CN113200856A - Trifluoromethyl propylene compound and preparation method and application thereof - Google Patents
Trifluoromethyl propylene compound and preparation method and application thereof Download PDFInfo
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- CN113200856A CN113200856A CN202110543451.XA CN202110543451A CN113200856A CN 113200856 A CN113200856 A CN 113200856A CN 202110543451 A CN202110543451 A CN 202110543451A CN 113200856 A CN113200856 A CN 113200856A
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- methacrylate
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- allyl alcohol
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- -1 Trifluoromethyl propylene compound Chemical class 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 238000005712 Baylis-Hillman reaction Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 15
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 14
- 229910052786 argon Inorganic materials 0.000 claims description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 229930182830 galactose Natural products 0.000 claims description 9
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 7
- 235000012000 cholesterol Nutrition 0.000 claims description 7
- 229940041616 menthol Drugs 0.000 claims description 7
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- HORQDNOFAWZODY-UHFFFAOYSA-N CC(C(OC1C=CC(Cl)=CC1(O)Cl)=O)=C Chemical compound CC(C(OC1C=CC(Cl)=CC1(O)Cl)=O)=C HORQDNOFAWZODY-UHFFFAOYSA-N 0.000 claims description 5
- XGPOMXSYOKFBHS-UHFFFAOYSA-M sodium;trifluoromethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(F)(F)F XGPOMXSYOKFBHS-UHFFFAOYSA-M 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims 1
- VXTQKJXIZHSXBY-UHFFFAOYSA-N butan-2-yl 2-methylprop-2-enoate Chemical compound CCC(C)OC(=O)C(C)=C VXTQKJXIZHSXBY-UHFFFAOYSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000002243 precursor Substances 0.000 abstract description 3
- 230000004071 biological effect Effects 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 229910014033 C-OH Inorganic materials 0.000 abstract 1
- 229910014570 C—OH Inorganic materials 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 12
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- IBGQQDVGVLAJGD-JXMROGBWSA-N methyl (2E)-2-benzylidene-4,4,4-trifluorobutanoate Chemical compound COC(=O)C(\CC(F)(F)F)=C\C1=CC=CC=C1 IBGQQDVGVLAJGD-JXMROGBWSA-N 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- KAVUKAXLXGRUCD-UHFFFAOYSA-M sodium trifluoromethanesulfinate Chemical compound [Na+].[O-]S(=O)C(F)(F)F KAVUKAXLXGRUCD-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- GWTKXURKPNYOPX-UHFFFAOYSA-N (2,4-dichlorophenyl) 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC1=CC=C(Cl)C=C1Cl GWTKXURKPNYOPX-UHFFFAOYSA-N 0.000 description 1
- XJBRSZAYOKVFRH-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) prop-2-enoate Chemical compound CC(C)C1CCC(C)CC1OC(=O)C=C XJBRSZAYOKVFRH-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- MFYGZXFLQZJCHQ-UHFFFAOYSA-N C=CC(OCC1C=CC(Cl)=CC1(O)Cl)=O Chemical compound C=CC(OCC1C=CC(Cl)=CC1(O)Cl)=O MFYGZXFLQZJCHQ-UHFFFAOYSA-N 0.000 description 1
- GBJWQWFJJIOCPG-UHFFFAOYSA-N CC(C(CCC1=O)C(C=CC(Cl)=C2)=C2Cl)=C1O Chemical compound CC(C(CCC1=O)C(C=CC(Cl)=C2)=C2Cl)=C1O GBJWQWFJJIOCPG-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZHNSYNYLKYUVAH-GTPODGLVSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-methylprop-2-enoate Chemical compound C1C=C2C[C@@H](OC(=O)C(C)=C)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 ZHNSYNYLKYUVAH-GTPODGLVSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
- C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
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- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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Abstract
Disclosure of the inventionA trifluoromethyl propylene compound and its preparing process and application are disclosed. The invention directly uses allyl alcohol as raw material, selects CF3SO2Na is used as a trifluoromethylating reagent, a metal-free and cheap photo-oxidation-reduction catalyst is used, and a by-product SO generated in situ under the catalysis of an organic photo-oxidation-reduction agent2Is reused to activate the C-OH bond, thereby allowing the reaction to occur in an environmentally friendly manner under mild conditions. The allyl alcohol used in the preparation method is a Morita-Baylis-Hillman alcohol allyl alcohol raw material with simple synthesis and high conversion rate, the applicable substrate range is wide, and the preparation cost is low; in addition, the preparation method has simple steps, and has the characteristics of convenient operation, environmental protection, excellent stereoselectivity and tolerance of broad-spectrum functional groups; the trifluoromethyl propenyl compound of the invention is the relevant CF for preparation3The universal precursor of the molecule has potential pharmaceutical activity and biological activity, and can be widely applied to biological and pharmaceutical active molecules.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a trifluoromethyl propenyl compound and a preparation method and application thereof.
