新型α-氨基膦酸酯及其酰胺衍生物的合成与生物活性研究
摘要
α-氨基膦酸酯是一类具有较高生物活性的化合物，本课题组近年来合成了一系列含氟和杂环取代的α-氨基膦酸酯类新化合物，并进行了抗烟草花叶病毒活性筛选，在2002年筛选出高效抗烟草花叶病毒药剂——“病毒星”。
为了进一步寻找具有较高生物活性的α-氨基膦酸酯类化合物及其衍生物，作者采用活性拼接法，以没食子酸为先导化合物，经过醚化、酯化、酰肼化、氧化四步反应得到重要的医药中间体3，4，5-三甲氧基苯甲醛(TMB)，再在其结构中引入三氟甲基与膦酸酯基团，无溶剂条件下一锅法，首次合成4个未见文献报道的含3，4，5-三甲氧基苯基与三氟甲基的新型α-氨基膦酸酯类化合物；与此同时，以取代苯甲醛为原料，经过氨化、酯化、磺化、氨解四步反应成功得到3个性质活泼含有伯胺的α-氨基膦酸酯类化合物，再在其结构中引入活性基团酰胺，DCC催化下一步法，首次合成19个含膦酸酯基团与酰胺基团的新型α-氨基膦酸酯衍生物。通过元素分析、IR、~1H NMR、~(13)C NMR、~(31)P NMR对所有化合物的结构进行表征。生物活性测试结果表明：这两类化合物对烟草花叶病毒均具有一定的活体治疗作用，其中Ⅲ_(6f)的治疗效果较好，与对照药剂宁南霉素相当(500μg／mL浓度下Ⅲ_(6f)为53.63％，同浓度下对照药剂宁南霉素为55.45％)。
另外，从绿色合成、环境友好的角度出发，首次对O，O′-二烷基-α-(4-三氟甲基苯基)氨基-(取代苯基)甲基膦酸酯的绿色合成方法如微波辐射、离子液体、无溶剂无催化剂进行比较研究，优选出无溶剂无催化剂原料比为1：1：1，在100℃进行类Mannich反应的合成方法，实验结果表明该法经济、简便、产率高、反应时间短。
α-Aminophosphonate is a kind of compounds with high biological activities. A series of fluorinated and heterocyclicα-aminophosphonates were synthesized, and their anti-TMV activities were evaluated. In 2002, Bing DuXing, which showed a remarkable activity against mosaic disease of tobacco, was screened out as a kind of anti-TMV medicament.
In order to find new a-aminophosphonates and their derivatives with high activity, 3,4,5-trimethoxybenzaldhyde (TMB) was synthesized via a four step synthetic sequence involving etherification, esterification, hydrazidation and oxidation using galic acid as a lead compound. Subsequently, four of newα-aminophosphonates which possessed 3,4,5-trimethoxy- benzyl and trifluoromethyl were firstly synthesized through introducing trifluoromethyl and phosphonate to TMB. The reaction was carried out without solvent in one-pot synthesis. Meantime, active a-aminophosphonates containing amino was successfully obtained via a four step synthetic sequence involving ammoniation, esterification, sulfonation and aminolysis using substituted-benzaldhyde as a reactant. Active amide was introduced to their structures in the catalysis of DCC by one step, and then nineteen of novelα-aminophosphonate derivatives containing phosphonate and amide groups were firstly synthesized. All compounds were confirmed by elemental analysis, infrared spectrum, ~1H NMR, ~(13)C NMR and ~(31)P NMR. The results of bioassay showed that the two type compounds exhibited certain anti-TMV activity in vivo treatment, especially, III_(6f) exhibited equivalent curative activity to Ningnanmycin (the efficient rate was 53.63% for III_(6f) and 55.45% for ningnanmycin at a concentration of 500μg/mL).
From the viewpoint of green synthesis and environment-friendly, the green synthetic method of O,O'-dialkyl-α-(4-trifluoromethylanilino)-substitutented benzylphosphonate was compared under different conditions firstly, such as microwave irradiation, ionic liquid, solvent and catalyst free. The optimal synthetic method was screened out and summarized as follows: the ratio of raw materials was 1:1:1, and then the mixture reacted at 100℃without solvent and catalyst, which was economic, convenient, high yields and environment-friendly.
