CN118005596A - Method for preparing beta-elemene chromanol derivatives by palladium catalysis - Google Patents
Method for preparing beta-elemene chromanol derivatives by palladium catalysis Download PDFInfo
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- CN118005596A CN118005596A CN202310598447.2A CN202310598447A CN118005596A CN 118005596 A CN118005596 A CN 118005596A CN 202310598447 A CN202310598447 A CN 202310598447A CN 118005596 A CN118005596 A CN 118005596A
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- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 title claims abstract description 50
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-N 0.000 title claims abstract description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 31
- -1 beta-elemene chromanol derivatives Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- KVZQPAQBIFDZPX-UHFFFAOYSA-N 3,4-dihydro-2h-chromene-2,3-diol Chemical class C1=CC=C2OC(O)C(O)CC2=C1 KVZQPAQBIFDZPX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims 2
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 238000001212 derivatisation Methods 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- 238000011068 loading method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- KJXSIXMJHKAJOD-LSDHHAIUSA-N (+)-dihydromyricetin Chemical compound C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC(O)=C(O)C(O)=C1 KJXSIXMJHKAJOD-LSDHHAIUSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 1
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- KQDJTBPASNJQFQ-UHFFFAOYSA-N 2-iodophenol Chemical compound OC1=CC=CC=C1I KQDJTBPASNJQFQ-UHFFFAOYSA-N 0.000 description 1
- VSMDINRNYYEDRN-UHFFFAOYSA-N 4-iodophenol Chemical compound OC1=CC=C(I)C=C1 VSMDINRNYYEDRN-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000963390 Curcuma wenyujin Species 0.000 description 1
- 235000003394 Curcuma wenyujin Nutrition 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 1
- 241001018563 Nekemias grossedentata Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241000234299 Zingiberaceae Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229950001002 cianidanol Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 description 1
- 229940030275 epigallocatechin gallate Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical group 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing beta-elemene chromanol derivatives by palladium catalysis. The beta-elemene chromanol derivative is a compound with the following structural formula or an enantiomer and raceme of the compound:
Description
Technical Field
The invention relates to a method for synthesizing beta-elemene chromanol derivatives by palladium catalysis, belonging to the technical field of organic synthesis.
Background
Beta-elemene is an anticancer active ingredient of mushroom-ene extracted from Curcuma wenyujin Y.H.Chen et C.Ling of Zingiberaceae, and the compound is a new anti-tumor drug of the national class II, but the clinical application of the compound is limited due to the defects of poor water solubility, low bioavailability and the like. In order to further improve the anti-tumor activity and water solubility of the beta-elemene, the main method at present is to modify the beta-elemene allylic position, introduce active functional groups such as hydroxyl, amino and the like, and then connect with other structural fragments through hydroxyl or amino. The beta-elemene derivatives reported at present mainly comprise: amines, esters, amino acids, ethers, alcohols, glycosides, organometallic compounds, etc., which have been developed to some extent in terms of antitumor activity and water solubility. And the research on the beta-elemene olefin locus is slow. The beta-elemene is only composed of two elements of hydrocarbon, the structure of the beta-elemene contains three carbon-carbon double bonds, and a derivative product of beta-elemene double bond sites is developed, so that a beta-elemene derivative method can be expanded, and more possibilities are expected to be provided in the aspects of improving antitumor activity and bioavailability.
Chiral 3-hydroxy chromanol compounds are widely existing in natural products, and many substances in the compounds have important biological activity effects of resisting cancer, reducing blood fat, resisting cardiovascular diseases, resisting viruses, resisting bacteria and oxidation, protecting nerves, treating liver diseases and the like. For example, epigallocatechin gallate in 3-hydroxy chromanol derivatives has antitumor, antioxidant and antibacterial effects. The dihydromyricetin is extract of Ampelopsis grossedentata, and its main active ingredient is flavonoid, and the extract has antithrombotic, antitumor and antiinflammatory effects. Catechin is a natural antioxidant, and has various functions of preventing and treating cardiovascular diseases and preventing cancer. Therefore, developing a new method to realize the coupling of the antitumor activity beta-elemene olefin and the active 3-hydroxy chromanol compound to construct the beta-elemene-chromanol derivative and exploring more biological activities has important significance.
