CN108239021A - 一种溴代吡啶及其衍生物的三氟甲基化工艺 - Google Patents
一种溴代吡啶及其衍生物的三氟甲基化工艺 Download PDFInfo
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Abstract
本发明属于有机化学领域，涉及一种溴代吡啶及其衍生物的三氟甲基化工艺。本发明以式a结构溴代吡啶化合物为原料在式c结构梅本试剂氟代‑S‑(三氟甲基)‑二苯并噻吩盐的作用下经三氟甲基化工艺制备得到式b结构三氟甲基吡啶化合物的工艺，其中，X‑为布朗斯特共轭碱，R为H或‑CN或卤素或C1‑C6的烷基或C1‑C6的烷氧基或‑OH或‑R1OH或COR2或‑CO2R3或‑CONR4或‑NR5R6；R1为C1‑C6的烷基，R2、R3、R4相同或不同地为H或C1‑C6的烷基，R5、R6相同或不同地为H或O或C1‑C6的烷基或C1‑C6的烷氧基。
Description
技术领域
本发明属于有机化学领域,尤其涉及有机氟化学领域。
背景技术
近年来，科学家在研究中发现，将三氟甲基引入有机化合物分子中，能够提高化合物的亲脂性，进而提高对生物体膜和组织的渗透性及与生物体反应时的电子吸引性，最终实现增强化合物生理活性的目的，随着研究的逐步深入，三氟甲基类化合物在医药、农药、化学材料等方面的应用越来越广泛，因此迫切需要开发低成本、高收率、适合工业化生产的三氟甲基化工艺。
三氟甲基吡啶类化合物是用于合成医药、农药、化学材料的常见中间体，可由卤代吡啶类化合物经三氟甲基化制备得到。
在中国专利CN101973829B(授权公告日：2013年06月19日)的实施例1中，提供了一种以4-碘吡啶为原料、以[Ph2SCF3]+[OTf]-为三氟甲基化试剂制备4-三氟甲基吡啶的方法：
在2mL封管中，将4-碘吡啶(20.5mg,0.1mmol)和[Ph2SCF3]+[OTf]-(三氟甲基二苯基锍盐，81mg,0.2mmol)溶于DMF(1mL)，加入铜粉(20mg,0.3mmol)，然后于60℃下，密封反应11h。氟谱产率：91％。
该方法存在两点缺陷：
1.[Ph2SCF3]+[OTf]-试剂需要经过5步反应方能合成，市价较高；
2.碘代试剂较贵，而用溴代吡啶类化合物替代碘代吡啶后，试剂[Ph2SCF3]+[OTf]-的三氟甲基化反应活性很差，导致氟谱产率低。
在期刊文献Copper-Mediated Perfluoroalkylation of Heteroaryl Bromideswith(phen)CuRF(Organic Letters,2014,16(6),1744-1747)中，公开了如下工艺路线：
虽然在该文献中提及，采用该方法时溴代吡啶及其衍生物的三氟甲基化产率较高，但在该文献中公开的实验数据都是在微量试验下获得的，经对该制备工艺的复核，当进行吨量生产时，该工艺无法达到如文献中的产率，且该工艺中使用的三氟甲基化试剂需要经过6步反应方能制得，市价较高。
综上所述，现有技术方法不适合以商业规模操作制备溴代吡啶及其衍生物，所以需要一种改进的和商业上可行的方法，以解决现有技术方法中的相关问题并且使之适合大规模生产。
发明内容
为解决上述问题，本发明提供了溴代吡啶及其衍生物在一种梅本试剂的作用下制备三氟甲基类化合物的工艺，该工艺低成本、高产率、高纯度、绿色、环保、可持续，适合工业化生产。
该工艺具体方案如下：
一种式b结构三氟甲基吡啶化合物的制备方法，由式a结构溴代吡啶化合物在式c结构梅本试剂作用下经三氟甲基化工艺制备，所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐，
其中，X-为布朗斯特共轭碱，R为H或-CN或卤素或C1-C6的烷基或C1-C6的烷氧基或-OH或-R1OH或COR2或-CO2R3或-CONR4或-NR5R6；R1为C1-C6的烷基，R2、R3、R4相同或不同地为H或C1-C6的烷基，R5、R6相同或不同地为H或O或C1-C6的烷基或C1-C6的烷氧基；
优选的，R为H，-CH3,-CH2CH3,-CN，-COOH，-COOCH3，-COOCH2CH3，-OH，-CH2OH，-Boc，-CONCH3，-CONH，-NO2，-NH2,-CHO,-F,-COCH3,-OCH3；
