CN114276321A - Method for preparing 7, 8-dihydroxyflavone - Google Patents
Method for preparing 7, 8-dihydroxyflavone Download PDFInfo
- Publication number
- CN114276321A CN114276321A CN202111577334.1A CN202111577334A CN114276321A CN 114276321 A CN114276321 A CN 114276321A CN 202111577334 A CN202111577334 A CN 202111577334A CN 114276321 A CN114276321 A CN 114276321A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- sodium
- potassium
- hydroxide
- 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
- COCYGNDCWFKTMF-UHFFFAOYSA-N 7,8-dihydroxyflavone Chemical compound OC=1C(O)=CC=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 COCYGNDCWFKTMF-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 18
- WWGFXSLWIRYIBP-UHFFFAOYSA-N 7,8-dihydroxy-4H-chromen-4-one Natural products O1C=CC(=O)C=2C1=C(O)C(O)=CC=2 WWGFXSLWIRYIBP-UHFFFAOYSA-N 0.000 title claims abstract description 13
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940079877 pyrogallol Drugs 0.000 claims abstract description 7
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 4
- 238000006676 Baker-Venkataraman rearrangement reaction Methods 0.000 claims abstract description 3
- 230000032050 esterification Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 229940125782 compound 2 Drugs 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229940125898 compound 5 Drugs 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 229940125904 compound 1 Drugs 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- -1 chloro, bromo, iodo, trifluoromethanesulfonyloxy, methylsulfonyloxy, benzenesulfonate Chemical group 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 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
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 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
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 3
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 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
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 3
- 239000008096 xylene Substances 0.000 claims 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 235000011054 acetic acid Nutrition 0.000 claims 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 235000011181 potassium carbonates Nutrition 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
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 claims 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims 1
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 229910015900 BF3 Inorganic materials 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 1
- 239000012345 acetylating agent Substances 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims 1
- 229910001863 barium hydroxide Inorganic materials 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- ODYJZKDNEJGBSE-UHFFFAOYSA-N calcium;2-methylpropan-2-olate Chemical compound [Ca+2].CC(C)(C)[O-].CC(C)(C)[O-] ODYJZKDNEJGBSE-UHFFFAOYSA-N 0.000 claims 1
- JHLCADGWXYCDQA-UHFFFAOYSA-N calcium;ethanolate Chemical compound [Ca+2].CC[O-].CC[O-] JHLCADGWXYCDQA-UHFFFAOYSA-N 0.000 claims 1
- AMJQWGIYCROUQF-UHFFFAOYSA-N calcium;methanolate Chemical compound [Ca+2].[O-]C.[O-]C AMJQWGIYCROUQF-UHFFFAOYSA-N 0.000 claims 1
- MMLSWLZTJDJYJH-UHFFFAOYSA-N calcium;propan-2-olate Chemical compound [Ca+2].CC(C)[O-].CC(C)[O-] MMLSWLZTJDJYJH-UHFFFAOYSA-N 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims 1
- 229960002089 ferrous chloride Drugs 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229940071870 hydroiodic acid Drugs 0.000 claims 1
- 229910052741 iridium Inorganic materials 0.000 claims 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims 1
- 229910052808 lithium carbonate Inorganic materials 0.000 claims 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims 1
- 229910000103 lithium hydride Inorganic materials 0.000 claims 1
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 claims 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims 1
- 229910001386 lithium phosphate Inorganic materials 0.000 claims 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims 1
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 claims 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims 1
- 239000000347 magnesium hydroxide Substances 0.000 claims 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 claims 1
- ORPJQHHQRCLVIC-UHFFFAOYSA-N magnesium;propan-2-olate Chemical compound CC(C)O[Mg]OC(C)C ORPJQHHQRCLVIC-UHFFFAOYSA-N 0.000 claims 1
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- 229910052763 palladium Inorganic materials 0.000 claims 1
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- 239000011736 potassium bicarbonate Substances 0.000 claims 1
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- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims 1
