CN110028395A - A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone - Google Patents
A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone Download PDFInfo
- Publication number
- CN110028395A CN110028395A CN201910457269.5A CN201910457269A CN110028395A CN 110028395 A CN110028395 A CN 110028395A CN 201910457269 A CN201910457269 A CN 201910457269A CN 110028395 A CN110028395 A CN 110028395A
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- CN
- China
- Prior art keywords
- protecting group
- cyclohexanone
- solvent
- acid
- hydroxy phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- SLJYPZJZQIHNGU-UHFFFAOYSA-N 4-(4-hydroxyphenyl)cyclohexan-1-one Chemical compound C1=CC(O)=CC=C1C1CCC(=O)CC1 SLJYPZJZQIHNGU-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 4
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 56
- 125000006239 protecting group Chemical group 0.000 claims description 56
- -1 phenylcyclohexanol ethylene glycol Chemical compound 0.000 claims description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- BCBMRSQLCNPJFR-UHFFFAOYSA-N 1-cyclohexyl-1-phenylethane-1,2-diol Chemical compound C=1C=CC=CC=1C(O)(CO)C1CCCCC1 BCBMRSQLCNPJFR-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 10
- 239000003223 protective agent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012024 dehydrating agents Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 8
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 8
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 6
- 150000001241 acetals Chemical class 0.000 claims description 6
- NBZANZVJRKXVBH-GYDPHNCVSA-N alpha-Cryptoxanthin Natural products O[C@H]1CC(C)(C)C(/C=C/C(=C\C=C\C(=C/C=C/C=C(\C=C\C=C(/C=C/[C@H]2C(C)=CCCC2(C)C)\C)/C)\C)/C)=C(C)C1 NBZANZVJRKXVBH-GYDPHNCVSA-N 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011814 protection agent Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical group C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 239000007787 solid Substances 0.000 abstract description 8
- 239000007818 Grignard reagent Substances 0.000 abstract description 6
- 150000004795 grignard reagents Chemical class 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 150000001336 alkenes Chemical class 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000013461 design Methods 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000011084 recovery Methods 0.000 description 9
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 8
- 229910001623 magnesium bromide Inorganic materials 0.000 description 8
- 238000012805 post-processing Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 6
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical class O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- GZGPRZYZKBQPBQ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decane Chemical compound O1CCOC11CCCCC1 GZGPRZYZKBQPBQ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ULKGULQGPBMIJU-UHFFFAOYSA-N benzene;hydron;bromide Chemical compound Br.C1=CC=CC=C1 ULKGULQGPBMIJU-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- KFUSEUYYWQURPO-UHFFFAOYSA-N 1,2-dichloroethene Chemical compound ClC=CCl KFUSEUYYWQURPO-UHFFFAOYSA-N 0.000 description 1
- FWAHEVVMELQPIJ-UHFFFAOYSA-N 2-(4-hydroxyphenyl)cyclohexan-1-one Chemical compound C1=CC(O)=CC=C1C1C(=O)CCCC1 FWAHEVVMELQPIJ-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- WCMSFBRREKZZFL-UHFFFAOYSA-N 3-cyclohexen-1-yl-Benzene Chemical compound C1CCCC(C=2C=CC=CC=2)=C1 WCMSFBRREKZZFL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- KUITVSQJOZQHAX-UHFFFAOYSA-N cyclohexane-1,2-dione ethane-1,2-diol Chemical compound C(CO)O.C1(C(CCCC1)=O)=O KUITVSQJOZQHAX-UHFFFAOYSA-N 0.000 description 1
- YEYVEBLJQHVBRT-UHFFFAOYSA-N cyclohexanol;ethane-1,2-diol Chemical compound OCCO.OC1CCCCC1 YEYVEBLJQHVBRT-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RMOLGHGEBSECTG-UHFFFAOYSA-N ethane-1,2-diol;hexan-1-ol Chemical compound OCCO.CCCCCCO RMOLGHGEBSECTG-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- BOTNYLSAWDQNEX-UHFFFAOYSA-N phenoxymethylbenzene Chemical compound C=1C=CC=CC=1COC1=CC=CC=C1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- PVCCZEUVTSHZCZ-UHFFFAOYSA-N tert-butyl-chloro-dimethylsilane;silicon Chemical compound [Si].CC(C)(C)[Si](C)(C)Cl PVCCZEUVTSHZCZ-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
- C07C41/50—Preparation of compounds having groups by reactions producing groups
- C07C41/56—Preparation of compounds having groups by reactions producing groups by condensation of aldehydes, paraformaldehyde, or ketones
-
- 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
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/02—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2
- C07D317/06—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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Abstract
The present invention relates to technical field of chemical synthesis, specifically disclose a kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone.The preparation method is using p bromophenol as raw material; through hydroxyl protection; grignard reaction prepares Grignard Reagent; then the Grignard Reagent and 1 being prepared is utilized; the coupling of 4- cyclohexanedione monoethylene acetal; it is dehydrated into alkene, double blocking groups is taken off after adding hydrogen, prepares target product 4- (4- hydroxy phenyl) cyclohexanone.The preparation method of 4- (4- hydroxy phenyl) cyclohexanone provided by the invention has technological design reasonable, high income, the low advantage of production cost, 4- (4- hydroxy phenyl) cyclohexanone being prepared is white solid, and HPLC content is greater than 99.5%, and total yield of products can reach 75-80%, and raw material is easy to get, it is easy to operate, it is highly-safe, realize the industrialized production of 4- (4- hydroxy phenyl) cyclohexanone.
