solvent Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 150000001336 alkenes Chemical class 0.000 description 8
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 6
- 238000003430 hydroarylation reaction Methods 0.000 description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000007306 functionalization reaction Methods 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 150000002815 nickel Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 150000005012 8-aminoquinolines Chemical group 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 238000005913 hydroamination reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- DSGQWDHZUIZVCR-UHFFFAOYSA-N n-but-3-enylacetamide Chemical compound CC(=O)NCCC=C DSGQWDHZUIZVCR-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 238000011911 α-alkylation Methods 0.000 description 1
Abstract
The invention relates to an alpha-arylamine compound, a preparation method and application thereof, which uses an alkenyl amine derivative as a reaction substrate, aryl iodide as an arylating reagent, nickel bromide ethylene glycol dimethyl ether complex as a catalyst, 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline as a ligand, anhydrous potassium carbonate as a base, trimethoxysilane as a hydrogen source, N, N-dimethylacetamide as a reaction solvent, wherein the reaction temperature is room temperature, and the reaction time is 24 h. The method has higher reaction yield and regioselectivity, wide substrate range and good compatibility of functional groups, and can be applied to the later modification of drug molecules such as indometacin, fenofibrate, sulbactam, glucose and the like.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and in particular relates to an alpha-arylamine compound and a preparation method and application thereof.
Background
Fatty amines are key structural motifs in natural products, pharmaceuticals and agrochemicals (t.c. Nugent, m.el-Shazly, adv. Synth. Catalyst, 2010, 352, 753; a. Trollbridge, s.m. Walton, m.j. Gap, chem. Rev. 2020,120, 2613.). Wherein, the N-acyl benzylamine exists in medicines such as taxol, piperacillin, maraviroc and the like, and has wide and obvious biological activity. Selective functionalization of amine compounds can rapidly increase molecular complexity, while inexpensive transition metal-catalyzed hydrofunctionalization of alkenylamines has substantially higher atomic economy and reaction efficiency, receiving widespread attention from researchers. In general, both the hydroamination of common olefinic substrates and the hydro-functionalization of alkenyl amines occur with carbon-carbon double bonds in situ, with direct functionalization at the distal end of the carbon-carbon double bond still being challenging.
Transition metal catalyzed functionalization can directly and efficiently build new C-X (x=c, N, P, S, etc.) and C-H bonds to obtain complex compounds. The transition metal catalysis enables the olefin to be regioselectively functionalized by a rapid migration insertion and β -H elimination process thanks to the formation of a stable organometallic nickel ring. More recently, switchable site-selective hydrofunctionalization of non-reactive olefins has proven to be a compact and efficient strategy by means of pre-installed directing groups such as 8-aminoquinolines, thioethers, protected amines, which facilitate the formation of metallo-rings, directing the functional groups to specific positions within the starting olefinic substrate. Martin (J. Rodriga alvarez, H. Wang, R. Martin, J. Am. chem. Soc. 2023,1453869), shu (P-F, yang, W, shu, angew, chem, int, ed., 2022, 61, e 202208018), lu (J-W, wang+, D-G, liu, Z, C, Z, li, Y, fu, X, lu, angew, chem, int, ed., 2022, 61, e 202205537) and Wang (L.zhao, Y, zhu, M, liu, L, xie, J, liang, H, shi, X, meng, Z, chen, J, han, C, wang,Angew. Chem. Int. Ed.2022,61examples of ligand-controlled regional and remote divergent hydroalkylation of olefins have been developed by the subject group of e 202204716), but the functional groups are limited to alkylating agents, nevado (S.Curesta-Galisteo, J.S., X.Wei, E.Merno, C.Nevado, angew.chem.int. Ed. 2021, 60, 1605), zhu (Y.He, C.Liu, L.Yu, S.Zhu, angew.chem.int. Ed. 2020,59, 9186; Y.He, H.Song, J.Chen, S.Zhu, nat.Commun.2021,12, 638) and the like, an asymmetric alpha-selective hydroarylation reaction of an alkenylamine substrate is achieved using an aryl halide or an arylboronic acid as an arylating reagent, unfortunately the substrate is limited to a substrate in which a polar group is directly attached to an olefinic double bond.
