CN116813452A - 一种制备二氢和厚朴酚的方法 - Google Patents
一种制备二氢和厚朴酚的方法 Download PDFInfo
- Publication number
- CN116813452A CN116813452A CN202310684770.1A CN202310684770A CN116813452A CN 116813452 A CN116813452 A CN 116813452A CN 202310684770 A CN202310684770 A CN 202310684770A CN 116813452 A CN116813452 A CN 116813452A
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- CN
- China
- Prior art keywords
- compound
- acetate
- sodium
- bis
- lithium
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- IBKNHHZQPPUDQJ-UHFFFAOYSA-N 2-(4-hydroxy-3-prop-2-enylphenyl)-4-propylphenol Chemical compound CCCC1=CC=C(O)C(C=2C=C(CC=C)C(O)=CC=2)=C1 IBKNHHZQPPUDQJ-UHFFFAOYSA-N 0.000 title description 5
- VVOAZFWZEDHOOU-UHFFFAOYSA-N magnolol Chemical compound OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 claims abstract description 29
- -1 p-hydroxyphenylboronic acid compound Chemical class 0.000 claims abstract description 28
- 229940126214 compound 3 Drugs 0.000 claims abstract description 15
- 229940125898 compound 5 Drugs 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000005821 Claisen rearrangement reaction Methods 0.000 claims abstract description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 8
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 229940125904 compound 1 Drugs 0.000 claims abstract description 5
- 229940125782 compound 2 Drugs 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 3
- 239000004305 biphenyl Substances 0.000 claims abstract 2
- 238000006266 etherification reaction Methods 0.000 claims abstract 2
- 229910052723 transition metal Inorganic materials 0.000 claims abstract 2
- 150000003624 transition metals Chemical class 0.000 claims abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 8
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims 8
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims 7
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 7
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 5
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims 3
- 229950005499 carbon tetrachloride Drugs 0.000 claims 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims 3
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims 3
- 235000011181 potassium carbonates Nutrition 0.000 claims 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims 3
