CN117886742A - 一种制备吡啶衍生物的方法 - Google Patents

一种制备吡啶衍生物的方法 Download PDF

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CN117886742A
CN117886742A CN202410035930.4A CN202410035930A CN117886742A CN 117886742 A CN117886742 A CN 117886742A CN 202410035930 A CN202410035930 A CN 202410035930A CN 117886742 A CN117886742 A CN 117886742A
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刘文博
史秋
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Sun Yat Sen University
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Abstract

本发明公开了一种制备吡啶衍生物的方法，包括以下步骤：S1、在亲电活化试剂的存在下，脲类化合物与吡啶类化合物进行反应，制得吡啶胍；S2、所述吡啶胍与亲核试剂或自由基前体进行反应，制得二氢吡啶中间体；S3、所述二氢吡啶中间体与氧化剂进行水解反应，制得吡啶衍生物和脲类化合物。本发明通过将廉价易得的吡啶类化合物与活化后的脲反应形成吡啶盐，高选择性的得到各种附加值很高的复杂吡啶衍生物。本发明将脲作为一种大位阻基团用来选择性合成复杂吡啶衍生物，脲类化合物价格低廉、对水和空气都非常稳定，所制得的吡啶胍具有很好的C‑4位官能团化区域选择性，对于离子前体和自由基前体都能兼容。

