CN116283876A - Process for preparing benzopyrone - Google Patents
Process for preparing benzopyrone Download PDFInfo
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- CN116283876A CN116283876A CN202310230351.0A CN202310230351A CN116283876A CN 116283876 A CN116283876 A CN 116283876A CN 202310230351 A CN202310230351 A CN 202310230351A CN 116283876 A CN116283876 A CN 116283876A
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- nitro
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- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 105
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000006467 substitution reaction Methods 0.000 claims abstract description 42
- -1 1, 2-difluoro-4-nitro-3-nitromethylbenzene Chemical compound 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000002994 raw material Substances 0.000 claims abstract description 30
- 238000006722 reduction reaction Methods 0.000 claims abstract description 29
- ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000003333 secondary alcohols Chemical class 0.000 claims abstract description 25
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 18
- 150000004703 alkoxides Chemical class 0.000 claims abstract description 16
- 238000005935 nucleophilic addition reaction Methods 0.000 claims abstract description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 238000006987 Nef reaction Methods 0.000 claims abstract description 11
- 230000009471 action Effects 0.000 claims abstract description 9
- 238000006462 rearrangement reaction Methods 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 238000006479 redox reaction Methods 0.000 claims abstract description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 9
- 239000000047 product Substances 0.000 claims description 58
- 239000002904 solvent Substances 0.000 claims description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 238000000746 purification Methods 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000012265 solid product Substances 0.000 claims description 15
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
- 239000011261 inert gas Substances 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000654 additive Substances 0.000 claims description 10
- 230000000996 additive effect Effects 0.000 claims description 10
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 10
- 239000004246 zinc acetate Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000007800 oxidant agent Substances 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical group C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 5
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 4
- JHCKVPVXWBVGDI-UHFFFAOYSA-N hydrazine;dihydrate Chemical compound O.O.NN JHCKVPVXWBVGDI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000178 monomer Substances 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 3
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000007344 nucleophilic reaction Methods 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000011698 potassium fluoride Substances 0.000 claims description 3
- 235000003270 potassium fluoride Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000011775 sodium fluoride Substances 0.000 claims description 3
- 235000013024 sodium fluoride Nutrition 0.000 claims description 3
- 238000005266 casting Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 1
- 150000001299 aldehydes Chemical class 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000004973 liquid crystal related substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000008375 benzopyrones Chemical class 0.000 description 4
- 230000008707 rearrangement Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003172 aldehyde group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical group [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- BBSIIHZRYLIJOT-UHFFFAOYSA-N 2-(4-ethoxy-3-fluorophenyl)acetaldehyde Chemical compound CCOC1=CC=C(CC=O)C=C1F BBSIIHZRYLIJOT-UHFFFAOYSA-N 0.000 description 1
- RYVOZMPTISNBDB-UHFFFAOYSA-N 4-bromo-2-fluorophenol Chemical compound OC1=CC=C(Br)C=C1F RYVOZMPTISNBDB-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical group C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007766 curtain coating Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of benzopyrone. The preparation method comprises the following steps: s1, performing ortho-position substitution reaction on trifluoronitrobenzene serving as a first raw material and nitromethane to obtain 1, 2-difluoro-4-nitro-3-nitromethylbenzene, and performing para-position substitution reaction on the 1, 2-difluoro-4-nitro-3-nitromethylbenzene and alkoxide to obtain a first intermediate; s2, converting the nitromethyl into carboxyl by a Nef reaction on the first intermediate to obtain a second intermediate; s3, converting the nitro into the aldehyde hydrazine through reduction reaction, oxidation reaction and denitrification rearrangement reaction of the second intermediate to obtain an aldehyde hydrazine intermediate; and S4, under the action of a catalyst, carrying out nucleophilic addition reaction on the aldehyde hydrazine intermediate and a second raw material to generate a secondary alcohol intermediate, and carrying out ring closure reaction on the secondary alcohol intermediate to obtain a target product. The method for preparing benzopyrone has the advantages of wide sources of raw materials, mild reaction conditions and high overall yield of the reaction.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of benzopyrone.
Background
A liquid crystal compound having a benzopyrone skeleton and having negative dielectric anisotropy can be widely used in the manufacture of liquid crystal materials because it satisfies high stability to heat and light, high maximum temperature of nematic phase, low minimum temperature of liquid crystal phase, small viscosity, suitable optical anisotropy, large negative dielectric anisotropy, suitable elastic constant, and good compatibility with other liquid crystal compounds.
At present, benzopyrone compounds are mainly prepared by the following technical routes:
route one
Route two
The first route uses 2-fluoro-4-bromophenol as raw material, and adopts the steps of etherification, LDA aldehyde formation, aldehyde group oxidation, carboxyl protection, coupling cyclization and the like to prepare alkyl substituted benzopyrone derivative, wherein the total yield of the alkyl substituted benzopyrone in the original text is about 16%, and the yield is lower; the second route uses 3-fluoro-4-ethoxyphenylacetaldehyde as a raw material, and needs to be prepared in addition, a lithium reagent is needed in the process, the reaction conditions are harsh, and the yield in the process is mostly 30-40%.
In view of the above, the synthesis of benzopyrone compounds is difficult and the conditions are severe, and a more easily implemented synthesis method of benzopyrone is needed.
Disclosure of Invention
The invention mainly aims to provide a preparation method of benzopyrone, which aims to solve the problems of high preparation difficulty and low yield of benzopyrone in the prior art.