优选的,X-为HSO4 -,CH3OSO3 -,ClSO3 -,FSO3 -,CH3SO3 -,CF3SO3 -,CF2HSO3 -,CCl3SO3 -,CF3CH2SO3 -,C2F5SO3 -,C3F7SO3 -,C4F9SO3 -,C6H5SO3 -,CH3C6H4SO3 -,O2NC6H4SO3 -,(O2N)2C6H3SO3 -,CF3C02 -,CCl3CO2 -,Cl-,Br-,BF4 -,BF3Cl-,BFCl3 -,BCl4 -,SbF6 -,SbCl5F-,SbCl6 -,AsF6 -，AlCl4 -，AlCl3F-，AlF4 -，PF6 -，PF5Cl-，ClO4 -。上述合成工艺优选地为:一种式b-2结构三氟甲基吡啶化合物的制备方法，由式a-2结构溴代吡啶化合物在式c结构的梅本试剂作用下经三氟甲基化工艺制备，所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐，
所述R，X-与权利要求1中的定义相同；
或者优选地为：
一种式b-3结构三氟甲基吡啶化合物的制备方法，由式a-3结构溴代吡啶化合物在式c结构的梅本试剂作用下经三氟甲基化工艺制备,所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐，
所述R，X-与权利要求1中的定义相同。
最优选的,上述合成工艺为:
其中，X-为CF3SO3 -,Cl-,Br-,BF4 -,PF6 -，HSO4 -。
进一步地，上述制备方法中，加入了铜粉；
所述制备方法具体按照如下步骤进行：
在氮气保护下，将三氟甲基吡啶化合物、铜粉、梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐投入四口瓶中，在冰水浴下搅拌反应，反应完毕经后处理得到目标化合物。
根据上述制备方法，所述反应溶剂可以为非质子极性有机溶剂；其中，所述非质子极性溶剂可以为非质子极性含硫有机物或非质子极性有机胺类；所述非质子极性含硫有机物优选地为DMSO，所述非质子极性有机胺类优选地为DMF或DMA或NMP；
根据上述制备方法，所述三氟甲基吡啶化合物与梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐的摩尔用量比可以为1：(2.5-4.5)；
根据上述制备方法，所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐与铜粉的摩尔
用量比可以为1：(1.0-1.5)；
根据上述制备方法，所述反应温度可以为70-100℃；
根据上述制备方法，所述反应时间优选为3-5h。
进一步的，所述后处理步骤可以为：稀释反应液，用缓冲溶液调节pH，抽滤，洗涤，取滤液上层，干燥，抽滤，得到目标化合物。
所述稀释液和滤饼洗涤液可以为非质子极性有机溶剂；其中，所述非质子极性有机溶剂可以为低级酯类或低级醚类或卤代烷烃类；所述低级酯类优选地为醋酸异丙酯或乙酸乙酯，所述低级醚类优选地为甲基叔丁基醚，所述卤代烷烃类优选地为二氯甲烷；
所述缓冲溶液可以为KH2PO4水溶液。
本发明提供的溴化吡啶及其衍生物的三氟甲基化工艺，具有的有益效果为：(1)本发明以溴化吡啶为原料，相对于碘化吡啶，制备所需溴化试剂更便宜，更适合大规模生产；(2)本发明使用的三氟甲基化试剂仅需一步合成；(2)本发明使用的三氟甲基化试剂，在反应结束后，可分离回收、套用投料；(3)本发明使用式c结构的梅本试剂进行三氟甲基化，与现有技术相比，三氟甲基化试剂的制备方法更简单，更环保，放大试验后三氟甲基化产率依旧高达93％，能够实现吨位生产。因此，本发明提供的溴化吡啶及其衍生物的三氟甲基化工艺，具有很高的工业应用和经济价值。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例对本发明提供的一种溴化吡啶及其衍生物的三氟甲基化工艺进行详细说明。需要理解的是，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。
实施例1：2-溴异烟叔丁酯的制备
向1L三口烧瓶中加入2-溴异烟酸(48.1g，0.238mol)，NMP(120ml)，开启搅拌，再加入二碳酸二叔丁酯(126ml,0.547mol)，DMAP(5.82g,0.056mol)，25℃反应16h。1HNMR监测，原料完全转化。将NaCl(25g)和KH2PO4(25g)溶于250ml水中，滴加到反应瓶，温度无明显变化。滴加完毕，加入250ml甲基叔丁基醚，搅拌15min，萃取。用100ml水洗涤。减压浓缩后得白色固体，收率92.6％。