Description
Technical field
The present invention relates to technical field of chemical synthesis more particularly to a kind of preparation sides of 4- (4- hydroxy phenyl) cyclohexanone
Method.
Background technique
4- (4- hydroxy phenyl) cyclohexanone, structural formula are as follows:
Molecular formula is C12H14O2, it is a kind of white solid, is a kind of important chemical and medicine industry intermediate, and prepare a variety of
The important intermediate of liquid crystal material.In recent years, with the fast development of liquid crystal industry and pharmaceuticals industry, to 4- (4- hydroxy benzenes
Base) demand of cyclohexanone increases year by year.
In existing literature report, the synthetic route of synthesis 4- (4- hydroxy phenyl) cyclohexanone is mainly with 4,4'- biphenyl two
Phenol is raw material, is reduced to 4- (4- hydroxycyclohexan) phenol through reducing agent, is protected to obtain 4- (4- benzyloxy benzene) hexamethylene with benzyl chloride
Alcohol obtains 4- (4- benzyloxy benzene) cyclohexanone through oxidation, then prepares through palladium-carbon catalyst catalytic hydrogenation.But in the technique
The selectivity of palladium charcoal catalytic hydrogenation step is poor, causes the yield of 4- (4- hydroxy phenyl) cyclohexanone lower, and the technique is also deposited
The disadvantages of environmental pollution is big, preparation cost is high.Therefore, it in order to improve the yield of 4- (4- hydroxy phenyl) cyclohexanone, and reduces
Environmental pollution reduces production cost, it is necessary to find a kind of more environmentally friendly, capable of being industrialized production technology.
Summary of the invention
For the technique of prior art preparation 4- (4- hydroxy phenyl) cyclohexanone, there are yield is low and environmental pollution is big, system
Standby problem at high cost, the present invention provide a kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone.
In order to solve the above technical problems, present invention provide the technical scheme that
A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone, includes the following steps:
Step 1: p bromophenol is reacted with hydroxy-protecting agent, obtain to protecting group bromobenzene；
Step 2: carrying out grignard reaction to protecting group bromobenzene and magnesium metal, obtain to protecting group phenyl-magnesium-bromide；
Step 3: to protecting group phenyl-magnesium-bromide and Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal progress coupling reaction, acidolysis,
It obtains to protecting group phenylcyclohexanol ethylene glycol single ketal；
Step 4: dehydration is carried out under dehydrating agent catalytic action to protecting group phenylcyclohexanol ethylene glycol single ketal,
It obtains to protecting group phenyl cyclohexene ethylene glycol single ketal；
Step 5: carrying out catalytic hydrogenation reaction to protecting group phenyl cyclohexene ethylene glycol single ketal and hydrogen, obtain to protection
Base phenylcyclohexyl ethylene glycol single ketal；
Step 6: being reacted with deprotection agent protecting group phenylcyclohexyl ethylene glycol single ketal, 4- (4- hydroxy phenyl) is obtained
Cyclohexanone.
The reaction equation of above-mentioned preparation process is as follows:
Compared with the existing technology, the present invention provides a kind of new 4- (4- hydroxy benzenes by designing new synthetic route
Base) cyclohexanone preparation method, using p bromophenol as raw material, through hydroxyl protection, grignard reaction prepares Grignard Reagent, then utilizes
Grignard Reagent and Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal being prepared are coupled, and are dehydrated into alkene, take off double protecting groups after adding hydrogen
Group, prepares target product 4- (4- hydroxy phenyl) cyclohexanone.The preparation side of 4- (4- hydroxy phenyl) cyclohexanone provided by the invention
Method has technological design reasonable, high income, the low advantage of production cost, and the 4- being prepared (4- hydroxy phenyl) cyclohexanone is white
Color solid, HPLC content are greater than 99.5%, and total yield of products can reach 75-80%, and raw material is easy to get, easy to operate, safety
Height realizes the industrialized production of 4- (4- hydroxy phenyl) cyclohexanone.
