5-氧代四氢苯并［b］吡喃衍生物的合成及结构表征
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摘要
近年来,含有苯并[b]吡喃结构的杂环类化合物已成为新药研究与开发的热点领域之一。该类化合物具有抗肿瘤、利胆排石、抗凝抗血栓、抗骨质疏松、抗炎、抗真菌、血管扩张、降血糖、抗病毒、抗血吸虫等较为广泛的药理作用。在临床上,它们作为抗炎镇痛药、抗骨质疏松药、利胆排石药、抗凝抗血栓药已有应用。其中作为降血糖、抗病毒及抗血吸虫等药物都含有苯并[b]吡喃结构,具体为含有5-氧代四氢苯并[b]吡喃的结构。为此,本文主要针对5-氧代四氢苯并[b]吡喃类化合物的合成及结构表征进行研究。
目前,有关5-氧代四氢苯并[b]吡喃类物质的合成主要有固碱环合法、酸酐脱水法、三氟化硼-乙醚配合物催化法、氯化锌催化共沸除水法等方法。就此而言,其主要不足在于使用了大量乙酸、酸酐、甲苯等易污染环境的试剂、反应介质适用范围较小、产品纯化难,更重要的是难于工业化生产,严重阻碍了含5-氧代四氢苯并[b]吡喃结构类药物的进一步研究与开发。
为此,本文拟以寻求环境污染小、反应介质适用范围较广、纯化简便以及能工业化生产的合成方法为目的,在结合文献报道的合成方法基础上,完成了7个5-氧代四氢苯并[b]吡喃类化合物的设计、合成、结构确证等几个方面的工作:
1.结合文献报道,采用逆合成分析法,提出经Micheal加成-环合反应合成5-氧代四氢苯并[b]吡喃类化合物的合成路线。其中以离子液体[bmim][BF4]为反应介质,以TMSCl为助溶剂,InCl3作为催化剂。
2.合成了7个带有不同取代基的5-氧代四苯并[b]吡喃衍生物,其中5个为新化合物。
3.采用IR、1H NMR、MS、HRMS等方法对目标化合物进行了结构测定,其图谱数据与目标化合物的结构完全一致。
4.考察了反应物与催化剂的mol比例对产率的影响,其中反应物与催化剂的mol比例为1∶0.2时产率可达55%。
5.考察了含有InCl3催化剂[bmim][BF4]反应介质的回收再利用,发现其回收率可达90%,且重复使用四次后产物产率尚未明显降低。
6.产物选用乙酸乙酯-环己烷混合溶剂结晶,得到的晶型好、纯度高、易于操作,革除了不利于工业化生产的柱层析纯化法。
综上所述,本文设计的合成路线革除了酸酐脱水剂和易挥发性溶剂。本合成路线具有环保、反应介质适用范围广、纯化简便等优点,并且可用于工业化生产,因此为含5-氧代四氢苯并[b]吡喃类结构的药物工业化生产奠定了基础。
Recently , Compouds containing Benzo[b]pyran structure is the hotspot of new drugs development, which possess antitumor, choleretic treatment and eliminating urolith, anticoagulation, anti-osteoporosis, anti-inflammatory, anti-fungus, hemangiectasis, reducing blood sugar , antivirus, anti-schistosomiasis, and so on. Now, the anti-osteoporosis drug, anticoagulation drug, anti-inflamatory drug of benzo[b]pyran have been applied to clinical; and drugs of reducing blood sugar, antivirus, anti-schistosomiasis contain Benzo[b]pyran structure.Thus, this paper mainly studies on the synthesis and characterization of 5-oxo-tetrahydro-4H-benzo[b] pyran derivatives.
Nowadays, there are few reports on the synthesis of 5-oxo-tetrahydro -4H-benzo[b]pyran derivatives, mainly including cyclization in solid alkali, dehydrolysis with acid anhydride, catalysis by PF3-Et2O in CH3COOH, catalysis by ZnCl2 coupling with the azeotropic water removing. However, these present methods are imperfect for the lower yields, difficulty to separate the products, narrower application range and environment pollution. Thus,these drawbacks seriously affect its industrial production and further study.
In this paper, aiming to seek the synthesis method which is environment friendly and easily available in industry with extensive application range, convenient purification way , we have completed synthesis design, synthesis and characterization of seven 5-oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran derivatives in combination with related literature. The main work in the paper is as follows:
1. On the Combination of related literature, we first put forward the synthesis of 5-Oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran derivatives by Micheal addition-condensation reaction in [bmim][BF4] promoted by InCl3/TMSCl.
2. Seven 5-Oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran derivatives with Non-identical Groups have been synthesized, five of which are new compouds.
3. Structure determination of the target compound by IR, 1H NMR, MS and HRMS, which shows that the spectra data is consistent with structure.
4. The effect of catalyst amount on yield was investigated. When the molar ratio of reactant to catalyst was 1∶0.2, the yield was 55%.
5. Research on recycle of [bmim][BF4] containing InCl3, the cyclic utilization rateis up to 90%; It is obvious that the reaction can give the product with a yield almost as high as that of the first roundactivity after four times of repeated use.
6. Taking ethyl acetate-cyclohexane as the solvents of crystallization, results show that high purity and fine crystal shape products can be obtained, abolishing column chromatography which goes against industrialization.