The invention realizes the high alpha-selective hydroarylation reaction of the alkenyl amine substrate by the catalysis of low-cost metal nickel salt, and aims to synthesize the alpha-aryl amine compound. The method is simple to operate, mild in reaction conditions, capable of simply and efficiently synthesizing the alpha-arylamine derivatives, suitable for different alkenylamine substrates (distal end olefin and proximal end olefin) and arylating reagents, and has the advantages of wide substrate range, high functional group compatibility and the like. The method is also suitable for arylating reagents derived from drug molecules such as indomethacin, fenofibrate, sulbactam, glucose and the like, has higher yield and alpha-selectivity, for example, the fenofibrate is modified into the arylating reagent, the arylating reagent can selectively go to the alpha-position of a nitrogen atom in an alkenylamine substrate, the yield can reach 68%, and the method can efficiently introduce amino into the drug molecules and increase the complexity of the molecules.
Disclosure of Invention
The invention aims to solve the problem of high alpha-selective hydroarylation of an alkenylamine substrate, and provides a method for efficiently preparing alpha-arylamine derivatives under mild conditions. The method has the advantages of simple operation, high reaction efficiency, good regioselectivity, wide substrate range and good functional group compatibility, and can be applied to the post modification of drug molecules. In particular to an alpha-arylamine compound and a preparation method and application thereof.
In order to achieve the above purpose, the invention discloses the following technical scheme:
an alpha-arylamine compound is characterized by having the following structure:
wherein:
the invention further discloses a high alpha-selective hydroarylation method of nickel-catalyzed alkenyl amine, which comprises the following preparation steps:
step one, in a glove box filled with argon, a metal nickel catalyst, a ligand, a base, an additive, an alkenylamine substrate, a corresponding arylating reagent, and a solvent are weighed into a dry reaction tube. The reaction system is closed, and stirred at room temperature until the reaction is finished.
After the reaction is finished, concentrating the obtained solution in vacuum, purifying the crude product by silica gel column chromatography, and separating an aromatic alpha-alkylation product;
the synthetic method comprises the following steps:
preferably, the alkenylamine is an aroyl-protected alkenylamine, an alkanoyl-protected alkenylamine, a benzoyl-protected substituted alkene; further preferred are substituents in the alkenylamine substrate
Preferably, the arylating reagent ArI is:
preferably, the molar ratio of alkenylamine substrate to arylating reagent is 1:1.5;
optionally, the catalyst is nickel bromide ethylene glycol dimethyl ether complex;
preferably, the ligand is a 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand;
preferably, the base is anhydrous potassium carbonate;
preferably, the additive is trimethoxysilane;
preferably, the temperature is room temperature;
preferably, the solvent is N, N-dimethylacetamide;
preferably, the reaction time is 24 hours;
preferably, the volume ratio of ethyl acetate to n-hexane as eluent is 1:8.
the invention further discloses application of the alpha-arylamine compound in preparing the medicines for indometacin, fenofibrate, sulbactam and glucose for later modification of molecular structures. The experimental results show that: the preparation example 43 is a high alpha-selective hydroaryl method of the indomethacin derived arylating reagent suitable for the nickel catalytic alkenyl amine of the invention, the post-modified indomethacin derivative is obtained, the preparation example 44 is a high alpha-selective hydroaryl method of the fenofibrate derived arylating reagent suitable for the nickel catalytic alkenyl amine of the invention, the post-modified fenofibrate derivative is obtained, the preparation example 45 is a high alpha-selective hydroaryl method of the sulbactam derived arylating reagent suitable for the nickel catalytic alkenyl amine of the invention, the post-modified sulbactam derivative is obtained, the preparation example 46 is a glucose derived arylating reagent suitable for the high alpha-selective hydroaryl method of the nickel catalytic alkenyl amine of the invention, the post-modified glucose derivative is obtained, and the method is efficient to introduce an amino group into the indomethacin, fenofibrate, sulbactam and glucose drug molecules, so that the complexity of the drug molecules is increased.