Preferably, the preparation method of 4- (4- hydroxy phenyl) cyclohexanone includes the following steps:
Step 1: p bromophenol and acid binding agent are added in the first solvent, it is uniformly mixed, under inert gas protection, drop
Add hydroxyl protection agent solution, in 0-50 DEG C of reaction 2-5h, obtains to protecting group bromobenzene；
Step 2: protecting group bromobenzene is added in the second solvent by described, obtain to protecting group bromobenzene solution, in inert gas
It under protection, is added dropwise in magnesium metal, in 0-80 DEG C of reaction 1-3h, is obtained to protecting group phenyl-magnesium-bromide；
Step 3: Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal is added in second solvent, Isosorbide-5-Nitrae-cyclohexanedione list is obtained
Ethylene ketal solution, under inert gas protection, be added dropwise to it is described in protecting group phenyl-magnesium-bromide, in 30-100 DEG C
4-12h is reacted, acid hydrolysis solution is added and obtains in 0-30 DEG C of progress acidolysis to protecting group phenylcyclohexanol ethylene glycol single ketal；
Step 4: protecting group phenylcyclohexanol ethylene glycol single ketal is added in third solvent by described, dehydrating agent is added,
Reflux dewatering 4-12h is obtained to protecting group phenyl cyclohexene ethylene glycol single ketal；
Step 5: protecting group phenyl cyclohexene ethylene glycol single ketal is added in the 4th solvent by described, catalyst is added,
It is passed through hydrogen, in 20-80 DEG C, under conditions of reaction pressure is 1-5 atmospheric pressure, 2-12h is reacted, obtains to protecting group phenyl hexamethylene
Ethyl glycol single ketal；
Step 6: protecting group phenylcyclohexyl ethylene glycol single ketal is added in the 5th solvent by described, deprotection is added
Agent, 0-100 DEG C of reaction 2-8h obtain 4- (4- hydroxy phenyl) cyclohexanone.
Preferred above-mentioned reaction condition, can be such that reaction raw materials in each step sufficiently react, improve the conversion ratio of raw material, as far as possible
The generation for reducing side reaction is conducive to the yield and purity that improve product.
Heretofore described inert gas can be the inert gas of this field routine, such as nitrogen, argon gas.
Preferably, the hydroxy-protecting agent is dihydropyran, dimethoxym ethane, trim,ethylchlorosilane or tert-butyldimethylsilyl chloride silicon
Alkane.
Preferred hydroxy-protecting agent is successfully realized the reaction for being prepared Grignard Reagent using p bromophenol as raw material, and made
The Grignard Reagent of preparation hydroxy-protective group in subsequent coupling, acidolysis, dehydration and hydrogenation process can be stabilized, together
When, during also helping step 6 deprotection, the difunctional protection of hydroxyl and ethylene ketal can be directly taken off, thus
So that the target that 4- (4- hydroxy phenyl) cyclohexanone is prepared in the synthetic route designed through the invention is smoothly realized.
Preferably, the acid binding agent is pyridine, triethylamine, imidazoles, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide
At least one of.
Preferred acid binding agent may advantageously facilitate reaction forward progress, improve the conversion ratio of reaction rate and reaction raw materials.
Preferably, the catalyst is at least one of Raney's nickel, palladium charcoal or ruthenium carbon.
Preferred catalyst has reactivity high, and selectivity is good, and the mild advantage of reaction condition can be improved to guarantor
The reaction rate of base phenyl cyclohexene ethylene glycol single ketal and hydrogen is protected, and can repeat to recycle, advantageously reduces production
Cost.
Preferably, in step 1, time for adding 50-60min.
Preferably, in step 2, time for adding 30-60min.
Preferably, in step 3, time for adding 10-30min.
Preferred time for adding can be such that dropwise addition object in system is in suitable and lower concentration range always, avoid pair
The generation of reaction reduces the content of impurity in product, improves the utilization rate that object is added dropwise, to be conducive to improve total receipts of product
Rate and purity.
Preferably, first solvent be toluene, methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, tetrahydrofuran or
At least one of ether.
Preferably, second solvent be ether, tetrahydrofuran, dioxane, toluene or methyl tertiary butyl ether(MTBE) in extremely
Few one kind.
Preferably, the third solvent is at least one of hexamethylene, n-hexane or toluene.
Preferably, the 4th solvent is at least one of methanol, ethyl alcohol, petroleum ether or tetrahydrofuran.
Preferably, the 5th solvent is at least one in methanol, ethyl alcohol, methylene chloride, toluene, acetic acid or trifluoroacetic acid
Kind.
Preferred solvent is conducive to be sufficiently mixed between reaction raw materials, improves the utilization rate of raw material, reduces the hair of side reaction
It is raw, while also helping the product that each step reaction is prepared and being dissolved in reaction system, it ensure that the smooth of reaction in next step
It carries out, it is often more important that, the reactivity of reaction raw materials can be improved in preferred solvent, improves the reaction rate of each step.