实施例2:2-三氟甲基异烟叔丁酯的制备
在N2保护下，向1L三口瓶中加入2-溴异烟酸叔丁酯(25.7g,0.1mol)，250ml DMF,Cu粉(19.2g,0.3mol)，开启搅拌，冰水浴冷却至0-5℃。投入梅本试剂(87.6g,0.2mol)。冰水浴下搅拌1h后，再升温至80℃，反应3h。取反应液进行19FNMR分析，以OTf为内标，收率为93％。用500ml醋酸异丙酯稀释反应液，滴加40.4g KH2PO4的500ml水溶液。滴完后，搅拌1h。抽滤，用160ml醋酸异丙酯淋洗滤饼。滤液静置，分出上层有机相，无水硫酸镁干燥。抽滤，减压浓缩干后得黄色油状物21.0g,收率85.1％。
实施例3：2-三氟甲基异烟酸的制备
将2-三氟甲基异烟叔丁酯(14.82g，0.06mol)加入到150ml质量分数25％盐酸中，80℃反应3h。冷却至25℃，抽滤，得灰白色固体。烘干后10.54g，收率为92.0％。
实施例4：2-三氟甲基-4-甲基吡啶的制备
在N2保护下，向1L三口瓶中加入2-溴-4-甲基吡啶(17.2g,0.1mol)，250ml DMF,Cu粉(19.2g,0.3mol)，开启搅拌，冰水浴冷却至0-5℃。投入梅本试剂(87.6g,0.2mol)。冰水浴下搅拌1h后，再升温至80℃，反应3h。取反应液进行19FNMR分析，以OTf为内标，收率为93％。
实施例5：2-三氟甲基-4-氰基吡啶的制备
在N2保护下，向100ml三口瓶中加入2-溴-4-氰基吡啶(1.83g,0.01mol)，25mlDMF,Cu粉(1.92g,0.03mol)，开启搅拌，冰水浴冷却至0-5℃。投入梅本试剂(8.76g,0.02mol)。冰水浴下搅拌1h后，再升温至80℃，反应3h。取反应液进行19FNMR分析，以OTf为内标，收率为93％。
实施例6：2-三氟甲基吡啶的制备
在N2保护下，向100ml三口瓶中加入2-溴吡啶(1.58g,0.01mol)，25ml DMF,Cu粉(1.92g,0.03mol)，开启搅拌，冰水浴冷却至0-5℃。投入梅本试剂(8.76g,0.02mol)。冰水浴下搅拌1h后，再升温至80℃，反应3h。取反应液进行19FNMR分析，以OTf为内标，收率为96％。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落在本发明权利要求的保护范围。
Claims (10)
1.一种式b结构三氟甲基吡啶化合物的制备方法，其特征在于，由式a结构溴代吡啶化合物在式c结构梅本试剂作用下经三氟甲基化工艺制备，所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐，
其中，X-为布朗斯特共轭碱，R为H或-CN或卤素或C1-C6的烷基或C1-C6的烷氧基或-OH或-R1OH或COR2或-CO2R3或-CONR4或-NR5R6；R1为C1-C6的烷基，R2、R3、R4相同或不同地为H或C1-C6的烷基，R5、R6相同或不同地为H或O或C1-C6的烷基或C1-C6的烷氧基。
2.一种式b-2结构三氟甲基吡啶化合物的制备方法：其特征在于，由式a-2结构溴代吡啶化合物在式c结构梅本试剂作用下经三氟甲基化工艺制备，所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐，
所述R，X-与权利要求1中的定义相同。
3.一种式b-3结构三氟甲基吡啶化合物的制备方法：其特征在于，由式a-3结构溴代吡啶化合物在式c结构梅本试剂作用下经三氟甲基化工艺制备，所述梅本试剂为氟代-S-(三氟甲基)-二苯并噻吩盐，
所述R，X-与权利要求1中的定义相同。
4.根据权利要求1，2或3所述的制备方法，其特征在于，上述反应中需加入铜粉。
5.根据权利要求1，2或3所述的制备方法，其特征在于，上述反应中溶剂为非质子极性有机溶剂。
6.根据权利要求1，2或3所述的制备方法，其特征在于，上述反应中反应温度为70℃-100℃。
7.根据权利要求1，2或3所述的制备方法，其特征在于，所述溴代吡啶化合物与梅本试剂氟代-S-(三氟甲基)-二苯并噻吩盐的摩尔用量比为1：2.5-4.5。
8.根据权利要求4所述的制备方法，其特征在于，所述梅本试剂氟代-S-(三氟甲基)-二苯并噻吩盐与铜粉的摩尔用量比为1：1.0-1.5。
9.根据权利要求1，2或3所述的制备方法，其特征在于，进一步的包括下述后处理步骤，稀释反应液，用缓冲溶液调节pH，抽滤，洗涤，取滤液上层，干燥，抽滤，得到目标化合物。