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- 150000003839 salts Chemical class 0.000 claims 1
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- 238000002360 preparation method Methods 0.000 abstract description 15
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- 230000000144 pharmacologic effect Effects 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
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- 229940126585 therapeutic drug Drugs 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- 235000009486 Crataegus bullatus Nutrition 0.000 description 1
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- 235000009840 Crataegus x incaedua Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- SQGLUEWZRKIEGS-UHFFFAOYSA-N Ginkgetin Natural products C1=CC(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(OC)C(C=3C(=CC=C(C=3)C=3OC4=CC(O)=CC(O)=C4C(=O)C=3)O)=C2O1 SQGLUEWZRKIEGS-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A method for preparing 7, 8-dihydroxyflavone relates to the preparation technology of (3-pentylphenyl) acetic acid, take pyrogallol as raw materials, carry on the friedel-crafts reaction with acetyl chloride and prepare 2, 3, 4-trihydroxy acetophenone, utilize benzyl chloride to selectively protect 3-position and 4-position hydroxy group, unprotected 2-position hydroxy group and benzoyl chloride carry on esterification reaction, esterification product get 8-dihydroxyflavone through Baker-Venkataraman rearrangement, ring closure and debenzylation.
Description
Technical Field
The invention belongs to the field of medicine and health care, and particularly relates to a natural product 7, 8-dihydroxyflavone and a preparation method thereof.
Background
Flavone is an important natural product, and is widely present in various plants such as vegetables, fruits and the like. Researches show that the flavonoid compounds show a plurality of biological activities, such as whitening, antioxidation, antivirus, antitumor, antiphlogosis, neuron protection, cardiovascular protection and the like. Flavone is an important lead compound because of having various pharmacological activities, provides valuable design basis for researchers to develop therapeutic drugs for various diseases, and many natural flavonoid products are already used as therapeutic drugs in clinic, such as ginkgetin, hawthorn flavone, puerarin, quercetin and the like.
7, 8-dihydroxy flavone is an important member of flavone family, and because it has the action of brain-derived neurotrophic factor and is also TrkB receptor agonist, 7, 8-dihydroxy flavone has very good pharmacological activity in the aspects of protecting cranial nerve, improving memory capacity and improving Alzheimer's disease, Huntington's chorea, Parkinson's disease, Rett syndrome and the like. Therefore, the development of the production process of the 7, 8-dihydroxyflavone is of great significance.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the method comprises the steps of taking pyrogallol as a raw material, carrying out friedel-crafts reaction with acetyl chloride to prepare 2, 34-trihydroxyacetophenone, selectively protecting 3-position hydroxyl and 4-position hydroxyl by using a benzyl protective reagent, carrying out esterification reaction on unprotected 2-position hydroxyl and benzoyl chloride, and carrying out Baker-Venkataraman rearrangement, ring closure and debenzylation on an esterification product to obtain 8-dihydroxyflavone. The process route provides a reliable solution for the large-scale production of the 7, 8-dihydroxyflavone.
In order to realize the process, the invention provides the following specific technical scheme:
wherein, X ═ chlorine, bromine, iodine, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonate group, p-toluenesulfonate group;
1. in the preparation process of the compound 1, as pyrogallol has poor solubility in organic solvents such as dichloromethane, carbon disulfide, chlorobenzene, nitrobenzene, 1, 4-dioxane and the like, acetic acid which has high solubility to the pyrogallol and does not interfere with the reaction is selected as a solvent, so that the reaction liquid is always homogeneous in the reaction process.
Acetyl chloride or acetic anhydride is used as an acetylation reagent, anhydrous aluminum trichloride, anhydrous stannic chloride, anhydrous zinc chloride, anhydrous ferric chloride, sulfuric acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and benzenesulfonic acid are used as catalysts, wherein when protonic acid is used as a catalyst, the compound 1 is difficult to separate and purify, and when Lewis acid is used as a catalyst, the compound 1 is easy to separate out from a reaction system, so that the purification of the compound 1 is facilitated.
