CN113773246A - 一种2-取代-4-三氟甲基吡啶的制备方法 - Google Patents

一种2-取代-4-三氟甲基吡啶的制备方法 Download PDF

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CN113773246A
CN113773246A CN202111086895.1A CN202111086895A CN113773246A CN 113773246 A CN113773246 A CN 113773246A CN 202111086895 A CN202111086895 A CN 202111086895A CN 113773246 A CN113773246 A CN 113773246A
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trifluoromethylpyridine
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刘钦胜
肖才根
张作山
李磊
蒋爱忠
刘军
徐玉梅
孙启霞
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Shandong Huimeng Biotechnology Co ltd
SHANDONG ACADEMY OF PESTICIDE SCIENCES
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Abstract

本发明属于一类化工中间体的生产方法，具体涉及一种2‑取代‑4‑三氟甲基吡啶的制备方法。所述方法以2‑氯‑4三氯甲基吡啶为原料，经过水解、卤化、三氟甲基化和亲核取代得到2‑取代‑4‑三氟甲基吡啶；反应路线：
Figure DDA0003265879240000011
其中，Y为氨基、羟基、硫醇基、肼基、氰基、氟、溴或碘；X为氯或溴。该方法以廉价易得的2‑氯‑4‑三氯甲基吡啶为原料，大大降低制备成本，同时具有收率较高、步骤简单、副反应少、稳定可靠的特点。

Description

一种2-取代-4-三氟甲基吡啶的制备方法
技术领域
本发明属于一类化工中间体的生产方法，具体涉及一种2-取代-4-三氟甲基吡啶的制备方法。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
由于三氟甲基吡啶或其衍生物表现出非凡的生物活性，因而它们被广泛用于医药和农药领域。比如，2-氯或2,6-二氯-4-三氟甲基化吡啶是通用的介导具有生物活性的含有三氟甲基化合物。然而，目前为止，只有有限的数种方法可以制备取代的三氟甲基吡啶。其中，2-位取代的4-三氟甲基吡啶，由于其特殊的电子效应，尤其难以大量的获得，导致其价格高昂。目前，常见的2-取代-4-三氟甲基吡啶有以下几种方法可以获得，其中应用价值较大的举例如下：
(1)通过相应的4-甲基吡啶与氯反应三氯甲基化，然后高温高压，在锑或钼的催化下和HF反应，进行氟化。但该法反应条件苛刻，需要高温高压，副产物严重，收率不高。
(2)相应的4-碘/溴代吡啶或4-吡啶硼酸和三氟甲基铜、三氟乙酸钠、三氟甲基取代的硅烷或氟代烃，在极性非质子溶剂中，有碱存在下，加热催化氟化。但该法原料价高，不易得。
(3)4-乙氧基-1,1,1-三氟-3-丁烯-2-酮和乙腈-丁基锂或氯乙腈-金属锌作用下，获得5-乙氧基-3-羟基-3-(三氟甲基)-戊-4-烯腈，然后氯化合环，得到2-氯-4-三氟甲基吡啶，如果进一步氨化，得到2-氨基-4-三氟甲基吡啶；如果在氯化前缩合成环，则得到2-羟基-4-三氟甲基吡啶。然而，该法反应原料价格较高，丁基锂需要很低的温度，试剂昂贵且不宜操作，设备抗腐蚀性要求比较高，原料不太稳定，价格也比较高，但是相对比较可行。
