CN112010803B - 二甲基取代杂环化合物的三氟甲基化反应 - Google Patents

二甲基取代杂环化合物的三氟甲基化反应 Download PDF

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CN112010803B
CN112010803B CN201910451021.8A CN201910451021A CN112010803B CN 112010803 B CN112010803 B CN 112010803B CN 201910451021 A CN201910451021 A CN 201910451021A CN 112010803 B CN112010803 B CN 112010803B
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dibenzothiophene
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CN112010803A (zh
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周晓聪
何鑫奕
严普查
李原强
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Zhejiang Raybow Pharmaceutical Co ltd
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Abstract

本发明涉及一种通过三氟甲基化反应引入三氟甲基基团的方法，该方法使用的三氟甲基化试剂为Umemoto试剂，底物为广泛的含有二甲基取代基的化合物。本发明的优势体现在底物的普遍性上，Umemoto试剂以往作用的底物，反应位点往往是在环上，本发明的三氟甲基化作用的位点是二甲基链上的碳，这在底物的丰富性选择以及三氟甲基化反应上是一次飞跃和突破。

Description

二甲基取代杂环化合物的三氟甲基化反应
技术领域
本发明涉及一种通过三氟甲基化反应引入三氟甲基基团的方法，该方法使用的氟化试剂为Umemoto试剂，底物为广泛的含有二甲基取代基的化合物。
背景技术
本发明旨在通过三氟甲基化反应制备得到更多的具有药用活性的药物结构化合物或中间体化合物，如辉瑞公司的国际专利申请WO2008059370中，涉及的如下结构的化合物：
如诺华公司的国际专利申请WO2012175522中，涉及如下结构的化合物：
还有一些中间体化合物，如：Bioorg.Med.Chem.Lett.23(2013)3741–3748和WO2012175522中的中间体，
如WO2012016970中的中间体，
如Org.Lett.2018,20,5497-5501中的中间体，
本发明提供的三氟甲基化的方法，能够高选择性的制备得到这些中间体化合物，进一步用于药用化合物结构的制备。
发明内容
本发明提供了一种经三氟甲基化反应引入三氟甲基基团的方法，该方法使用的三氟甲基化试剂为Umemoto试剂，底物为广泛的含有二甲基取代基的化合物。本发明的优势体现在底物的普遍性上，Umemoto试剂以往作用的底物，反应位点往往是在环上，本发明的三氟甲基化作用的位点是二甲基链上的碳，这在底物的丰富性选择以及三氟甲基化反应上是一次飞跃和突破。
首先，本发明提供的三氟甲基化反应的技术方案为：
其中，Het环表示芳环，R1为芳环上的取代基，Het芳环可以与R1一起形成并芳环或稠芳环，R1还可以为氢。
较优选地，所述芳环为杂芳环，如吡啶，嘧啶，吡咯，哌嗪或它们之间的并环或稠环。所述R1为烷基，烷氧基，硝基，氨基或卤素等，其中，卤素较优选地为溴或氯。
所述三氟甲基化试剂为Umemoto试剂，结构式为：
R1,R2,R3和R4各自独立地是氢原子、卤素原子或具有1至4个碳的烷基；X-是酸的共轭碱；Y是碱金属原子、铵基团或磷基团；Z是卤素原子。
Umemoto试剂即S-(三氟甲基)二苯并噻吩盐可经商业市售获得或可根据期刊文献中报导的制备方法制备获得(参见J.Org.Chem.,2017,82,7708-7719；WO 2016/146040；Eur.J.Org.Chem.,2009,1390-1397；J.Am.Chem.Soc.,1993,115,2156-2164；J.FluorineChem.,1999,98,75-81).下述列举的都是合适的S-(三氟甲基)二苯并噻吩盐，例如S-(三氟甲基)二苯并噻吩三氟酸盐、S-(三氟甲基)二苯并噻吩四氟硼酸盐、2,8-二氟-S-(三氟甲基)二苯并噻吩三氟酸盐、2,8-二氟-S-(三氟甲基)二苯并噻吩四氟酸盐、2，8-二氟-S-(三氟甲基)二苯并噻吩氯化物，2，8-二氟-S-(三氟甲基)二苯并噻吩氯化物，2，8-二氟-S-(三氟甲基)二苯并噻吩氯/乙腈复合物，2，8-二氟-S-(三氟甲基)二苯并噻吩溴化物，2，8-二氟-S-(三氟甲基)甲基)二苯并噻吩六氟磷酸盐，2，8-二氟-S-(三氟甲基)二苯并噻吩硫酸氢盐，2，6-二氟-S-(三氟甲基)二苯并噻吩三亚硫酸盐，3，7-二氟-S-(三氟甲基)二苯并噻吩三亚硫酸盐，2，3，7，8-四氟-S-(三氟甲基)二苯并噻吩三氟甲磺酸盐，2，3，7，8-四氟-S-(三氟甲基)二苯并四氟硼酸二苯并噻吩，2，3，7，8-四氟-S-(三氟甲基)二苯并噻吩氯化物，2，8-二甲基-S-(三氟甲基)二苯并噻吩三氟甲磺酸盐，3，7-二(叔丁基)-S-(三氟甲基)二苯并噻吩，2，4，6，8-四甲基-S-四甲基-(三氟甲基)二苯并噻吩三氟甲磺酸盐等。
进一步地，本发明提供的三氟甲基化反应的技术方案为：