Most drugs, natural products and materials contain aromatic structures that have a large impact on the activity of the drug and the function of the material. The research and development of the method for coupling and derivatizing the beta-elemene double bond and the aromatic group not only can modify the beta-elemene more variously, but also is expected to provide more possibilities in the aspects of antitumor activity, water solubility, bioavailability and the like, thereby having great application potential and economic value in the fields of biology and medicine and having important significance for research and development of medicines and treatment of cancers.
Disclosure of Invention
The invention aims at the problems and defects existing in the prior art and develops a novel method for preparing beta-elemene chromanol derivatives by palladium catalysis.
In order to achieve the above purpose, the invention adopts the following technical scheme:
Taking a certain amount of 3-hydroxy chromanol derivatives, palladium acetate, antPhos, beta-elemene and potassium carbonate in a reaction bottle, adding a certain amount of DMF as a reaction solvent into the reaction bottle, sealing the bottle mouth, and stirring for a certain time at 100 ℃. After the reaction is finished, adding water for quenching reaction, extracting by ethyl acetate, combining organic phases, drying by anhydrous sodium sulfate, filtering, recovering the solvent under reduced pressure, and purifying the residues by silica gel column chromatography to obtain the target product.
The specific reaction is as follows:
The invention has the advantages that: the Pd/AntPhos is used for efficiently synthesizing the beta-elemene-chromanol derivatives, so that the aryl derivatization of the beta-elemene olefin is realized for the first time, and meanwhile, the method has the advantages of higher reaction yield, simple operation, low catalyst loading and simple separation and purification process.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Compound 1a
FIG. 2 is a nuclear magnetic resonance carbon spectrum of Compound 1a
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of Compound 1a
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of Compound 2a
FIG. 5 is a nuclear magnetic resonance carbon spectrum of Compound 2a
Detailed Description
Examples
(1) Synthesis of starting Compound 1a
Synthesis of Compound S1 by weighing 2g (9.1 mmol,1 equiv) of o-iodophenol, 1.86g (13.5 mmol,1.5 equiv) of potassium carbonate respectively into 50mL of a reaction flask, adding 15mL of LDMF into the reaction flask, placing the reaction flask in an ice-water bath, stirring for 30 minutes, then adding 1.9g (9.45 mmol,1.05 equiv) of 2-bromoacetophenone into the reaction flask and stirring at room temperature for 12 hours, adding 50mL of water quench reaction after completion of the reaction, each time extracting with 50mL of ethyl acetate for 3 times, combining the organic phases, washing the organic phases with saturated brine, adding an appropriate amount of anhydrous sodium sulfate, drying for 2 hours, filtering, distilling the recovered solvent under reduced pressure, separating and purifying the remaining concentrate by silica gel column chromatography using a mixed solvent of petroleum ether/ethyl acetate=95:5, collecting an eluent of the second band product, distilling the recovered solvent under reduced pressure to obtain 3g of white solid compound S1, the yield is leaching yield 95％.1H NMR(500MHz,CDCl3)δ8.07–7.99(m,2H),7.78(d,J＝7.8Hz,1H),7.60(t,J＝7.9Hz,1H),7.49(t,J＝7.5Hz,2H),7.29–7.18(m,1H),6.79–6.68(m,2H),5.29(s,2H).13C NMR(126MHz,CDCl3)δ194.11,156.85,139.83,134.44,133.95,129.47,128.83,128.42,123.49,112.68,86.47,72.05.