(4)三氟乙酸乙酯和烯丙基溴格式试剂发生加成-消去反应，生成4-(三氟甲基)庚-1,6-二烯-4-醇，接着进行臭氧化-还原，氨化合环，氮氧化，氯化得到2-氯-4-三氟甲基吡啶。该法需要使用大量臭氧，但是臭氧的供应是个问题。
(5)4-乙氧基-1,1,1-三氟-3-丁烯-2-酮或4-氯-4-乙氧基-1,1,1-三氟-3-丁基-2-酮与二乙氧基磷酰乙酸乙酯(卤代乙酸乙酯和亚磷酸三乙酯反应获得)反应，得到5,5-二乙氧基-3-(三氟甲基)戊-2-烯酸酯，然后250℃高温下和氨反应或155℃左右和醋酸铵、甲酰胺反应，得到2-羟基-4-三氟甲基吡啶。该法反应温度很高，操作不便，收率不高，产生大量含磷物质需要处理。
(6)相应的异烟酸在六氟化钼催化下，180℃反应40小时，完成羧基的三氟甲基化。该法反应条件苛刻，而且副反应严重，效果不好。
(7)相应的异烟酸在无水氟化氢中，75-150℃范围下，与四氟化硫反应获得相应的4-三氟甲基吡啶。该法用来制备难以获得的4-三氟甲基吡啶类化合物，效果较好，理论上硫元素最后转化为二氧化硫，副产物主要是相对少量的取代的双二氟亚甲基醚，易于分离。四氟化硫是一种有毒气体，不便于操作，目前使用四氟化硫进行三氟甲基化的研究，多集中于如何把羧基转化为三氟甲基上。
因此，如何通过简单易得的原料，来以一种步骤少、操作方便的通用的方式制备2-取代的-4-三氟甲基吡啶类化合物将具有重要意义。
发明内容
为了解决现有技术的不足，本发明提供一种通用的2-取代-4-三氟甲基吡啶的制备方法，以廉价易得的2-氯-4-三氯甲基吡啶为原料，经过水解、卤化、三氟甲基化和亲核取代等过程，可以方便、稳定地获得2-取代-4-三氟甲基吡啶类化合物，这种方法具有原料易得、收率较高、步骤简单、副反应少、稳定可靠的特点。
具体提供如下方案：
一种2-取代-4-三氟甲基吡啶的制备方法，以2-氯-4三氯甲基吡啶为原料，经过水解、卤化、三氟甲基化和亲核取代得到2-取代-4-三氟甲基吡啶；
反应路线：
Figure BDA0003265879220000021
其中，Y为氨基、羟基、硫醇基、肼基、氰基、氟、溴或碘；
X为氯或溴。
所述制备方法具体包含如下步骤：
(1)在强碱或强质子酸的水溶液中，2-氯-4三氯甲基吡啶经过水解，转化为2-羟基吡啶-4-甲酸；
(2)2-羟基吡啶-4-甲酸经过卤化试剂卤化，得到2-卤吡啶-4-甲酸；
(3)2-卤吡啶-4-甲酸与氟化试剂进行氟化反应，得到2-卤代-4-三氟甲基吡啶；
(4)2-卤代-4-三氟甲基吡啶与能够提供Y的亲核试剂反应，得到2-取代-4-三氟甲基吡啶类化合物。
本发明的一个或多个实施方式至少具有以下有益效果：
(1)本发明所提供的2-取代-4-三氟甲基吡啶类化合物的制备方法，以廉价易得的2-氯-4-三氯甲基吡啶为原料，大大降低制备成本。
(2)本发明所提供的2-取代-4-三氟甲基吡啶类化合物的制备方法，工艺简单、易于操作、工艺稳定、利于工业化生产、收率高，易于提纯。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为实施例1所制备的2-氯-4-三氯甲基吡啶气质谱图；
图2为实施例1所制备的2-氯-4-三氟甲基吡啶气质谱图；
图3为实施例1所制备的2-羟基-4-三氟甲基吡啶气质谱图；
图4为实施例1所制备的2-氨基-4-三氟甲基吡啶气质谱图。
具体实施方式
应该指出，以下详细说明都是示例性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
正如背景技术所介绍的，现有技术中制备2-取代-4-三氟甲基吡啶的方法，存在反应条件苛刻、副产物严重、原料价高、收率低等问题，制约了2-取代-4-三氟甲基吡啶的广泛应用。
为了解决如上的技术问题，本发明提出一种2-取代-4-三氟甲基吡啶的制备方法，以2-氯-4三氯甲基吡啶为原料，经过水解、卤化、三氟甲基化和亲核取代得到2-取代-4-三氟甲基吡啶；