In order to achieve the above object, according to one aspect of the present invention, there is provided a process for preparing benzopyrone, comprising:
s1, performing ortho-position substitution reaction on trifluoronitrobenzene serving as a first raw material and nitromethane to obtain 1, 2-difluoro-4-nitro-3-nitromethylbenzene, and performing para-position substitution reaction on 1, 2-difluoro-4-nitro-3-nitromethylbenzene and alkoxide to obtain a first intermediate, wherein the structure of the first intermediate is shown as a formula I, and R is shown as a formula I 1 Selected from alkyl groups having 1 to 4 carbon atoms;
s2, converting the nitromethyl into carboxyl by a Nef reaction on the first intermediate to obtain a second intermediate;
s3, converting the nitro into the aldehyde hydrazine through reduction reaction, oxidation reaction and denitrification rearrangement reaction of the second intermediate to obtain an aldehyde hydrazine intermediate;
step S4, under the action of a catalyst, carrying out nucleophilic addition reaction on the aldehyde hydrazine intermediate and a second raw material with a structure shown as a formula II to generate a secondary alcohol intermediate, carrying out ring closure reaction on the secondary alcohol intermediate to obtain a target product with a structure shown as a formula II,
in the formula I and the formula II, R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, each substituent being independently C 1 ～C 5 Any one of alkyl groups; in the formula II, R 1 Selected from alkyl groups having 1 to 4 carbon atoms.
Further, the using amount of nitromethane is 5-20 times of the mole amount of the trifluoronitrobenzene as the first raw material;
preferably, an organic base is added in the ortho-substitution reaction of step S1; preferably, the organic base comprises any one or more of triethylamine, triethylenediamine, tetramethylguanidine, N-methylmorpholine and quaternary ammonium base; preferably, the organic base is used in an amount of 1 to 3 times the molar amount of the first starting material trifluoronitrobenzene.
Further, in the step S1, the temperature of the ortho-substitution reaction is-10 to-30 ℃, and preferably, the ortho-substitution reaction is carried out in an inert gas atmosphere;
preferably, the ortho-substitution reaction comprises: adding nitromethane and organic base into a reaction container, cooling to the reaction temperature of substitution reaction in an inert gas atmosphere, and adding first raw material trifluoronitrobenzene to perform substitution reaction; preferably, the first raw material trifluoronitrobenzene is added in a dropwise manner;
preferably, after the ortho-substitution reaction is completed, the reaction system is washed with water, and the nitromethane is recovered by concentrating under reduced pressure to obtain the 1, 2-difluoro-4-nitro-3-nitromethylbenzene.
Further, in step S1, the para-substitution reaction includes: mixing 1, 2-difluoro-4-nitro-3-nitrotoluene with a first solvent and alkoxide, heating and refluxing, reacting for 5-10 hours, adding a first acidic aqueous solution into the system to adjust the pH value, concentrating, pulping and washing to obtain a first intermediate;
preferably, the alkoxide comprises any one or more of sodium alkoxide and potassium alkoxide; preferably, the alkoxide is used in an amount of 1 to 2 times the molar amount of 1, 2-difluoro-4-nitro-3-nitromethylbenzene;
preferably, the first solvent comprises any one or more of ethanol, methanol, propanol and isopropanol;
preferably, the pH is adjusted to neutral;
preferably, the first acidic aqueous solution comprises any one or more of hydrochloric acid solution, sulfuric acid solution, acetic acid solution, ammonium chloride aqueous solution and ammonium sulfate aqueous solution.
Further, in step S2, a first catalyst is added in the schiff reaction, the first catalyst including any one or more of tetrabutylammonium iodide, zinc acetate, and zinc iodide;
preferably, the first catalyst comprises tetrabutylammonium iodide and zinc acetate, more preferably, the tetrabutylammonium iodide is used in an amount of 2 to 10% of the molar amount of the first intermediate, and the zinc acetate is used in an amount of 5 to 20% of the molar amount of the first intermediate;
preferably, the Nev reaction is carried out in a second solvent, the second solvent being water; preferably, the second solvent is used in an amount of 1 to 5 times the volume of the first intermediate;
preferably, step S2 includes: mixing the first intermediate with a second solvent and a first catalyst, performing a Nef reaction, and acidizing and first purifying after the reaction is finished to obtain a second intermediate;
preferably, the temperature of the Nev reaction is 80-100 ℃ and the reaction time is 10-30 hours;
preferably, the first purification comprises solvent extraction of the acidified product with methyl tertiary butyl ether, water washing, concentration, and washing the concentrated solid product with petroleum ether to provide the second intermediate.
Further, in step S3, the reduction reaction is performed by reacting with hydrogen under the action of a second catalyst, where the second catalyst includes any one or more of raney nickel, palladium carbon and platinum carbon;
preferably, the pressure of the hydrogen is 0.2-1MPa;
preferably, the reduction reaction is carried out in a third solvent comprising any one or more of ethanol, methanol and water;
preferably, the temperature of the reduction reaction is 30-50 ℃, and the reaction time is 5-10 hours;
preferably, the reduction reaction is performed by: and mixing the second intermediate with a second catalyst and a third solvent, filling hydrogen into a reaction device for reaction, and filtering, concentrating and crystallizing after the reaction is finished to obtain a reduction product.
Further, in step S3, the oxidation reaction includes mixing a product of the reduction reaction with trioxymethylene and a fourth solvent, reacting for a first time, adding an oxidant, continuing the reaction for a second time, and purifying for a second time after the reaction is completed to obtain a product of the oxidation reaction, wherein the fourth solvent is an organic solvent;
preferably, the oxidizing agent is selected from any one or more of aqueous hydrogen peroxide and tert-butyl hydroperoxide;
preferably, the molar amount of formaldehyde monomer in the trioxymethylene is 1-3 times of the molar amount of the product of the reduction reaction;
preferably, the fourth solvent comprises acetonitrile;
preferably, the temperature of the reaction is 75-85 ℃, more preferably, the oxidant is added at 60-70 ℃;
preferably, the first time is 8-10 hours, and the second time is 5-8 hours;
preferably, the second purification comprises separating the fourth solvent by distillation or distillation under reduced pressure, filtering, washing with water to remove hydrogen peroxide, and drying to obtain the oxidation reaction product.