Synthesis of Compound S2 g (5.94 mmol,1 equiv.) of Compound S1,0.21g (3 mmol%) of tetrakis triphenylphosphine palladium, 0.10g (9 mmol%) of cuprous iodide, 0.72g (8.90 mmol,1.5 equiv.) of trimethylsilylene are dissolved in 10mL of tetrahydrofuran under nitrogen protection, then 0.72g (7.13 mmol,1.2 equiv.) of triethylamine is slowly added to the reaction flask, and stirred at room temperature for 12 hours. After the reaction, adding 20mL of saturated ammonium chloride solution to quench the reaction, extracting with 30mL of ethyl acetate each time for 3 times, combining organic phases, adding a proper amount of anhydrous sodium sulfate to dry for 2 hours, filtering, distilling under reduced pressure to recover the solvent, separating and purifying the residual concentrate by using petroleum ether/ethyl acetate=95:5 mixed solution as a leaching solvent through silica gel column chromatography, collecting eluent of the first band product, and distilling under reduced pressure to recover the solvent to obtain 1.77g of white solid compound S2, wherein the yield is 97％.1H NMR(500MHz,CDCl3)δ8.08–8.01(m,2H),7.59(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),7.43(dd,J＝7.6,1.7Hz,1H),7.25–7.20(m,1H),6.92(t,J＝8.0Hz,1H),6.83(d,J＝8.3Hz,1H),5.30(s,2H),0.21(s,9H).13C NMR(126MHz,CDCl3)δ194.60,158.99,134.68,134.18,133.76,129.86,128.72,128.53,121.65,113.44,113.43,100.93,99.15,72.25,0.04.
Synthesis of Compound S3 1g (3.25 mmol,1 equiv) of Compound S2 and 0.38g (6.5 mmol,2 equiv) of potassium fluoride were taken in a 25mL reaction flask, and 10mL of methanol was added to the reaction flask and stirred at room temperature for 12 hours. After the reaction was completed, methanol was removed under reduced pressure, then 20mL of water was added to the reaction flask, each time extracted with 20mL of ethyl acetate, 3 times of extraction were performed, the organic phases were combined, dried over anhydrous sodium sulfate for 2 hours, filtered, the solvent was recovered by distillation under reduced pressure, the remaining concentrate was separated and purified by silica gel column chromatography using a mixed solvent of petroleum ether/ethyl acetate=95:5 as eluent, the eluent of the first band product was collected, and after the solvent was recovered by distillation under reduced pressure, 0.614g of white solid compound S3 was obtained in a yield of 82％.1HNMR(500MHz,CDCl3)δ8.06–7.99(m,2H),7.59(t,J＝7.4Hz,1H),7.52–7.41(m,3H),7.24(t,J＝8.8Hz,1H),6.97–6.89(m,1H),6.79(d,J＝8.4Hz,1H),5.35(s,2H),3.29(s,1H).13C NMR(126MHz,CDCl3)δ194.25,159.22,134.53,134.38,133.88,130.13,128.80,128.32,121.55,112.78,112.18,81.66,79.83,71.74.
Synthesis of Compound S4 500mg (2.12 mmol,1 equiv.) of Compound S3, 73.5mg (3 mmol%) of tetrakis triphenylphosphine palladium, 40.25mg (10 mmol%) of cuprous iodide, 550mg (2.5 mmol,1.2 equiv.) of 4-iodophenol and 10mL of anhydrous tetrahydrofuran are added to a 25mL reaction flask under nitrogen. 258mg (0.25 mmol,1.2 equiv) of triethylamine are then added dropwise to the flask and stirred at room temperature for 12 hours. At the end of the reaction, the reaction was quenched by adding 20mL of saturated ammonium chloride solution, each time extracted with 30mL of ethyl acetate, extracted 3 times, dried over anhydrous sodium sulfate for 2 hours, filtered, distilled under reduced pressure to recover the solvent, the remaining concentrate was separated and purified by silica gel column chromatography using a petroleum ether/ethyl acetate=95:5 mixture as eluent, the eluent of the second band product was collected, distilled under reduced pressure to recover the solvent, and 0.636g of white solid compound S4 was obtained in the yield of 91％.1H NMR(600MHz,CDCl3)δ8.05(d,J＝7.3Hz,2H),7.57(t,J＝7.4Hz,1H),7.48(dd,J＝7.6,1.5Hz,1H),7.45(t,J＝7.8Hz,2H),7.31(d,J＝8.6Hz,2H),7.23(t,J＝8.7Hz,1H),6.97(t,J＝7.5Hz,1H),6.85(d,J＝8.3Hz,1H),6.76(d,J＝8.6Hz,2H),5.55(s,1H),5.35(s,2H).13C NMR(151MHz,CDCl3)δ195.07,158.29,155.83,134.55,133.89,133.46,133.23,129.25,128.77,128.48,121.79,115.57,115.44,113.86,113.12,94.05,83.97,72.05.