其中，R为氢，烷基，烷氧基，硝基，氨基或卤素等，其中，卤素较优选地为溴或氯。
本发明提供地上述方法主要涉及对杂芳环化合物上的二甲基取代基碳链位点上的三氟甲基化。
比较优选地，本发明反应步骤还包括：先对二甲基取代基碳链位点上的碳进行去质子化处理，
，
进行去质子化处理的条件为在碱性条件下。所述碱为碱金属氢氧化物如NaOH、KOH、LiOH等；金属醇盐如甲醇钠、乙醇钠、丙氧基丙酸钠、异丙醇钠、叔丁醇钠、甲醇钾、乙醇钾、丙氧基钾、异丙氧基钾、叔丁醇、甲醇锂、乙醇锂、叔丁醇锂等；金属氢化物如氢化钠、氢化钾或氢化锂；金属如锂、钠或钾；氢氧化铵如四甲基氢氧化铵、四乙基氢氧化铵；氢氧化四丁基铵、苄基三甲基氢氧化铵、苄基三乙基氢氧化铵等。
所述去质子化处理的溶剂为本领域常用的溶剂。所述溶剂可以为，酰胺类如N，N-二甲基甲酰胺、N-甲基甲酰胺、N，N-二甲基乙酰胺、N-甲基乙酰胺、1-甲基-2-吡咯烷酮、六甲基磷酸三酰胺等；腈类如乙腈、丙腈等；醚类如二乙醚、四氢呋喃、1，2-二甲氧基乙烷、二氧六环等；亚砜类或砜类如二甲基亚砜、四甲基砜(环丁砜)等；内酯类如丁内酯、戊内酯等；碳酸酯类如碳酸二甲酯、碳酸二乙酯、碳酸甲乙酯、碳酸亚乙酯、碳酸丙烯酯等；酮类如丙酮、乙基甲基酮、环己酮等；酯类如乙酸甲酯、乙酸乙酯等；醇类如甲醇、乙醇、丙醇、异丙醇、丁醇、仲丁醇、异丁醇、叔丁醇等；或水等。所述溶剂可以为上述列举的溶剂的单一溶剂或混合溶剂。
进一步地，本发明所提供地三氟甲基化反应的底物，可以为如下的结构：
较优选地，为如下结构的化合物：
本发明提供的上述经三氟甲基化反应引入三氟甲基基团的方法，该方法使用的三氟甲基化试剂为Umemoto试剂，在此之前，仅仅是对环上引入三氟甲基，而本发明变化了反应的位点，更多的三氟甲基化合物或中间体被制备得到。
具体实施方式
实施例1：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2a。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，收率77％。
实施例2：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2b。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，收率82％。
实施例3：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，收率84％。
实施例4：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率82％。
实施例5：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率65％。
实施例6：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-30℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率74％。
实施例7：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡啶，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-78℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率86％。
实施例8：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡啶，5mL DMF,冰水浴冷却，加入1.1mmol氢化钠。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率81％。
实施例9：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡啶，5mL DMF,冰水浴冷却，加入1.1mmol LiHMDS。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率78％。
实施例10：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-甲氧基吡啶，2.5mL DMF,2.5mL THF冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率79％。
实施例11：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-甲氧基吡啶，5mL THF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率71％。
实施例12：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基-4-溴吡嗪，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率83％。
实施例13：
氮气保护下，向10mL反应管中加入1.0mmol 2-异丙基喹啉，5mL DMF,冰水浴冷却，加入1.1mmol叔丁醇钾。冰水浴搅拌30min后，冷却至-50℃,加入1.2mmol梅本试剂2c。反应混合物-50℃搅拌1h，然后移至室温搅拌0.5h。加入20mL水，乙酸乙酯萃取3次(25mL×3)，合并乙酸乙酯层，水洗，无水硫酸镁干燥。抽滤，减压浓缩干后，柱层析纯化得无色液体，产率80％。