Further, in step S3, the treatment process of the denitrification rearrangement reaction includes: dissolving the oxidation reaction product by a fifth solvent, mixing with hydrazine hydrate monohydrate, reacting in a reflux state, and carrying out third purification to obtain an aldehyde hydrazine intermediate;
preferably, the fifth solvent comprises ethanol;
preferably, the third purification comprises: concentrating under reduced pressure, extracting with methyl cyclopentyl ether, and washing with water.
Further, in step S4, the nucleophilic addition reaction is performed under the action of a second base reagent and a catalyst;
preferably, the second base reagent comprises any one or more of potassium carbonate, potassium phosphate and potassium tert-butoxide; more preferably, the second base reagent is used in an amount of 2 to 10% of the molar amount of the aldehyde hydrazine intermediate;
preferably, the catalyst comprises Fe (dmpe) 2 Cl 2 ；
Optionally, an additive is further added in the nucleophilic reaction, wherein the additive is selected from any one or more of sodium fluoride, potassium fluoride and cesium fluoride, and preferably, the dosage of the additive is 2-10% of the molar amount of the aldehyde hydrazine intermediate;
preferably, the nucleophilic addition reaction is carried out in an inert gas atmosphere.
Further, the ring closure reaction is a curtain coating reaction; preferably, the process of the ring closure reaction comprises: mixing a secondary alcohol intermediate with triphenylphosphine and a sixth solvent, dripping diethyl azodicarboxylate for reaction, adding water for quenching reaction after the reaction is finished, and performing fourth purification to obtain a target product;
preferably, the temperature of the ring closure reaction is 0-10 ℃;
preferably, the sixth solvent includes any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride and methylcyclopentyl ether;
preferably, the fourth purification comprises concentration under reduced pressure, freeze washing with ethanol, filtration and drying.
Further, R 1 Selected from alkyl groups having 2 to 4 carbon atoms, R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, each substituent being independently C 1 ～C 5 Any one of alkyl groups;
preferably, R 1 Selected from ethyl or n-butyl, R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl and dicyclohexylalkyl, preferably wherein the substituents are in the para position and wherein the substituents are C 1 ～C 4 Any one of alkyl groups.
By using the technical scheme of the invention, trifluoronitrobenzene is used as a starting material, ortho-position substitution is firstly carried out with nitromethane, para-position substitution is carried out with alkoxide, the obtained nitro substituent is subjected to a Nef reaction, then reduced, oxidized denitrification and rearrangement are carried out to convert nitro into aldehyde hydrazine, nucleophilic addition is carried out with aldehyde with a specific structure under the catalysis of an iron catalyst to generate a secondary alcohol intermediate, and finally the target product is obtained through ring closure. The method for preparing benzopyrone has the advantages of wide sources of raw materials, mild reaction conditions, high overall yield of the reaction, easy separation and purification of the prepared product and capability of effectively reducing the process cost of the benzopyrone compound.
Detailed Description
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present invention will be described in detail with reference to examples.
As analyzed in the background of the present application, the prior art has problems of difficult preparation and low yield of benzopyrone, and in order to solve the problems, the present application provides a preparation method of benzopyrone. The preparation method comprises the following steps: step S1, performing ortho-substitution reaction on trifluoronitrobenzene serving as a first raw material and nitromethane to obtainTo the 1, 2-difluoro-4-nitro-3-nitrotoluene, the 1, 2-difluoro-4-nitro-3-nitrotoluene and alkoxide undergo para-substitution reaction to obtain a first intermediate, the structure of the first intermediate is shown as a formula I, wherein R is 1 Selected from alkyl groups having 1 to 4 carbon atoms;
s2, converting the nitromethyl into carboxyl by a Nef reaction on the first intermediate to obtain a second intermediate; s3, converting the nitro into the aldehyde hydrazine through reduction reaction, oxidation reaction and denitrification rearrangement reaction of the second intermediate to obtain an aldehyde hydrazine intermediate; step S4, under the action of a catalyst, carrying out nucleophilic addition reaction on the aldehyde hydrazine intermediate and a second raw material with a structure shown as a formula II to generate a secondary alcohol intermediate, carrying out ring closure reaction on the secondary alcohol intermediate to obtain a target product with a structure shown as a formula II,
in the formula I and the formula II, R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, where substituted cyclohexyl, phenyl or dicyclohexylalkyl is taken, the substituents are each independently C 1 ～C 5 Any one of alkyl groups; in the formula II, R 1 Selected from alkyl groups having 1 to 4 carbon atoms.
The invention uses trifluoro nitrobenzene as initial raw material, firstly makes ortho-position substitution with nitromethane, then makes para-position substitution with alkoxide, the obtained nitro substituent is undergone the process of Nef reaction, then makes reduction, oxidation and denitrification rearrangement to convert nitro into aldehyde hydrazine, under the catalysis of iron catalyst, makes nucleophilic addition with aldehyde with specific structure to produce secondary alcohol intermediate, and finally makes ring closure so as to obtain the invented target product. The method for preparing benzopyrone has the advantages of wide sources of raw materials, mild reaction conditions, high overall yield of the reaction, easy separation and purification of the prepared product and capability of effectively reducing the process cost of the benzopyrone compound.
In some embodiments of the present application, R 1 Selected from alkyl groups having 2 to 4 carbon atoms, such as ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, each substituent being independently C 1 ～C 5 Any one of alkyl groups; preferably, R 1 Selected from ethyl or n-butyl, R 2 Selected from the group consisting of a substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl group, and when the cyclohexyl, phenyl or dicyclohexylalkyl group has a substituent, the substituent is preferably located at the para position to the aldehyde group, and the substituent is C 1 ～C 4 Any one of alkyl groups. In view of the application of the target product to the anisotropic liquid crystal monomer, it is preferable that the second raw material is an aldehyde having a trans structure.
