香豆素衍生物的合成及活性检测
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摘要
香豆素类化合物是重要的有机杂环化合物,具有抗菌、消炎和抗肿瘤等多种生理活性和光学性能。已被广泛应用于医药、农药、食品、染料、光学等领域,同时在农业上也有广泛的应用。
本课题以7-羟基香豆素为原料,通过醚化,Claisen重排、甲基化、氟化合成一系列的香豆素衍生物,并研究了醚化试剂的种类、物料比、反应时间、催化剂的种类和用量、溶剂的种类对反应的影响,对工艺进行了优化。
实验表明:醚化的较优条件为n(7-羟基香豆素):n(碳酸钾):n(3-溴丙烯)=1:1.5:1.5,反应时间为17 h,收率为95.6%,纯度为98%(GC)。重排的较优条件:反应物浓度为0.07 g/mL时,反应温度为190℃,反应时间为3 h产率最高,经过重结晶后得到产物收率55%,纯度为98%(GC)。
同时对产物进行活性检测,活性检测结果表明:8-烯丙基-7-甲氧基香豆素对辣椒疫霉有很好的抑制作用,其作用强于蛇床子素,可用来替代较难合成的蛇床子素。
Coumarins, as a class of important heterocyclic compounds, have been widely used in medicines, pesticides, foodstuff , dyes and photochemistry, due to the large range of biological activities such as antimicrobial, antiphlogosis and anticancer, as well as their optical activities.
The coumarin derivatives were synthesized by Williamson etherification, Claisen rearrangement and fluorination successively from 7-hydroxycoumarin. Effects of etherification reagents, material molar ratios, reaction time, the kind and amount of catalyst and solvents were investigated, and the optimum conditions were obtained.
Many factors which affect the etherification and Claisen rearrangement reactions, such as raw material molar ratio, reaction temperature, catalyst and reaction time have been studied. Optimum conditions of synthesis of 7-allyloxy coumarin were obtained as follows: 7-hydroxy coumarin to allyl bromide to potassium carbonate is 1 : 1.5 : 1.5, reacting 17 h. The yield was 95.6%. Optimum conditions of synthesis of 8-allyl-7-hydroxy coumarin were as follows: The concertration of reactant is 0.07 g/mL,reacting 3h at 190℃. By recrystalization, The yield was 55 %.
The inhibitory effect of 8-allyI-7-hydroxy coumarin had been examined. The results showed that it had the batter active to Phytophthora capsici than Osthol., so it can be used as a substitute for Osthol Which was difficult to synthesis by chemical method.
本课题以7-羟基香豆素为原料,通过醚化,Claisen重排、甲基化、氟化合成一系列的香豆素衍生物,并研究了醚化试剂的种类、物料比、反应时间、催化剂的种类和用量、溶剂的种类对反应的影响,对工艺进行了优化。
实验表明:醚化的较优条件为n(7-羟基香豆素):n(碳酸钾):n(3-溴丙烯)=1:1.5:1.5,反应时间为17 h,收率为95.6%,纯度为98%(GC)。重排的较优条件:反应物浓度为0.07 g/mL时,反应温度为190℃,反应时间为3 h产率最高,经过重结晶后得到产物收率55%,纯度为98%(GC)。
同时对产物进行活性检测,活性检测结果表明:8-烯丙基-7-甲氧基香豆素对辣椒疫霉有很好的抑制作用,其作用强于蛇床子素,可用来替代较难合成的蛇床子素。
Coumarins, as a class of important heterocyclic compounds, have been widely used in medicines, pesticides, foodstuff , dyes and photochemistry, due to the large range of biological activities such as antimicrobial, antiphlogosis and anticancer, as well as their optical activities.
The coumarin derivatives were synthesized by Williamson etherification, Claisen rearrangement and fluorination successively from 7-hydroxycoumarin. Effects of etherification reagents, material molar ratios, reaction time, the kind and amount of catalyst and solvents were investigated, and the optimum conditions were obtained.
Many factors which affect the etherification and Claisen rearrangement reactions, such as raw material molar ratio, reaction temperature, catalyst and reaction time have been studied. Optimum conditions of synthesis of 7-allyloxy coumarin were obtained as follows: 7-hydroxy coumarin to allyl bromide to potassium carbonate is 1 : 1.5 : 1.5, reacting 17 h. The yield was 95.6%. Optimum conditions of synthesis of 8-allyl-7-hydroxy coumarin were as follows: The concertration of reactant is 0.07 g/mL,reacting 3h at 190℃. By recrystalization, The yield was 55 %.
The inhibitory effect of 8-allyI-7-hydroxy coumarin had been examined. The results showed that it had the batter active to Phytophthora capsici than Osthol., so it can be used as a substitute for Osthol Which was difficult to synthesis by chemical method.