The alpha-arylamine compound disclosed by the invention and the preparation method and application thereof have the advantages and positive effects that:
1. the alpha-arylamine compound disclosed by the invention, as well as the preparation method and application thereof, takes the low-cost metal nickel salt as a catalyst, has commercially available raw materials and simple experimental operation;
2. the alpha-arylamine compound disclosed by the invention, as well as the preparation method and application thereof, has mild reaction conditions, and can be stirred at room temperature for 24 hours to complete the reaction;
3. the alpha-arylamine compound disclosed by the invention, as well as the preparation method and application thereof, has high reaction yield and the highest separation yield can reach 97%;
4. the alpha-arylamine compound disclosed by the invention has wide substrate application range, is suitable for aroyl, alkanoyl and acyl-protected substituted olefin and cyclic olefin, has high separation yield up to 97%, has high functional group compatibility, can be compatible with various functional group substitutions such as methyl, tertiary butyl, phenyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, aldehyde, ketocarbonyl, ester, dimethyl tertiary butyl silyl ether and substituted hydroxyl and naphthyl, and can also be heterocyclic aromatic hydrocarbon such as pyridine, thiophene and the like, and the separation yield can be up to 96%;
5. the alpha-arylamine compound and the preparation method and application thereof disclosed by the invention are suitable for remote-end and near-end olefins, and provide an attractive and direct way for synthesizing N-acyl benzylamine derivatives under mild conditions;
6. the alpha-arylamine compound disclosed by the invention has the advantages of high reaction yield, excellent chemical selectivity and regioselectivity, and can realize high alpha-selective hydroarylation of the alkenyl amine by recognizing the reaction sites with high selectivity for the alkenyl amine substrate with a plurality of reaction sites, wherein the regioselectivity rr is more than 99:1, a step of;
7. the alpha-arylamine compound disclosed by the invention and the preparation method and application thereof can also perform high-efficiency reaction on arylating reagents derived from drug molecules such as indometacin, fenofibrate, sulbactam, glucose and the like, and provide a new method for the later modification of the drug molecules or complex natural products.
The invention is described in more detail below:
in order to meet the industrial requirement, an alpha-arylamine compound is synthesized by a method which is low in cost, mild in condition, convenient to operate, high in yield and high in regioselectivity. The examples mentioned are merely illustrative of the method of the invention and do not limit the remainder of the disclosure in any way whatsoever.
The basic synthetic method route is as follows:
refers to an alkenylamine substrate, and the substituent R is
ArI is an arylating reagent, and has the structural formula:
NiBr 2 DME means catalyst, na 2 CO 3 Refers to a base, and Ligand, (MeO) 3 SiH refers to the additive, DMA is N, N-dimethylacetamide refers to the solvent, rt is room temperature refers to the reaction temperature, and 24 h refers to the reaction time.
Detailed Description
The invention is described below by means of specific embodiments. The technical means used in the present invention are methods well known to those skilled in the art unless specifically stated. Further, the embodiments should be construed as illustrative, and not limiting the scope of the invention, which is defined solely by the claims. Various changes or modifications to the materials ingredients and amounts used in these embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The raw materials and reagents used in the invention are all commercially available. Aryl groups for use thereinThe chemical reagent, nickel bromide glycol dimethyl ether complex, 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand, N-dimethylacetamide, trimethoxysilane and the like are all commercially available. Synthesis of alkenylamine substrates all references except the following tableAngew. Chem. Int. Ed.2022,61, e202204716.