反应路线：
Figure BDA0003265879220000041
其中，Y为氨基、羟基、硫醇基、肼基、氰基、氟、溴或碘；
X为氯或溴。
其中，2-氯-4-三氟甲基吡啶的物理性质为：
分子式：C6H3ClF3N
分子量：181.54
密度：1.411g/mL at 25℃
沸点：146-147℃
熔点：-19℃
本发明以廉价易得的2-氯-4-三氯甲基吡啶为原料，相比于4-碘/溴代吡啶、4-吡啶硼酸、4-乙氧基-1,1,1-三氟-3-丁烯-2-酮等，价格更低，且更易获得，后续经过水解、卤化、三氟甲基化和亲核取代等过程，可以方便、稳定地获得2-取代-4-三氟甲基吡啶类化合物，具有原料易得、收率较高、步骤简单、副反应少、稳定可靠等诸多优势。
所述制备方法具体包含如下步骤：
(1)在强碱或强质子酸的水溶液中，2-氯-4三氯甲基吡啶经过水解，转化为2-羟基吡啶-4-甲酸；
(2)2-羟基吡啶-4-甲酸经过卤化试剂进行卤化反应，得到2-卤吡啶-4-甲酸；
(3)2-卤吡啶-4-甲酸与氟化试剂进行氟化反应，得到2-卤代-4-三氟甲基吡啶；
(4)2-卤代-4-三氟甲基吡啶与能够提供Y的亲核试剂反应，得到2-取代-4-三氟甲基吡啶类化合物。
在本发明的一个或多个实施方式中，当最终目标产物为2-羟基-4-三氟甲基吡啶类化合物时，步骤(2)、(4)省略，2-羟基-4-三氟甲基吡啶直接与氟化试剂反应，得到2-羟基-4-三氟甲基吡啶类化合物，反应路线如下所示：
Figure BDA0003265879220000042
在本发明的一个或多个实施方式中，步骤(1)所述的强碱和强质子酸，强碱优选为氢氧化钠、氢氧化钾或氢氧化钡；强碱的添加量为：4-6个化学摩尔当量，强碱水溶液的浓度为：5％-40％质量浓度。
强质子酸指非挥发性酸和固体超强酸及酸性离子交换树脂，非挥发性酸浓度为60％或更高，优选为硫酸、磷酸、硫酸氢盐、氯磺酸、氟磺酸等，更优选浓度70％及以上的硫酸、酸性离子交换树脂和固体超强酸；强质子酸的用量优选为2-氯-4-三氯甲基吡啶摩尔量的1-3倍；强质子酸的水溶液的质量浓度为：60-90％。
进一步的，步骤(1)中，在相转移催化剂的辅助下进行水解，所述相转移催化剂的量为2-氯-4-三氯甲基吡啶质量的0.1％-5.0％，优选0.5％-1.5％，所述相转移催化剂包括但不限于长链的直链或支链烷基磺酸碱金属盐(例如十二烷基磺酸钠)、长链的直链或支链季铵/季膦盐(例如双十二烷基二甲基溴化铵、四苯基溴化磷)、聚合的聚乙二醇(例如聚乙二醇400)。
进一步的，水解反应温度为150-180℃。
进一步的，水解反应时间为6-18h。
进一步的，当在强质子酸中水解时，水解压力为常压；当在强碱中进行水解，水解压力为0.1-2.0MPa。
在本发明的一个或多个实施方式中，步骤(2)的卤化试剂为三氯氧磷、三氯化磷、氯化亚砜、草酰氯、三溴化磷、三溴氧磷、五氯化磷、五溴化磷、三光气中的任意一种或两种及以上的组合。
进一步的，步骤(2)中，采用卤化试剂本身作为溶剂，进行无溶剂反应，或加入溶剂进行反应；
当进行无溶剂反应时，卤化试剂的量为化学反应所需要摩尔量的3-5倍。
当加入溶剂进行反应时，所述溶剂为卤代烃，优选为四氯化碳、二氯乙烷或氯苯。
进一步的，加入溶剂的质量优选为卤化原料质量的2-5倍；此时，加入卤化试剂的量需要减少，优选为化学反应所需要摩尔量的1.05-2.00倍，更优选为1.2-1.5倍。
在本发明的一个或多个实施方式中，卤化反应温度为70-120℃，反应时间为8-24小时，优选10-12小时。
在本发明的一个或多个实施方式中，步骤(3)的氟化反应中，以无水氟化氢、三氟化氢合三乙胺或氟化氢合吡啶作为反应溶剂反应，溶剂的加入量是2-卤代吡啶-4-甲酸质量的0.5-3倍。
进一步的，所述氟化试剂为苯基三氟化硫、取代的三氟化硫或四氟化硫。
进一步的，氟化试剂的加入量是2-卤代吡啶-4-甲酸摩尔量的2.0-3.5倍。