Background
The development of novel synthetic fluorination reactions is of great significance in agriculture, medicine and material chemistry. Fluorine and fluorine-containing compounds can affect the properties of organic compounds, whose electronegativity, all hydrophobicity/lipophilicity and electrostatic interactions can significantly affect chemical reactions. Even a fluorine atom can completely change the properties of a compound.
Among them, fluorine-containing drugs have been invested in a large number of resources in academia and industry, and the properties of drugs can be intentionally improved by selective fluorination, at least the biological half-life of drugs can be extended by hindering oxidative metabolism, and bioabsorption can be increased by lipophilic effects. According to investigation, a large number of fluorine-containing bioactive drug compounds are identified and confirmed, and the fluorine-containing compounds have great application potential. In particular, compounds having trifluoromethylpropenyl substitution are the preparation of the relevant CF3The universal precursor of the molecule has wide application prospect.
The synthesis of trifluoromethyl acrylic compounds is currently carried out by means of a superstoichiometric transition metal catalyst and a toxic or expensive high-valent iodine reagent, the olefins used being frequently highly reactive, pre-functionalized esters, halogenated hydrocarbons and the like. The method has harsh reaction conditions, depends on transition metal catalysis, is complex to treat after the reaction, and can also generate quantitative byproduct halogen salt/high-salinity wastewater. Therefore, from an environmental and economic point of view, it is very attractive to develop an energy-saving and efficient green synthesis method using non-toxic, cheap, readily available and relatively environmentally harmless raw materials.
Disclosure of Invention
The invention aims to provide a preparation method of a trifluoromethyl propylene compound, and aims to solve the problems that the existing method is harsh in reaction conditions, depends on transition metal catalysis, is complicated in subsequent treatment of reaction, and can generate quantitative byproduct halogen salt/high-salinity wastewater.
Still another object of the present invention is to provide a trifluoromethylacryl-based compound obtained by the above-mentioned preparation method.
Another object of the present invention is to provide the use of the above-mentioned trifluoromethylacryl based compound.
The present invention is achieved by a method for producing a trifluoromethylacryl-based compound, comprising the steps of:
(1) sequentially adding allyl alcohol, sodium trifluoromethanesulfonate and 3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate into a reaction solvent, and stirring and reacting for 4 hours under the conditions of inert gas atmosphere, blue light irradiation and room temperature to obtain a reaction solution; wherein the molar volume ratio of the allyl alcohol, the sodium trifluoromethanesulfonate, the 3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate to the reaction solvent is (0.2-0.4) mmol: (0.3-0.6) mmol: (0.008-0.016) mmol: (3-6) mL;
(2) removing the reaction solvent in the reaction solution, and purifying by thin layer chromatography, wherein the developing agent system is petroleum ether/ethyl acetate, so as to obtain the trifluoromethyl acrylic compound.
Preferably, in step (1), the inert gas is argon.
Preferably, in step (1), the allyl alcohol is Morita-Baylis-Hillman alcohol allyl alcohol.
Preferably, the allyl alcohol is selected from the group consisting of methyl 2-hydroxy (phenyl) methacrylate, methyl 2-hydroxy (4-fluorobenzene) methacrylate, methyl 2-hydroxy (4-trifluoromethylbenzene) methacrylate, methyl 2-hydroxy (4-nitrobenzene) methacrylate, methyl 2-hydroxy (4-carboxaldehydebenzene) methacrylate, methyl 2-hydroxy (4-methoxybenzene) methacrylate, methyl 2-hydroxy (4-tert-butylbenzene) methacrylate, methyl 2-hydroxy (3-fluorobenzene) methacrylate, methyl 2-hydroxy (2-chlorobenzene) methacrylate, methyl 2-hydroxy (3, 5-dimethylbenzene) methacrylate, methyl 2-hydroxy (naphthalen-1-yl) methacrylate, methyl 2-hydroxy (4-fluorobenzene) methacrylate, and mixtures thereof, Any one of methyl 2-hydroxy (pyridin-3-yl) methacrylate, methyl 2-hydroxy (thiophen-2-yl) methacrylate, ethyl 2-hydroxy (phenyl) methacrylate, tert-butyl 2-hydroxy (phenyl) methacrylate, menthol 2-hydroxy- (2, 4-dichlorophenyl) methacrylate, cholesterol 2-hydroxy- (2, 4-dichlorophenylmethyl) acrylate, and diacetone galactose 2-hydroxy- (2, 4-dichlorophenyl) methacrylate.