Preferably, in step 1, the molar ratio of the p bromophenol, the hydroxy-protecting agent and the acid binding agent is 1:1-
1.5:1.2-2.0。
Preferably, in step 2, the molar ratio to protecting group bromobenzene and the magnesium metal is 1:1.05-1.2.
Preferably, in step 2, the molar ratio to protecting group bromobenzene and the magnesium metal is 1:1.05-1.2.
Preferably, described is 1:1.1- to protecting group bromobenzene and the Isosorbide-5-Nitrae-cyclohexanedione ethylene glycol single ketal molar ratio
1.3。
Preferably, in step 1, the solvent of the hydroxyl protection agent solution is toluene, methylene chloride, chloroform, four chlorinations
At least one of carbon, dichloroethanes, tetrahydrofuran or ether, and the volume of solvent is 2-5 times of hydroxy-protecting agent quality,
In, the unit of volume is milliliter, and the unit of quality is gram.
Preferably, in step 3, the acid hydrolysis solution is the aqueous solution of hydrogen chloride, sulfuric acid, formic acid or ammonium chloride, the acidolysis
The mass concentration of solution is 20-70%, described to hydrogen chloride, sulfuric acid, formic acid or chlorination in protecting group bromobenzene and the acid hydrolysis solution
The molar ratio of ammonium is 1:1.5-2.5.
Preferably, in step 4, the dehydrating agent be the concentrated sulfuric acid, p-methyl benzenesulfonic acid, methanesulfonic acid or highly acidic resin in extremely
Few one kind, the additional amount of the dehydrating agent are the 5-20% to protecting group bromobenzene quality
The heretofore described concentrated sulfuric acid is the sulfuric acid that mass concentration conventional in industry is greater than 98%.
Preferably, in step 5, the additional amount of the catalyst is the 1-20% to protecting group bromobenzene quality.
Preferably, in step 6, the deprotection agent is the aqueous solution of acid, and the acid is formic acid, glacial acetic acid, trifluoro second
One or more of in acid, hydrogen chloride, the concentrated sulfuric acid, p-methyl benzenesulfonic acid or methanesulfonic acid, the mass concentration of the deprotection agent is 20-
50%, the acid is 1-2:1 with the molar ratio to protecting group bromobenzene.
Ratio between preferred each reactant, can be improved the utilization rate of raw material, to improve 4- (4- hydroxy phenyl)
The yield and purity of cyclohexanone product.
Preferred deprotection agent and the collocation of preferred hydroxy protecting agent use, and can make to carry out being deprotected in step 6 anti-
At once, while the difunctional of eliminating hydroxide blocking group and ethylene ketal is protected, and is simplified reaction step, is conducive to improve
Production efficiency.
Preferably, step 1 is into step 6, first solvent, the second solvent, third solvent, the 4th solvent and the 5th
The addition volume of solvent is respectively 2-5 times of corresponding dissolved substrate quality, wherein the unit of volume is milliliter, the list of quality
Position is gram.
Preferred solvent adding amount ensure that the abundant dissolution of reaction raw materials and reaction product, be conducive to every single step reaction
It goes on smoothly, other than first step preparation needs to purify to protecting group bromobenzene product, remaining step is not necessarily to purification can be direct
Next step reaction is carried out, reaction step is enormously simplified, is advantageously implemented continuous production, improve production efficiency.
The preparation method of 4- (4- hydroxy phenyl) cyclohexanone provided through the invention, raw materials used is common agents, is removed
Except Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal cost is slightly higher, remaining raw material is cheap, and production cost is low, and operates letter
Single, highly-safe, the three wastes are few, environmentally friendly, and 4- (4- hydroxy phenyl) cyclohexanone being prepared is white solid, and HPLC contains
Amount is greater than 99.5%, and total recovery realizes the industrialized production of 4- (4- hydroxy phenyl) cyclohexanone up to 75-80%.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone:
Step 1: triethylamine 242.9g is placed in 3000ml there-necked flask by p bromophenol 346g, 1000mL dichloromethane is added
Alkane is sufficiently stirred, and under the conditions of 0 DEG C of ice salt bath, the dichloromethane solution of trim,ethylchlorosilane is added dropwise, and (250g trim,ethylchlorosilane is molten
In 700mL methylene chloride), temperature control is no more than 30 DEG C, and after 60min is dripped, white salt, warming-in-water to 30 occurs in system
DEG C, 3h is stirred, 600ml water is added into system, after stirring 30min, post-processing can be obtained to the colourless of trimethylsiloxy group bromobenzene
Transparency liquid 463.48g, yield 94.6%, purity 99.3%；
Step 2: magnesium chips 8.7g is placed in 500mL there-necked flask under nitrogen protection, 40 DEG C of water-bath, will be prepared into above-mentioned
To trimethylsiloxy group bromobenzene 73.5g is dissolved in 300mL tetrahydrofuran, be added dropwise in there-necked flask, after 60min is added dropwise