进一步的，氟化反应温度为85-150℃。
进一步的，氟化反应时间为8-24小时，优选10-14小时。
进一步的，氟化反应压力为0.1-5.0MPa。
进一步的，氟化反应完成后，后处理方式为：在35-45℃时，泄压吸收中和无水氟化氢并移除残余的溶剂和氟化试剂，氮气吹扫残余的氟化氢去吸收装置吸收，使用碳酸钠、碳酸氢钠、氨水等中和后，后处理，获得所需要的2-卤代-4-三氟甲基吡啶。
在本发明的一个或多个实施方式中，步骤(4)中的亲核试剂包括但不限于醇钠、酚钠、氨基钠、液氨、氨水、硫化钠、硫氢化钠、硫醇钠、硫氰酸钠、***/钾、肼盐酸或硫酸盐、水合肼、碱金属的氟化物、碱金属的碘化物、碱金属溴化物。
进一步的，亲核试剂的加入量是2-卤代-4-三氟甲基吡啶摩尔量的1.05-15倍，具体视亲核试剂活性及是否容易除去、是否兼作为溶剂决定。
进一步的，步骤(4)采用溶剂进行反应，所述溶剂为非质子偶极溶剂，非质子偶极溶剂主要起到溶解原料和能够提供Y的亲核试剂，帮助反应进行的作用，包括但不限于低级脂肪腈类(比如乙腈)、低级脂肪醚/聚醚类(比如乙二醇二甲醚、聚乙二醇600、四乙二醇醚)、低级脂肪酮类(比如丙酮、丁酮)、低级脂肪酰胺类(比如N,N-二甲基甲酰胺；低级脂肪砜类、比如环丁砜)、低分子量的吗啉类(比如N-甲酰吗啉)、吡咯烷酮类(比如N-甲基吡咯烷酮)；非质子偶极溶剂加入的质量是2-卤代-4-三氟甲基吡啶质量的1-5倍，更优选为2-3倍。
进一步的，步骤(4)的反应温度为80-180℃。
进一步的，步骤(4)的反应时间为6-48小时。
进一步的，步骤(4)的反应在催化剂作用下进行，所述催化剂为氯化亚铜、溴化亚铜和碘化亚铜中一种或多种。
优选的，催化剂配合相转移催化剂使用，相转移催化剂的选用同步骤(1)。
进一步的，步骤(4)反应过程中，为了促使反应顺利进行，加入可以结合反应生成的卤化氢的缚酸剂，缚酸剂包括但不限于叔胺类(比如三甲胺、三乙胺)、吡啶类(比如吡啶、2-甲基吡啶)、无机或有机弱酸对应的碱金属盐(比如碳酸钾、磷酸三钠、磷酸氢二钠、乙酸钠)、有机或无机弱碱(比如六次甲基四胺、苯胺、苄胺、氢氧化镁)。
下面对本发明的方法做进一步的解释说明：
步骤(1)中，在酸解过程，采用液相色谱检测跟踪原料和产物的动态变化，检测条件为波长235nm，流量1.0ml/min，甲醇：水＝80：20，水中加入0.1％的醋酸，以普通的C18柱进行分离，规格4.6*250mm，5um；根据2-羟基吡啶-4-甲酸和2-氯-4-三氯甲基吡啶的摩尔相应因子，由归一化含量进行计算，产物和原料＝98：2时，作为反应控制终点，此时反应选择性约92％。
步骤(2)中，卤化反应过程，取样后和水混合震荡，充分水解，过滤，取少量样品，加入甲醇充分溶解，使用步骤(1)所用的液相色谱检测方法，进行检测，当2-卤代吡啶-4-甲酸和2-羟基吡啶-4-甲酸，由归一化含量进行计算，产物和原料＝98：2时，作为反应控制终点，此时反应选择性约88％。
步骤(3)中，氟化反应完毕，降至35-45℃，泄压，泄压吸收中和无水氟化氢并移除残余的溶剂和氟化试剂，加含有碳酸钠的水溶液中和，后处理，获得2-卤代-4-三氟甲基吡啶，釜底残余物质主要是式(Ⅰ)所示的物质。
Figure BDA0003265879220000071
其中，X：Cl或Br
步骤(4)中，反应跟踪使用的检测方法同步骤(1)，当归一化含量产物：原料不低于95：5时，视为反应终点；脱除溶剂后，后处理提纯。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
实施例1：
(1)水解反应
1000ml不锈钢高压釜中，加入2-氯-4-三氯甲基吡啶92.4g(0.40mol)、1.0g十二烷基磺酸钠和240.0g 40％(w/w)的氢氧化钠水溶液，搅拌，170℃下加热6小时，液相色谱跟踪，反应完毕，降至室温，加入约20ml浓盐酸调整pH到1.0左右，过滤，20ml水洗涤3次，得到黄色粉状固体，烘干，得到2-羟基吡啶-4-甲酸51.2g，收率92.1％，含量96％(HPLC235nm)。