Preferably, in the step (1), the reaction solvent is selected from any one of dimethyl sulfoxide, N-dimethylformamide, acetone and acetonitrile.
Preferably, the reaction solvent is acetonitrile.
The invention further provides a trifluoromethyl propylene compound obtained by the preparation method.
The invention further discloses application of the trifluoromethyl propenyl compound in preparing frameworks of biologically and pharmaceutically active molecules.
The invention overcomes the defects of the prior art and provides a trifluoromethyl propylene compound and a preparation method and application thereof3SO2Na is used as a trifluoromethylating reagent, a metal-free and cheap photo-oxidation-reduction catalyst is used, and a by-product SO generated in situ under the catalysis of an organic photo-oxidation-reduction agent2Is reused to activate the-OH bond, thereby allowing the reaction to occur in an environmentally friendly manner under mild conditions.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) the allyl alcohol used in the preparation method is a Morita-Baylis-Hillman alcohol allyl alcohol raw material with simple synthesis and high conversion rate, and the applicable substrate range is wide, for example, various substituted phenyl and alkyl can be on the allyl alcohol, so the preparation method has the characteristic of low preparation cost; in addition, the preparation method has simple steps, and has the characteristics of convenient operation, environmental protection, excellent stereoselectivity and tolerance of broad-spectrum functional groups;
(2) the trifluoromethyl propenyl compound is a general precursor for preparing related CF3 molecules, has potential pharmaceutical activity and biological activity, and can be widely applied to biological and pharmaceutical active molecules (such as antitumor drugs).
Drawings
FIG. 1 is a NMR spectrum of methyl (E) -2-benzylidene-4, 4, 4-trifluorobutyrate in example of the present invention;
FIG. 2 is a NMR carbon spectrum of methyl (E) -2-benzylidene-4, 4, 4-trifluorobutyrate in example of the present invention;
FIG. 3 is the NMR fluorine spectrum of (E) -methyl 2-benzylidene-4, 4, 4-trifluorobutyrate in the example of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
(1) In a 10mL Schlenk tube, under argon atmosphere, adding 0.2mmol 2-hydroxy (phenyl) methyl methacrylate, 0.3mmol sodium trifluoromethanesulfonate, 0.008mmol3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, adding 3mL acetonitrile, and stirring under argon, room temperature and 18W blue light irradiation for reaction, wherein the reaction equation is as follows:
(2) after TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system, product is light yellow liquid (E) -2-benzylidene-4, 4, 4-trifluoro methyl butyrate, yield is 71%.
Performing nuclear magnetic resonance test on (E) -2-benzylidene-4, 4, 4-trifluorobutyric acid methyl ester, wherein as shown in figures 1-3, figure 1 is a nuclear magnetic resonance hydrogen spectrum of (E) -2-benzylidene-4, 4, 4-trifluorobutyric acid methyl ester; FIG. 2 is a NMR carbon spectrum of methyl (E) -2-benzylidene-4, 4, 4-trifluorobutyrate; FIG. 3 is a nuclear magnetic resonance fluorine spectrum of methyl (E) -2-benzylidene-4, 4, 4-trifluorobutyrate.
Example 2
(1) In a 10mL Schlenk tube, under an argon atmosphere, 0.4mmol of 2-hydroxy (2, 4-dichlorophenyl) methylcyclohex-2-en-1-one, 0.6mmol of sodium trifluoromethylsulfinate, 0.016mmol of 3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate, 6mL of acetonitrile are added, and the reaction is stirred under argon, room temperature and 18W of blue light irradiation, the reaction equation is as follows:
(2) after TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system, product is light yellow liquid (E) -2- (2, 4-dichlorobenzylidene) -3- (trifluoromethyl) cyclohex-1-one, yield is 74%.
Example 3
This example is substantially the same as example 1 above, except that 10mmol of methyl 2-hydroxy (phenyl) methacrylate, 15mmol of sodium trifluoromethylsulfinate, 0.4mmol of 3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate and 150mL of acetonitrile were charged in a 250mL round-bottomed flask and the reaction was stirred under argon at room temperature under 18W of blue light irradiation to obtain 1.76g of methyl (E) -2-benzylidene-4, 4, 4-trifluorobutyrate with a yield of 72%.