In some embodiments of the present application, taking the target product 7-ethoxy-8-fluoro-3, 4-dihydro-3- (trans-4-propylcyclohexyl) -1H-2-benzopyran-1-one as an example, the reaction equation for the benzopyrone synthetic route of the present application is as follows:
in the step S1, the nitro ortho-fluorine can be replaced by the nitromethyl through the substitution reaction with the nitromethane, and the nitromethane can be used as a reaction reagent for the substitution reaction and also can be used as a solvent in the reaction process, so that the separation of subsequent products and the recovery and application of raw materials are facilitated; of course, the reaction can also be carried out with the addition of other solvents. In some preferred embodiments of the present application, nitromethane is used in an amount of 5 to 20 times the molar amount of the trifluoronitrobenzene starting material.
In some typical embodiments of the present application, in order to further increase the yield and reaction rate of the target product, an organic base is added to the ortho-substitution reaction of step S1; for example, the organic base may be any one or more of triethylamine, triethylenediamine, tetramethylguanidine (TMG), N-methylmorpholine, and a quaternary ammonium base; preferably, the dosage of the organic base is 1-3 times of the molar quantity of the first raw material trifluoro nitrobenzene, and the effect is particularly obvious.
In some embodiments of the present application, in step S1, the temperature of the ortho-substitution reaction is-10 to-30 ℃, and the yield of the target product is higher. In order to further increase the yield of the target product, the ortho-substitution reaction is performed in an inert gas atmosphere. In some exemplary embodiments of the present application, the ortho-substitution reaction described above includes: adding nitromethane and organic base into a reaction container, cooling to the reaction temperature of substitution reaction in an inert gas atmosphere, and adding first raw material trifluoronitrobenzene to perform substitution reaction; preferably, the first raw material trifluoronitrobenzene is added in a dropwise manner, so that the first raw material trifluoronitrobenzene is prevented from being added at one time to generate other byproducts. Those skilled in the art can separate and purify the reaction solution of the ortho-substitution reaction according to the prior art to obtain the target product, and in some embodiments of the present application, after the ortho-substitution reaction is completed, the reaction system is washed with water, and reduced pressure concentration is performed to recover nitromethane, and the remainder is subjected to subsequent reactions.
Para-substitution is performed on the product 1, 2-difluoro-4-nitro-3-nitromethylbenzene of the ortho-substitution reaction as a reaction raw material to obtain a compound with nitro para-alkoxy, and specific reaction conditions can be referred to the prior art, and in some embodiments of the present application, the para-substitution reaction includes: mixing 1, 2-difluoro-4-nitro-3-nitromethylbenzene with a first solvent and alkoxide, heating and refluxing, reacting for 5-10 hours, adding a first acidic aqueous solution into the system to adjust the pH value, concentrating, pulping and washing to obtain a solid product, namely the first intermediate, and directly using the solid product in the next preparation process without further purification; preferably, the alkoxide comprises any one or more of sodium alkoxide and potassium alkoxide; preferably, the alkoxide is used in an amount of 1 to 2 times the molar amount of 1, 2-difluoro-4-nitro-3-nitromethylbenzene, which is advantageous for further improving the yield of the target product. The first solvent is any one or more of ethanol, methanol, propanol and isopropanol. After the reaction is completed, an acid is added to react the remaining sodium alkoxide, and in some embodiments of the present application, the first acidic aqueous solution includes any one or more of a hydrochloric acid solution, a sulfuric acid solution, an acetic acid, an ammonium chloride aqueous solution, and an ammonium sulfate aqueous solution. Preferably, the first acidic aqueous solution is added to adjust the pH of the reaction solution to neutral.
In the step S2, the corresponding acid is prepared by the inner-furfur reaction of the nitromethyl in the product compound of the step S1, and the technological conditions and the operation method of the inner-furfur reaction can refer to the prior art, so the application is not limited. In some embodiments of the present application, a first catalyst is added to the above-described Nev reaction, where the first catalyst includes any one or more of tetrabutylammonium iodide, zinc acetate, and zinc iodide. In some preferred embodiments of the present application, to further increase the conversion of the target product, the first catalyst includes tetrabutylammonium iodide and zinc acetate; preferably, the amount of tetrabutylammonium iodide is 2-10% of the molar amount of the first intermediate, and the amount of zinc acetate is 5-20% of the molar amount of the first intermediate, so that the promotion effect on the target reaction is particularly obvious. In some embodiments of the present application, the above-described Nev reaction is performed in a second solvent, which is water, having an accelerating effect on the conversion of the target compound; preferably, the second solvent is used in an amount of 1 to 5 times the volume of the first intermediate, and the reaction is promoted more remarkably.
In some exemplary embodiments of the present application, the step S2 includes: mixing the first intermediate with a second solvent and a first catalyst, performing a Nef reaction, and acidizing and first purifying after the reaction is finished to obtain the second intermediate; preferably, the temperature of the Nev reaction is 80-100 ℃, the reaction time is 10-30 hours, and the yield of the target product is higher; in some embodiments of the present application, the first catalyst comprises zinc iodide and the reaction temperature of the Nef reaction is 95 to 100 ℃. The above acidification, which may be added with acids of the prior art, such as hydrochloric acid, and the above first purification may refer to the prior art, and in some embodiments of the present application, the first purification includes dissolution extraction of the acidified product with methyl tert-butyl ether, water washing, concentration, and washing the concentrated solid product with petroleum ether to obtain a solid product, i.e. the above second intermediate.