引文
[1]袁昌齐.国外医学药学分册,1980,289-291
[2]王军.从南海红树内生真菌No.2533分离出新的异香豆素.中山大学学报,2001,40(1):127-128
[3]姚新生.天然药物化学,2002,111
[4]沈寿国,石志琦,徐朗莱,范永坚.蛇床子素对小麦赤霉病菌葡萄糖、钙吸收和三磷酸腺苷酶活性的抑制.农药学学报,2005,7(2):135-139
[5]戴宇.白芷的研究进展,中国药业,2001,10(9):61-62
[6]Y Kashman.The Calanolides,a novel HIV Inhibitory class of coumarin Derivatives from thetropical rainforest tree Calophylum laniqeruun.J.Med.Chem.,1992,35(15):2735-2743
[7]张巧艳.蛇床子总香豆素对新生大鼠成骨细胞的作用.中成药,2001,23(2):111-113
[8]张巧艳.蛇床子总香豆素对去卵巢大鼠骨质疏松症的作用.中国药学杂志,2003,38(2):101-103
[9]谢华,李青南,黄连芳.蛇床子总香豆素对类固醇性骨质疏松的作用.中国药理学报,1994,4(15):371-374
[10]王萍,戴岳,符麟军.TCCM对维甲酸诱导大鼠骨质疏松的影响.江苏中医学,2004,25(4):54-55
[11]孔令义,裴月湖,李铣.凯林内酯类香豆素的研究进展.天然产物研究与开发,1994,6(1):50-65
[12]李颖仪,蔡先东.香豆素的药理研究进展.中药材,2004,27(3):218-222
[13]袁旭.滨蒿内酯对哮喘豚鼠气道炎症的抑制及其清除氧自由基作用.中国医科大学学报,2002,31:401-406
[14]韩兴梅.6,7-二甲氧基香豆素抗急性肾功能衰竭的作用机制研究.中国药理学学报,1999,15(4):332-335
[15]倪奕昌.瑞香素的抗溶血和抗膜脂质过氧化作用.中国寄生虫学与寄全虫病杂志,1999.2:87-89
[16]赵明沂.滨蒿内酯对豚鼠离体气管平滑肌作用的研究.中国医科大学学报,2000,29(5):335-337
[17]徐嵩,徐世平,李兰敏.取代4-苯乙烯香豆素的合成及其抗肿瘤活性.药学学报,2001,36(4):269-273
[18]徐嵩,徐世平,李兰敏.4-,6-或7-位取代苯基亚胺次甲基香豆素的合成及其抗癌活性.药学学报,2002,37(2):113-116
[19]S.R.Natala,R.M.Muralidhar,C.Stephen.Synthesis of new coumarin -3-(N-aryl)sulfon amides and their anticancer activity.Bioorganic& Medicinal Chemistry Letters,2004,14:4093-4100
[20]韩莹,屠树滋,周卫芬.香豆素磺酰脲类化合物的合成及其降血糖活性研究.中国医科大学学报,2002,33(2):93-97
[21]Makoto Komiyama,Hidefumi Hirai,Makromol.Selective Synthesis of 2,4-Dihyd -roxybenzaldehyde with β-Cyclodextrin as Catalyst.Macromol.Rapid Commun,1981,2(11):707-708
[22]Roger Adams,I.Levine.Simplification of the Gattermann Synthesis of Hydroxy Aldehydes.J.Am.Chem.Soc.,1923,45:2373-2377
[23]汪秋安.重要有机化学反应及机理速查手册,2007,418-419
[24]高鸿宾.有机化学,2006,368
[25]Loutfy,Mohammad.The Claisen rearrangement of umbelliferone allyl ether.Pharma -zie,1979,34(10):672
[26]乌锡康,包泉兴,吴达俊.有机人名反应集,1984,206-211
[27]曹科.有机合成中命名反应的战略性应用,2007,90-91
[28]张湛赋,刘新民,郭丽华.有机化学反应类型概论,2005,343-344
[29]Nicholas Cairns,Laurence M.Harwood.Regioselective Preparation of 6-allyl-7-hydr -oxy-coumarin from 7-allyloxycoumarin via Boron Halide catalysed ortho-Claisen Rearrangement of 4'-allyloxycoumarin acid derivative.J.Chem.Soc.,1986,182-183
[30]G.K Andrew.7-Alkoxy-1,2-benzopyrones as tobacco flavorants.US 4163453,1979
[31]薛建荣,钟宏,符剑刚.碳酸二甲酯的用途及合成研究进展.化工技术与开发,2006,35(3):8-13
[32]O.Samedy,T.Saophie,B.Elisabeth L.G.Pierre.High performance method for O-methylation of phenol with demethyl carbonate.Applied Cata.A:General,2003,241:227-233
[33]D.R.Maria,O.Gabriel,R.Araceli,A.Ismael.O-methylation of phenol in liquid phase over basic zeolites.Ind.Eng.Chem.Res.,2004,43:8194-8199
[34]O.Samedy,T.Saophie,B.Elisabeth,L.G.Pierre.O-Methylation of phenolic compounds with dimethyl carbonate under solid/liquid phase transfer system.Tetrahedron Lett.,2002,43:2661-2663
