具有手性轴的螺环化合物的合成与拆分
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摘要
手性化合物在农药、激素、食品添加剂、具有生理活性的氨基酸和醇类、尤其在医药行业等方面得到了越来越广泛的应用。20世纪90年代以来,手性药物的研发已成为世界新药发展的战略方向和热点领域。现行手性药物的合成方法主要有3种途径:从天然产物中提取手性药物、拆分法分离手性药物、不对称催化合成手性药物。目前应用最广的是不对称催化合成法,即是利用手性技术来合成手性药物,它也是近期研究最多的单一手性化合物的合成方法。
本文首先通过苯二甲醛单缩醛或对位取代基苯甲醛与季戊四醇的反应合成了一系列手性螺环化合物,然后通过高效液相色谱法、结晶法和化学法对其中五种化合物尝试进行了拆分。共有以下内容:
1.通过对R基苯甲醛与季戊四醇缩合制备了3,9-二(4-R基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷,其中R为二(2,2-二氰基)乙烯基、醛基、甲基、氰基、羧基、羟基、2,5-二硫杂环戊烷基,并分析了溶剂、催化剂等条件对反应的影响。
2.利用高效液相色谱法对其中四种螺环化合物进行了尝试拆分,在流动相为正己烷:异丙醇=98:2的条件下成功分离了3,9-二(4-甲基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷,并对其他三种化合物的分离也取得一定成果。
3.利用手性催化剂N-苄基氯化辛可宁对3,9-二(4-氰基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷进行拆分,L-苯乙胺对3,9-二(4-羧基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷进行拆分,并分别测定了一种对映异构体的旋光值,对反应机理进行了推测。
4.利用环己二酮单腙芳构化反应,得到芳构化产物,并与季戊四醇缩合通过一锅法制备了分子内含有潜在的手性螺环单元的树型化合物。
Chiral compounds were widely used in pesticides, hormone, food additives, and physiologically active amino acids and alcohols, especially in medicines. Since the 1990s, the research of the chiral pharmaceuticals has become the strategic direction and hot area in the development of the new medicines. There are mainly three methods for synthesizing chiral medicines: extraction from natural products, separation and synthesis by asymmetrical catalysis. At present the most widely used method is the last one. That is to synthesize chiral medicines by chiral technique, which is the most studied method for preparing single chiral compounds recently.
In this dissertation, a series of chiral spiro compounds were prepared by contrapuntal substituted benzaldehyde and pentaerythritol, and in which 5 compounds were separated by HPLC, crystallizing and chemical method. It was as follow:
1. 4,4'-(2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl)dibenzaldehyde and 7 other spiro compounds were prepared by对位substituted benzaldehyde and pentaerythritol, and the effects of different conditions like solvents and catalyst were studied;
2. Separation of four compounds were tried by HPLC, and 3,9-dip-tolyl-2,4,8,10- tetraoxaspiro[5.5]undecane was successfully separated with the hexane and iso- propanol (98:2) as mobile phase.
3. 4,4'-(2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl)dibenzonitrile was separated by reacting with (8R,9S)-(+)-N-benzylcinchonin chloride, and 4,4'-(2,4,8,10-tetraoxaspiro[5.5] undecane-3,9-diyl)dibenzoic acid was separated by L-phenylethylamine. The optical rotations were measured as well.
4. A novel dendrimer 9H,9H,11H,11H,12H,12H-hexahydrobenzo[9,10]-1H,1H,3H,3H, 4H,4H,5H,5H,7H,7H,8H,8H-dodecahydrophenanthrene-2,6,10-trioneketal-tri-(4-(4-(3-(9-(4-(2,6-disulfo-cyclohexyl)phenyl))-2,4,8,10-tetra-oxa-spiro[5.5]undecyl))phenyl-1,1-(2,6-dioxa)cyclohexanedimethanol was conveniently synthesized by the reaction of hexahydrobenzo [9,10]dodecahydrophenanthrene-2,6,10-trione ketal-tri-2,2-dihydromethyl-1,3-propanediol with 4-(4-(3-(9-(4-(2,6-disulfo-cyclohexyl)phenyl))-2,4,8,10-tetra-oxa-spiro[5.5]undecyl)) phenyl-1,1-(2,6-dioxa)cyclohexanedimethanol.