In the step S3, the second intermediate is reduced to convert the nitro group on the benzene ring into an amino group, that is, intermediate 5 in the reaction equation, and the reduction reaction can refer to a method and a process for reducing the nitro group into the amino group in the prior art. In some embodiments of the present application, in order to further increase the conversion rate of the target product, the reduction reaction is performed by reacting with hydrogen under the action of a second catalyst, where the second catalyst includes any one or more of raney nickel, palladium carbon, and platinum carbon; preferably, the pressure of the hydrogen is 0.2-1MPa, and the conversion rate of the target reduction product is high. In some embodiments of the present application, the above reduction reaction is performed in a third solvent, which includes any one or more of ethanol, methanol, and water, which is advantageous for further improving the yield and selectivity of the reaction. In some preferred embodiments, the reaction temperature of the reduction reaction is 30 to 50 ℃ and the reaction time is 5 to 10 hours. In some exemplary embodiments of the present application, the reducing reaction includes: and mixing the second intermediate with a second catalyst and a third solvent, filling hydrogen into a reaction device for reaction, and filtering, concentrating and crystallizing after the reaction is finished to obtain a reduction product.
In the step S3, the product prepared by the reduction reaction is further oxidized to convert the amino group into a —chnoh group, and in some embodiments of the present application, the oxidation reaction is performed by mixing the product of the reduction reaction with trioxymethylene and a fourth solvent, reacting for a first time, adding an oxidant, continuing the reaction for a second time, and purifying for a second time after the reaction is completed, so as to obtain the product of the oxidation reaction, wherein the fourth solvent is an organic solvent. In some embodiments of the present application, the oxidizing agent is selected from any one or more of aqueous hydrogen peroxide and t-butyl hydroperoxide. Preferably, the molar quantity of formaldehyde monomers in the trioxymethylene is 1-3 times of the molar quantity of products of the reduction reaction, which is more beneficial to the reaction and improves the conversion rate; preferably, the fourth solvent includes any one or more of acetonitrile, ethylene glycol, and glycerol. When the temperature of the reaction is 75-85 ℃, the yield of the target product is higher, more preferably, the oxidant is added at 60-70 ℃, so that the reaction is prevented from being too violent, byproducts are generated, and the yield of the target product is further influenced; in some preferred embodiments, the first time is 8-10 hours and the second time is 5-8 hours, which is advantageous for obtaining higher yield of target product. In some embodiments of the present application, the second purifying includes separating the fourth solvent by distillation or distillation under reduced pressure, filtering, washing with water to remove hydrogen peroxide, and drying to obtain the oxidation reaction product.
In the step S3, the —chnoh group on the benzene ring of the intermediate compound is further converted into a hydrazide group by a deazating rearrangement, and in some exemplary embodiments of the present application, the process of the deazating rearrangement reaction includes: and dissolving the oxidation reaction product by using a fifth solvent, mixing the solution with hydrazine hydrate monohydrate, reacting the mixture in a reflux state, and carrying out third purification to obtain the aldehyde hydrazine intermediate. The fifth solvent mentioned above may be selected from the prior art, such as ethanol; in some preferred embodiments of the present application, the third purification comprises: concentrating under reduced pressure, extracting with methyl cyclopentyl ether, and washing with water to obtain solution for the next reaction.
And S4, performing nucleophilic addition reaction on the hydrazide intermediate and a second raw material with an aldehyde group with a specific configuration to generate a secondary alcohol intermediate, and further closing the ring to obtain a target product. In some embodiments of the present application, the nucleophilic addition reaction described above is performed under the action of a second base reagent and a catalyst; in some embodiments of the present application, the second base reagent comprises any one or more of potassium carbonate, potassium phosphate, and potassium tert-butoxide; when the dosage of the second alkali reagent is 2-10% of the molar quantity of the aldehyde hydrazine intermediate, the promotion effect on the reaction is obvious; the catalyst is Fe (dmpe) 2 Cl 2 . In some embodiments of the present application, an additive is further added to the nucleophilic reaction, where the additive is selected from any one or more of sodium fluoride, potassium fluoride, and cesium fluoride, and preferably, the additive is used in an amount of 2-10% of the molar amount of the aldehyde hydrazine intermediate. In some embodiments of the present application, the aboveThe nucleophilic addition reaction is carried out in an inert gas atmosphere, and the yield of the target product is higher. In some embodiments of the present application, the nucleophilic addition reaction is performed as follows: sequentially adding a catalyst, a second alkali reagent and an additive into a three-mouth bottle under the protection of inert gas, then dripping the methyl cyclopentyl ether solution of the hydrazide intermediate prepared in the previous step, adding a second raw material into the system after the dripping is finished, and continuing to react for 10 hours at room temperature. The insoluble salts were removed by filtration, and the resulting solution was washed with water and concentrated to give an oily secondary alcohol intermediate, intermediate 9 in the above reaction equation.
In some exemplary embodiments of the present application, the ring-closing reaction is a casting reaction, and the specific operation method of the specific reaction may refer to the prior art, and in some embodiments of the present application, the treatment process of the ring-closing reaction includes: mixing the secondary alcohol intermediate with triphenylphosphine and a sixth solvent, dripping diethyl azodicarboxylate for reaction, adding water for quenching reaction after the reaction is finished, and performing fourth purification to obtain a target product. The sixth solvent may be selected from any one or more of organic solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride and methylcyclopentylether; preferably, the temperature of the ring closing reaction is 0-10 ℃, which is favorable for the yield of further products. In some preferred embodiments of the present application, the fourth purification includes concentration under reduced pressure, freeze washing with ethanol, filtration, and drying to obtain the target product with high purity.
The advantages that can be achieved by the present application will be further described below in connection with examples and comparative examples.