When anhydrous aluminium trichloride is used as the catalyst, the activity is strong, the reaction temperature is controlled below-20 ℃, so that a good reaction result can be obtained, and the reaction temperature can be carried out at normal temperature by using the catalyst with weak catalytic activity, such as anhydrous stannic chloride.
2. In the preparation process of the compound 2, the 3-position phenolic hydroxyl group and the 4-position phenolic hydroxyl group can be selectively protected by using a steric hindrance effect, for the process, acetone is used as a solvent, anhydrous potassium carbonate is used as an acid-binding agent, and after the reaction is finished, a reaction solution is poured into water to obtain the compound 2. When a solvent such as N, N-dimethylformamide or acetonitrile is used, the product becomes complicated and it is difficult to isolate and purify compound 2.
3. In the preparation process of the compound 3, pyridine is generally used as a solvent, benzoyl chloride is dropwise added into a pyridine solution of the compound 2 at a low temperature, and after the reaction is finished, the reaction solution is poured into low-temperature acidic water, so that the compound 3 is precipitated.
4. Under the condition of strong alkalinity, the compound 3 is rearranged by Baker-Venkataraman to generate a compound 4, the common strong base comprises sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydrogen, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like, the reaction solvent is usually an aprotic polar solvent such as pyridine, N-dimethylformamide, N-dimethylacetamide, acetonitrile, N-methylpyrrolidone and the like, and a potassium hydroxide/pyridine system is preferred, and the compound 3 can be converted into the compound 4 in high yield under the system, wherein the pyridine must ensure the absence of water, otherwise, the rearrangement yield is influenced. The compound 3 is reacted in a potassium hydroxide/pyridine system, and the reaction liquid becomes very viscous along with the reaction and is not beneficial to stirring, so that mechanical stirring is selected to be more suitable.
5. In the preparation process of the compound 5, acetic acid is generally used as a reaction solvent, protonic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid and the like are used as catalysts to catalyze the ring closure of the compound 4, and the ring closure reaction yield is generally more than 80%.
6. The debenzylation process of the compound 5 is usually performed by using palladium-carbon hydrogenation debenzylation, the hydrogenation pressure is 3-5MPa, and the reaction temperature is about 60 ℃. The solubility of the compound 5 in methanol or ethanol is poor, so that ethyl acetate/ethanol or ethyl acetate/ethanol mixed solvent is selected as a reaction solvent, and the whole reaction process is homogeneous.
The invention provides a specific preparation method of a compound 1, a compound 2, a compound 3, a compound 4, a compound 5 and 7, 8-dihydroxyflavone, which comprises the following steps:
detailed description of the preferred embodiments
Example 1: preparation of Compound 1
Acetic acid (1000mL) and pyrogallol (200g, 1.59mol) were added to a reaction flask, stirred, added with anhydrous tin chloride (98.26g, 0.48mol), slowly added dropwise with acetyl chloride (136.94g, 1.74mol), the temperature was controlled to 35 ℃ or lower, and after completion of the addition, the reaction was stirred for further 12 hours. The reaction solution was cooled to 0 ℃, ice water (1000mL) was added dropwise at a temperature below 10 ℃, after the addition was completed, the mixture was stirred at 0 ℃ for 1 hour with heat preservation, filtered, the filter cake was washed with ice water (500mL), and the filter cake was dried at 50 ℃ under reduced pressure to obtain 173.45g of compound 1 as a dark yellow solid.