10.根据权利要求9所述的制备方法，其特征在于，所述稀释液和滤饼洗涤液为非质子极性有机溶剂。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110627714A (zh) * | 2019-10-16 | 2019-12-31 | 安庆博曼生物技术有限公司 | 3-氟-2-三氟甲基异烟酸的合成方法 |
| CN112010803A (zh) * | 2019-05-28 | 2020-12-01 | 浙江瑞博制药有限公司 | 二甲基取代杂环化合物的三氟甲基化反应 |
| CN113214113A (zh) * | 2021-04-07 | 2021-08-06 | 苏州大学 | 一种苯胺对位三氟甲基化衍生物的制备方法 |
| CN115322143A (zh) * | 2022-07-21 | 2022-11-11 | 安徽德诺医药股份有限公司 | 一种4-哌啶甲酸叔丁酯盐酸盐的制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973829A (zh) * | 2010-09-02 | 2011-02-16 | 中国科学院上海有机化学研究所 | 三氟甲基芳基锍盐在金属引发下对杂环化合物的三氟甲基化 |
| CN105732573A (zh) * | 2014-12-31 | 2016-07-06 | 浙江九洲药业股份有限公司 | 卤代s-(全氟烷基)-二苯并噻吩盐及其制备方法 |
-
2016
- 2016-12-27 CN CN201611229515.4A patent/CN108239021B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973829A (zh) * | 2010-09-02 | 2011-02-16 | 中国科学院上海有机化学研究所 | 三氟甲基芳基锍盐在金属引发下对杂环化合物的三氟甲基化 |
| CN105732573A (zh) * | 2014-12-31 | 2016-07-06 | 浙江九洲药业股份有限公司 | 卤代s-(全氟烷基)-二苯并噻吩盐及其制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| MICHAEL G. MORMINO ET AL.: "Copper-Mediated Perfluoroalkylation of Heteroaryl Bromides with (phen)CuRF", 《ORGANIC LETTERS》 * |
| TERUO UMEMOTO ET AL.: "Powerful, Thermally Stable, One-Pot-Preparable, and Recyclable Electrophilic Trifluoromethylating Agents: 2,8-Difluoro- and 2,3,7,8-Tetrafluoro-S-(trifluoromethyl)dibenzothiophenium Salts", 《J. ORG. CHEM.》 * |
| 尉宏伟等: "芳香化合物三氟甲基化研究进展", 《农药》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112010803A (zh) * | 2019-05-28 | 2020-12-01 | 浙江瑞博制药有限公司 | 二甲基取代杂环化合物的三氟甲基化反应 |
| CN112010803B (zh) * | 2019-05-28 | 2024-02-20 | 浙江瑞博制药有限公司 | 二甲基取代杂环化合物的三氟甲基化反应 |
| CN110627714A (zh) * | 2019-10-16 | 2019-12-31 | 安庆博曼生物技术有限公司 | 3-氟-2-三氟甲基异烟酸的合成方法 |
| CN113214113A (zh) * | 2021-04-07 | 2021-08-06 | 苏州大学 | 一种苯胺对位三氟甲基化衍生物的制备方法 |
| CN115322143A (zh) * | 2022-07-21 | 2022-11-11 | 安徽德诺医药股份有限公司 | 一种4-哌啶甲酸叔丁酯盐酸盐的制备方法 |
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