CN114656430A - 一种3,3-二氟亚甲基核苷化合物及其制备方法与应用 - Google Patents
一种3,3-二氟亚甲基核苷化合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种3,3‑二氟亚甲基核苷化合物及其制备方法与应用。本发明在惰性气体氛围、搅拌条件下,将0.18~0.22mmol(E)‑3‑(二甲基氨基)‑1‑苯基丙‑2‑烯‑1‑酮、0.38~0.42mmol二氟溴乙酸乙酯依次加入到0.58~0.62mmol三正丙胺得到混合液,往混合液中加入1~3mL溶剂四氢呋喃得到反应液,将反应液在5min内升温至95~105℃后反应48小时;在反应结束后过滤除去反应液中的不溶性固体,将所得溶液减压蒸馏、浓缩分离,得到目标产物3,3‑二氟亚甲基核苷化合物。本发明制备方法所需工艺条件简单,反应条件温和;所得化合物可应用在药物分子的偕二氟亚甲基呋喃骨架的制备中。
Description
技术领域
本发明属于有机合成方法学技术领域,尤其涉及一种3,3-二氟亚甲基核苷化合物及其制备方法与应用。
背景技术
二氟卡宾是重要的化工中间体,广泛应用于含氟医药、农药和材料科学。但已发展的的二氟卡宾试剂多集中在XCF2COOR、FSO2CF2COOR、XCF2TMS和Ph3P+CF2CO2 -等,目前已开发的产生二氟卡宾的方法多使用昂贵的金属催化剂,从原子经济性和成本效率来说,需要一种更简单的二氟卡宾策略。
2017年,有研究团队在长期研究过渡金属催化的氟化反应基础上,利用廉价的工业原料二氟一氯甲烷(ClCF2H),对芳香化合物直接二氟甲基化。该方法中,虽然原料易得,但是反应仍然需要过量的底物,当量的添加剂,经过过渡金属催化二氟卡宾的形成。
发明内容
本发明的首要目的在于提供一种3,3-二氟亚甲基核苷化合物。
本发明的再一目的在于经由非金属化合物底物、非金属催化的二氟卡宾机理,提出上述3,3-二氟亚甲基核苷化合物的制备方法,旨在解决解决现有方法使用金属化合物底物和/或过渡金属条件的问题。
本发明的再一目的在于提供上述3,3-二氟亚甲基核苷化合物的应用。
本发明是这样实现的,一种3,3-二氟亚甲基核苷化合物,该化合物的化学结构式如下式(Ⅰ)所示:
本发明公开了一种3,3-二氟亚甲基核苷化合物的制备方法,该方法包括以下步骤:
(1)在惰性气体氛围、搅拌条件下,将0.18~0.22mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.38~0.42mmol二氟溴乙酸乙酯依次加入到0.58~0.62mmol三正丙胺得到混合液,往混合液中加入1~3mL溶剂四氢呋喃得到反应液,将反应液在5min内升温至95~105℃后反应48小时;
(2)反应结束后过滤除去反应液中的不溶性固体,将所得溶液减压蒸馏、浓缩分离,得到目标产物3,3-二氟亚甲基核苷化合物。
优选地,其特征在于,在步骤(1)中,所述惰性气体为氮气。
优选地,在步骤(1)中,将0.2mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.4mmol二氟溴乙酸乙酯依次加入到0.6mmol三正丙胺得到混合液,往混合液中加入2mL溶剂四氢呋喃得到反应液,将反应液升温至100℃后反应48小时。
优选地,在步骤(2)中,所述减压蒸馏通过旋转蒸发仪完成,具体参数为:压力150hPa、水浴温度40℃、蒸发时间15~25min;所述浓缩分离通过层析柱色谱分离技术完成,具体参数为:硅胶200~300目,展开剂极性乙酸乙酯/石油醚=5/95(v/v)。
本发明进一步公开了上述3,3-二氟亚甲基核苷化合物在制备药物分子中偕二氟亚甲基呋喃骨架中的应用。
优选地,所述药物分子包括西达尿苷、吉西他滨、阿兹夫定。
本发明克服现有技术的不足,提供一种3,3-二氟亚甲基核苷化合物及其制备方法与应用。本发明通过二氟溴乙酸乙酯在有机碱的条件下产生二氟卡宾,二氟卡宾与烯胺酮化合物发生环丙烷化反应,环丙烷进一步开环缩合得到3,3-二氟亚甲基核苷,反应方程式为:
本发明制备方法首次使用非金属化合物底物和非金属催化的二氟卡宾制备3,3-二氟亚甲基核苷衍生物,反应有较好的底物适用性和官能团耐受性。
该3,3-二氟亚甲基核苷化合物用于为包括西达尿苷、吉西他滨、阿兹夫定在内的药物分子的合成提供偕二氟亚甲基呋喃骨架,西达尿苷、吉西他滨、阿兹夫定的分子结构如下所示:
其中,本发明3,3-二氟亚甲基核苷化合物与以上药物分子都具有偕二氟亚甲基呋喃骨架,其氨基基团和苯基可以进一步修饰,双键可以通过先进行环氧化反应再还原从而引入羟基基团,其反应过程为:
相比于现有技术的缺点和不足,本发明具有以下有益效果:本发明制备方法所需工艺条件简单,反应条件温和,能够高效得到3,3-二氟亚甲基核苷衍生物,反应有较好的底物适用性和官能团耐受性;同时本发明是首次使用非金属化合物底物和非金属催化的二氟卡宾制备3,3-二氟亚甲基核苷衍生物。
附图说明
图1是本发明实施例中3,3-二氟亚甲基核苷衍生物的1H NMR图谱;
图2是本发明实施例中3,3-二氟亚甲基核苷衍生物的19F NMR图谱;
图3是本发明实施例中3,3-二氟亚甲基核苷衍生物的13C NMR图谱;
图4是本发明应用实施例中季铵盐的1H NMR图谱;
图5是本发明应用实施例中季铵盐的19F NMR图谱;
图6是本发明应用实施例中季铵盐的13C NMR图谱;
图7是本发明应用实施例中引入氮杂环后的3,3-二氟亚甲基核苷化合物的1H NMR图谱;
图8是本发明应用实施例中引入氮杂环后的3,3-二氟亚甲基核苷化合物的19F NMR图谱;
图9是本发明应用实施例中引入氮杂环后的3,3-二氟亚甲基核苷化合物的13C NMR图谱。
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
(1)将0.2mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.4mmol二氟溴乙酸乙酯依次加入到0.6mmol三正丙胺得到混合液,往混合液中加入2mL溶剂四氢呋喃得到反应液,将反应液升温至100℃后反应48小时。
(2)反应结束后过滤除去反应液中的不溶性固体,将所得溶液通过旋转蒸发仪减压蒸馏,具体参数为:压力150hPa、水浴温度40℃、蒸发时间15min;蒸馏产物通过层析柱色谱分离技术完成浓缩分离,具体参数为:硅胶200目,展开剂极性乙酸乙酯/石油醚=5/95(v/v),得到目标产物3,3-二氟亚甲基核苷化合物1。
对3,3-二氟亚甲基核苷化合物进行图谱分析,结果如图1~3所示,其中,图1是3,3-二氟亚甲基核苷衍生物1的1H NMR图谱,图2是其19F NMR图谱,图3是其13C NMR图谱。由谱图结果可以看出,该3,3-二氟亚甲基核苷化合物的化合结构为:
实施例2
(1)在惰性(氮气)气体氛围、搅拌条件下,将0.18mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.42mmol二氟溴乙酸乙酯依次加入到0.58mmol三正丙胺得到混合液,往混合液中加入3mL溶剂四氢呋喃得到反应液,将反应液在5min内升温至95℃后反应48小时;
(2)反应结束后过滤除去反应液中的不溶性固体,将所得溶液通过旋转蒸发仪减压蒸馏,具体参数为:压力150hPa、水浴温度40℃、蒸发时间20min;蒸馏产物通过层析柱色谱分离技术完成浓缩分离,具体参数为:硅胶250目,展开剂极性乙酸乙酯/石油醚=5/95(v/v),得到目标产物3,3-二氟亚甲基核苷化合物2。
实施例3
(1)在惰性(氮气)气体氛围、搅拌条件下,将0.22mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.38mmol二氟溴乙酸乙酯依次加入到0.62mmol三正丙胺得到混合液,往混合液中加入1mL溶剂四氢呋喃得到反应液,将反应液在5min内升温至105℃后反应48小时;