- 229940090181 propyl acetate Drugs 0.000 claims 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 3
- 239000008096 xylene Substances 0.000 claims 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 2
- 125000000746 allylic group Chemical group 0.000 claims 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims 2
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims 2
- REKWWOFUJAJBCL-UHFFFAOYSA-L dilithium;hydrogen phosphate Chemical compound [Li+].[Li+].OP([O-])([O-])=O REKWWOFUJAJBCL-UHFFFAOYSA-L 0.000 claims 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims 2
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 2
- 235000011056 potassium acetate Nutrition 0.000 claims 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 2
- 239000011736 potassium bicarbonate Substances 0.000 claims 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 239000001632 sodium acetate Substances 0.000 claims 2
- 235000017281 sodium acetate Nutrition 0.000 claims 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 2
- 239000012312 sodium hydride Substances 0.000 claims 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims 2
- 239000001488 sodium phosphate Substances 0.000 claims 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims 2
- CPWJKGIJFGMVPL-UHFFFAOYSA-K tricesium;phosphate Chemical compound [Cs+].[Cs+].[Cs+].[O-]P([O-])([O-])=O CPWJKGIJFGMVPL-UHFFFAOYSA-K 0.000 claims 2
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 claims 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims 1
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims 1
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Abstract
一种制备二氢和厚朴酚的方法，涉及二氢和厚朴酚的合成工艺过程及相关中间体：对羟基苯硼酸类化合物(化合物1)与烯丙基类化合物(化合物2)进行醚化反应并生成4‑烯丙氧基苯硼酸类化合物(化合物3)，在过渡金属催化剂作用下，化合物3与化合物4进行Suzuki偶联反应，生成联苯类化合物5，化合物5在高温或Lewis酸存在下发生Claisen重排，并得到目标产物二氢和厚朴酚。
Description
技术领域
本发明属于医药及保健领域，具体涉及二氢和厚朴酚，并提供了它的制备工艺。
背景技术
焦虑症是一类神经类疾病，这类疾病的患者往往需要长期服用抗焦虑药物。目前常用的地西泮、氟西泮等苯二氮类镇静催眠药在临床使用时，都具有头昏、乏力、嗜睡等不良反应，更严重的是长期用药后，患者会对这类药物产生成瘾性，且当患者在停止服用此类药物后，会出现戒断症状。因此，开发出化学结构新颖且副腹胀小的新型抗焦虑药物具有重要意义。
二氢和厚朴酚是和厚朴酚的部分氢化产物，研究表明，二氢和厚朴酚具有抗焦虑、催眠及镇静作用。与地西泮、氟西泮等苯二氮类镇静催眠药相比，二氢和厚朴酚没有明显的毒副作用，因此，二氢和厚朴酚有望被开发为新型抗焦虑药物。基于此，开发出二氢和厚朴酚制备新工艺，使其具有规模化生产潜力，成为急需解决的课题。
发明内容
本发明要解决的技术问题是：4-羟基苯硼酸或4-羟基苯硼酸酯(化合物1)与烯丙基衍生物(化合物2)进行取代反应并生成化合物3，化合物3与4-正丙基苯酚衍生物(化合物4)进行Suzuki偶联反应，生成4′-(烯丙氧基)-5-丙基-2-联苯酚(化合物5)，化合物5在Lewis酸或高温作用下发生重排并生成二氢和厚朴酚。该工艺路线为二氢和厚朴酚的生产提供了新的解决方案。