Example 2: preparation of Compound 2
Adding acetone (750mL) and benzyl bromide (305.08g, 1.78mol) into a reaction bottle, stirring, adding compound 1(150g, 0.89mol), potassium iodide (7.40g, 0.045mol) and anhydrous potassium carbonate (369.88g, 2.68mol), refluxing for 10 hours, cooling to normal temperature, filtering, washing with acetone (200mL), concentrating under reduced pressure to obtain a crude product, adding the crude product into ethanol (1200mL), heating to reflux for dissolving, continuing stirring for 10 minutes, cooling to 0-5 ℃ with cold water, stirring for crystallizing for 2 hours, filtering, washing a filter cake with ethanol, and drying the filter cake under reduced pressure at 40 ℃ to obtain 238.62g of compound 2, namely a white-like solid.
Example 3: preparation of Compound 2
Adding acetone (500mL) and benzyl chloride (150.56g, 1.19mol) into a reaction bottle, stirring, adding compound 1(100g, 0.59mol), potassium iodide (9.87g, 0.059mol) and anhydrous potassium carbonate (246.58g, 1.78mol), refluxing for reaction for 24 hours, cooling to normal temperature, filtering, washing with acetone (150mL), concentrating under reduced pressure to obtain a crude product, adding the crude product into ethanol (900mL), heating to reflux for dissolving, continuing stirring for 10 minutes, cooling to 0-5 ℃ with cold water, stirring for crystallization for 2 hours, filtering, washing a filter cake with ethanol, and drying the filter cake under reduced pressure at 40 ℃ to obtain 187.74g of compound 2, namely a white-like solid.
Example 4: preparation of Compound 3
Adding pyridine (800mL) into a reaction bottle, stirring, adding a compound 2(200g, 0.57mol), cooling to 0 ℃, slowly dropwise adding benzoyl chloride (88.76g, 0.63mol), controlling the temperature to be below 10 ℃, continuing stirring for 30 minutes after dropwise adding, slowly pouring the reaction liquid into 2mol/L diluted hydrochloric acid (700mL), stirring for 30 minutes, filtering, washing a filter cake with water, and drying the filter cake at 50 ℃ under reduced pressure to obtain 259.76g of a compound 3 white-like solid.
Example 5: preparation of Compound 4
Adding pyridine (1000mL) into a reaction bottle, stirring, adding 85% potassium hydroxide (72.94g, 1.10mol), adding compound 4(250g, 0.55mol), heating to 100 ℃, keeping the temperature for reaction for 2 hours, detecting and controlling by TLC to show that the raw materials disappear, cooling to normal temperature, slowly pouring the reaction liquid into 1mol/L diluted hydrochloric acid (1000mL), quickly stirring, filtering, washing a filter cake with water, and drying the filter cake under reduced pressure at 50 ℃ to obtain 204.34g of compound 4, namely an off-white solid.
Example 6: preparation of Compound 5
Adding acetic acid (1200mL) into a reaction bottle, stirring, adding sulfuric acid (25.99g, 0.265mol), adding compound 4(200g, 0.44mol), heating to 80-90 ℃, keeping the temperature for reaction for 5 hours, cooling to normal temperature, slowly adding cold water, continuing stirring for 2 hours, filtering, and drying a filter cake at 50 ℃ under reduced pressure to obtain 185.54g of compound 5, namely a yellowish solid.
Example 7: preparation of Compound 5
Adding acetic acid (100mL) into a reaction bottle, stirring, adding trifluoroacetic acid (2.52g, 0.022mol), adding compound 4(10g, 0.022mol), heating to 80-90 ℃, keeping the temperature for reaction for 5 hours, cooling to normal temperature, slowly adding cold water, continuing stirring for 2 hours, filtering, and drying a filter cake at 50 ℃ under reduced pressure to obtain 6.54g of compound 5 which is a yellowish solid.
