CN101244994B - 制备2,4,5-三氟苯乙酸的方法 - Google Patents
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Abstract
本发明涉及一种医药中间体2，4，5-三氟苯乙酸的制备方法。本方法以1，2，4-三氟苯为原料，经过傅克乙酰化、Willegerodt-Kindler反应、水解得到2，4，5-三氟苯乙酸(最终产品的含量>99.9％)。该合成新工艺简洁高效、反应条件温和、操作安全，适合工业化生产。
Description
技术领域
本发明涉及医药化工中间体的制备方法，具体涉及一种医药化工中间体2，4，5-三氟苯乙酸的制备方法
背景技术
2，4，5-三氟苯乙酸是一个重要的医药化工中间体，用于合成治疗II型糖尿病的药物sitagliptin(商品名：JANUVIA)(见WO2004085378，WO2004085661，WO2004087650)。Sitagliptin是Merck公司最新上市的首个DPP-IV抑制剂，其治疗糖尿病的疗效优异，副作用小，安全性和耐受性好，可望近期成为重磅炸弹级药物。
美国专利(US20040068141)报道了以2，4，5-三氟溴苯和丙二酸二乙酯为原料，在碱性条件下发生取代反应后，水解得到2，4，5-三氟苯乙酸。该路线的反应条件要求较高，不适合工业化生产。合成路线如下：
美国专利(US20040077901)报道了同样以2，4，5-三氟溴苯原料，与金属镁反应制成格氏试剂后，和烯丙基溴发生取代，得到1-(2-烯丙基)-2，4，5-三氟苯。1-(2-烯丙基)-2，4，5-三氟苯，在催化剂RuCl3和氧化剂NalO4的存在下，被氧化得到2，4，5-三氟苯乙酸。该路线对无水的要求较高，不适合工业化生产，此外，催化剂RuCl3和氧化剂NalO4的价格也较高。合成路线如下：
中国专利(公开号：CN1749232)报道了以1，2，4-三氟苯为原料，经过氯甲基化、氰化、水解得到2，4，5-三氟苯乙酸。该工艺使用了剧毒的氰化钠，在工业化生产中具有一定的安全隐患。合成路线如下：
发明内容
本发明的目的在于提供制备2，4，5-三氟苯乙酸的一个新的工艺路线，旨在克服以上合成工艺中的缺点、降低成本、使之操作简便、安全、更适合工业化生产。
本发明以1，2，4-三氟苯为原料，经过傅克乙酰化、Willegerodt-Kindler反应、水解得到2，4，5-三氟苯乙酸。合成路线如下：
具体合成步骤详述如下：
(1)2，4，5-三氟苯乙酮的制备：以1，2，4-三氟苯为原料，在Lewis酸的存在下，与乙酰化试剂经傅克反应得到2，4，5-三氟苯乙酮。Lewis酸选自以下试剂：三氯化铝、三氟化硼、二氯化锌、四氯化锡、三氟甲磺酸、硫酸、磷酸、多聚磷酸等，优选为三氯化铝。乙酰化试剂选自以下试剂：乙酸酐、乙酰氯、乙酸和乙酸酯，优选为乙酰氯。
(2)硫代2，4，5-三氟苯乙酸酰胺的制备：2，4，5-三氟苯乙酮与硫、伯(仲)胺或其盐、醋酸钠在有机溶剂中一起共热得到硫代2，4，5-三氟苯乙酸酰胺。伯(仲)胺选自NHR1R2(R1，R2＝H，C1～8的烷基)和吗啉等，优选为二甲胺盐酸盐；有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺和吡啶等，优选为N，N-二甲基甲酰胺；共热的温度为50℃至回流温度，优选为90℃～110℃。
(3)2，4，5-三氟苯乙酸的制备：硫代2，4，5-三氟苯乙酸酰胺在碱性或酸性水溶液中共热，得到2，4，5-三氟苯乙酸。碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等无机碱，酸选自盐酸、硫酸、磷酸、多聚磷酸等无机酸，优选为氢氧化钠或氢氧化钾碱性水溶液；共热的温度为50℃至回流温度，优选为90℃至回流温度。
具体实施方式
以下典型反应用来举例说明本发明，在本领域内的技术人员对本发明所做的简单替换或改进等均属于本发明所保护的技术方案之内。