Example 4
This example is essentially the same as example 1 above, except that the allyl alcohol used is one with a natural product menthol molecular structure, and the allyl alcohol is synthesized by the steps of:
(1) adding menthol into a dichloromethane solution under the condition of room temperature under the protection of argon, adding triethylamine at the temperature of 0 ℃, and stirring for 0.5 h. Dripping a dichloromethane solution of acryloyl chloride into the reaction solution at the temperature of 0 ℃, and stirring and reacting for 12 hours at room temperature to obtain a reaction mixture; wherein the mol ratio of the menthol to the triethylamine to the acryloyl chloride is 1.2: 2: 1; the reaction equation is:
(2) the reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted 3 times with ether, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA) to give menthyl acrylate as a colorless liquid in 93% yield.
(3) Under the protection of argon and at room temperature, 2, 4-dichlorobenzaldehyde, acrylic acid menthol ester and triethylene diamine are mixed, and stirred at room temperature for 1 week. Obtaining a reaction mixture; wherein the molar ratio of the 2, 4-dichlorobenzaldehyde to the menthol acrylate to the triethylene diamine is 1: 1.2: 0.5;
(4) the reaction mixture was purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA) to give menthyl 2- (hydroxy- (2, 4-dichlorophenyl) meth) acrylate as a colorless liquid in 89% yield.
This example is essentially the same as example 1 above, except that the allyl alcohol is the menthyl 2-hydroxy (2, 4-dichlorophenyl) methacrylate obtained above, and the reaction equation is:
example 5
This example is essentially the same as example 1 above, except that the allyl alcohol used is one with a molecular structure of the natural product cholesterol, and the allyl alcohol is synthesized by the steps of:
(1) under the protection of argon and at room temperature, the cholesterol is added into a dichloromethane solution, the triethylamine is added at the temperature of 0 ℃, and the mixture is stirred for 0.5 h. Dripping a dichloromethane solution of acryloyl chloride into the reaction solution at the temperature of 0 ℃, and stirring and reacting for 12 hours at room temperature to obtain a reaction mixture; wherein the mol ratio of the cholesterol to the triethylamine to the acryloyl chloride is 1.2: 2: 1; the reaction equation is:
(2) the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted 3 times with ether, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA) to give cholesterol acrylate as a white solid in 61% yield.
(3) Under the protection of argon and at room temperature, dissolving 2, 4-dichlorobenzaldehyde, acrylic acid cholesterol ester and triethylene diamine in tetrahydrofuran, and stirring at room temperature for 1 week to obtain a reaction mixture; wherein the molar ratio of the 2, 4-dichlorobenzaldehyde to the acrylic acid cholesterol ester to the triethylene diamine is 1: 1.2: 0.5;
(4) the reaction mixture was removed of the solvent under reduced pressure and the residue was purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA) to give cholesterol 2- (hydroxy- (2, 4-dichlorophenyl) meth) acrylate as a white solid in 58% yield.
This example is essentially the same as example 1 above, except that allyl alcohol is the 2-hydroxy ((2, 4-dichlorophenyl) cholesterol methacrylate obtained above, the reaction equation is:
example 6
This example is substantially the same as example 1 above, except that the allyl alcohol used is one having a natural product diacetone galactose molecular structure, and the allyl alcohol is synthesized by the steps of:
(1) adding diacetone galactose into dichloromethane solution under the condition of room temperature under the protection of argon, adding triethylamine at the temperature of 0 ℃, and stirring for 0.5 h. Dripping a dichloromethane solution of acryloyl chloride into the reaction solution at the temperature of 0 ℃, and stirring and reacting for 12 hours at room temperature to obtain a reaction mixture; wherein the molar ratio of diacetone galactose to triethylamine to acryloyl chloride is 1.2: 2: 1; the reaction equation is:
(2) the reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted 3 times with ether, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA) to give diacetone galactose acrylate as a white solid in a yield of 95%.
(3) Under the protection of argon and at room temperature, dissolving 2, 4-dichlorobenzaldehyde, diacetone galactosyl acrylate and triethylene diamine in tetrahydrofuran, and stirring at room temperature for 1 week to obtain a reaction mixture; wherein the molar ratio of the 2, 4-dichlorobenzaldehyde to the diacetone galactose acrylate to the triethylene diamine is 1: 1.2: 0.5;
(4) the reaction mixture was freed of solvent under reduced pressure and the residue was purified by column silica gel chromatography with petroleum ether and ethyl acetate (PE/EA) to give diacetone galactose 2- (hydroxy- (2, 4-dichlorophenyl) meth) acrylate as a white solid in 94% yield.