Example 8: preparation of 7, 8-dihydroxyflavone
Adding ethyl acetate (500mL) and ethanol (1000mL) into a hydrogenation kettle, stirring, adding a compound 5(150g, 0.345mol) and 10% palladium-charcoal (20g), replacing hydrogen, increasing the pressure of the hydrogen to 5MPa, increasing the reaction temperature to 60 ℃, reacting for 9 hours, filtering, and concentrating under reduced pressure to obtain a yellow-green solid crude product, and recrystallizing the crude product with an ethanol aqueous solution to obtain 83.38g of 7, 8-dihydroxyflavone.
Claims (10)
1. A method for preparing 7, 8-dihydroxyflavone is characterized in that pyrogallol reacts with an acetylation reagent to generate a compound 1, the compound 1 reacts with a benzyl protection reagent to generate a compound 2, the compound 2 reacts with benzoyl chloride to generate a compound 3, the compound 3 undergoes Baker-Venkataraman rearrangement to generate a compound 4, the compound 4 undergoes ring closure under an acidic condition to generate a compound 5, and the compound 5 undergoes debenzylation to obtain the 7, 8-dihydroxyflavone.
2. The process of claim 1, wherein X is chloro, bromo, iodo, trifluoromethanesulfonyloxy, methylsulfonyloxy, benzenesulfonate, p-toluenesulfonate; x is chloro, bromo, iodo, acetoxy.
3. Process conditions according to claims 1-2 for the reaction of pyrogallol with an acetylating agent, characterized in that the catalyst used is anhydrous aluminum trichloride, anhydrous ferric bromide, anhydrous ferric chloride, anhydrous ferrous chloride, anhydrous stannic chloride, anhydrous zinc chloride, boron trifluoride, boron trichloride, anhydrous titanium tetrachloride, preferably anhydrous stannic chloride.
4. Process conditions according to claims 1-3, compound 2 being condensed with a benzylating agent, characterised in that the base used is lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, caesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, caesium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, caesium phosphate, lithium acetate, sodium acetate, potassium acetate, caesium acetate, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, ammonia, aqueous ammonia, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecen-7-ene, preferably potassium carbonate.
5. Process conditions according to claims 1-4, compound 2 being condensed with a benzylating agent, characterised in that the solvent used is water, methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, phase butyl acetate, methyl tert-butyl ether, phenylmethyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulphoxide, sulfolane or a mixture thereof, preferably acetone.
6. The process conditions of claims 1-5, esterification of compound 2 with benzoyl chloride, the solvent is water, methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenyl methyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, pyridine, picoline, lutidine, collidine, N-dimethylaminophenyl, 1, 8-diazabicycloundecene-7-ene, triethylamine, diisopropylethylamine, sulfolane or a mixture thereof, preferably pyridine.
7. Process conditions according to claims 1-6, in which compound 3 rearranges to compound 4, characterized in that the solvent used is methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, butyronitrile, acetone, butanone, pentanone, ethyl acetate, propyl acetate, butyl acetate, methyl tert-butyl ether, phenylmethyl ether, tetrahydrofuran, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, pyridine, picoline, lutidine, collidine, N-dimethylaminobenzene, 1, 8-diazabicycloundecene-7-ene, triethylamine, diisopropylethylamine, sulfolane or a mixture thereof, preferably pyridine.
8. Process conditions according to claims 1-7, in which compound 3 rearranges to compound 4, characterized in that the base used is lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, zinc hydroxide, sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium isopropoxide, lithium isopropoxide, potassium isopropoxide, magnesium isopropoxide, calcium isopropoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide, sodium hydride, calcium hydride, lithium hydride, potassium hydride, preferably potassium hydroxide.
9. Process conditions according to claims 1-8, compound 4 being a ring-closing compound 5, characterized in that the acid used is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, nitrobenzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof, preferably a sulfuric acid/acetic acid mixed system.
10. Process conditions according to claims 1-9, compound 5 being hydrodebenzylated, characterized in that the catalyst used is a salt or complex containing copper, iron, nickel, cobalt, ruthenium, rhodium, palladium, iridium, platinum, gold, preferably palladium on carbon.
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