45 DEG C of water-bath, 2h is stirred, is obtained to trimethylsiloxy group magnesium bromide crude product；
Step 3: under nitrogen protection, to dropwise addition Isosorbide-5-Nitrae-cyclohexanedione second two in trimethylsiloxy group magnesium bromide crude product
The toluene solution (51.5g1,4- cyclohexanedione monoethylene acetal are dissolved in 200ml toluene) of alcohol single ketal, time for adding is
10min is heated to 82 DEG C, back flow reaction 6h, after being down to room temperature after being added dropwise, total overall reaction liquid is added in dilute hydrochloric acid
(50mL concentrated hydrochloric acid is dissolved in 200g ice water), stirs ten minutes, liquid separation, water phase is thrown aside, and is obtained to protecting group benzyl ring by 0 DEG C of temperature control
Hexanol ethylene glycol single ketal crude product 95g；
Step 4: take 1000mL there-necked flask, be added it is above-mentioned to protecting group phenylcyclohexanol ethylene glycol single ketal crude product 95g,
400ml toluene, 5g p-methyl benzenesulfonic acid, 110 DEG C of back flow reaction 6h, washing, revolving obtain trimethylsiloxy group phenyl cyclohexene second
Glycol single ketal crude product 97g；
Step 5: above-mentioned trimethylsiloxy group phenyl cyclohexene ethylene glycol single ketal crude product 97g is dissolved in 400mL ethyl alcohol
In, 1.0g palladium-carbon catalyst is added, under the conditions of an atmospheric pressure, 30 DEG C, is passed through hydrogen, reacts 6h, Filtration of catalyst,
Obtain trimethylsiloxy group cyclohexanone ethylene ketal crude product；
Step 6: 50mL concentrated hydrochloric acid and 180mL water is added in above-mentioned trimethylsiloxy group cyclohexanone ethylene ketal crude product
Mixed solution in, in 100 DEG C of reaction 2h, 4- (4- hydroxy phenyl) cyclohexanone solid 46.74g is can be obtained in post-processing recrystallization,
Purity is 99.5%.
In terms of to trimethylsiloxy group bromobenzene, five step total recoverys are 82%, and in terms of p bromophenol, six step total recoverys are
77.5%.
Embodiment 2
A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone:
Step 1: pyridine 237.3g is placed in 3000ml there-necked flask by p bromophenol 346g, 1038mL toluene is added, fills
Divide and stir, under the conditions of ice salt bath, the toluene solution (182.6g dimethoxym ethane is dissolved in 913mL toluene) of dimethoxym ethane is added dropwise, temperature control is not
More than 50 DEG C, after 60min is dripped, there is white salt in system, is stirred to react 1h in 30 DEG C, and 600ml water is added into system, stirs
After mixing 30min, post-processing can obtain the colourless transparent liquid 417.07g to methoxy methoxy bromide benzene shown in formula I, yield
96.1%, purity 99.5%；
Step 2: magnesium chips 7.56g is placed in 500mL there-necked flask under nitrogen protection, 0 DEG C of ice salt bath, it will be to above-mentioned preparation
What is obtained is dissolved in 148mL ether methoxy methoxy bromide benzene 65.1g, is added dropwise in there-necked flask, rear water-bath is added dropwise in 30min
30 DEG C, 2.5h is stirred, is obtained to methoxy methoxy base magnesium bromide crude product solution；
Step 3: under nitrogen protection, to dropwise addition cyclohexanedione ethylene glycol in methoxy methoxy base magnesium bromide crude product solution
The toluene solution (60.84g1,4- cyclohexanedione monoethylene acetal are dissolved in 127ml tetrahydrofuran) of single ketal, time for adding is
10min is heated to 66 DEG C, back flow reaction 10h, after being down to room temperature after being added dropwise, total overall reaction liquid is added in dilute sulfuric acid
(the 51g concentrated sulfuric acid is dissolved in 100g ice water), stirs ten minutes, liquid separation, water phase is thrown aside, and is obtained to methoxy methoxy base benzene by 10 DEG C of temperature control
Cyclohexanol ethylene glycol single ketal crude product 89g；
Step 4: taking 1000mL there-necked flask, it is added above-mentioned to methoxy methoxy base phenylcyclohexanol ethylene glycol single ketal crude product
89g, 180ml hexamethylene, 3.7g methanesulfonic acid, 80 DEG C of back flow reaction 8h, washing, revolving are obtained to methoxy methoxy base phenyl cyclohexene
Ethylene glycol single ketal 85g；
Step 5: above-mentioned trimethylsiloxy group phenyl cyclohexene ethylene glycol single ketal crude product 85g is dissolved in 170mL methanol
In, 3.7g Raney's nickel catalyst is added, under the conditions of three atmospheric pressure, 50 DEG C, is passed through hydrogen, reacts 8h, be filtered to remove catalysis
Agent is obtained to methoxy methoxy base phenylcyclohexyl ethylene glycol single ketal crude product solution；
Step 6: the dense sulphur of 30.1g is added to methoxy methoxy base phenyl cyclohexene ethylene glycol single ketal crude product solution by above-mentioned
In the mixed solution of acid and 120mL water, 4- (4- hydroxy phenyl) cyclohexanone solid is can be obtained in 0 DEG C of reaction 8h, post-processing recrystallization
43.8g, purity 99.7%.