为实现上述过程，本发明提供如下具体技术方案：
其中，R1＝氢、甲基、亚甲基、乙基、正丙基、异丙基、亚异丙基、正丁基、异丁基、叔丁基；R2＝氢、甲基、亚甲基、乙基、正丙基、异丙基、亚异丙基、正丁基、异丁基、叔丁基；X＝氯、溴、碘、甲磺酰氧基、三氟甲磺酰氧基、三氟乙酰氧基、苯磺酰氧基、对甲苯磺酰氧基；Y＝氯、溴、碘、甲磺酰氧基、三氟甲磺酰氧基、三氟乙酰氧基、苯磺酰氧基、对甲苯磺酰氧。
本发明有关二氢和厚朴酚制备工艺中所涉及的技术问题：
1、以4-羟基苯硼酸及烯丙基溴为原料，可制备4-烯丙氧基苯硼酸，该反应可利用丙酮为溶剂，碳酸钾作为缚酸剂，该反应往往以中等收率得到4-烯丙氧基苯硼酸，通常在60％左右。
2、以4-羟基苯硼酸频哪醇酯及烯丙基溴为原料，制备4-烯丙氧基苯硼酸频哪醇酯，该反应收率较高，且易于分离目标产物。
3、4-烯丙氧基苯硼酸频哪醇酯制备过程中，以N，N-二甲基甲酰胺或丙酮为溶剂，均可以高收率得到产物，但以丙酮为溶剂时，后处理更简便，且可回收溶剂，有利于降低成本。
4、化合物4结构中，Y为溴或碘原子时，化合物3与化合物4进行Suzuki偶联反应时，化合物3均可完全转化，且高收率得到化合物5。
5、化合物3与化合物4进行Suzuki偶联反应时，尝试过多种钯类催化剂，包括二氯化钯、钯炭、二(三苯基膦)二氯化钯、四三苯基膦钯、醋酸钯、1，1’-双(二苯基膦基)二茂铁二氯化钯，尽管这些钯类催化剂均有催化该反应的活性，以1，1’-双(二苯基膦基)二茂铁二氯化钯催化效果最好。
6、化合物5在高温条件下进行Claisen重排，并顺利转化成二氢和厚朴酚，且该反应可在无溶剂条件下进行，因此易于进行后处理。通过对温度筛选发现，在温度大于220℃时，该重排反应可在3-5小时内完成，如果温度较低，则反应时间明显变长。
7、在低温条件下，化合物5也可在三氟化硼乙醚溶液作用下进行Claisen重排并得到二氢和厚朴酚，且化合物5能完全转化，然而利用三氯化硼催化化合物5进行Claisen重排时，往往伴随5-正丙基-[1，1′-联苯]-2，4′-二酚的生成，即使在液氮冷却下，也会有少量该杂质生成，这主要由于三氟化硼作为强酸性Lewis酸，也具有脱烷基功能，从而导致5-正丙基-[1，1′-联苯]-2，4′-二酚的生成。
本发明提供了化合物3、化合物5及二氢和厚朴酚的具体制备方法：
附图说明
图1是二氢和厚朴酚氢谱图。
具体实施方案
实施例1：4-烯丙氧基苯硼酸的制备
向反应瓶中加入丙酮(500mL)及烯丙基溴(87.7g，0.725mol)，搅拌，加入对羟基苯硼酸(50g，0.363mol)、碳酸钾(100.2g，0.725mol)及碘化钾(6g，36.3mmol)，升温至回流，并在该条件下反应10小时，冷却，过滤，减压浓缩母液，所得残留物进行硅胶柱层析，得4-烯丙氧基苯硼酸43.2g。
实施例2：4-烯丙氧基苯硼酸频哪醇酯的制备
向反应瓶中加入丙酮(300mL)及烯丙基溴(55g，0.454mol)，搅拌，加入4-羟基苯硼酸频哪醇酯(50g，0.227mol)、碳酸钾(62.8g，0.454mol)及碘化钾(3.8g，22.7mmol)，升温至回流，并在该条件下反应7小时，冷却，过滤，减压浓缩母液，向残留物中加入乙酸乙酯(300mL)及水(300mL)，搅拌30分钟，静置分液，有机层用水(300mL)洗涤，分液，无水硫酸钠干燥有机层，过滤，减压浓缩母液，残留物直接用于下一步反应。
实施例3：4’-(烯丙基氧基)-5-正丙基-[1，1’-联苯]-2-酚的制备
向反应瓶中加入N，N-二甲基甲酰胺(500mL)，搅拌，加入4-烯丙氧基苯硼酸频哪醇酯(54.4g，0.209mol)、2-溴-4-正丙基苯酚(30g，0.139mol)、1，1’-双(二苯基膦基)二茂铁二氯化钯(10.1g，13.9mmol)及碳酸钾(38.5g，0.279mol)，氮气保护，升温至110℃，在该温度下反应6-8小时。冷却至常温，过滤，向滤液中加入水(700mL)及乙酸乙酯(300mL)，分液，水层用乙酸乙酯(3×200mL)萃取，合并有机层，分别用饱和氯化钠溶液(500mL)及水(500mL)洗涤，分液，无水硫酸钠干燥有机层，过滤，减压浓缩滤液，得暗红色油状物31.2g。
实施例4：二氢和厚朴酚的制备
向反应瓶中加入二氯甲烷，搅拌，加入41’(烯丙基氧基)-5-正丙基-[1，1’-联苯]-2-酚(10g)，冰盐浴冷却，缓慢滴加三氟化硼乙醚溶液，控制反应温度不高于5℃，滴加完后，继续保温反应至原料消失，向反应液中缓慢滴加冰水，分液，有机层分别用饱和碳酸氢钠溶液、饱和氯化钠溶液及水洗涤，分液，无水硫酸钠干燥有机层，过滤，减压浓缩滤液，得红棕色油状物，将该残留物进行硅胶柱层析，得及白色二氢和厚朴酚5.4g。
实施例4：二氢和厚朴酚的制备
向反应瓶中加入4’-(烯丙基氧基)-5-正丙基-[1，1’-联苯]-2-酚(10g)，搅拌，氮气保护，升温至220℃，并保温5小时。冷却至常温，所得反应物进行硅胶柱层析，得及白色二氢和厚朴酚7.1g。
Claims (10)
1.一种制备二氢和厚朴酚的方法，其特征在于包含如下工艺过程：
对羟基苯硼酸类化合物(化合物1)与烯丙基类化合物(化合物2)进行醚化反应并生成4-烯丙氧基苯硼酸类化合物(化合物3)，在过渡金属催化剂作用下，化合物3与化合物4进行Suzuki偶联反应，生成联苯类化合物5，化合物5在高温或Lewis酸存在下发生Claisen重排，并得到目标产物二氢和厚朴酚。