Synthesis of Compound S5 0.647g (3.35 mmol,1.1 equiv) triisopropylchlorosilane (TIPSCl) was added dropwise to a solution of 1.0g (3.05 mmol,1.0 equiv) of Compound S4 and 0.311g (4.58 mmol,1.5 equiv) of imidazole in acetone (20 mL) and the reaction was stirred at room temperature for 12 hours. Quenching the reaction by adding 30mL of saturated ammonium chloride solution, extracting with 40mL of ethyl acetate each time for 3 times, combining the organic phases, drying the mixture for 2 hours with anhydrous sodium sulfate, filtering, distilling the mixture under reduced pressure to recover the solvent, separating and purifying the residual concentrate by using petroleum ether/ethyl acetate=97:3 as a leaching solution and silica gel column chromatography, collecting the eluent of the first band product, and obtaining 1.4g of colorless oily compound S5 after distilling the mixture under reduced pressure to recover the solvent, wherein the yield is 95％.1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.8Hz,2H),7.54(t,J＝7.4Hz,1H),7.47(d,J＝7.6Hz,1H),7.43(t,J＝7.6Hz,2H),7.32(d,J＝8.2Hz,2H),7.22(t,J＝7.9Hz,1H),6.95(t,J＝7.5Hz,1H),6.85(d,J＝8.3Hz,1H),6.81(d,J＝8.2Hz,2H),5.31(s,2H),1.25(dt,J＝15.0,7.5Hz,3H),1.09(d,J＝7.5Hz,18H).13C NMR(151MHz,CDCl3)δ194.68,158.37,156.31,134.72,133.68,133.39,133.02,129.19,128.69,128.51,121.69,119.92,115.91,113.88,113.06,94.15,84.20,72.16,17.86,12.65.
Synthesis of Compound S6 21mg (7.5 mmol%) Ni (cod) 2, 28mg (7.5 mmol%) R-AntPhos and 4mL dioxane were added to an 8mL screw vial with a magnet under nitrogen blanket, and 484mg (1.0 mmol,1.0 equiv) Compound S5 was then added to the reaction flask and stirred for 2 minutes. Finally 350mg (3 mmol,3.0 equiv) of triethylsilane were added, the vial was closed and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with 10mL of saturated sodium bicarbonate solution, extracted with 20mL of ethyl acetate each time, extracted 3 times, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate for 2 hours, filtered, and concentrated under vacuum, and the remaining concentrate was purified by column chromatography on silica gel using a petroleum ether/ethyl acetate=98:2 mixture as a eluting solvent, and the eluent of the first band product was collected, and after recovering the solvent by distillation under reduced pressure, 0.438g of colorless oily compound S6 was obtained in 73% yield. 94:6er, er number determined by High Performance Liquid Chromatography (HPLC), separation conditions: chiral AD-H column, flow rate of 1mL/min at 25 ℃, n-hexane/isopropanol of 99.5/0.5,254nm,3.66min (S), 3.47min (R). 1H NMR(600MHz,CDCl3)δ7.54(d,J＝7.7Hz,2H),7.29–7.16(m,6H),7.11(d,J＝7.9Hz,1H),6.97(d,J＝15.2Hz,1H),6.83(s,1H),6.80(d,J＝8.2Hz,2H),6.73(d,J＝8.2Hz,1H),6.48(t,J＝7.5Hz,1H),4.64(d,J＝11.0Hz,1H),4.25(d,J＝11.0Hz,1H),1.25(q,J＝7.4Hz,3H),1.10(d,J＝7.5Hz,18H),0.86(t,J＝7.9Hz,9H),0.49–0.35(m,6H).13C NMR(151MHz,CDCl3)δ155.13,154.22,141.60,136.46,130.64,130.00,129.72,128.87,127.97,127.70,127.24,123.90,120.01,119.65,116.53,74.85,73.54,17.90,12.68,7.01,6.19.
