CN102311298A - 一种由芳环上溴的氯代制备氯代芳烃的方法 - Google Patents
一种由芳环上溴的氯代制备氯代芳烃的方法 Download PDFInfo
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Abstract
本发明属于精细化工领域,涉及医药化工中间体及相关化学技术,具体地说是一种由芳环上溴的氯代制备氯代芳烃的方法。其特征在于:以溴代芳烃为原料,以铜的氧化物或铜盐作催化剂,并使用L-脯氨酸等双齿配体,在有机溶剂中通过芳环上溴的氯代反应制备氯代芳烃。本发明主要是提供一种新的氯代芳烃的制备方法,该方法具有反应条件温和、官能团兼容性好、底物范围广、环境友好等优点。
Description
技术领域
本发明涉及医药化工中间体及相关化学技术领域,涉及到一种由芳环上溴的氯代制备氯代芳烃的方法。
背景技术
氯代芳烃是重要的化工中间体,也是许多医药和农药分子的重要组成单元,而且氯原子的引入还可以改变芳香族化合物的一些物理和生物学性质。制备氯代芳烃的经典方法有芳烃的直接亲电取代氯化以及通过Sandmeyer反应的氯化等。但是,由于前者反应剧烈而存在反应选择性差的缺点,通常生成一氯取代、二氯取代及多氯取代产物的混合物;而后者需经硝化反应、还原反应、重氮化反应和氯代反应等多个反应步骤,因而存在环境污染严重、能耗高等不足。
1958年,Hardy等人首次报道了芳环上溴的氯代反应,使用氯化亚铜作氯源,成功的将2-乙酰胺基-3-溴蒽醌转变成2-乙酰氨基-3-氯蒽醌,该氯代物是一种重要的水溶性还原染料的中间体,使用通常的氯化方法是难以制备的(参见:W.B.Hardy,R.B.Fortenbaugh,J.Am.Chem.Soc.,1958,80:1716-1718.)。1975年,Cramer小组首次实现了氯化镍催化剂作用下溴代芳烃上溴的氯代反应,但是该反应需要210℃的高温(参见:R.Cramer,D.R.Coulson,J.Org.Chem.,1975,40:2267-2273.)。此外,还有一些化学计量的过渡金属作用下芳环上溴的氯代反应报道(参见:(a)R.G.R.Bacon,H.A.O.Hill,J.Chem.Soc.,1964,1097-1107;(b)R.G.R.Bacon,H.A.O.Hill,J.Chem.Soc.,1964,1108-1112;(c)R.K.Arvela,N.E.Leadbeater,Synlett,2003,1145-1148.),但通常需要较为较苛刻的反应条件(反应温度大于150℃或两倍量以上的过渡金属),或需要在微波条件下进行。因此,如何在较温和的条件下通过过渡金属催化溴代芳环上溴的氯代、进而转化为相应的氯代芳烃是一项十分有意义的研究工作。
发明内容
本发明提供了一种新的氯代芳烃的制备方法,该方法的合成路线短、条件温和、环境友好、易实现工业化;该方法在L-脯氨酸等N,N-双齿或N,O-双齿配体存在下,使用铜的氧化物或铜盐作催化剂,具有易得、廉价的优点。
本发明是以溴代芳烃为原料,通过芳环上溴的催化氯代合成氯代芳烃。合成路线如下:
该方法采用的技术方案如下:
(1)氯代芳烃的合成:将溴代芳烃、氯源、铜的氧化物或铜盐催化剂、配体,依次加入到反应器中,氮气置换三次后,加入一定量的有机溶剂,置于油浴中反应。
溴代芳烃包括溴代苯化合物、溴代萘化合物或溴代杂环化合物。
溴代芳烃上的R是氢、卤素、烷基、氨基、氰基、酰基、羧基、醛基、酯基或硝基等;其可以在芳环上的邻位、间位或对位。
溶剂包括:苯、甲苯、邻二甲苯、1,4-二氧六环、二甲基亚砜、乙醇、甲醇、叔丁醇、异丙醇、三氯甲烷、二氯甲烷、乙醚、丙醚、正丁醚、四氯化碳、己二酸二甲酯、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、环己烷、正己烷或正庚烷。优选乙酸乙酯、乙醇、1,4-二氧六环、二甲基亚砜。
反应温度范围为50℃~200℃,优选80℃~120℃。
反应时间范围为12小时~36小时,优选20小时~30小时。
所用氯源包括以下试剂:氯化铵、氯化钠、N-(N,N-二甲基咪唑啉)四甲基氯化胍、四甲基氯化铵或四正丁基氯化铵等,优选N-(N,N-二甲基咪唑啉)四甲基氯化胍、四甲基氯化铵或四正丁基氯化铵。
铜的氧化物或铜盐催化剂选自碘化亚铜、溴化亚铜、氯化亚铜、氧化亚铜、醋酸铜、氯化铜或氧化铜等。优选碘化亚铜、氧化亚铜或醋酸铜。