Example 1
Synthesizing 2-nitro-5-ethoxy-6-fluoronitrobenzyl benzene, wherein the reaction equation is as follows:
610g of nitromethane and 176g of tetraethylammonium hydroxide are added into a 2L three-port bottle, the system is cooled to-10 to-15 ℃ under the protection of inert gas, then 177g of 2,3, 4-trifluoronitrobenzene is dropwise added, and after the addition is finished, the system is heated and stirred to react until the central control is qualified. Washing with water, concentrating under reduced pressure to recover nitromethane, adding ethanol 1L, sodium ethoxide 82g into the residue, and carrying out reflux reaction for 5 hours. The pH value of the system is adjusted to be neutral by adding dilute hydrochloric acid, the system is concentrated, the remainder is pulped and washed, the obtained yellow solid product 3 is 196g, no further purification is needed, the yellow solid product can be directly used in the next preparation process, and the total yield of two steps is 80 percent calculated by trifluoronitrobenzene.
Example 2
2-nitro-5-ethoxy-6-fluorobenzoic acid is synthesized, and the reaction equation is shown as follows:
200g of the solid product 3 prepared in example 1, 800ml of water, 6g of tetrabutylammonium iodide and 15g of zinc acetate are placed in a 2L three-mouth bottle, the temperature is controlled to be 80-85 ℃ for reaction for 20 hours, the temperature is reduced, hydrochloric acid is added to adjust the pH value to be 1-2, methyl tertiary butyl ether is dissolved and extracted, water washing and concentration are carried out, and the solid product is washed by 500ml of petroleum ether, so as to obtain 169g of solid product, namely an intermediate 4 shown in a reaction equation, and the process yield is 90%.
Example 3
2-amino-5-ethoxy-6-fluorobenzoic acid is synthesized, and the reaction equation is shown as follows:
160g of intermediate 4, 600ml of absolute ethyl alcohol and 5g of Raney nickel are added into a 2L autoclave, the hydrogen pressure of 0.5MPa is maintained, and the temperature is controlled between 30 ℃ and 35 ℃ for hydrogenation reaction for 5 hours. Filtration, concentration and crystallization of the residue with 300ml of toluene petroleum ether (1:2) are carried out, and 128g of the target product, namely the intermediate 5 shown in the reaction equation, is finally obtained, and the process yield is 92%.
Example 4
Synthesizing 2-carboxyl-3-fluoro-4-ethoxybenzaldehyde hydrazine, wherein the reaction equation is shown as follows:
all the intermediate 5 prepared in the example 3 is put into a 1L three-mouth bottle, 300ml of acetonitrile, 30g of paraformaldehyde are added, the temperature is controlled to reflux and react for 8 hours, the temperature is reduced to 65 ℃, then 250ml of 35% hydrogen peroxide is added, and the reflux and stirring reaction is continued for 6 hours. The acetonitrile is distilled off under reduced pressure, cooled and filtered, the solid product is rinsed with water until no oxidizing property is achieved (the rinsed water phase is detected by starch potassium iodide test paper, and the solid product is dried to obtain 116g of intermediate 6, and the process yield is about 80%. Putting the dried substance into a 2L three-mouth bottle, adding 115g of hydrazine hydrate monohydrate, 800ml of absolute ethyl alcohol, carrying out reflux reaction for 2h, recovering the alcohol under reduced pressure, reducing the temperature, adding 600ml of methyl cyclopentyl ether for extraction, and washing with water to obtain a methyl cyclopentyl ether solution of the intermediate 7, wherein the methyl cyclopentyl ether solution contains about 124g of the intermediate 7, and the yield is about 95%.
Example 5
The secondary alcohol intermediate is synthesized, and the reaction equation is as follows:
12g of catalyst Fe (dmpe) were reacted under nitrogen 2 Cl 2 58g of potassium phosphate and 42g of cesium fluoride are added sequentially to a three-necked flask, and then the entire methyl cyclopentyl ether solution containing intermediate 7 prepared in example 4 is added dropwise, and after the completion of the addition, 84g of aldehyde 8 (as shown in the equation) is added to the system, and the reaction is continued at room temperature for 10 hours. The insoluble salts were removed by filtration, and the resulting solution was washed with water and concentrated to give 180g of oily intermediate 9 in 85% yield.
Example 6
Synthesis of 7-ethoxy-8-fluoro-3, 4-dihydro-3- (trans-4-alkylcyclohexyl) -1H-2-benzopyran-1-one, the reaction equation is shown below:
180g of the concentrate, 134g of triphenylphosphine and 500ml of tetrahydrofuran are placed in a 2L three-mouth bottle, the temperature is reduced to 5-10 ℃ under the protection of nitrogen, 93g of diethyl azodicarboxylate is dropwise added, the mixture is stirred for 30 minutes under the condition of heat preservation after the addition, 10ml of water is added into the system, the mixture is decompressed and concentrated, ethanol is subjected to repeated freezing and washing, the filtration and the drying are carried out, 140g of a target product refined product is obtained, the yield is 90%, the GC purity is 99.9%, and the mp is 102-104 ℃.
Example 7
The difference from example 1 was that nitromethane was added in an amount of 305g.
The resulting yellow solid product 3 was about 171g in 70% overall yield over two steps, calculated as trifluoronitrobenzene.
Example 8
The difference from example 1 is that the nitromethane is added in an amount of 183g,
the yellow solid product 3 was obtained in about 122g in 50% of the total yield of the two steps, calculated as trifluoronitrobenzene.
Example 9
The difference from example 4 is that the temperature was not lowered and hydrogen peroxide was added at the reflux temperature.
The methyl cyclopentyl ether solution of intermediate 7 was obtained, containing about 111g of intermediate 7, in a yield of about 85%.
Example 10
The difference from example 5 is that cesium fluoride is not added.
The same procedure as in example 5 was followed to obtain 42g of oily intermediate 9.
Example 11
The difference from example 5 is that aldehyde 8 has the formula
The amount added was 76g, giving 160g of secondary alcohol intermediate. Then, 160g of the secondary alcohol intermediate was subjected to ring closure reaction under the same conditions as in example 6 to give 122g of the aimed product in a yield of 85%, with a GC purity of 99.8% and an mp of 92-93 ℃.