Synthesis of Compound 1a 300mg (0.5 mmol,1.0 equiv) of S6 and 5mL of THF were added to a 25mL reaction flask, and the flask was placed in an ice-water bath, then 2mL of 1mol/L TBAF (0.2 mmol,4 equiv) dissolved in tetrahydrofuran was added to the flask, and the reaction was stirred for 30 minutes. After the reaction, 15mL of water is added to quench the reaction, 30mL of ethyl acetate is used for extraction for 3 times each time, the organic phases are combined, the saturated sodium chloride solution is used for washing the organic phases, the organic phases are dried for 2 hours by using a proper amount of anhydrous sodium sulfate, the filtration is carried out, the solvent is recovered by reduced pressure distillation, and the residual concentrate is separated and purified by using petroleum ether/ethyl acetate=80:20 mixed liquor as eluent for silica gel column chromatography, thus obtaining colorless oily matter for standby. The desilication product obtained in the above step and 178.5mg (0.5 mmol,1.0 equiv) of N-phenylbis (trifluoromethanesulfonyl) imide were taken in a 25mL reaction flask, 5mL of methylene chloride was added to the reaction flask, and the reaction flask was stirred under an ice-water bath. 61mg (0.6 mmol,1.2 equiv) of triethylamine are then added to the reaction flask, the ice-water bath is removed and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction was quenched by adding 15mL of saturated ammonium chloride solution, each time of extraction with 30mL of ethyl acetate, extraction was performed 3 times, the organic phase was dried over anhydrous sodium sulfate for 2 hours, filtration was performed, the solvent was recovered by distillation under reduced pressure, the remaining concentrate was separated and purified by silica gel column chromatography using a petroleum ether/ethyl acetate=95:5 mixture as a eluent, and the eluent of the second band product was collected, and after the solvent was recovered by distillation under reduced pressure, 0.145g of colorless oily compound 1a was obtained, the total yield was 63%.94:6er, er number determined by High Performance Liquid Chromatography (HPLC), separation conditions: chiral AD-H column, flow rate 1mL/min, n-hexane/isopropanol 95/5,254nm,28.77min (S), 21.46min (R). 1H NMR(600MHz,CDCl3)δ7.56(d,J＝7.7Hz,2H),7.40(d,J＝8.4Hz,2H),7.37(t,J＝7.5Hz,2H),7.31(t,J＝7.3Hz,1H),7.19(d,J＝8.5Hz,2H),7.11(t,J＝7.7Hz,1H),7.07(d,J＝7.9Hz,1H),6.85(d,J＝8.2Hz,1H),6.66(s,1H),6.61(t,J＝7.6Hz,1H),4.63(d,J＝11.4Hz,1H),4.30(d,J＝11.4Hz,1H),2.37(s,1H).13C NMR(151MHz,CDCl3)δ154.50,148.34,140.53,138.90,138.23,130.75,130.13,129.54,128.57,128.26,126.63,122.56,121.42,120.28,120.04–117.47(m),117.23,73.81,72.72.19F NMR(565MHz,CDCl3)δ-72.82.