本文首先通过苯二甲醛单缩醛或对位取代基苯甲醛与季戊四醇的反应合成了一系列手性螺环化合物,然后通过高效液相色谱法、结晶法和化学法对其中五种化合物尝试进行了拆分。共有以下内容:
1.通过对R基苯甲醛与季戊四醇缩合制备了3,9-二(4-R基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷,其中R为二(2,2-二氰基)乙烯基、醛基、甲基、氰基、羧基、羟基、2,5-二硫杂环戊烷基,并分析了溶剂、催化剂等条件对反应的影响。
2.利用高效液相色谱法对其中四种螺环化合物进行了尝试拆分,在流动相为正己烷:异丙醇=98:2的条件下成功分离了3,9-二(4-甲基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷,并对其他三种化合物的分离也取得一定成果。
3.利用手性催化剂N-苄基氯化辛可宁对3,9-二(4-氰基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷进行拆分,L-苯乙胺对3,9-二(4-羧基苯基)- 2,4,8,10-四氧杂-螺环[5.5]十一烷进行拆分,并分别测定了一种对映异构体的旋光值,对反应机理进行了推测。
4.利用环己二酮单腙芳构化反应,得到芳构化产物,并与季戊四醇缩合通过一锅法制备了分子内含有潜在的手性螺环单元的树型化合物。
Chiral compounds were widely used in pesticides, hormone, food additives, and physiologically active amino acids and alcohols, especially in medicines. Since the 1990s, the research of the chiral pharmaceuticals has become the strategic direction and hot area in the development of the new medicines. There are mainly three methods for synthesizing chiral medicines: extraction from natural products, separation and synthesis by asymmetrical catalysis. At present the most widely used method is the last one. That is to synthesize chiral medicines by chiral technique, which is the most studied method for preparing single chiral compounds recently.
In this dissertation, a series of chiral spiro compounds were prepared by contrapuntal substituted benzaldehyde and pentaerythritol, and in which 5 compounds were separated by HPLC, crystallizing and chemical method. It was as follow:
1. 4,4'-(2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl)dibenzaldehyde and 7 other spiro compounds were prepared by对位substituted benzaldehyde and pentaerythritol, and the effects of different conditions like solvents and catalyst were studied;
2. Separation of four compounds were tried by HPLC, and 3,9-dip-tolyl-2,4,8,10- tetraoxaspiro[5.5]undecane was successfully separated with the hexane and iso- propanol (98:2) as mobile phase.
3. 4,4'-(2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl)dibenzonitrile was separated by reacting with (8R,9S)-(+)-N-benzylcinchonin chloride, and 4,4'-(2,4,8,10-tetraoxaspiro[5.5] undecane-3,9-diyl)dibenzoic acid was separated by L-phenylethylamine. The optical rotations were measured as well.
4. A novel dendrimer 9H,9H,11H,11H,12H,12H-hexahydrobenzo[9,10]-1H,1H,3H,3H, 4H,4H,5H,5H,7H,7H,8H,8H-dodecahydrophenanthrene-2,6,10-trioneketal-tri-(4-(4-(3-(9-(4-(2,6-disulfo-cyclohexyl)phenyl))-2,4,8,10-tetra-oxa-spiro[5.5]undecyl))phenyl-1,1-(2,6-dioxa)cyclohexanedimethanol was conveniently synthesized by the reaction of hexahydrobenzo [9,10]dodecahydrophenanthrene-2,6,10-trione ketal-tri-2,2-dihydromethyl-1,3-propanediol with 4-(4-(3-(9-(4-(2,6-disulfo-cyclohexyl)phenyl))-2,4,8,10-tetra-oxa-spiro[5.5]undecyl)) phenyl-1,1-(2,6-dioxa)cyclohexanedimethanol.
引文
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