Example 12
The difference from example 5 is that aldehyde 8 has the formula
The amount added was 92g, yielding 188g of secondary alcohol intermediate. Then 188g of the secondary alcohol intermediate was subjected to ring closure reaction under the same conditions as in example 6 to give 147g of the desired product in 92% yield with a GC purity of 99.9% and an mp of 108-109 ℃.
Example 13
The difference from example 1 is that 116g of sodium n-butoxide are used instead of 82g of sodium ethoxide. The reaction equation is as follows,
the total yield of the two steps is 72 percent based on the trifluoronitrobenzene.
The desired product was then synthesized in the same manner as in examples 2 to 6, with a total yield of 54.4%, a GC purity of 99.9% and an mp of 88-90 ℃.
Example 14
The difference from example 5 is that aldehyde 8 has the formula
The amount added was 58g, giving 160g of secondary alcohol intermediate. Then, 160g of the secondary alcohol intermediate was subjected to ring closure reaction under the same conditions as in example 6 to give 130g of the corresponding target product in 92% yield with a GC purity of 99.9% and an mp of 109-111 ℃.
Example 15
The difference from example 5 is that aldehyde 8 has the formula
The amount added was 129g, yielding 229g of secondary alcohol intermediate. 229g of the secondary alcohol intermediate was then subjected to the same conditions as in example 6The ring closure reaction was carried out to give 188g of the corresponding target product in 95% yield, 99.9% GC purity and 132-133℃mp.
From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects by using trifluoronitrobenzene as a starting material, performing ortho-substitution with nitromethane, performing para-substitution with alkoxide, performing a lactone-type reaction on the obtained nitro substituent, performing reduction, oxidative denitrification and rearrangement to convert nitro into aldehyde hydrazine, performing nucleophilic addition with aldehyde of a specific structure under the catalysis of an iron catalyst to generate a secondary alcohol intermediate, and finally performing ring closure to obtain the target product. The method for preparing benzopyrone has the advantages of wide sources of raw materials, mild reaction conditions, high overall yield of the reaction, easy separation and purification of the prepared product and capability of effectively reducing the process cost of the benzopyrone compound. The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (11)
1. A method for preparing benzopyrone, comprising:
s1, performing ortho-position substitution reaction on trifluoronitrobenzene serving as a first raw material and nitromethane to obtain 1, 2-difluoro-4-nitro-3-nitromethylbenzene, performing para-position substitution reaction on the 1, 2-difluoro-4-nitro-3-nitromethylbenzene and alkoxide to obtain a first intermediate, wherein the structure of the first intermediate is shown as a formula I,
wherein R is 1 Selected from alkyl groups having 1 to 4 carbon atoms;
s2, converting the nitromethyl into carboxyl by the first intermediate through a Nef reaction to obtain a second intermediate;
s3, converting the nitro into aldehyde hydrazine through reduction reaction, oxidation reaction and denitrification rearrangement reaction of the second intermediate to obtain an aldehyde hydrazine intermediate;
step S4, under the action of a catalyst, carrying out nucleophilic addition reaction on the aldehyde hydrazine intermediate and a second raw material with a structure shown as a formula II to generate a secondary alcohol intermediate, carrying out ring closure reaction on the secondary alcohol intermediate to obtain a target product with a structure shown as a formula II,
in the formula I and the formula II, R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, each substituent being independently C 1 ～C 5 Any one of alkyl groups; in the formula II, R 1 Selected from alkyl groups having 1 to 4 carbon atoms.
2. The preparation method according to claim 1, wherein the nitromethane is used in an amount of 5 to 20 times the molar amount of the first raw material trifluoronitrobenzene;
preferably, an organic base is added to the ortho-substitution reaction of step S1; preferably, the organic base comprises any one or more of triethylamine, triethylenediamine, tetramethylguanidine, N-methylmorpholine and quaternary ammonium base; preferably, the organic base is used in an amount of 1 to 3 times the molar amount of the first starting material trifluoronitrobenzene.
3. The method according to claim 2, wherein in the step S1, the ortho-substitution reaction is performed at a temperature of-10 to-30 ℃, preferably in an inert gas atmosphere;
preferably, the ortho-substitution reaction comprises: adding nitromethane and the organic base into a reaction container, cooling to the reaction temperature of the substitution reaction in the inert gas atmosphere, and adding the first raw material trifluoronitrobenzene to perform the substitution reaction; preferably, the first raw material trifluoronitrobenzene is added in a dropwise manner;
preferably, after the ortho-substitution reaction is completed, the reaction system is washed with water, and nitromethane is recovered by concentrating under reduced pressure to obtain 1, 2-difluoro-4-nitro-3-nitromethylbenzene.
4. The method according to claim 1, wherein in the step S1, the para-substitution reaction includes: mixing 1, 2-difluoro-4-nitro-3-nitrotoluene with a first solvent and alkoxide, heating and refluxing, reacting for 5-10 hours, adding a first acidic aqueous solution into the system to adjust the pH value, concentrating, pulping and washing to obtain a first intermediate;
preferably, the alkoxide comprises any one or more of sodium alkoxide and potassium alkoxide; preferably, the alkoxide is used in an amount of 1 to 2 times the molar amount of 1, 2-difluoro-4-nitro-3-nitromethylbenzene;
preferably, the first solvent includes any one or more of ethanol, methanol, propanol and isopropanol;
preferably, the pH is adjusted to neutral;
preferably, the first acidic aqueous solution includes any one or more of hydrochloric acid solution, sulfuric acid solution, acetic acid solution, ammonium chloride aqueous solution and ammonium sulfate aqueous solution.