Description

一种制备吡啶衍生物的方法
技术领域
本发明属于有机物合成技术领域，具体涉及一种制备吡啶衍生物的方法。
背景技术
吡啶是公认的药物、配体、催化剂和材料中最常见的芳香杂环之一。鉴于吡啶类化合物的广泛应用，从简单易得的吡啶类化合物高效和区域选择性官能团化吡啶是获得复杂吡啶衍生物的最直接途径，但由于吡啶的惰性，吡啶类化合物的选择性官能团化一直是一个具有挑战性的难题。与已经发展成熟的吡啶的C-2位和C-3位官能团化相比，吡啶C-4位官能团化在最近几十年才得到发展，目前实现吡啶的C-4选择性官能团化主要是通过引入大位阻的基团与N原子相互作用遮蔽C-2位的竞争反应，大位阻的基团主要包括富马酸酯、三嗪基盐、三芳基硼烷、氮杂卡宾镍铝化合物、硅正离子等。上述每种大位阻基团往往只能通过一种方式(离子型加成或者自由基加成)得到某种特定类型的吡啶化合物，这些大位阻基团大多对水和空气特别敏感，实用性极差，并且加成的前体种类单一。因此，亟需发展一种新的价格低廉、能在空气中存在的用于制备吡啶衍生物的大位阻基团，并且通过该大位阻基团可以实现种类多样的前体离子和自由基两种方式对吡啶的加成。
发明内容
为了克服上述现有技术存在的问题，本发明的目的在于提供一种制备吡啶衍生物的方法。
为了实现上述目的，本发明所采取的技术方案是：
本发明提供了一种制备吡啶衍生物的方法，包括以下步骤：
S1、在亲电活化试剂的存在下，脲类化合物与吡啶类化合物进行反应，制得吡啶胍；
S2、所述吡啶胍与亲核试剂或自由基前体进行反应，制得二氢吡啶中间体；
S3、所述二氢吡啶中间体与氧化剂进行水解反应，制得吡啶衍生物和脲类化合物；
所述脲类化合物与吡啶胍的结构式分别如式a和式b所示：
其中，R1和R3分别独立选自具有1至10个C原子的取代或未取代烷基、具有2至10个C原子的取代或未取代烯基、具有2至10个C原子的取代或未取代炔基；R2和R4分别独立选自具有1至10个C原子的取代或未取代烷基、具有2至10个C原子的取代或未取代烯基、具有2至10个C原子的取代或未取代炔基，并且相邻的基团可以相互成环；
通常，术语“取代的”，是指存在于基团(例如，碳或氮原子)上的至少一个氢被可允许的取代基取代，例如，在取代时产生稳定的化合物的取代基，例如，不自发地进行转变(例如通过重排、环化、消除或其它反应)的化合物。除非另外说明，否则，“取代的”基团在所述基团的一个或多个可取代的位置处具有取代基，且当在任何给定结构中的一个以上的位置被取代时，在每个位置处的取代基是相同或不同的。
其中，R5选自氢、烷基、芳基、酯基或卤素；
所述吡啶衍生物如式c所示：
其中，Nu为亲核试剂中的取代或未取代烷基、取代或未取代芳基、取代或未取代环烷基；R为自由基中的取代或未取代烷基、取代或未取代芳基；R5选自氢、烷基、芳基、酯基或卤素。
优选地，所述取代烷基、取代烯基、取代炔基中的取代基分别独立选自卤素(氟、氯、溴、碘中的任意一种或多种)、羟基、羧基、缩醛基、氨基、伯氨基、仲氨基、酯基、羰基、酰胺基、氰基中的一种或多种。
优选地，R1和R3分别独立选自具有1至10个C原子的未取代烷基、具有2至10个C原子的未取代烯基、具有2至10个C原子的未取代炔。
优选地，所述脲类化合物为对称脲类化合物。
更优选地，所述R1和R3同为具有1至6个C原子的未取代烷基。
优选地，所述制备吡啶衍生物的方法的反应式如下所示：
步骤1：
步骤2：
步骤3：
实际反应：
优选地，所述脲类化合物与吡啶胍的结构式分别如式d和式e所示：
其中，R1、R3和R5如上述；n为1或2。
优选地，所述吡啶衍生物具有如下任意一种结构式：
优选地，所述亲电活化试剂为三氟甲磺酸酐。
优选地，步骤S1，所述反应温度为0-40℃。
优选地，步骤S1，所述反应时间为4h-48h。
优选地，步骤S1，所述脲类化合物与吡啶类化合物的摩尔比为(1-1.5)：1。
优选地，步骤S1，所述亲电活化试剂与脲类化合物的摩尔比为(0.9-3)：1。
优选地，步骤S2，所述反应温度为-78-50℃。
优选地，步骤S2，所述反应时间为5min-24h。
优选地，步骤S2，所述吡啶胍与亲核试剂或自由基前体的摩尔比为1：(1.2-4)。
优选地，步骤S3，所述反应温度为室温到70℃。
优选地，步骤S3，所述反应时间为2h-48h。
优选地，步骤S3，所述二氢吡啶中间体与氧化剂的摩尔比为1：(1.5-5)。
优选地，所述亲核试剂选自格氏试剂、锂试剂、氰基亲核试剂、烯醇式亲核试剂中的一种或多种。
更优选地，所述格氏试剂选自环烷基卤化镁或烷基卤化镁。
优选地，所述自由基前体选自羧酸类化合物、硼酸类化合物或者烷烃。
优选地，所述氧化剂选自亚硝酸、铁氰化钾、醋酸碘苯、醋酸锰、硝酸银中的一种或多种。
本发明的有益效果是：
本发明提供了一种制备吡啶衍生物的方法，通过将廉价易得的吡啶类化合物与活化后的脲反应形成吡啶盐，高选择性的得到各种附加值很高的复杂吡啶衍生物。该方法通过一锅反应将吡啶连续进行脲保护，加成和氧化的操作，从吡啶原料出发仅需进行一次柱层析分离就可以得到高附加值的吡啶衍生物。本发明将脲作为一种大位阻基团用来选择性合成复杂吡啶衍生物，脲类化合物价格低廉、对水和空气都非常稳定，所制得的吡啶胍具有很好的C-4位官能团化区域选择性，对于离子前体和自由基前体都能兼容。
附图说明
图1为产物核磁氢谱图；
图2为产物核磁碳谱。
具体实施方式
实施例1
按照下列反应式制备4-正戊基吡啶：
步骤1：
步骤2：
步骤3：
根据上述化学反应式，制备过程包括以下步骤：
S1、称量4.2mmol的N,N-二异丁基丙烯基脲(1,3-二异丁基-3,4,5,6-四氢-2-嘧啶酮)和4.0mmol的吡啶作为原料；称取4.08mmol的三氟甲磺酸酐作为亲电活化试剂；量取12.0mL干燥的二氯甲烷作为溶剂。将N,N-二异丁基丙烯基脲置于反应管中，抽真空，灌氮气，缓慢滴加三氟甲磺酸酐活化脲的酰胺键，活化完滴加吡啶原料，在0℃下反应4h，得到吡啶胍盐白色固体，该胍盐不需要过柱纯化，在室温搅拌会直接从溶液体系里析出来，通过砂芯漏斗过滤和二氯甲烷洗涤可以得到(分离产率：86％)。
S2、将5mL四氢呋喃加到吡啶胍盐的反应瓶中形成悬浊液，以戊基溴化镁作为亲核试剂，在-78℃低温条件下缓慢滴加0.75mmol戊基溴化镁对吡啶胍盐进行加成，在加成的过程中悬浊液逐渐变得澄清，总反应时间为10min，通过加水淬灭过量的格氏试剂即可得到二氢吡啶中间体混合物，该中间体可以分离也可以直接往后加氧化剂进行氧化水解。
S3、在上述淬灭完的反应液中加入1mL亚硝酸钠水溶液(0.5M)和0.1mL冰醋酸，室温搅拌8h即可得到完全对位戊基取代的吡啶(分离产率：79％)和原料异丁基脲。所得对戊基吡啶产物核磁氢、碳谱图分别如图1、图2所示。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

