CN108689893A - 一种炔丙基砜类化合物及其制备方法与应用 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
本发明公开了一种炔丙基砜类化合物及其制备方法与应用。本发明通过将炔醇加入反应溶剂中，按反应摩尔比再加入亚磺酸底物，在温和的反应温度下搅拌进行反应，将得到的反应体系除去反应溶剂后进一步纯化后得到炔丙基砜类化合物。本发明制备方法所需反应条件十分温和、绿色，原子经济性高，适用的底物范围广泛，所得到的炔丙基砜类化合物有潜在的药物活性和生物活性，是在生物和药物活性分子中广泛存在的重要骨架，例如存在于组织蛋白抑制剂、癌症抑制剂，DNA切断剂、除草剂等生物和药物活性分子中。
Description
技术领域
本发明属于有机化学合成技术领域，尤其涉及一种炔丙基砜类化合物及其制备方法与应用。
背景技术
砜类化合物在有机合成中起着重要的作用，由于其独特的化学，生物学和药学活性，砜骨架作为重要的结构部分在各种天然产物中普遍存在，广泛用于制药，农业化学和材料科学。例如偏头痛药和抑制剂，以及一些用于治疗前列腺癌的药物中，在一些抗菌剂和除草剂等生物药物活性分子中也广泛分布。
炔丙基砜由于其独特的反应活性而存在于在许多天然产物和药物中。然而，传统的方法通常受到化学计量氧化剂和添加剂的影响，从而限制了它们的应用。另外，考虑到环境和经济问题，从无毒，廉价，易得和无害环境的原料开发节能和绿色合成炔丙基砜方法是非常有吸引力和必不可少的。
发明内容
本发明的目的在于提供一种炔丙基砜类化合物，不需金属催化的脱水偶联构建C-S键。
本发明的再一目的在于提供上述炔丙基砜类化合物的制备方法，该方法操作简单，条件温和，绿色环保，原子经济性高，底物适用范围较广。
本发明的再一目的在于提供上述炔丙基砜类化合物的应用。
本发明是这样实现的，一种炔丙基砜类化合物的制备方法，该方法包括以下步骤：将炔醇加入反应溶剂中，按反应摩尔比再加入亚磺酸底物，在温和的反应温度下搅拌进行反应，将得到的反应体系除去反应溶剂后进一步纯化后得到目标产物。
优选地，所述炔醇包括二级炔醇、三级炔醇。
优选地，所述炔醇为1,3-二苯基-2-丙炔-1-醇、1,3-二苯基-2-丁炔-1-醇、1-(4-溴苯基)-3-苯基-2-丙炔-1-醇、2-(1-羟基-3-苯基-2-丙炔基)苯酚、2-(4-氯苯基)-4-苯基-3-丁炔-2-醇、4-苯基-2-(对甲苯基)-3-丁炔-2-醇、2-(3-氯苯基)-4-苯基-3-丁炔-2-醇、4-苯基-2-(邻甲苯基)3-丁炔-2-醇、2-苯基-4-(对甲苯基)-3-丁炔-2-醇中的任意一种。
优选地，所述炔醇为1,3-二苯基-2-丙炔-1-醇，该1,3-二苯基-2-丙炔-1-醇的合成方法包括以下步骤：
A、在-78℃下，将含有正丁基锂的(1.30～1.32)mL正己烷溶液加入到含有苯乙炔的(5～6)mL无水四氢呋喃溶液中，搅拌1小时，加入0.305mL苯甲醛，得到反应混合物；其中，所述正丁基锂、苯乙炔的摩尔比为1:1；
B、将反应混合物转到室温并搅拌1小时，用饱和的氯化铵水溶液淬灭，所得水溶液用(2～15)mL乙酸乙酯萃取，合并的有机层用20mL饱和食盐水洗涤；
C、将有机层用无水硫酸钠干燥后，减压除去溶剂，通过硅胶色谱法用石油醚和乙酸乙酯(PE/EA)纯化残余物，得到淡黄色油状液体1,3-二苯基-2-丙炔-1-醇。
优选地，在步骤A中，所述正己烷溶液中正丁基锂的浓度为3.3mmol/1.32mL；所述四氢呋喃溶液中苯乙炔的浓度为3.3mmol/6mL。