(2)卤化反应
在500ml三口烧瓶中，加入2-羟基吡啶-4-甲酸55.6g(0.40mol)和氯化亚砜190.40g(1.60mol，4.0eq.)，5.0g五氯化磷，在80℃搅拌加热回流10小时，产生的酸性气体，使用30％液碱吸收，液相色谱跟踪，反应完毕，常压蒸出未能反应的氯化亚砜，完毕，加水100ml搅拌，控温45℃，保持30min，过滤，析出类黄色粉末状固体，依次使用100ml饱和磷酸氢二钠溶液和100ml水洗涤，过滤，烘干，得到2-氯异烟酸58.6g，收率93％，含量98.5％(HPLC 235nm)。
(3)氟化反应
1000ml高压釜中，低温0℃左右，加入2-氯吡啶-4-甲酸157.50g(1.00mol)，四氟化硫324.0g(3.0mol)，无水氟化氢200.00g，加热升温到120℃，压力约3.5MPa，保持12小时，降温到45℃左右，泄压吸收中和无水氟化氢，完毕，加入25％的氨水溶液中和到pH7.0-8.0，放出物料，转移到500ml三口瓶中，精馏，得到2-氟-4-三氟甲基吡啶8.20g，2-氯-4-三氟甲基吡啶156.10g，合计总收率约92.0％。
(4)亲核取代反应
在1000ml的高压釜中，加入2-氯-4-三氟甲基吡啶181.5g(1.00mol),9.9g(0.10mol)氯化亚铜，1.0g四苯基溴化磷，637.5g 40％的氨水溶液(15.0eq.)，150℃加热搅拌反应16小时，完毕，降温，开釜，加入500ml甲苯搅拌溶解，过滤，回收氯化亚铜，液体分液，加入无水硫酸钠15g干燥30min，活性炭脱色，有机相转移到1000ml烧瓶中，缓缓通入无水氯化氢气体，析出白色固体，是2-氨基-4-三氟甲基吡啶的盐酸盐，过滤，水洗，干燥，得到2-氨基-4-三氟甲基吡啶150.65g，收率93.0％；剩余甲苯浓缩，得到橙红色油状液体17g左右，加入水250ml进行水蒸气精馏，获得3.50g 2-氯-4-三氟甲基吡啶(2.0％mol)，水蒸气蒸馏残余物，干燥得到黄色固体，7.50g，经气质分析，主要是2-羟基-4-三氟甲基吡啶(4.60％mol)。
实施例2：
(1)水解反应
在1000ml三口烧瓶中，加入2-氯-4-三氯甲基吡啶462g(2.0mol)、1.0g四苯基溴化磷和533g 75％(w/w)的硫酸水溶液，搅拌，160℃下加热14小时，通过不断滴加水，控制反应温度在160℃上下波动，累计加水65-75ml，物料颜色由无色透明-黄色-橙黄-橙-橙红-红棕，液相色谱跟踪，反应完毕，降至100℃，加水600ml，降温到室温，搅拌，过滤，滤饼用300ml水洗涤到pH约3.0，烘干，得到2-羟基吡啶-4-甲酸250.5g，收率90.11％，含量97.5％(HPLC235nm)。
(2)卤化反应
在500ml三口烧瓶中，加入2-羟基吡啶-4-甲酸27.8g(0.20mol)、三溴氧磷229.36g(0.80mol，4.0eq.)，3g五溴化磷和四氯化碳123.07g(0.8mol)，在80℃搅拌加热回流10小时，产生的酸性气体，使用30％液碱吸收，液相色谱跟踪，反应完毕，常压蒸出未能反应的三溴氧磷和四氯化碳，完毕，冰水浴中，滴加水50ml搅拌，控温45℃，保持30min，过滤，析出类黄色粉末状固体，依次使用100ml饱和磷酸氢二钠溶液和100ml水洗涤，烘干，得到2-溴吡啶-4-甲酸37.2g，收率92％，含量98.7％(HPLC 235nm)。
(3)氟化反应
1000ml高压釜中，低温0℃左右，加入2-溴吡啶-4-甲酸202.0g(1.00mol)，苯基三氟化硫415.0g(2.5mol，2.5eq.)，无水氟化氢200.00g，加热升温到120℃，压力约3.5MPa，保持13小时，降温到35℃以上，泄压吸收中和无水氟化氢，完毕，加入25％的氨水溶液中和到pH 7.0-8.0，放出物料，转移到500ml三口瓶中，精馏，得到2-氟-4-三氟甲基吡啶8.0g，2-溴-4-三氟甲基吡啶188.05g，合计总收率约88.0％。