Example 1
In a glove box filled with argon, nickel bromide ethylene glycol dimethyl ether complex (NiBr) was weighed into a dry reaction tube 2 DME) (0.02 mmol, 10 mol%), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand (0.024 mmol, 12 mol%), anhydrous potassium carbonate (0.40 mmol, 2.0 equiv), alkenylamine substrate N- (but-3-en-1-yl) -4-methoxybenzamide (0.2 mmol, 1.0 equiv), arylating reagent 1-iodo-4-methoxybenzene (0.40 mmol, 2.0 equiv), N-dimethylacetamide (1 mL), trimethoxysilane (0.5 mmol, 2.5 equiv). The reaction system was stirred at room temperature for 24 hours. After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using ethyl acetate: n-hexane=1:8 as eluent with an isolation yield of 86%, rr > 99:1.
1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d,J= 8.2 Hz, 2H), 7.40–7.30 (m, 4H),7.27 (d,J= 4.0 Hz, 2H), 6.90 (d,J= 8.1 Hz, 2H), 6.32 (d,J= 6.9 Hz, 1H), 5.17 (q,J= 7.4 Hz, 1H), 3.83 (s, 2H), 1.98–1.79 (m, 2H), 1.49–1.23 (m, 2H), 0.94 (t,J= 7.3 Hz, 3H).; 13 C NMR (101 MHz, CDCl 3 ) δ 166.21, 162.14, 142.64, 128.74, 128.69,127.32, 126.97, 126.65, 113.72, 55.43, 53.61, 38.51, 19.61, 13.90. HRMS (ESI) m/z calculated for C 18 H 21 NO 2 [M+H] + : 284.1645, found: 284.1652.
Example 2
In a glove box filled with argon, nickel bromide ethylene glycol dimethyl ether complex (NiBr) was weighed into a dry reaction tube 2 DME) (0.02 mmol, 10 mol%), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand (0.024 mmol, 12 mol%), anhydrous potassium carbonate (0.40 mmol, 2.0 equiv), alkenylamine substrate N- (but-3-en-1-yl) -2-methylbenzamide (0.2 mmol, 1.0 equiv), arylating reagent 1-iodo-4-methoxybenzene (0.40 mmol, 2.0 equiv), N-dimethylacetamide (1 mL), trimethoxysilane (0.5 mmol, 2.5 equiv). The reaction system was stirred at room temperature for 24 hours. After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using ethyl acetate: n-hexane=1:6 as eluent with an isolated yield of 87%, rr=93:7.
1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (dd,J= 15.6, 7.8 Hz, 4H), 7.23–7.13 (m, 2H), 6.88 (d,J= 8.0 Hz, 2H), 5.94 (d,J= 7.7 Hz, 1H), 5.11 (q,J= 7.7 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H), 1.96–1.72(m, 2H), 1.48–1.27 (m, 2H), 0.96 (t,J= 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 169.20, 158.82, 136.74, 136.02, 134.53, 130.96, 129.76, 127.73, 126.57, 125.70, 114.07, 55.31, 52.92, 38.39, 19.76, 19.63, 13.89. HRMS(ESI) m/z calculated for C 19 H 23 NO 2 [M+H] + : 298.1802, found: 298.1804.
Example 3
In a glove box filled with argon, nickel bromide ethylene glycol dimethyl ether was weighed into a dry reaction tubeComplex (NiBr) 2 DME) (0.02 mmol, 10 mol%), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand (0.024 mmol, 12 mol%), anhydrous potassium carbonate (0.40 mmol, 2.0 equiv), alkenylamine substrate N- (but-3-en-1-yl) -4-chlorobenzamide (0.2 mmol, 1.0 equiv), arylating reagent 1-iodo-4-methoxybenzene (0.40 mmol, 2.0 equiv), N-dimethylacetamide (1 mL), trimethoxysilane (0.5 mmol, 2.5 equiv). The reaction system was stirred at room temperature for 24 hours. After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using ethyl acetate: n-hexane=1:6 as eluent with an isolation yield of 78%, rr=99:1.