Claims (4)

1.一种经三氟甲基化反应制备三氟甲基化合物的方法，其特征在于，以式I化合物为底物，先在碱性条件下和溶剂存在的条件下对式I化合物中二甲基取代基碳链位点上的碳进行去质子化处理，再在三氟甲基化试剂的作用下，经三氟甲基化反应制备得到式II化合物，
所述式I化合物选自如下化合物：
所述三氟甲基化试剂结构式为：
R1,R2,R3和R4各自独立地是氢原子、卤素原子或具有1至4个碳的烷基；
X-是酸的共轭碱；
所述碱性条件中的碱选自叔丁醇钠、叔丁醇锂、氢化钠、氢化钾或氢化锂。
2.根据权利要求1所述的制备方法，其特征在于，所述三氟甲基化试剂为S-(三氟甲基)二苯并噻吩三氟酸盐、S-(三氟甲基)二苯并噻吩四氟硼酸盐、2,8-二氟-S-(三氟甲基)二苯并噻吩三氟酸盐、2,8-二氟-S-(三氟甲基)二苯并噻吩四氟酸盐、2，8-二氟-S-(三氟甲基)二苯并噻吩氯化物、2，8-二氟-S-(三氟甲基)二苯并噻吩氯化物、2，8-二氟-S-(三氟甲基)二苯并噻吩溴化物、2，8-二氟-S-(三氟甲基)甲基)二苯并噻吩六氟磷酸盐、2，8-二氟-S-(三氟甲基)二苯并噻吩硫酸氢盐、2，6-二氟-S-(三氟甲基)二苯并噻吩三亚硫酸盐、3，7-二氟-S-(三氟甲基)二苯并噻吩三亚硫酸盐、2，3，7，8-四氟-S-(三氟甲基)二苯并噻吩三氟甲磺酸盐、2，3，7，8-四氟-S-(三氟甲基)二苯并噻吩氯化物、2，8-二甲基-S-(三氟甲基)二苯并噻吩三氟甲磺酸盐或2，4，6，8-四甲基-S-四甲基-(三氟甲基)二苯并噻吩三氟甲磺酸盐。
3.根据权利要求1或2所述的制备方法，其特征在于，所述有机溶剂为酰胺类，腈类，醚类，亚砜类，砜类，酮类，酯类，醇类或水的单一溶剂或混合溶剂。
4.根据权利要求1所述的制备方法，其特征在于，所述式I化合物为如下结构的化合物，
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108239021A (zh) * 2016-12-27 2018-07-03 浙江九洲药物科技有限公司 一种溴代吡啶及其衍生物的三氟甲基化工艺

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108239021A (zh) * 2016-12-27 2018-07-03 浙江九洲药物科技有限公司 一种溴代吡啶及其衍生物的三氟甲基化工艺

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Hao Wang et al.."Visible-light-promoted and photocatalyst-free trifluoromethylation of enamides".《Science China: Chemistry》.2016,第59卷(第2期),第195–198页. *
Hiromichi Egami et al.."Simple Photo-Induced Trifluoromethylation of Aromatic Rings".《Synthesis》.2018,第50卷第2948-2953页. *

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