(4)亲核取代反应
在1000ml的高压釜中，加入2-溴-4-三氟甲基吡啶226.0g(1.00mol),19.9g(0.10mol)碘化亚铜，1.0g四苯基溴化磷，80.0g 80％的水合肼溶液(2.0eq.)，乙二醇二甲醚200ml，无水乙酸钠100g，150℃加热搅拌反应16小时，完毕，降温，开釜，过滤，滤饼用水100ml洗涤，回收碘化亚铜，液体浓缩，得到的类白色固体粉末，使用饱和碳酸钠溶液100ml洗涤，过滤，100ml清水洗涤，过滤，烘干，得到2-肼基-4-三氟甲基吡啶164.8g，收率93.1％，含量99.2％(HPLC 235nm)。
实施例3：
(1)水解反应
1000ml不锈钢高压釜中，加入2-氯-4-三氯甲基吡啶92.4g(0.40mol)、1.0g双十二烷基二甲基溴化铵和240.0g 40％(w/w)的氢氧化钠水溶液，搅拌，160℃下加热12小时，液相色谱跟踪，反应完毕，降至室温，加入约67ml浓盐酸调整pH到1.0左右，过滤，20ml水洗涤3次，得到浅黄色粉状固体，烘干，得到2-羟基吡啶-4-甲酸53.0g，收率95.3％，含量98.5％(HPLC 235nm)。
(2)卤化反应
在500ml三口烧瓶中，加入2-羟基吡啶-4-甲酸55.6g(0.40mol)和三氯氧磷245.0g(1.60mol，4.0eq.)，在106℃搅拌加热回流10小时，产生的酸性气体，使用30％液碱吸收，液相色谱跟踪，反应完毕，80℃油浴加热，水泵减压蒸出未能反应的三氯氧磷，完毕，滴加水50ml搅拌，剧烈释放氯化氢气体，待释放完毕，冰水浴降温，搅拌保持30min，减压过滤，析出类黄色粉末状固体，烘干，得到2-氯异烟酸56.70g，收率90％，含量95.5％(HPLC 235nm)。
(3)氟化反应
1000ml高压釜中，低温0℃左右，加入2-氯吡啶-4-甲酸157.50g(1.00mol)，苯基三氟化硫498.0g(3.0mol，3.0eq.)，无水氟化氢200.00g，加热升温到120℃，压力约3.5MPa，保持10小时，降温到35℃以上，泄压吸收中和无水氟化氢，完毕，加入25％的氨水溶液中和到pH 7.0-8.0，放出物料，转移到500ml三口瓶中，精馏，得到2-氟-4-三氟甲基吡啶8.60g，2-氯-4-三氟甲基吡啶163.0g，合计总收率约95.0％。
(4)亲核取代反应
在1000ml的三口烧瓶中，氮气气氛中，加入2-氯-4-三氟甲基吡啶181.5g(1.00mol),19.9g(0.10mol)碘化亚铜，N,N-二甲基甲酰胺350ml，68％的水合硫氢化钠247g(3.0eq.)，99g三乙胺，150℃加热搅拌回流反应16小时，尾气导入氢氧化钠水溶液吸收，反应完毕，降温，减压蒸除大部分N,N-二甲基甲酰胺，加入饱和氯化铵水溶液300ml，搅拌洗涤，过滤，得到黄色粉末，把黄色粉末用1000ml甲醇加热搅拌溶解，趁热过滤，回收碘化亚铜，滤液加入活性炭10g，加热回流脱色30min，完毕，降温，趁热过滤，浓缩，得到类白色固体粉末，烘干得到2-巯基-4-三氟甲基吡啶147.0g，收率82.1％，含量96.8％(HPLC235nm)。
实施例4：
(1)水解反应
1000ml不锈钢高压釜中，加入2-氯-4-三氯甲基吡啶92.4g(0.40mol)、1.0g聚乙二醇800和240.0g 40％(w/w)的氢氧化钠水溶液，搅拌，170℃下加热7小时，液相色谱跟踪，反应完毕，降至室温，加入约67ml浓盐酸调整pH到1.0左右，过滤，20ml水洗涤3次，得到浅黄色粉状固体，烘干，得到2-羟基吡啶-4-甲酸52.15g，收率93.8％，含量97.0％(HPLC235nm)。
(2)卤化反应