实施例1：2，4，5-三氟苯乙酮的制备
在反应釜中加入1摩尔的1，2，4-三氟苯原料和2.5摩尔的三氯化铝，开启搅拌.控制温度不超过40℃的情况下，滴加2.5摩尔的乙酰氯。滴加完毕后，慢慢升温至100～110℃，TLC检测反应，直至1，2，4-三氟苯原料点消失。反应结束后，将反应液加入到冰水混合物中，搅拌，静置分层。分出有机相，水相用二氯甲烷萃取，合并有机相，干燥后蒸干溶剂得到黄色至深黄色油状物，收率93％。该油状物不用纯化，直接用于下一步反应。
实施例2：硫代2，4，5-三氟苯乙酸酰胺的制备
在反应釜中加入1摩尔的2，4，5-三氟苯乙酮、1.5摩尔的硫、1.5摩尔的二甲胺盐酸盐和1.5摩尔的醋酸钠于400mL的N，N-二甲基甲酰胺中，开启搅拌。慢慢加热到100℃，反应 3～4小时，TLC检测反应，直至2，4，5-三氟苯乙酮原料点消失。将反应液倒入冰水混合物中，过滤，滤饼用水洗涤，乙醇重结晶，得硫代2，4，5-三氟苯乙酸酰胺，收率90％。
实施例3：2，4，5-三氟苯乙酸的制备
将1摩尔的硫代2，4，5-三氟苯乙酸酰胺加入到70％乙醇(1L)和50％氢氧化钠溶液(200mL)组成的混合溶剂中，开启搅拌，加热至回流，反应4～5小时，TLC检测反应，直至原料点消失。反应结束后，过滤，滤液加水适量，用稀盐酸调节pH＝1～2，析出固体，抽滤，得2，4，5-三氟苯乙酸粗品。粗品用60％乙醇重结晶，得2，4，5-三氟苯乙酸精品，收率80％。
Claims (7)
1.一种医药中间体2，4，5-三氟苯乙酸的制备方法，其特征在于，以1，2，4-三氟苯为原料，经过傅克乙酰化、Willegerodt-Kindler反应、水解得到2，4，5-三氟苯乙酸，具体步骤为：
(1)以1，2，4-三氟苯为原料，在Lewis酸的存在下，经傅克乙酰化反应得到2，4，5-三氟苯乙酮；
(2)2，4，5-三氟苯乙酮经Willegerodt-Kindler反应得到硫代2，4，5-三氟苯乙酸酰胺；
(3)硫代2，4，5-三氟苯乙酸酰胺，在酸性或碱性条件下，水解得到2，4，5-三氟苯乙酸。
2.根据权利要求1所述的2，4，5-三氟苯乙酸的制备方法，其特征在于，反应步骤(1)中，在Lewis酸的存在下，1，2，4-三氟苯与乙酰化试剂经傅克反应得到2，4，5-三氟苯乙酮，Lewis酸选自以下试剂：三氯化铝、三氟化硼、二氯化锌、四氯化锡，乙酰化试剂选自以下试剂：乙酸酐、乙酰氯、乙酸。
3.根据权利要求2所述的2，4，5-三氟苯乙酸的制备方法，其特征在于，Lewis酸为三氯化铝，乙酰化试剂为乙酸酐或乙酰氯。
4.权利要求1所述的2，4，5-三氟苯乙酸的制备方法，其特征在于，反应步骤(2)中，2，4，5-三氟苯乙酮与硫、伯仲胺或其盐、醋酸钠在有机溶剂中一起共热得到硫代2，4，5-三氟苯乙酸酰胺，伯仲胺选自吗啉和NHR1R2，R1，R2＝H，C1～8的烷基，有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺和吡啶，共热的温度为50℃至回流温度。
5.根据权利要求4所述的2，4，5-三氟苯乙酸的制备方法，其特征在于，反应步骤(2)中伯仲胺或其盐为二甲胺盐酸盐，有机溶剂为N，N-二甲基甲酰胺，共热的温度为90℃～110℃。
6.根据权利要求1所述的2，4，5-三氟苯乙酸的制备方法，其特征在于，反应步骤(3)中，硫代2，4，5-三氟苯乙酸酰胺在碱性或酸性水溶液中共热，得到2，4，5-三氟苯乙酸，碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾，酸选自盐酸、硫酸、磷酸、多聚磷酸，共热的温度为50℃至回流温度。
7.根据权利要求6所述的2，4，5-三氟苯乙酸的制备方法，其特征在于，反应步骤(3)中硫代2，4，5-三氟苯乙酸酰胺在碱性水溶液中共热，得到2，4，5-三氟苯乙酸，碱为氢氧化钠或氢氧化钾，共热的温度为90℃至回流温度。
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