配体选自含4-[2-(二苯基膦)苯基]吗啉、乙二胺、L-脯氨酸、1,6-己二胺等N,N-双齿配体或N,O-双齿配体。优选乙二胺、L-脯氨酸、1,6-己二胺。
有机溶剂的量为0.1~10mL。
溴代芳烃与氯源的摩尔比为1∶1~1∶20。
溴代芳烃与催化剂的摩尔比为1∶0.01~1∶1。
配体与催化剂的摩尔比为1∶0.01~1∶1。
(2)氯代芳烃的定量分析:反应步骤(1)中得到的反应液,经硅胶柱滤至10mL的容量瓶中,并用有机溶剂将溶液体积定量至指定刻度。使用气相色谱进行分析。
用于定量的有机溶剂包括:苯、甲苯、邻二甲苯、1,4-二氧六环、二甲基亚砜、乙醇、甲醇、叔丁醇、异丙醇、三氯甲烷、二氯甲烷、乙醚、丙醚、正丁醚、四氯化碳、己二酸二甲酯、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、环己烷、正己烷或正庚烷等。
具体实施方式
本发明所述的氯代芳烃的制备方法,具有反应步骤少、催化剂和配体价格低廉、反应条件温和及环境友好等优点,展现出良好的应用前景。
下面结合具体实施例,进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。在本领域内的技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案之内。
实施例1:
准确称取对溴甲苯(34.2mg,0.2mmol)、四甲基氯化铵(TMAC,43.9mg,0.4mmol)、氯化亚铜(2.0mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的异丙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯甲苯的产率为98%。
实施例2:
准确称取对溴苯胺(34.4mg,0.2mmol)、TMAC(43.9mg,0.4mmol)、氯化亚铜(2.0mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的异丙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯苯胺的产率为93%。
实施例3:
准确称取对溴甲苯(34.2mg,0.2mmol)、TMAC(43.9mg,0.4mmol)、氧化亚铜(2.9mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的DMSO(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯甲苯的产率为65%。
实施例4:
准确称取对溴甲苯(34.2mg,0.2mmol)、TMAC(43.9mg,0.4mmol)、CuI(3.8mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯甲苯的产率为83%。
实施例5:
准确称取对溴甲苯(34.2mg,0.2mmol)、TMAC(43.9mg,0.4mmol)、氧化亚铜(2.9mg,0.02mmol),并依次加入到25mL的Schlenk瓶中,加入乙二胺(2.4μL,0.04mmol)、精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯甲苯的产率为51%。
实施例6:
准确称取对溴甲苯(34.2mg,0.2mmol)、氯化钠(23.4mg,0.4mmol)、氧化亚铜(2.9mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯甲苯的产率为72%。
实施例7:
准确称取间溴硝基苯(40.4mg,0.2mmol)、TMAC(43.9mg,0.4mmol)、氧化亚铜(2.9mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,间氯硝基苯的产率为92%。
实施例8:
准确称取1-溴代萘(27.8μL,0.2mmol)、TMAC(87.7mg,0.8mmol)、氧化亚铜(5.8mg,0.04mmol)、L-脯氨酸(9.2mg,0.08mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,1-氯代萘的产率为86%。