1.一种制备吡啶衍生物的方法，其特征在于，包括以下步骤：
S1、在亲电活化试剂的存在下，脲类化合物与吡啶类化合物进行反应，制得吡啶胍；
S2、所述吡啶胍与亲核试剂或自由基前体进行反应，制得二氢吡啶中间体；
S3、所述二氢吡啶中间体与氧化剂进行水解反应，制得吡啶衍生物和脲类化合物；
所述脲类化合物与吡啶胍的结构式分别如式a和式b所示：
其中，R1和R3分别独立选自具有1至10个C原子的取代或未取代烷基、具有2至10个C原子的取代或未取代烯基、具有2至10个C原子的取代或未取代炔基；R2和R4分别独立选自具有1至10个C原子的取代或未取代烷基、具有2至10个C原子的取代或未取代烯基、具有2至10个C原子的取代或未取代炔基，并且相邻的基团可以相互成环；
其中，R5选自氢、烷基、芳基、酯基或卤素；
所述吡啶衍生物如式c所示：
其中，Nu为亲核试剂中的取代或未取代烷基、取代或未取代芳基、取代或未取代环烷基；R为自由基中的取代或未取代烷基、取代或未取代芳基；R5选自氢、烷基、芳基、酯基或卤素。
2.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，所述脲类化合物与吡啶胍的结构式分别如式d和式e所示：
其中，R1、R3和R5如权利要求1所述；n为1或2。
3.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，所述啶衍生物具有如下任意一种结构式：
4.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，所述亲电活化试剂为三氟甲磺酸酐。
5.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，步骤S1，所述反应的反应条件选自以下的一种或多种：
A)所述反应温度为0-40℃；
B)所述反应时间为4h-48h；
C)所述脲类化合物与吡啶类化合物的摩尔比为(1-1.5)：1；
D)所述亲电活化试剂与脲类化合物的摩尔比为(0.9-3)：1。
6.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，步骤S2，所述反应的反应条件选自以下的一种或多种：
E)所述反应温度为-78-50℃；
F)所述反应时间为5min-24h；
G)所述吡啶胍与亲核试剂或自由基前体的摩尔比为1：(1.2-4)。
7.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，步骤S3，所述反应的反应条件选自以下的一种或多种：
H)所述反应温度为室温到70℃；
I)所述反应时间为2h-48h；
J)所述二氢吡啶中间体与氧化剂的摩尔比为：1：(1.5-5)。
8.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，所述亲核试剂选自格氏试剂、锂试剂、氰基亲核试剂、烯醇式亲核试剂中的一种或多种；
和/或，所述自由基前体选自羧酸类化合物、硼酸类化合物或烷基氢化合物。
9.根据权利要求8所述的制备吡啶衍生物的方法，其特征在于，所述格氏试剂选自环烷基卤化镁或烷基卤化镁。
10.根据权利要求1所述的制备吡啶衍生物的方法，其特征在于，所述氧化剂选自亚硝酸、铁氰化钾、醋酸碘苯、醋酸锰、硝酸银中的一种或多种。
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