2.权利要求1的制备工艺中，其特征在于R1＝氢、甲基、亚甲基、乙基、正丙基、异丙基、亚异丙基、正丁基、异丁基、叔丁基；R2＝氢、甲基、亚甲基、乙基、正丙基、异丙基、亚异丙基、正丁基、异丁基、叔丁基；X＝氯、溴、碘、甲磺酰氧基、三氟甲磺酰氧基、三氟乙酰氧基、苯磺酰氧基、对甲苯磺酰氧基；Y＝氯、溴、碘、甲磺酰氧基、三氟甲磺酰氧基、三氟乙酰氧基、苯磺酰氧基、对甲苯磺酰氧基。
3.权利要求1-2的工艺条件，化合物1与烯丙基类化合物(化合物2)进行醚化反应并生成4-烯丙氧基苯硼酸类化合物(化合物3)，其特征在于该反应所用溶剂为水、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙二醇、丙三醇、二氯甲烷、三氯甲烷、四氯甲烷、乙腈、丙腈、丁腈、丙酮、丁酮、戊酮、乙酸乙酯、乙酸丙酯、乙酸相丁酯、乙醚、异丙醚、甲基叔丁基醚、苯基甲醚、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、甲苯、二甲苯、三甲苯、二甲基亚砜、吡啶、甲基吡啶、二甲基吡啶、三甲基吡啶、N，N-二甲氨基苯、1，8-二氮杂二环十一碳-7-烯、三乙胺、二异丙基乙胺、环丁砜或它们的混合，优选丙酮。
4.权利要求1-3的工艺条件，化合物1与烯丙基类化合物(化合物2)进行醚化反应并生成4-烯丙氧基苯硼酸类化合物(化合物3)，其特征在于该反应所用缚酸剂为氢化钠、正丁基锂、叔丁基锂、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸氢锂、碳酸氢钠、碳酸氢钾、碳酸氢铯、磷酸三锂、磷酸氢二锂、磷酸三钠、磷酸氢二钠、磷酸三钾、磷酸氢二钾、磷酸铯、醋酸锂、醋酸钠、醋酸钾、醋酸铯、乙醇钠、甲醇钠、叔丁醇钠、叔丁醇钾、叔丁醇锂、叔丁醇镁、三乙胺、二异丙基乙胺、4-二甲氨基吡啶、吡啶、甲基吡啶、二甲基吡啶、三甲基吡啶、N，N-二甲氨基苯、1，8-二氮杂二环十一碳-7-烯，优选碳酸钾。
5.权利要求1-4的工艺条件，化合物3与化合物4进行Suzuki偶联反应，其特征在于所用催化剂为Pd-C、二氯化钯、二(三苯基膦)二氯化钯、四三苯基膦钯、醋酸钯、乙酰丙酮钯、三(二亚苄基丙酮)二钯、双(二亚苄基丙酮)钯、二(乙腈)二氯化钯、二(苯腈)二氯化钯、1，1’-双(二苯基膦基)二茂铁二氯化钯、1，1’-双(二苯基膦基)二茂铁二氯化钯二氯甲烷复合物、1，4-双(二苯基膦)丁烷二氯化钯、二(三环己基膦)二氯化钯、1，2-双(二苯基膦)乙烷二氯化钯、1，3-双(二苯基膦)丙烷二氯化钯、三氯化钌、醋酸钌、二(三苯基膦)环戊二烯基氯化钌、五甲基环戊二烯基双(三苯基膦)氯化钌、(对甲基异丙基苯基)三苯膦二氯化钌、二氯(4-甲基异丙基苯基)钌二聚体、乙酰丙酮钌、三乙酰丙酮铑、三氯化铑、醋酸铑二聚体、辛酸铑二聚体、三(三苯基膦)氯化铑、(1，5-环辛二烯)氯铑二聚体，优选1，1’-双(二苯基膦基)二茂铁二氯化钯，即Pd(dppf)Cl2。
6.权利要求1-5的工艺条件，化合物3与化合物4进行Suzuki偶联反应，其特征在于所用其特征在于所用溶剂为水、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、二氯甲烷、三氯甲烷、四氯甲烷、乙腈、丙腈、丁腈、丙酮、丁酮、戊酮、乙酸乙酯、乙酸丙酯、乙酸相丁酯、甲基叔丁基醚、苯基甲醚、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、甲苯、二甲苯、三甲苯、二甲基亚砜、吡啶、甲基吡啶、二甲基吡啶、三甲基吡啶、N，N-二甲氨基苯、1，8-二氮杂二环十一碳-7-烯、三乙胺、二异丙基乙胺、环丁砜或它们的混合，优选N，N-二甲基甲酰胺与水混合作为溶剂。
7.权利要求1-6的工艺条件，化合物3与化合物4进行Suzuki偶联反应，其特征在于该反应所用缚酸剂为氢化钠、正丁基锂、叔丁基锂、氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸氢锂、碳酸氢钠、碳酸氢钾、碳酸氢铯、磷酸三锂、磷酸氢二锂、磷酸三钠、磷酸氢二钠、磷酸三钾、磷酸氢二钾、磷酸铯、醋酸锂、醋酸钠、醋酸钾、醋酸铯、乙醇钠、甲醇钠、叔丁醇钠、叔丁醇钾、叔丁醇锂、叔丁醇镁、三乙胺、二异丙基乙胺、4-二甲氨基吡啶、吡啶、甲基吡啶、二甲基吡啶、三甲基吡啶、N，N-二甲氨基苯、1，8-二氮杂二环十一碳-7-烯，优选碳酸钠。
8.权利要求1-7的工艺条件，化合物5在Lewis酸存在下发生Claisen重排，其特征在于所用Leewis酸为三氯化铝、三溴化铝、三碘化铝、三氯化铁、三溴化铁、三碘化铁、二氯化铁、二溴化铁、二碘化铁、四氯化钛、四溴化钛、五氯化铌、氯化镁、溴化镁、碘化镁、三氟化硼、三氯化硼、三溴化硼、三碘化硼、氯化锌、溴化锌、碘化锌、氯化铜、溴化铜、碘化铜，优选三氟化硼。
9.权利要求1-8的工艺条件，化合物5在Lewis酸存在下发生Claisen重排，其特征在于所用二氯甲烷、三氯甲烷、四氯甲烷、乙腈、丙腈、丁腈、苯腈、苯甲醚、丙酮、丁酮、戊酮、乙酸乙酯、乙酸丙酯、乙酸相丁酯、乙醚、异丙醚、甲基叔丁基醚、苯基甲醚、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基吡咯烷酮、甲苯、二甲苯、三甲苯、二甲基亚砜或它们的混合，优选乙醚。
10.权利要求1-7的工艺条件，化合物5在高温下发生Claisen重排，其特征在于反应温度为100℃-350℃，优选180℃-220℃。
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