为了进一步寻找具有较高生物活性的α-氨基膦酸酯类化合物及其衍生物，作者采用活性拼接法，以没食子酸为先导化合物，经过醚化、酯化、酰肼化、氧化四步反应得到重要的医药中间体3，4，5-三甲氧基苯甲醛(TMB)，再在其结构中引入三氟甲基与膦酸酯基团，无溶剂条件下一锅法，首次合成4个未见文献报道的含3，4，5-三甲氧基苯基与三氟甲基的新型α-氨基膦酸酯类化合物；与此同时，以取代苯甲醛为原料，经过氨化、酯化、磺化、氨解四步反应成功得到3个性质活泼含有伯胺的α-氨基膦酸酯类化合物，再在其结构中引入活性基团酰胺，DCC催化下一步法，首次合成19个含膦酸酯基团与酰胺基团的新型α-氨基膦酸酯衍生物。通过元素分析、IR、~1H NMR、~(13)C NMR、~(31)P NMR对所有化合物的结构进行表征。生物活性测试结果表明：这两类化合物对烟草花叶病毒均具有一定的活体治疗作用，其中Ⅲ_(6f)的治疗效果较好，与对照药剂宁南霉素相当(500μg／mL浓度下Ⅲ_(6f)为53.63％，同浓度下对照药剂宁南霉素为55.45％)。
另外，从绿色合成、环境友好的角度出发，首次对O，O′-二烷基-α-(4-三氟甲基苯基)氨基-(取代苯基)甲基膦酸酯的绿色合成方法如微波辐射、离子液体、无溶剂无催化剂进行比较研究，优选出无溶剂无催化剂原料比为1：1：1，在100℃进行类Mannich反应的合成方法，实验结果表明该法经济、简便、产率高、反应时间短。
α-Aminophosphonate is a kind of compounds with high biological activities. A series of fluorinated and heterocyclicα-aminophosphonates were synthesized, and their anti-TMV activities were evaluated. In 2002, Bing DuXing, which showed a remarkable activity against mosaic disease of tobacco, was screened out as a kind of anti-TMV medicament.
In order to find new a-aminophosphonates and their derivatives with high activity, 3,4,5-trimethoxybenzaldhyde (TMB) was synthesized via a four step synthetic sequence involving etherification, esterification, hydrazidation and oxidation using galic acid as a lead compound. Subsequently, four of newα-aminophosphonates which possessed 3,4,5-trimethoxy- benzyl and trifluoromethyl were firstly synthesized through introducing trifluoromethyl and phosphonate to TMB. The reaction was carried out without solvent in one-pot synthesis. Meantime, active a-aminophosphonates containing amino was successfully obtained via a four step synthetic sequence involving ammoniation, esterification, sulfonation and aminolysis using substituted-benzaldhyde as a reactant. Active amide was introduced to their structures in the catalysis of DCC by one step, and then nineteen of novelα-aminophosphonate derivatives containing phosphonate and amide groups were firstly synthesized. All compounds were confirmed by elemental analysis, infrared spectrum, ~1H NMR, ~(13)C NMR and ~(31)P NMR. The results of bioassay showed that the two type compounds exhibited certain anti-TMV activity in vivo treatment, especially, III_(6f) exhibited equivalent curative activity to Ningnanmycin (the efficient rate was 53.63% for III_(6f) and 55.45% for ningnanmycin at a concentration of 500μg/mL).
From the viewpoint of green synthesis and environment-friendly, the green synthetic method of O,O'-dialkyl-α-(4-trifluoromethylanilino)-substitutented benzylphosphonate was compared under different conditions firstly, such as microwave irradiation, ionic liquid, solvent and catalyst free. The optimal synthetic method was screened out and summarized as follows: the ratio of raw materials was 1:1:1, and then the mixture reacted at 100℃without solvent and catalyst, which was economic, convenient, high yields and environment-friendly.
引文
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