(2) Synthesis of beta-elemene chromanol derivative 2a
46Mg (0.1 mmol,1.0 equiv.) of Compound 1a,0.9mg (4 mmol%) of palladium acetate, 3mg (8 mmol%) of rac-AntPhos,24.5mg (0.12 mmol,1.2 equiv.) of β -elemene and 21mg (0.15 mmol,1.5 equiv.) of potassium carbonate were each weighed into an 8mL screw flask, 1mL of MF was added to the flask, the flask was closed, and the flask was stirred at 100deg.C for 24 hours. After the reaction, 10mL of water is added for quenching reaction, 10mL of ethyl acetate is used for extraction for 3 times each time, the organic phases are combined, a proper amount of anhydrous sodium sulfate is added into the organic phases for drying for 2 hours, the filtration and the reduced pressure distillation are carried out to recover the solvent, the crude product is separated and purified by using petroleum ether/ethyl acetate=95:5 mixed solvent as eluent by silica gel column chromatography, the second eluent is collected, the reduced pressure distillation is carried out to recover the solvent, and 42mg of colorless oily compound 2a is obtained, and the yield is 82%.93:7er, er number determined by High Performance Liquid Chromatography (HPLC), separation conditions: chiral AD-H column, flow rate 1mL/min, n-hexane/isopropanol 90/10,254nm,9.49min (S), 6.93min (R). 1H NMR(600MHz,CDCl3)δ7.57(d,J＝7.5Hz,2H),7.35(t,J＝7.6Hz,2H),7.28(d,J＝31.0Hz,6H),7.09(t,J＝7.6Hz,1H),6.85(d,J＝8.2Hz,1H),6.66–6.55(m,2H),6.24(s,2H),4.84(s,1H),4.73(d,J＝11.9Hz,2H),4.63(s,1H),4.57(d,J＝11.3Hz,1H),4.27(d,J＝11.3Hz,1H),2.34(s,1H),2.16–2.06(m,1H),2.02–1.93(m,1H),1.76(s,3H),1.71(s,3H),1.64–1.55(m,4H),1.52–1.40(m,2H),1.11(s,3H).13C NMR(151MHz,CDCl3)δ154.37,150.31,147.60,142.84,140.95,137.12,136.66,129.80,129.54,129.10,128.41,127.98,126.76,126.03,125.15,124.74,120.17,119.75,116.99,112.34,108.33,74.12,53.12,45.72,40.03,39.47,32.89,26.84,24.91,21.06,17.21.
Claims (8)
1. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the structure of the beta-elemene chromanol derivative is a compound with the following structure or an enantiomer and a racemate of the compound:
2. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the compound of claim 1 is synthesized by the reaction of potassium carbonate as a base, ligand AntPhos and Pd (OAc) 2 as catalysts, catalyzing the coupling reaction of β -elemene and 3-hydroxychroman alcohol derivatives as follows:
3. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the reaction of claim 2, wherein the mass ratio of 3-hydroxy chromanol derivative 1a to β -elemene is: 1:1.2.
4. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the reaction of claim 2, wherein the mass ratio of Pd (OAc) 2 to 3-hydroxychroman alcohol derivative 1a is: 1:25.
5. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the reaction of claim 2, wherein the ratio of the amount of ligand AntPhos to the amount of 3-hydroxychroman alcohol derivative 1a is: 1:12.5.
6. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the reaction according to claim 2, wherein the mass ratio of 3-hydroxychroman alcohol derivative 1a to potassium carbonate is: 1:1.5.
7. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the reaction according to claim 2, wherein the solvent used for the reaction is N, N-Dimethylformamide (DMF) in an amount of 10mL/mmol of the compound 1a.
8. A method for preparing beta-elemene chromanol derivatives by palladium catalysis is characterized in that: the reaction of claim 2, wherein the reaction temperature is 100℃and the reaction time is 24 hours.
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