优选地，所述反应溶剂为水、无水乙醇、二氯甲烷、甲苯、1，4-二氧六环、四氢呋喃、乙腈、异丙醇中的任意一种。
优选地，所述反应溶剂为水。
优选地，所述反应是在室温下进行，反应时长为12h；所述除去反应溶剂为采用真空旋转蒸发器除去反应溶剂。
优选地，所述纯化采用的是柱层析法，展开剂为石油醚/乙酸乙酯＝95：5。
本发明进一步公开了上述制备方法得到的炔丙基砜类化合物在做为生物和药物活性分子中的骨架方面的应用。该炔丙基砜类化合物是在生物和药物活性分子中广泛存在的重要骨架，例如存在于组织蛋白抑制剂、癌症抑制剂，DNA切断剂、除草剂等生物和药物活性分子中。
相比于现有技术的缺点和不足，本发明具有以下有益效果：
(1)本发明炔丙基砜类化合物的制备方法所需要的条件十分温和、绿色，原子经济性高，底物适用范围广，如磺酰基S上可以是各种取代苯基、杂环、烷基；此外，二级醇、三级醇也可以和亚磺酸顺利反应得到目标产物。
(2)该炔丙基砜类化合物有潜在的药物活性和生物活性，是在生物和药物活性分子中广泛存在的重要骨架，例如存在于组织蛋白抑制剂、癌症抑制剂，DNA切断剂、除草剂等生物和药物活性分子中。
附图说明
图1是本发明实施例中1,3-二苯基-3-对甲苯磺酰基-1-丙炔的核磁共振氢谱图；
图2是本发明实施例中1,3-二苯基-3-对甲苯磺酰基-1-丙炔的核磁共振碳谱图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
实施例1
A、在-78℃下，将含有正丁基锂的1.32mL正己烷溶液加入到含有苯乙炔的6mL无水四氢呋喃溶液中，搅拌1小时，加入0.305mL苯甲醛，反应方程式为：
得到反应混合物；其中，所述正丁基锂、苯乙炔的摩尔比为1:1；
B、将反应混合物转到室温并搅拌1小时，用饱和的氯化铵水溶液淬灭，所得水溶液用(2～15)mL乙酸乙酯萃取，合并的有机层用20mL饱和食盐水洗涤；
C、将有机层用无水硫酸钠干燥后，减压除去溶剂，通过硅胶色谱法用石油醚和乙酸乙酯(PE/EA)纯化残余物，得到淡黄色油状液体1,3-二苯基-2-丙炔-1-醇，产率95％。
实施例2
与实施例1相同，不同之处在于，所述正己烷溶液中正丁基锂的浓度为3.3mmol/1.32mL；所述四氢呋喃溶液中苯乙炔的浓度为3.3mmol/6mL，得到淡黄色油状液体1,3-二苯基-2-丙炔-1-醇产率为97％。
实施例3
(1)在10ml反应管中加入1,3-二苯基-2-丙炔-1-醇(0.3mmol)，加入乙腈2ml,再加入对甲基苯亚磺酸(0.45mmol)，室温搅拌12h，反应方程式为：
(2)TLC监测反应完全后，将反应液转移至25ml鸡心瓶中，用真空旋转蒸发器除去乙腈，柱层析法分离产物，展开剂为石油醚/乙酸乙酯＝95：5，产物为淡黄色固体1,3-二苯基-3-对甲苯磺酰基-1-丙炔，收率91％。
实施例4
该实施例与上述实施例3相同，不同之处在于，在10ml反应管中加入1,3-二苯基-2-丙炔-1-醇(0.3mmol)，得到1,3-二苯基-3-对甲苯磺酰基-1-丙炔。
实施例5
该实施例与上述实施例3相同，不同之处在于，在10ml反应管中加入4-苯基-2-(对甲苯基)-3-丁炔-2-醇(0.3mmol)，得到1-甲基-4-(4-苯基-2-对甲苯磺酰基-3-丁炔基)苯。
实施例6
该实施例与上述实施例3相同，不同之处在于，在10ml反应管中加入2-苯基-4-(对甲苯基)-3-丁炔-2-醇(0.3mmol)，得到1-甲基-4-(3-苯基-3-对甲苯磺酰基-1-丁炔基)苯。