1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d,J= 7.9 Hz, 2H), 7.35 (d,J= 7.6 Hz, 2H), 7.27 (d,J= 7.3 Hz, 2H), 6.87 (d,J= 7.9 Hz, 2H), 6.39 (s, 1H), 5.19–5.04 (q, 1H), 3.79 (s, 3H), 1.87 (m,J= 17.1, 10.4 Hz, 2H), 1.46–1.27 (m, 2H), 0.94 (t,J= 7.1 Hz, 3H).; 13 C NMR (101 MHz, CDCl 3 ) δ 158.90, 137.59, 134.35, 133.25, 128.76, 128.41, 128.35, 127.85, 114.11, 55.31, 53.29, 38.27, 19.63, 13.87. HRMS (ESI) m/z calculatedfor C 17 H 18 ClNO [M+H] + : 288.1150, found: 288.1147.
Example 4
In a glove box filled with argon, nickel bromide ethylene glycol dimethyl ether complex (NiBr) was weighed into a dry reaction tube 2 DME) (0.02 mmol, 10 mol%), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand (0.024 mmol, 12 mol%), anhydrous potassium carbonate (0.40 mmol, 2.0 equiv), alkenylamine substrate N- (but-3-en-1-yl) -4- (trifluoromethyl) benzamide (0.2 mmol, 1.0 equiv), arylating reagent 1-iodo-4-methoxybenzene (0.40 mmol, 2.0 equiv), N-dimethylacetamide (1 mL), trimethoxysilane (0.5 mmol, 2.5 equiv). The reaction system was stirred at room temperature for 24 hours. After the reaction, the resulting solution was concentrated in vacuo, and the crude product was purified byPurification by column chromatography on silica gel using ethyl acetate: n-hexane=1:8 as eluent with an isolation yield of 78%, rr=99:1.
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (d,J= 7.8 Hz, 2H), 7.60 (d,J= 7.7 Hz, 2H), 7.25 (d,J= 8.3 Hz, 2H), 6.85 (d,J= 7.9 Hz, 2H), 6.51 (d,J= 7.4 Hz, 1H), 5.09 (q,J= 7.4 Hz, 1H), 3.76 (s, 3H), 1.97–1.74 (m, 2H), 1.43–1.25 (m, 2H), 0.92 (t,J= 7.2 Hz, 3H).; 13 C NMR (101 MHz, CDCl 3 ) δ 165.46, 158.96, 138.05, 134.13, 133.24, 132.91, 127.85, 127.45, 125.59, 125.56, 125.52, 125.48, 125.02, 122.31, 114.13, 55.29, 53.47,38.19, 19.64, 13.83. HRMS (ESI) m/z calculated for C 19 H 20 F 3 NO 2 [M+H] + : 352.1519, found: 351.1521.
Example 5
In a glove box filled with argon, nickel bromide ethylene glycol dimethyl ether complex (NiBr) was weighed into a dry reaction tube 2 DME) (0.02 mmol, 10 mol%), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand (0.024 mmol, 12 mol%), anhydrous potassium carbonate (0.40 mmol, 2.0 equiv), alkenylamine substrate N- (but-3-en-1-yl) -2-naphtalenamide (0.2 mmol, 1.0 equiv), arylating reagent 1-iodo-4-methoxybenzene (0.40 mmol, 2.0 equiv), N-dimethylacetamide (1 mL), trimethoxysilane (0.5 mmol, 2.5 equiv). The reaction system was stirred at room temperature for 24 hours. After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using ethyl acetate: n-hexane=1:8 as eluent, isolated in yields (60%), rr > 99:1.
1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d,J= 8.4 Hz, 1H), 7.91–7.85 (m, 1H),7.80 (d,J= 8.2 Hz, 1H), 7.75 (dd,J= 5.2, 3.3 Hz, 2H), 7.59–7.43 (m, 5H), 7.41–7.34 (m, 2H), 6.49 (d,J= 8.3 Hz, 1H), 6.06 (q,J= 15.4, 7.5 Hz, 1H), 2.15–2.04 (m, 2H), 1.59–1.43 (m, 2H), 1.00 (t,J= 7.4 Hz, 3H).; 13 C NMR (101 MHz, CDCl 3 ) δ 166.67, 137.95, 134.60, 134.06, 131.48, 131.45, 128.85, 128.55, 128.27, 126.96,126.62, 125.87, 125.25, 123.43, 122.90, 49.23, 37.93, 19.94, 14.05. HRMS (ESI) m/z calculated for C 22 H 23 NO 2 [M+H] + :334.1802, found: 334.1810.