实施例9:
准确称取2-溴吡啶(19.1μL,0.2mmol)、TMAC(43.9mg,0.4mmol)、氧化亚铜(2.9mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,2-氯吡啶的产率为94%。
实施例10:
准确称取对溴氟苯(22.0μL,0.2mmol)、TMAC(43.9mg,0.4mmol)、氧化亚铜(2.9mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对氯氟苯的产率为95%。
实施例11:
准确称取对二溴苯(47.2mg,0.2mmol)、TMAC(87.7mg,0.8mmol)、氧化亚铜(2.9mg,0.02mmol)、L-脯氨酸(4.6mg,0.04mmol),并依次加入到25mL的Schlenk瓶中,加入精制过的乙醇(1.0mL),置于110℃油浴中反应20h。反应结束后,将反应液通过硅胶柱滤至10mL的容量瓶中,并用乙酸乙酯将溶液体积定量至指定刻度。使用气相色谱进行分析,对二氯苯的产率为99%。
Claims (9)
1.一种由芳环上溴的氯代制备氯代芳烃的方法,以溴代芳烃为原料,与氯源反应,氯取代芳环上的溴得到氯代芳烃,其特征是合成路线如下:
将溴代芳烃、氯源、催化剂、配体,依次加入到反应器中,加入有机溶剂进行反应,反应温度50℃~200℃;反应时间12~36h;催化剂为铜的氧化物或铜盐;将获得的反应液,经硅胶柱分离制得氯代芳烃;
溴代芳烃包括溴代苯化合物、溴代萘化合物或溴代杂环化合物;
溴代芳烃上的R是氢、卤素、烷基、氨基、氰基、酰基、羧基、醛基、酯基或硝基,在芳环上的邻位、间位或对位。
2.根据权利要求1中所述的方法,其特征在于,所述氯源选自氯化铵、氯化钠、N-(N,N-二甲基咪唑啉)四甲基氯化胍、四甲基氯化铵或四正丁基氯化铵;溴代芳烃与氯源的摩尔比为1∶1~1∶20。
3.根据权利要求书1中所述的方法,其特征在于,所述铜的氧化物或铜盐催化剂选自碘化亚铜、溴化亚铜、氯化亚铜、氧化亚铜、醋酸铜、氯化铜或氧化铜;溴代芳烃与催化剂的摩尔比为1∶0.01~1∶1。
4.根据权利要求书1中所述的方法,其特征在于,所述的配体选自含4-[2-(二苯基膦)苯基]吗啉、乙二胺、L-脯氨酸、1,6-己二胺等N,N-双齿配体或N,O-双齿配体。
5.根据权利要求书1中所述的方法,其特征在于,所述的配体与催化剂的摩尔比为1∶0.01~1∶1。
6.根据权利要求1中所述的方法,其特征还在于,所述有机溶剂选自苯、甲苯、 邻二甲苯、1,4-二氧六环、二甲基亚砜、乙醇、甲醇、叔丁醇、异丙醇、三氯甲烷、二氯甲烷、乙醚、丙醚、正丁醚、四氯化碳、己二酸二甲酯、乙酸乙酯、石油醚、甲基叔丁基醚、四氢呋喃、环己烷、正己烷或正庚烷。
7.根据权利要求书6中所述的方法,其特征在于,所述的有机溶剂的量为0.1~10mL。
8.根据权利要求1中所述的方法,其特征还在于,反应在氮气保护下进行。
9.根据权利要求6或7所述的一种氯代芳烃的制备方法,其特征在于,所述的有机溶剂是单一溶剂或混合溶剂。
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CN104140347A (zh) * | 2014-07-15 | 2014-11-12 | 大连理工大学 | 一种由芳环上溴的碘代制备碘代芳烃的方法 |
CN111825702A (zh) * | 2019-04-22 | 2020-10-27 | 成都科岭源医药技术有限公司 | 一种氮杂*并吲唑类衍生物及其制备方法和用途 |
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CN111825702A (zh) * | 2019-04-22 | 2020-10-27 | 成都科岭源医药技术有限公司 | 一种氮杂*并吲唑类衍生物及其制备方法和用途 |
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CN113480483A (zh) * | 2021-08-17 | 2021-10-08 | 浙江致新医药科技有限公司 | 一种依曲韦林氯代杂质的制备方法 |
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