In summery, the synthesis method which is environment friendly and easily available in industry with extensive application range and convenient purification way in this paper can be applied in the industrialized production, thus providing a basis for the research and development of the 5-Oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran drugs.
目前,有关5-氧代四氢苯并[b]吡喃类物质的合成主要有固碱环合法、酸酐脱水法、三氟化硼-乙醚配合物催化法、氯化锌催化共沸除水法等方法。就此而言,其主要不足在于使用了大量乙酸、酸酐、甲苯等易污染环境的试剂、反应介质适用范围较小、产品纯化难,更重要的是难于工业化生产,严重阻碍了含5-氧代四氢苯并[b]吡喃结构类药物的进一步研究与开发。
为此,本文拟以寻求环境污染小、反应介质适用范围较广、纯化简便以及能工业化生产的合成方法为目的,在结合文献报道的合成方法基础上,完成了7个5-氧代四氢苯并[b]吡喃类化合物的设计、合成、结构确证等几个方面的工作:
1.结合文献报道,采用逆合成分析法,提出经Micheal加成-环合反应合成5-氧代四氢苯并[b]吡喃类化合物的合成路线。其中以离子液体[bmim][BF4]为反应介质,以TMSCl为助溶剂,InCl3作为催化剂。
2.合成了7个带有不同取代基的5-氧代四苯并[b]吡喃衍生物,其中5个为新化合物。
3.采用IR、1H NMR、MS、HRMS等方法对目标化合物进行了结构测定,其图谱数据与目标化合物的结构完全一致。
4.考察了反应物与催化剂的mol比例对产率的影响,其中反应物与催化剂的mol比例为1∶0.2时产率可达55%。
5.考察了含有InCl3催化剂[bmim][BF4]反应介质的回收再利用,发现其回收率可达90%,且重复使用四次后产物产率尚未明显降低。
6.产物选用乙酸乙酯-环己烷混合溶剂结晶,得到的晶型好、纯度高、易于操作,革除了不利于工业化生产的柱层析纯化法。
综上所述,本文设计的合成路线革除了酸酐脱水剂和易挥发性溶剂。本合成路线具有环保、反应介质适用范围广、纯化简便等优点,并且可用于工业化生产,因此为含5-氧代四氢苯并[b]吡喃类结构的药物工业化生产奠定了基础。
Recently , Compouds containing Benzo[b]pyran structure is the hotspot of new drugs development, which possess antitumor, choleretic treatment and eliminating urolith, anticoagulation, anti-osteoporosis, anti-inflammatory, anti-fungus, hemangiectasis, reducing blood sugar , antivirus, anti-schistosomiasis, and so on. Now, the anti-osteoporosis drug, anticoagulation drug, anti-inflamatory drug of benzo[b]pyran have been applied to clinical; and drugs of reducing blood sugar, antivirus, anti-schistosomiasis contain Benzo[b]pyran structure.Thus, this paper mainly studies on the synthesis and characterization of 5-oxo-tetrahydro-4H-benzo[b] pyran derivatives.
Nowadays, there are few reports on the synthesis of 5-oxo-tetrahydro -4H-benzo[b]pyran derivatives, mainly including cyclization in solid alkali, dehydrolysis with acid anhydride, catalysis by PF3-Et2O in CH3COOH, catalysis by ZnCl2 coupling with the azeotropic water removing. However, these present methods are imperfect for the lower yields, difficulty to separate the products, narrower application range and environment pollution. Thus,these drawbacks seriously affect its industrial production and further study.
In this paper, aiming to seek the synthesis method which is environment friendly and easily available in industry with extensive application range, convenient purification way , we have completed synthesis design, synthesis and characterization of seven 5-oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran derivatives in combination with related literature. The main work in the paper is as follows:
1. On the Combination of related literature, we first put forward the synthesis of 5-Oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran derivatives by Micheal addition-condensation reaction in [bmim][BF4] promoted by InCl3/TMSCl.
2. Seven 5-Oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran derivatives with Non-identical Groups have been synthesized, five of which are new compouds.
3. Structure determination of the target compound by IR, 1H NMR, MS and HRMS, which shows that the spectra data is consistent with structure.
4. The effect of catalyst amount on yield was investigated. When the molar ratio of reactant to catalyst was 1∶0.2, the yield was 55%.
5. Research on recycle of [bmim][BF4] containing InCl3, the cyclic utilization rateis up to 90%; It is obvious that the reaction can give the product with a yield almost as high as that of the first roundactivity after four times of repeated use.
6. Taking ethyl acetate-cyclohexane as the solvents of crystallization, results show that high purity and fine crystal shape products can be obtained, abolishing column chromatography which goes against industrialization.
In summery, the synthesis method which is environment friendly and easily available in industry with extensive application range and convenient purification way in this paper can be applied in the industrialized production, thus providing a basis for the research and development of the 5-Oxo-5,6,7,8-tetrahydro-4H-benzo[b]pyran drugs.
引文
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[2] Thawom Jaipetch, Sujin Kanghae, Orasa Pancharoen eta1. Constituents of Boesenbergia pandurata(syn. Kaempferia Pandura-ta): Isolation, Crystal Structure and Synthesis Of(±)- Boesenbergia A [J]. Aust. J. Chem.1982, 35:351-361
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