[35]G.Jacob,D.Soundar.Influence of embedded phenol groups inside β-cyclodextrin cavity in selective methylation of 2,4-dihydroxybenzaldehyde.Ind.J.Chem.,1995,34B,1098-1101
[36]H.H.Pattekhan,S.Divakar.Regioselectivity in the preparation of 2-hydroxy-4-meth -oxybenzaldehyde from resorcinol.J.Mol.Cat.A:Chemical,2001,169:185-191
[37]杜春华,张文玉,彭鹏.含氟生理活性物质的特性及创制.精细与专用化学品,2007,15(20):15-18
[38]P D.Schuman,P.Tarrant,D.A.Warner,et al.Process for fluorinating uracil and deriva-tires thereof.US 3954758
[39]R.E.Banks Selectfluor reagent F-TEDA-BF4 in action:tamed fluorine at your service.J Fluorine Chem.,1998,87:1-17
[40]R.S.Mali,R.Manekar,S.Anita,.G.Tilve.A convenient synthesis of 2,3-dihy -dro-2-methyl-5H-furo[2,3-h][1]benzopyran-5-ones.Indian J.Chem.,Sect.B,1990,29B(2):113-116
[41]Y.E.Orlov,,A.P.Prokopenka.Polarography of natural coumarins Ⅱ influence of structure on the half-wave potential during reduction in water-alcohol media on a mercury drop electrode.Zh.Obshch.Khim,1970,40(5):1159-1164
[42]Nicholas Cairns,M.Laurence,Harwood,P.David.Astlesb.Tandem Thermal Claisen -Cope Rearrangements of Coumarate Derivatives.Total Syntheses of the Naturally Occ -urring Coumarins:Suberosin,Demethylsuberosin,Ostruthin,Balsa -miferone and Gra -velliferone.J.Chem.Soc.Perkin Trans.1,1994,21:3101-3107
[2]王军.从南海红树内生真菌No.2533分离出新的异香豆素.中山大学学报,2001,40(1):127-128
[3]姚新生.天然药物化学,2002,111
[4]沈寿国,石志琦,徐朗莱,范永坚.蛇床子素对小麦赤霉病菌葡萄糖、钙吸收和三磷酸腺苷酶活性的抑制.农药学学报,2005,7(2):135-139
[5]戴宇.白芷的研究进展,中国药业,2001,10(9):61-62
[6]Y Kashman.The Calanolides,a novel HIV Inhibitory class of coumarin Derivatives from thetropical rainforest tree Calophylum laniqeruun.J.Med.Chem.,1992,35(15):2735-2743
[7]张巧艳.蛇床子总香豆素对新生大鼠成骨细胞的作用.中成药,2001,23(2):111-113
[8]张巧艳.蛇床子总香豆素对去卵巢大鼠骨质疏松症的作用.中国药学杂志,2003,38(2):101-103
[9]谢华,李青南,黄连芳.蛇床子总香豆素对类固醇性骨质疏松的作用.中国药理学报,1994,4(15):371-374
[10]王萍,戴岳,符麟军.TCCM对维甲酸诱导大鼠骨质疏松的影响.江苏中医学,2004,25(4):54-55
[11]孔令义,裴月湖,李铣.凯林内酯类香豆素的研究进展.天然产物研究与开发,1994,6(1):50-65
[12]李颖仪,蔡先东.香豆素的药理研究进展.中药材,2004,27(3):218-222
[13]袁旭.滨蒿内酯对哮喘豚鼠气道炎症的抑制及其清除氧自由基作用.中国医科大学学报,2002,31:401-406
[14]韩兴梅.6,7-二甲氧基香豆素抗急性肾功能衰竭的作用机制研究.中国药理学学报,1999,15(4):332-335
[15]倪奕昌.瑞香素的抗溶血和抗膜脂质过氧化作用.中国寄生虫学与寄全虫病杂志,1999.2:87-89
[16]赵明沂.滨蒿内酯对豚鼠离体气管平滑肌作用的研究.中国医科大学学报,2000,29(5):335-337
[17]徐嵩,徐世平,李兰敏.取代4-苯乙烯香豆素的合成及其抗肿瘤活性.药学学报,2001,36(4):269-273
[18]徐嵩,徐世平,李兰敏.4-,6-或7-位取代苯基亚胺次甲基香豆素的合成及其抗癌活性.药学学报,2002,37(2):113-116
[19]S.R.Natala,R.M.Muralidhar,C.Stephen.Synthesis of new coumarin -3-(N-aryl)sulfon amides and their anticancer activity.Bioorganic& Medicinal Chemistry Letters,2004,14:4093-4100
[20]韩莹,屠树滋,周卫芬.香豆素磺酰脲类化合物的合成及其降血糖活性研究.中国医科大学学报,2002,33(2):93-97