5. The method according to claim 1, wherein in the step S2, a first catalyst including any one or more of tetrabutylammonium iodide, zinc acetate, and zinc iodide is added to the schiff reaction;
preferably, the first catalyst comprises tetrabutylammonium iodide and zinc acetate, more preferably, the amount of tetrabutylammonium iodide is 2-10% of the molar amount of the first intermediate, and the amount of zinc acetate is 5-20% of the molar amount of the first intermediate;
preferably, the Nev reaction is carried out in a second solvent, the second solvent being water; preferably, the second solvent is used in an amount of 1 to 5 times the volume of the first intermediate;
preferably, the step S2 includes: mixing the first intermediate with the second solvent and the first catalyst, performing a Nef reaction, and acidizing and first purifying after the reaction is finished to obtain a second intermediate;
preferably, the temperature of the Nef reaction is 80-100 ℃ and the reaction time is 10-30 hours;
preferably, the first purification comprises dissolution extraction of the acidified product with methyl tert-butyl ether, water washing, concentration, and washing the concentrated solid product with petroleum ether to give the second intermediate.
6. The method according to claim 1, wherein in the step S3, the reduction reaction is performed by reacting hydrogen with a second catalyst, the second catalyst including any one or more of raney nickel, palladium on carbon, and platinum on carbon;
preferably, the pressure of the hydrogen is 0.2-1MPa;
preferably, the reduction reaction is carried out in a third solvent comprising any one or more of ethanol, methanol and water;
preferably, the temperature of the reduction reaction is 30-50 ℃, and the reaction time is 5-10 hours;
preferably, the reduction reaction treatment process comprises: and mixing the second intermediate with a second catalyst and a third solvent, filling hydrogen into a reaction device for reaction, and filtering, concentrating and crystallizing after the reaction is finished to obtain a reduction product.
7. The preparation method according to claim 1, wherein in the step S3, the oxidation reaction includes mixing the product of the reduction reaction with trioxymethylene and a fourth solvent, reacting for a first time, adding an oxidant, continuing the reaction for a second time, and purifying for a second time after the reaction is completed to obtain the product of the oxidation reaction, wherein the fourth solvent is an organic solvent;
preferably, the oxidant is selected from any one or more of aqueous hydrogen peroxide and tert-butyl hydroperoxide;
preferably, the molar amount of formaldehyde monomer in the trioxymethylene is 1-3 times of the molar amount of the product of the reduction reaction;
preferably, the fourth solvent comprises acetonitrile;
preferably, the temperature of the reaction is 75-85 ℃, more preferably, the oxidant is added at 60-70 ℃;
preferably, the first time is 8-10 hours, and the second time is 5-8 hours;
preferably, the second purification comprises separating the fourth solvent by distillation or reduced pressure distillation, filtering, washing with water to remove hydrogen peroxide, and drying to obtain the oxidation reaction product.
8. The method according to claim 7, wherein in the step S3, the treatment process of the denitrification rearrangement reaction includes: dissolving the product of the oxidation reaction by a fifth solvent, mixing with hydrazine hydrate monohydrate, reacting in a reflux state, and carrying out third purification to obtain the aldehyde hydrazine intermediate;
preferably, the fifth solvent comprises ethanol;
preferably, the third purification comprises: concentrating under reduced pressure, extracting with methyl cyclopentyl ether, and washing with water.
9. The method according to claim 1, wherein in the step S4, the nucleophilic addition reaction is performed under the action of a second base reagent and a catalyst;
preferably, the second alkaline agent comprises any one or more of potassium carbonate, potassium phosphate and potassium tert-butoxide; more preferably, the second alkaline reagent is used in an amount of 2 to 10% of the molar amount of the aldehyde hydrazine intermediate;
preferably, the catalyst comprises Fe (dmpe) 2 Cl 2 ；
Optionally, an additive is further added in the nucleophilic reaction, wherein the additive is selected from any one or more of sodium fluoride, potassium fluoride and cesium fluoride, and preferably, the dosage of the additive is 2-10% of the molar amount of the aldehyde hydrazine intermediate;
preferably, the nucleophilic addition reaction is performed in an inert gas atmosphere.
10. The method of claim 1, wherein the ring closure reaction is a casting reaction;
preferably, the treatment process of the ring closing reaction comprises the following steps: mixing the secondary alcohol intermediate with triphenylphosphine and a sixth solvent, dripping diethyl azodicarboxylate for reaction, adding water for quenching reaction after the reaction is finished, and performing fourth purification to obtain a target product;
preferably, the temperature of the ring closing reaction is 0-10 ℃;
preferably, the sixth solvent includes any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride and methylcyclopentyl ether;
preferably, the fourth purification comprises reduced pressure concentration, ethanol freeze washing, filtration and drying.
11. The method of claim 1, wherein R is 1 Selected from alkyl groups having 2 to 4 carbon atoms, R being 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, each substituent being independently C 1 ～C 5 Any one of alkyl groups;
preferably, said R 1 Selected from ethyl or n-butyl, said R 2 Selected from the group consisting of substituted or unsubstituted cyclohexyl, phenyl or dicyclohexylalkyl, preferably with the substituent at the para position, said substituent being C 1 ～C 4 Any one of alkyl groups.
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| CN1785993A (en) * | 2005-12-14 | 2006-06-14 | 南开大学 | Preparation method of non natural isocumarin and its 3,4-dihydro derivative and use thereof |
| CN101326174A (en) * | 2005-12-08 | 2008-12-17 | 智索株式会社 | Compound having hydrocoumarin skeleton, liquid crystal composition and liquid crystal display element |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101326174A (en) * | 2005-12-08 | 2008-12-17 | 智索株式会社 | Compound having hydrocoumarin skeleton, liquid crystal composition and liquid crystal display element |
| CN1785993A (en) * | 2005-12-14 | 2006-06-14 | 南开大学 | Preparation method of non natural isocumarin and its 3,4-dihydro derivative and use thereof |
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