In terms of to methoxy methoxy bromide benzene, five step total recoverys are 76.88%, and in terms of p bromophenol, six step total recoverys are
80.00%.
Embodiment 3
A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone:
Step 1: sodium carbonate 424g is placed in 3000ml there-necked flask by p bromophenol 346g, bis- chloroethene of 1730mL is added
Alkane is sufficiently stirred, and under the conditions of ice salt bath, the dichloroethane solution of dihydropyran is added dropwise, and (252.4g dihydropyran alkane is dissolved in 758mL
In dichloroethanes), temperature control is no more than 40 DEG C, and after 50min is dripped, white salt occurs in system, is stirred to react 4h, Xiang Ti in 30 DEG C
600ml water is added in system, after stirring 30min, post-processing can obtain the colorless and transparent of p bromophenol tetrahydropyranyl ethers shown in formula II
Liquid 474.72g, yield 91.6%, purity 99.4%；
Step 2: magnesium chips 8.1g is placed in 500mL there-necked flask under nitrogen protection, 30 DEG C of water-bath, will be prepared into above-mentioned
To p bromophenol tetrahydropyranyl ethers 77.4g be dissolved in 253mL methyl tertiary butyl ether(MTBE), be added dropwise in there-necked flask, 50min is dripped
80 DEG C of water-bath after finishing stirs 1.5h, obtains p bromophenol tetrahydropyranyl ethers magnesium bromide crude product；
Step 3: under nitrogen protection, cyclohexanedione second two is added dropwise into p bromophenol tetrahydropyranyl ethers magnesium bromide crude product
The dioxane solution (56.16g1,4- cyclohexanedione monoethylene acetal are dissolved in 170mL dioxane) of alcohol single ketal is added dropwise
Time is 20min, and 100 DEG C, back flow reaction 4h, after being down to room temperature are heated to after being added dropwise, and dilute salt is added in total overall reaction liquid
In acid (132mL concentrated hydrochloric acid is dissolved in 100g ice water), 20 DEG C of temperature control, stir ten minutes, liquid separation, water phase is thrown aside, and oxinane is obtained
Ether phenylcyclohexanol ethylene glycol single ketal crude product 98g；
Step 4: taking 1000mL there-necked flask, above-mentioned tetrahydropyranyl ethers phenylcyclohexanol ethylene glycol single ketal crude product is added
98g, 290ml n-hexane, the 8.6g concentrated sulfuric acid, 70 DEG C of back flow reaction 12h, washing, revolving obtain tetrahydropyranyl ethers phenyl cyclohexene
Ethylene glycol single ketal 94g；
Step 5: above-mentioned tetrahydropyranyl ethers phenyl cyclohexene ethylene glycol single ketal crude product 94g is dissolved in 400mL petroleum ether
In, 8.5g ruthenium C catalyst is added, under the conditions of five atmospheric pressure, 80 DEG C, is passed through hydrogen, reacts 2h, Filtration of catalyst,
Obtain tetrahydropyranyl ethers phenylcyclohexyl ethylene glycol single ketal crude product solution；
Step 6: 60mL concentrated hydrochloric acid and 145mL is added in above-mentioned tetrahydropyranyl ethers phenylcyclohexyl ethylene glycol crude product solution
In the mixed solution of water, 4- (4- hydroxy phenyl) cyclohexanone solid 46.67g is can be obtained in 50 DEG C of reaction 4h, post-processing recrystallization, pure
Degree is 99.6%.
In terms of p bromophenol tetrahydropyranyl ethers, five step total recoverys are 81%, and in terms of p bromophenol, six step total recoverys are
75%.