Example 6
In a glove box filled with argon, nickel bromide ethylene glycol dimethyl ether complex (NiBr) was weighed into a dry reaction tube 2 DME) (0.02 mmol, 10 mol%), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand (0.024 mmol, 12 mol%), anhydrous potassium carbonate (0.40 mmol, 2.0 equiv), alkenylamine substrate N- (but-3-en-1-yl) acetamide (0.2 mmol, 1.0 equiv), arylating reagent 1-iodo-4-methoxybenzene (0.40 mmol, 2.0 equiv), N-dimethylacetamide (1 mL), trimethoxysilane (0.5 mmol, 2.5 equiv). The reaction system was stirred at room temperature for 24 hours. After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using ethyl acetate: n-hexane=1:2 as eluent, isolated in yields (61%), rr > 99:1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37–7.30 (m, 2H), 7.30–7.21 (m, 3H), 5.80 (d,J= 7.2 Hz, 1H), 4.96 (q,J= 7.7 Hz, 1H), 1.98 (s, 3H)1.84–1.69 (m, 2H), 1.40–1.26 (m, 2H), 0.95–0.88(m, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 157.94, 137.26, 131.33, 128.60, 113.90, 55.23, 49.29, 39.94, 33.31, 28.31. HRMS (ESI) m/z calculated for C 13 H 19 NO 2 [M+H] + :222.1489, found: 222.1493.
The following examples 7-46 were conducted in the same manner as in examples 1-6 above, and the structures and names of the synthesized target compounds, nuclear magnetic resonance hydrogen spectra, carbon spectra and high resolution mass spectrum data, the yields and rr values are shown in the following table:
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conclusion: the alpha-arylamine compound prepared by the method has higher reaction yield and regioselectivity, wide substrate range and good functional group compatibility, and can be applied to the later structural modification of indometacin, fenofibrate, sulbactam and glucose drug molecules.
Claims (7)
1. An alpha-arylamine compound is characterized by having the following structure:
wherein:
。
2. the method for producing an α -arylamine compound according to claim 1, characterized by comprising the steps of:
step one in a glove box filled with argon at room temperature, the catalyst nickel bromide ethylene glycol dimethyl ether complex (NiBr) was added by weighing to a dry reaction tube 2 DME), 2, 9-dimethyl-4, 7-diphenyl-1, 10-phenanthroline ligand, anhydrous potassium carbonate, an alkenylamine substrate, a corresponding arylating reagent, a solvent of N, N-dimethylacetamide and an additive trimethoxysilane, and stirring the reaction system at normal temperature for 24 hours; wherein the molar ratio of alkenylamine substrate to arylating reagent is 1:1.5;
after the reaction is finished, concentrating the obtained solution in vacuum, purifying the crude product by silica gel column chromatography, and calculating the separation yield by using a mixture of ethyl acetate and n-hexane as an eluent; wherein the volume ratio of the eluent ethyl acetate to the normal hexane is 1:2-8;
wherein the method comprises the steps of
Wherein the alkenylamine substrate refers to:
the arylating reagent refers to:
。
3. the method for producing an α -arylamine compound according to claim 2, characterized in that: the catalyst addition was 10 mol%.
4. The method for producing an α -arylamine compound according to claim 2, characterized in that: the ligand addition ratio was 12 mol%.
5. The method for producing an α -arylamine compound according to claim 2, characterized in that: the base addition ratio was 2.0 equiv.
6. The method for producing an α -arylamine compound according to claim 2, characterized in that: the additive ratio was 2.5 equiv.
7. The use of an α -arylamine compound according to claim 1 for the preparation of a pharmaceutical composition for post-modification of the molecular structure of indomethacin, fenofibrate, sulbactam and glucose.
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