在500ml三口烧瓶中，加入2-羟基吡啶-4-甲酸55.6g(0.40mol)和草酰氯203.2g(1.60mol，4.0eq.)，5g五氯化磷，在70℃搅拌加热回流24小时，产生的酸性气体，使用30％液碱吸收，液相色谱跟踪，反应完毕，常压蒸出未能反应的草酰氯，完毕，加水50ml搅拌，控温45℃，保持30min，过滤，析出类黄色粉末状固体，烘干，得到2-氯异烟酸57.47g，收率91.2％，含量98.5％(HPLC 235nm)。
(3)氟化反应
1000ml高压釜中，室温25-30℃，加入2-氯吡啶-4-甲酸157.50g(1.00mol),苯基三氟化硫498.0g(3.0mol，3.0eq.)，三氟化氢三乙胺163g，加热升温到130℃，压力约5MPa，保持12小时，降温到35℃左右，产物导入搅拌中的冰水浴碳酸钠饱和溶液中，中和到pH约6-7，完毕，过滤，每次加入250ml二氯乙烷，萃取，共2次，转移到1000ml三口瓶中，精馏，得到2-氟-4-三氟甲基吡啶7.95g，2-氯-4-三氟甲基吡啶151.0g,合计总收率约88.1％。
(4)亲核取代反应
在1000ml的三口烧瓶中，氮气气氛中，加入2-氯-4-三氟甲基吡啶90.75g(0.5mol)，9.5g(0.05mol)碘化亚铜，N,N-二甲基甲酰胺350ml，苯酚70.5(1.5eq.)，三乙胺74.3g，180℃加热搅拌回流反应8小时，完毕，降温，减压蒸除大部分N,N-二甲基甲酰胺，加入饱和碳酸钾水溶液300ml，搅拌洗涤，过滤，得到类白色粉末，把类白色粉末用500ml甲醇加热搅拌溶解，趁热过滤，回收碘化亚铜，滤液浓缩，得到类白色固体粉末，烘干得到2-苯氧基-4-三氟甲基吡啶108.8g，收率91.0％，含量95.6％(HPLC 235nm)。
实施例5：
1000ml高压釜中，室温25-30℃，加入2-羟基吡啶-4-甲酸139.1g(1.00mol),四氟化硫324.0g(3.0mol，3.0eq.)，三氟化氢三乙胺163g，加热升温到130℃，保持12小时，降温到100℃左右排出反应后的气体，产物倒入搅拌中的冰水浴碳酸钠饱和溶液中，中和到pH约1-2，完毕，过滤，每次加入250ml乙酸正丁酯，萃取，共3次，浓缩，用150ml水洗涤3次，烘干，得到白色粉末状固体2-羟基-4-三氟甲基吡啶，共计122.5g，收率约88.1％。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种2-取代-4-三氟甲基吡啶的制备方法，其特征在于：以2-氯-4三氯甲基吡啶为原料，经过水解、卤化、三氟甲基化和亲核取代得到2-取代-4-三氟甲基吡啶；
反应路线：
Figure FDA0003265879210000011
其中，Y为氨基、羟基、硫醇基、肼基、氰基、氟、溴或碘；
X为氯或溴。
2.如权利要求1所述的制备方法，其特征在于：具体包含如下步骤：
(1)在强碱或强质子酸的水溶液中，2-氯-4三氯甲基吡啶经过水解，转化为2-羟基吡啶-4-甲酸；
(2)2-羟基吡啶-4-甲酸经过卤化试剂卤化，得到2-卤吡啶-4-甲酸；
(3)2-卤吡啶-4-甲酸与氟化试剂进行氟化反应，得到2-卤代-4-三氟甲基吡啶；
(4)2-卤代-4-三氟甲基吡啶与能够提供Y的亲核试剂反应，得到2-取代-4-三氟甲基吡啶类化合物。
3.如权利要求2所述的制备方法，其特征在于：当最终目标产物为2-羟基-4-三氟甲基吡啶类化合物时，步骤(2)、(4)省略，2-羟基-4-三氟甲基吡啶直接与氟化试剂反应，得到2-羟基-4-三氟甲基吡啶类化合物。
4.如权利要求2所述的制备方法，其特征在于：步骤(1)所述的强碱和强质子酸，强碱优选为氢氧化钠、氢氧化钾、氢氧化钡；强碱的添加量为：4-6个化学摩尔当量，强碱水溶液的浓度为：5％-40％质量浓度；