This example is essentially the same as example 1 above, except that allyl alcohol is the 2-hydroxy diacetone galactose ((2, 4-dichlorophenyl) methacrylate) obtained above, the reaction equation being:
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (8)
1. A method for producing a trifluoromethylacryl-based compound, comprising the steps of:
(1) sequentially adding allyl alcohol, sodium trifluoromethanesulfonate and 3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate into a reaction solvent, and stirring and reacting for 4 hours under the conditions of inert gas atmosphere, blue light irradiation and room temperature to obtain a reaction solution; wherein the molar volume ratio of the allyl alcohol, the sodium trifluoromethanesulfonate, the 3, 6-di-tert-butyl-9-mesityl-10-phenylacridine-10-tetrafluoroborate to the reaction solvent is (0.2-0.4) mmol: (0.3-0.6) mmol: (0.008-0.016) mmol: (3-6) mL;
(2) removing the reaction solvent in the reaction solution, and purifying by thin layer chromatography, wherein the developing agent system is petroleum ether/ethyl acetate, so as to obtain the trifluoromethyl acrylic compound.
2. The method of producing a trifluoromethylacryl-based compound according to claim 1, wherein in the step (1), the inert gas is argon.
3. The method of producing a trifluoromethylacrylic compound according to claim 1, wherein in the step (1), the allyl alcohol is Morita-Baylis-Hillman alcohol allyl alcohol.
4. The method of producing a trifluoromethylacrylic compound according to claim 3, wherein the allyl alcohol is selected from the group consisting of methyl 2-hydroxy (phenyl) methacrylate, methyl 2-hydroxy (4-fluorobenzene) methacrylate, methyl 2-hydroxy (4-trifluoromethylbenzene) methacrylate, methyl 2-hydroxy (4-nitrobenzene) methacrylate, methyl 2-hydroxy (4-carboxaldehydebenzene) methacrylate, methyl 2-hydroxy (4-methoxybenzene) methacrylate, methyl 2-hydroxy (4-tert-butylbenzene) methacrylate, methyl 2-hydroxy (3-fluorobenzene) methacrylate, methyl 2-hydroxy (2-chlorobenzene) methacrylate, methyl 2-hydroxy (3, 5-dimethylbenzene) methacrylate, methyl 2-hydroxy (4-nitrobenzene) methacrylate, methyl tert-butyl methacrylate, methyl 2-hydroxy (4-nitrobenzene) methacrylate, methyl-propyl methacrylate, methyl ester, methyl methacrylate, methyl acrylate, and methyl acrylate, any one of methyl 2-hydroxy (naphthalen-1-yl) methacrylate, methyl 2-hydroxy (pyridin-3-yl) methacrylate, methyl 2-hydroxy (thiophen-2-yl) methacrylate, ethyl 2-hydroxy (phenyl) methacrylate, tert-butyl 2-hydroxy (phenyl) methacrylate, menthol 2-hydroxy- (2, 4-dichlorophenyl) methacrylate, cholesterol 2-hydroxy- (2, 4-dichlorophenyl) methacrylate, and diacetone galactose 2-hydroxy- (2, 4-dichlorophenyl) methacrylate.
5. The method of producing a trifluoromethylacryl-based compound according to claim 1, wherein in the step (1), the reaction solvent is selected from any one of dimethylsulfoxide, N-dimethylformamide, acetone, and acetonitrile.
6. The method for producing a trifluoromethylacryl-based compound according to claim 5, wherein the reaction solvent is acetonitrile.
7. A trifluoromethylacryl-based compound obtained by the process according to any one of claims 1 to 6.
8. Use of the trifluoromethylpropenyl compound of claim 7 for the preparation of scaffolds for biologically and pharmaceutically active molecules.
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| Title |
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| ARVIND KUMAR YADAV,ET AL.,: ""Visible light enabled γ -trifluoromethylation of Baylis- Hillman acetates: stereoselective synthesis of trisubstituted alkenes"", 《ORG. CHEM. FRONT》 * |
| BOWEN LI,ET AL.,: ""Visible-Light-Induced Tri fl uoromethylation of Allylic Alcohols"", 《ORG. LETT.》 * |
| HONG-LI HUANG,ET AL.,: ""Metal-Free Direct Aryltrifluoromethylation of Allylic Alcohols with Langlois’ Reagent through Concomitant 1,2-Aryl Migration"", 《ASIAN J. ORG. CHEM.》 * |
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