应用实施例
本发明上述实施例3～6中所制得的炔丙基砜类化合物是癌症调节剂(抑制剂)和除草剂结构中存在的重要骨架，例如，本发明炔丙基砜类化合物与癌症调节剂结合后的结构如下式所示：
本发明炔丙基砜类化合物与除草剂结合后的结构如下式所示：
效果实施例
将实施例3中制得的产物1,3-二苯基-3-对甲苯磺酰基-1-丙炔进行核磁共振试验，如图1～2所示，图1是1,3-二苯基-3-对甲苯磺酰基-1-丙炔的核磁共振氢谱，图2是1,3-二苯基-3-对甲苯磺酰基-1-丙炔的核磁共振碳谱。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种炔丙基砜类化合物的制备方法，其特征在于，该方法包括以下步骤：将炔醇加入反应溶剂中，按反应摩尔比再加入亚磺酸底物，在温和的反应温度下搅拌进行反应，将得到的反应体系除去反应溶剂后进一步纯化后得到目标产物。
2.如权利要求1所述的炔丙基砜类化合物的制备方法，其特征在于，所述炔醇包括二级炔醇、三级炔醇。
3.如权利要求2所述的炔丙基砜类化合物的制备方法，其特征在于，所述炔醇为1,3-二苯基-2-丙炔-1-醇、1,3-二苯基-2-丁炔-1-醇、1-(4-溴苯基)-3-苯基-2-丙炔-1-醇、2-(1-羟基-3-苯基-2-丙炔基)苯酚、2-(4-氯苯基)-4-苯基-3-丁炔-2-醇、4-苯基-2-(对甲苯基)-3-丁炔-2-醇、2-(3-氯苯基)-4-苯基-3-丁炔-2-醇、4-苯基-2-(邻甲苯基)3-丁炔-2-醇、2-苯基-4-(对甲苯基)-3-丁炔-2-醇中的任意一种。
4.如权利要求3所述的炔丙基砜类化合物的制备方法，其特征在于，所述炔醇为1,3-二苯基-2-丙炔-1-醇，该1,3-二苯基-2-丙炔-1-醇的合成方法包括以下步骤：
A、在-78℃下，将含有正丁基锂的(1.30～1.32)mL正己烷溶液加入到含有苯乙炔的(5～6)mL无水四氢呋喃溶液中，搅拌1小时，加入0.305mL苯甲醛，得到反应混合物；其中，所述正丁基锂、苯乙炔的摩尔比为1:1；
B、将反应混合物转到室温并搅拌1小时，用饱和的氯化铵水溶液淬灭，所得水溶液用(2～15)mL乙酸乙酯萃取，合并的有机层用20mL饱和食盐水洗涤；
C、将有机层用无水硫酸钠干燥后，减压除去溶剂，通过硅胶色谱法用石油醚和乙酸乙酯(PE/EA)纯化残余物，得到淡黄色油状液体1,3-二苯基-2-丙炔-1-醇。
5.如权利要求4所述的炔丙基砜类化合物的制备方法，其特征在于，在步骤A中，所述正己烷溶液中正丁基锂的浓度为3.3mmol/1.32mL；所述四氢呋喃溶液中苯乙炔的浓度为3.3mmol/6mL。
6.如权利要求1所述的炔丙基砜类化合物的制备方法，其特征在于，所述反应溶剂为水、无水乙醇、二氯甲烷、甲苯、1，4-二氧六环、四氢呋喃、乙腈、异丙醇中的任意一种。
7.如权利要求6所述的炔丙基砜类化合物的制备方法，其特征在于，所述反应溶剂为水。
8.如权利要求1所述的炔丙基砜类化合物的制备方法，其特征在于，所述反应是在室温下进行，反应时长为12h；所述除去反应溶剂为采用真空旋转蒸发器除去反应溶剂。
9.如权利要求1所述的炔丙基砜类化合物的制备方法，其特征在于，所述纯化采用的是柱层析法，展开剂为石油醚/乙酸乙酯＝95：5。
10.权利要求1～9任一项所述的制备方法得到的炔丙基砜类化合物在做为生物和药物活性分子中的骨架方面的应用。
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