强质子酸指非挥发性酸和固体超强酸及酸性离子交换树脂，非挥发性酸浓度为60％或更高，优选为硫酸、磷酸、硫酸氢盐、氯磺酸、氟磺酸等，更优选浓度70％及以上的硫酸、酸性离子交换树脂和固体超强酸，用量优选为2-氯-4-三氯甲基吡啶摩尔量的1-3倍；强质子酸的水溶液的质量浓度为：60-90％；
或，在相转移催化剂的辅助下进行水解，所述相转移催化剂的量为2-氯-4-三氯甲基吡啶质量的0.1％-5.0％，优选0.5％-1.5％，所述相转移催化剂包括但不限于长链的直链或支链烷基磺酸碱金属盐、长链的直链或支链季铵/季磷盐、聚合的聚乙二醇；
优选的，水解反应温度为150-180℃；
进一步的，水解反应时间为6-18h；
进一步的，当在强质子酸中水解时，水解压力为常压；当在强碱中进行水解，水解压力为0.1-2.0MPa。
5.如权利要求2所述的制备方法，其特征在于：步骤(2)中，卤化试剂为三氯氧磷、三氯化磷、氯化亚砜、草酰氯、三溴化磷、三溴氧磷、五氯化磷、五溴化磷或三光气中的任意一种及两种及以上。
6.如权利要求2所述的制备方法，其特征在于：步骤(2)中，采用卤化试剂本身作为溶剂，进行无溶剂反应；
进一步的，步骤(2)所述的无溶剂反应中，采用的卤化试剂的量为化学反应所需要摩尔量的3-5倍。
7.如权利要求2所述的制备方法，其特征在于：步骤(2)中，加入溶剂进行反应，所述溶剂为卤代烃，优选为四氯化碳、二氯乙烷、氯苯；
进一步的，加入溶剂的质量优选为卤化原料质量的2-5倍；此时，加入卤化试剂的量，优选为化学反应所需要摩尔量的1.05-2.00倍，更优选为1.2-1.5倍。
8.如权利要求2所述的制备方法，其特征在于：步骤(2)的反应温度为70-120℃，反应时间为8-24h，优选10-12小时。
9.如权利要求2所述的制备方法，其特征在于：步骤(3)所述的氟化反应中，以无水氟化氢、三氟化氢合三乙胺或氟化氢合吡啶作为反应溶剂反应，溶剂的加入量是2-卤代吡啶-4-甲酸质量的0.5-3倍；
进一步的，步骤(3)中，所述的氟化试剂为苯基三氟化硫、取代的三氟化硫或四氟化硫；
进一步的，氟化试剂的加入量是2-卤代吡啶-4-甲酸摩尔量的2.0-3.5倍；
进一步的，氟化反应温度为85-150℃；
进一步的，氟化反应时间为8-24小时，优选10-14小时；
进一步的，氟化反应压力为0.1-5.0MPa；
进一步的，氟化反应完成后，后处理方式为：在35-45℃时，泄压吸收中和无水氟化氢并移除残余的溶剂和氟化试剂，氮气吹扫残余的氟化氢去吸收装置吸收，使用碳酸钠、碳酸氢钠、氨水等中和后，后处理，获得所需要的2-卤代-4-三氟甲基吡啶。
10.如权利要求2所述的制备方法，其特征在于：步骤(4)中，所述亲核试剂包括但不限于醇钠、酚钠、氨基钠、液氨、氨水、硫化钠、硫氢化钠、硫醇钠、硫氰酸钠、***/钾、肼盐酸或硫酸盐、水合肼、碱金属的氟化物、碱金属的碘化物、碱金属溴化物；
进一步的，亲核试剂的加入量是2-卤代-4-三氟甲基吡啶摩尔量的1.05-15倍，具体视亲核试剂活性及是否容易除去、是否兼作为溶剂决定；
进一步的，步骤(4)采用溶剂进行反应，所述溶剂为非质子偶极溶剂，非质子偶极溶剂主要起到溶解原料和能够提供Y的亲核试剂，帮助反应进行的作用，包括但不限于低级脂肪腈类、低级脂肪醚/聚醚类、低级脂肪酮类、低级脂肪酰胺类、低分子量的吗啉类、吡咯烷酮类；非质子偶极溶剂加入的质量是2-卤代-4-三氟甲基吡啶质量的1-5倍，更优选为2-3倍；
进一步的，步骤(4)的反应温度为80-180℃；
进一步的，步骤(4)的反应时间为6-48小时；
进一步的，步骤(4)的反应在催化剂作用下进行，所述催化剂为氯化亚铜、溴化亚铜和碘化亚铜中一种或多种；
优选的，催化剂配合相转移催化剂使用；
进一步的，步骤(4)反应过程中，为了促使反应顺利进行，加入可以结合反应生成的卤化氢的缚酸剂，缚酸剂包括但不限于叔胺类、吡啶类、无机或有机弱酸对应的碱金属盐、有机或无机弱碱。
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