[21]Makoto Komiyama,Hidefumi Hirai,Makromol.Selective Synthesis of 2,4-Dihyd -roxybenzaldehyde with β-Cyclodextrin as Catalyst.Macromol.Rapid Commun,1981,2(11):707-708
[22]Roger Adams,I.Levine.Simplification of the Gattermann Synthesis of Hydroxy Aldehydes.J.Am.Chem.Soc.,1923,45:2373-2377
[23]汪秋安.重要有机化学反应及机理速查手册,2007,418-419
[24]高鸿宾.有机化学,2006,368
[25]Loutfy,Mohammad.The Claisen rearrangement of umbelliferone allyl ether.Pharma -zie,1979,34(10):672
[26]乌锡康,包泉兴,吴达俊.有机人名反应集,1984,206-211
[27]曹科.有机合成中命名反应的战略性应用,2007,90-91
[28]张湛赋,刘新民,郭丽华.有机化学反应类型概论,2005,343-344
[29]Nicholas Cairns,Laurence M.Harwood.Regioselective Preparation of 6-allyl-7-hydr -oxy-coumarin from 7-allyloxycoumarin via Boron Halide catalysed ortho-Claisen Rearrangement of 4'-allyloxycoumarin acid derivative.J.Chem.Soc.,1986,182-183
[30]G.K Andrew.7-Alkoxy-1,2-benzopyrones as tobacco flavorants.US 4163453,1979
[31]薛建荣,钟宏,符剑刚.碳酸二甲酯的用途及合成研究进展.化工技术与开发,2006,35(3):8-13
[32]O.Samedy,T.Saophie,B.Elisabeth L.G.Pierre.High performance method for O-methylation of phenol with demethyl carbonate.Applied Cata.A:General,2003,241:227-233
[33]D.R.Maria,O.Gabriel,R.Araceli,A.Ismael.O-methylation of phenol in liquid phase over basic zeolites.Ind.Eng.Chem.Res.,2004,43:8194-8199
[34]O.Samedy,T.Saophie,B.Elisabeth,L.G.Pierre.O-Methylation of phenolic compounds with dimethyl carbonate under solid/liquid phase transfer system.Tetrahedron Lett.,2002,43:2661-2663
[35]G.Jacob,D.Soundar.Influence of embedded phenol groups inside β-cyclodextrin cavity in selective methylation of 2,4-dihydroxybenzaldehyde.Ind.J.Chem.,1995,34B,1098-1101
[36]H.H.Pattekhan,S.Divakar.Regioselectivity in the preparation of 2-hydroxy-4-meth -oxybenzaldehyde from resorcinol.J.Mol.Cat.A:Chemical,2001,169:185-191
[37]杜春华,张文玉,彭鹏.含氟生理活性物质的特性及创制.精细与专用化学品,2007,15(20):15-18
[38]P D.Schuman,P.Tarrant,D.A.Warner,et al.Process for fluorinating uracil and deriva-tires thereof.US 3954758
[39]R.E.Banks Selectfluor reagent F-TEDA-BF4 in action:tamed fluorine at your service.J Fluorine Chem.,1998,87:1-17
[40]R.S.Mali,R.Manekar,S.Anita,.G.Tilve.A convenient synthesis of 2,3-dihy -dro-2-methyl-5H-furo[2,3-h][1]benzopyran-5-ones.Indian J.Chem.,Sect.B,1990,29B(2):113-116
[41]Y.E.Orlov,,A.P.Prokopenka.Polarography of natural coumarins Ⅱ influence of structure on the half-wave potential during reduction in water-alcohol media on a mercury drop electrode.Zh.Obshch.Khim,1970,40(5):1159-1164
[42]Nicholas Cairns,M.Laurence,Harwood,P.David.Astlesb.Tandem Thermal Claisen -Cope Rearrangements of Coumarate Derivatives.Total Syntheses of the Naturally Occ -urring Coumarins:Suberosin,Demethylsuberosin,Ostruthin,Balsa -miferone and Gra -velliferone.J.Chem.Soc.Perkin Trans.1,1994,21:3101-3107