(2)反应结束后过滤除去反应液中的不溶性固体,将所得溶液通过旋转蒸发仪减压蒸馏,具体参数为:压力150hPa、水浴温度40℃、蒸发时间25min;蒸馏产物通过层析柱色谱分离技术完成浓缩分离,具体参数为:硅胶300目,展开剂极性乙酸乙酯/石油醚=5/95(v/v),得到目标产物3,3-二氟亚甲基核苷化合物3。
应用实施例
对3,3-二氟亚甲基核苷化合物上的二甲氨基实现转化:通过合成季铵盐,在金属催化剂条件下引入了其它氮杂环:
该方法包括以下步骤:
(1)在空气氛围、搅拌条件下,向1.0mmol 3,3-二氟亚甲基核苷化合物在3.0mL的乙醚溶液中加入1.1mmol三氟甲磺酸甲酯,在室温下反应30分钟,通过薄层色谱监测完全转化(甲醇/二氯甲烷=1/9,Rf=0.25),然后过滤粗产物,粗产物用乙醚洗涤,得到相应的纯季铵盐。
对该季铵盐进行图谱分析,结果如图4~6所示,其中,图4是季铵盐的1HNMR图谱,图5是其19F NMR图谱,图6是其13C NMR图谱。由谱图结果可以看出,该季铵盐的化合结构为:
(2)在空气氛围、搅拌条件下,向0.1mmol季铵盐在2.0mL的甲苯溶液中加入0.1mmol四氢喹啉和0.2mmol叔丁醇钾。将混合物在室温搅拌约0.5小时。随后将0.005mmol醋酸钯和0.01mmol 2-二-叔丁膦基-2',4',6'-三异丙基联苯添加到反应管中。将反应混合物在100℃搅拌24小时。反应结束后过滤除去反应液中的不溶性固体,将所得溶液通过旋转蒸发仪减压蒸馏,具体参数为:压力150hPa、水浴温度40℃、蒸发时间25min;蒸馏产物通过层析柱色谱分离技术完成浓缩分离,具体参数为:硅胶300目,展开剂极性乙酸乙酯/石油醚=5/95(v/v),得到目标产物。
对该目标产物进行图谱分析,结果如图7~9所示,其中,图7是引入氮杂环后的3,3-二氟亚甲基核苷化合物的1H NMR图谱,图8是其19F NMR图谱,图9是其13C NMR图谱。由谱图结果可以看出,该引入氮杂环后的3,3-二氟亚甲基核苷化合物的化合结构为:
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 (7)
2.权利要求1所述的3,3-二氟亚甲基核苷化合物的制备方法,其特征在于,该方法包括以下步骤:
(1)在惰性气体氛围、搅拌条件下,将0.18~0.22mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.38~0.42mmol二氟溴乙酸乙酯依次加入到0.58~0.62mmol三正丙胺得到混合液,往混合液中加入1~3mL溶剂四氢呋喃得到反应液,将反应液在5min内升温至95~105℃后反应48小时;
(2)反应结束后过滤除去反应液中的不溶性固体,将所得溶液减压蒸馏、浓缩分离,得到目标产物3,3-二氟亚甲基核苷化合物。
3.如权利要求2所述的3,3-二氟亚甲基核苷化合物的制备方法,其特征在于,在步骤(1)中,所述惰性气体为氮气。
4.如权利要求2所述的3,3-二氟亚甲基核苷化合物的制备方法,其特征在于,在步骤(1)中,将0.2mmol(E)-3-(二甲基氨基)-1-苯基丙-2-烯-1-酮、0.4mmol二氟溴乙酸乙酯依次加入到0.6mmol三正丙胺得到混合液,往混合液中加入2mL溶剂四氢呋喃得到反应液,将反应液升温至100℃后反应48小时。
5.如权利要求2所述的3,3-二氟亚甲基核苷化合物的制备方法,其特征在于,在步骤(2)中,所述减压蒸馏通过旋转蒸发仪完成,具体参数为:压力150hPa、水浴温度40℃、蒸发时间15~25min;所述浓缩分离通过层析柱色谱分离技术完成,具体参数为:硅胶200~300目,展开剂极性乙酸乙酯/石油醚=5/95(v/v)。
6.权利要求1所述的3,3-二氟亚甲基核苷化合物在制备药物分子中偕二氟亚甲基呋喃骨架中的应用。
7.如权利要求6所述的应用,其特征在于,所述药物分子包括西达尿苷、吉西他滨、阿兹夫定。
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