Embodiment 4
A kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone:
Step 1: sodium hydroxide 160g is placed in 3000ml there-necked flask by p bromophenol 346g, 1384mL ether is added,
It is sufficiently stirred, under the conditions of ice salt bath, diethyl ether solution (the 391.9g tert-butyldimethylsilyl chloride silicon of tert-butyl chloro-silicane is added dropwise
Alkane is dissolved in 1568mL ether), temperature control is no more than 30 DEG C, and after 60min is dripped, white salt occurs in system, anti-in 30 DEG C of stirrings
5h is answered, 600ml water is added into system, after stirring 30min, post-processing can be obtained shown in formula III to tertiary butyl dimethyl Si base
The colourless transparent liquid 543.20g of bromobenzene, yield 94.8%, purity 99.7%；
Step 2: magnesium chips 8.7g is placed in 500mL there-necked flask under nitrogen protection, 20 DEG C of water-bath, will be prepared into above-mentioned
To tertiary butyl dimethyl Si bromide benzene 86.1g is dissolved in 378mL dioxane, be added dropwise in there-necked flask, 60min be added dropwise
After 70 DEG C of water-bath, stir 1.5h, obtain to tertiary butyl dimethyl Si base magnesium bromide crude product；
Step 3: under nitrogen protection, to dropwise addition cyclohexanedione second in tertiary butyl dimethyl Si base magnesium bromide crude product
The diethyl ether solution (56.16g1,4- cyclohexanedione monoethylene acetal are dissolved in 283ml ether) of glycol single ketal, time for adding is
30min is heated to 35 DEG C, back flow reaction 12h, after being down to room temperature after being added dropwise, total overall reaction liquid is added in dilute hydrochloric acid
(165mL concentrated hydrochloric acid is dissolved in 200g ice water), stirs ten minutes, liquid separation, water phase is thrown aside, and is obtained to tert-butyl diformazan by 30 DEG C of temperature control
Base siloxy phenylcyclohexanol ethylene glycol list protects ketone crude product 106g；
Step 4: taking 1000mL there-necked flask, it is added above-mentioned to tertiary butyl dimethyl Si base phenylcyclohexanol ethylene glycol list
Guarantor ketone 106g, 475ml toluene, 18.9g p-methyl benzenesulfonic acid, 110 DEG C of back flow reaction 4h, washing, revolving are obtained to tert-butyl diformazan
Base siloxy phenyl cyclohexene ethylene glycol list protects ketone crude product 102g；
Step 5: being dissolved in above-mentioned to tertiary butyl dimethyl Si base phenyl cyclohexene ethylene glycol list guarantor ketone crude product 102g
In 485mL ethyl alcohol, 18.9g palladium-carbon catalyst is added, under the conditions of three atmospheric pressure, 20 DEG C, is passed through hydrogen, reacts 12h, filtering
Catalyst is removed, obtains and ketone crude product solution is protected to tertiary butyl dimethyl Si base phenylcyclohexyl ethylene glycol list；
Step 6: protecting the addition of ketone crude product solution to tertiary butyl dimethyl Si base phenylcyclohexyl ethylene glycol list for above-mentioned
In the mixed solution of 45mL concentrated hydrochloric acid and 160mL water, 4- (4- hydroxy phenyl) ring is can be obtained in 70 DEG C of reaction 3h, post-processing recrystallization
Hexanone solid 46.97g, purity 99.7%.
In terms of p bromophenol tetrahydropyranyl ethers, five step total recoverys are 82.4%, and in terms of p bromophenol, six step total recoverys are
78.2%.
As long as acid binding agent, the first solvent, the second solvent, third solvent, the 4th solvent, the 5th solvent and dehydrating agent take off
It protects reagent, acid hydrolysis solution in currently preferred range, can reach the identical technology effect in 1-4 of the embodiment of the present invention
Fruit.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement or improvement etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of preparation method of 4- (4- hydroxy phenyl) cyclohexanone, which comprises the steps of:
Step 1: p bromophenol is reacted with hydroxy-protecting agent, obtain to protecting group bromobenzene；
Step 2: carrying out grignard reaction to protecting group bromobenzene and magnesium metal, obtain to protecting group phenyl-magnesium-bromide；
Step 3: carry out coupling reaction to protecting group phenyl-magnesium-bromide and Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, acidolysis is obtained pair
Protecting group phenylcyclohexanol ethylene glycol single ketal；
Step 4: carry out dehydration under dehydrating agent catalytic action to protecting group phenylcyclohexanol ethylene glycol single ketal, obtain pair
Protecting group phenyl cyclohexene ethylene glycol single ketal；
Step 5: carrying out catalytic hydrogenation reaction to protecting group phenyl cyclohexene ethylene glycol single ketal and hydrogen, obtain to protecting group benzene
Butylcyclohexyl ethylene glycol single ketal；
Step 6: being reacted with deprotection agent protecting group phenylcyclohexyl ethylene glycol single ketal, 4- (4- hydroxy phenyl) hexamethylene is obtained
Ketone.
2. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as described in claim 1, which is characterized in that including walking as follows
It is rapid:
Step 1: p bromophenol and acid binding agent are added in the first solvent, it is uniformly mixed, under inert gas protection, hydroxyl is added dropwise
Base protection agent solution is obtained in 0-50 DEG C of reaction 2-5h to protecting group bromobenzene；
Step 2: protecting group bromobenzene is added in the second solvent by described, obtain to protecting group bromobenzene solution, in inert gas shielding
Under, it is added dropwise in magnesium metal, in 0-80 DEG C of reaction 1-3h, is obtained to protecting group phenyl-magnesium-bromide；
Step 3: Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal is added in second solvent, Isosorbide-5-Nitrae-cyclohexanedione list second two is obtained
Alcohol ketal solution is added dropwise to described in protecting group phenyl-magnesium-bromide under inert gas protection, is reacted in 30-100 DEG C
4-12h is added acid hydrolysis solution and obtains in 0-30 DEG C of progress acidolysis to protecting group phenylcyclohexanol ethylene glycol single ketal；
Step 4: protecting group phenylcyclohexanol ethylene glycol single ketal is added in third solvent by described, dehydrating agent, reflux is added
It is dehydrated 4-12h, is obtained to protecting group phenyl cyclohexene ethylene glycol single ketal；
Step 5: protecting group phenyl cyclohexene ethylene glycol single ketal is added in the 4th solvent by described, catalyst is added, is passed through
Hydrogen under conditions of reaction pressure is 1-5 atmospheric pressure, reacts 2-12h, obtains to protecting group phenylcyclohexyl second in 20-80 DEG C
Glycol single ketal；
Step 6: protecting group phenylcyclohexyl ethylene glycol single ketal is added in the 5th solvent by described, deprotection agent, 0- is added
100 DEG C of reaction 2-8h obtain 4- (4- hydroxy phenyl) cyclohexanone.
3. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 1 or 2, which is characterized in that the hydroxyl
Protective agent is dihydropyran, dimethoxym ethane, trim,ethylchlorosilane or tert-butyl chloro-silicane；And/or
The acid binding agent is at least one in pyridine, triethylamine, imidazoles, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide
Kind；And/or
The catalyst is at least one of Raney's nickel, palladium charcoal or ruthenium carbon.
4. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that in step 1, drop
It is 50-60min between added-time；And/or
In step 2, time for adding 30-60min；And/or
In step 3, time for adding 10-30min.
5. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that first solvent
For at least one of toluene, methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, tetrahydrofuran or ether；And/or
Second solvent is at least one of ether, tetrahydrofuran, dioxane, toluene or methyl tertiary butyl ether(MTBE)；And/or
The third solvent is at least one of hexamethylene, n-hexane or toluene；And/or
4th solvent is at least one of methanol, ethyl alcohol, petroleum ether or tetrahydrofuran；And/or
5th solvent is at least one of methanol, ethyl alcohol, methylene chloride, toluene, acetic acid or trifluoroacetic acid.
6. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that in step 1, institute
The molar ratio for stating p bromophenol, the hydroxy-protecting agent and the acid binding agent is 1:1-1.5:1.2-2.0；And/or
In step 2, the molar ratio to protecting group bromobenzene and the magnesium metal is 1:1.05-1.2；And/or
In step 3, described is 1:1.1- to protecting group bromobenzene and the Isosorbide-5-Nitrae-cyclohexanedione ethylene glycol single ketal molar ratio
1.3。
7. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that in step 1, institute
The solvent for stating hydroxyl protection agent solution is in toluene, methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, tetrahydrofuran or ether
At least one, and the volume of solvent is 2-5 times of hydroxy-protecting agent quality, wherein the unit of volume is milliliter, the list of quality
Position is gram；And/or
In step 3, the acid hydrolysis solution is the aqueous solution of hydrogen chloride, sulfuric acid, formic acid or ammonium chloride, the quality of the acidolysis solution
Concentration is 20-70%, the molar ratio to hydrogen chloride, sulfuric acid, formic acid or ammonium chloride in protecting group bromobenzene and the acid hydrolysis solution
For 1:1.5-2.5.
8. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that in step 4, institute
Stating dehydrating agent is at least one of the concentrated sulfuric acid, p-methyl benzenesulfonic acid, methanesulfonic acid or highly acidic resin, and the additional amount of the dehydrating agent is
The 5-20% to protecting group bromobenzene quality；And/or
In step 5, the additional amount of the catalyst is the 1-20% to protecting group bromobenzene quality.
9. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that in step 6, institute
The aqueous solution that deprotection agent is acid is stated, the acid is formic acid, glacial acetic acid, trifluoroacetic acid, hydrogen chloride, the concentrated sulfuric acid, p-methyl benzenesulfonic acid
Or it is one or more of in methanesulfonic acid, the mass concentration of the deprotection agent is 20-50%, described sour and described to protecting group bromobenzene
Molar ratio be 1-2:1.
10. the preparation method of 4- (4- hydroxy phenyl) cyclohexanone as claimed in claim 2, which is characterized in that step 1 to step
In rapid six, the addition volume respectively correspondence of first solvent, the second solvent, third solvent, the 4th solvent and the 5th solvent
2-5 times of dissolved substrate quality, wherein the unit of volume is milliliter, and the unit of quality is gram.
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