CN114671795B - 吲哚类化合物、制备方法及其在醛酮检测中的应用 - Google Patents
吲哚类化合物、制备方法及其在醛酮检测中的应用 Download PDFInfo
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Abstract
本发明公开了新型吲哚类化合物作为衍生化试剂,使用超高效液相色谱‑三重四级杆质谱(UHPLC‑MS/MS)测定水中醛酮类化合物的检测方法。新型吲哚类化合物与醛酮化合物反应条件简单,产物质谱响应灵敏,该检测方法具有基质干扰小、检出限低、分析时间短、定量准确的优点。本发明还公开了制备吲哚类化合物的实验方法,其从已知可得的原料出发,通过多步化学反应成功合成了可用于UHPLC‑MS/MS检测水中的醛酮类化合物的新型化合物。
Description
技术领域
本发明涉及醛酮检测技术领域,具体涉及吲哚类化合物、制备方法及其在醛酮检测中的应用。
背景技术
醛酮类化合物对人的眼睛、皮肤和呼吸道粘膜具有强烈的刺激,部分醛酮化合物可以诱导动物致癌。检测醛酮类化合物一般有分光光度法、液相色谱法、液相色谱质谱法、气相色谱法等。一般使用2,4-二硝基苯肼(DNPH)与醛酮反应生成腙类化合物,使用液相色谱或者气相色谱进行分离,紫外或者电子捕获检测器进行检测。现有技术存在以下问题:
1. 前处理繁琐,各醛酮的最优化衍生条件差异性大;
2. 溶剂用量大,易对环境产生二次污染,不利于绿色环保;
3. 紫外检测器灵敏度低,检出限较高,准确度差;
4. 分析时间长,检测效率低,不利于大量样品的检测;
5. DNPH与醛酮类反应生成的腙类化合物很难达到基线分离,检测结果极易造成假阳性。
发明内容
本发明的一个目的是解决至少上述问题和/或缺陷,并提供至少后面将说明的优点。
本发明还有一个目的是提供一种吲哚类化合物,其易与醛酮类化合物进行反应,反应产物经超高效液相色谱分离后,使用质谱检测器检测,该醛酮-吲哚类衍生化产物质谱响应灵敏,线性关系好,检出限低,分析时间短,定量准确。
本发明还有另外一个目的是提供一种制备吲哚类化合物的方法,其从已知可得的原料出发,通过多步反应成功合成了可用于超高效液相色谱-质谱法检测水中的醛酮类化合物的新型化合物。
本发明还有另外一个目的是提供了吲哚类化合物作为醛酮衍生化试剂在水环境中醛酮检测中的应用。
为了实现根据本发明的这些目的和其它优点,提供了一种吲哚类化合物,其中,所述含能盐具有如下式(I)的结构:
(I)
其中,R1、R3为卤素, R2、R4为 H、F、 Cl、 Br或 N(CH3)3,R5 为 CH3或CD3。
优选的是,其中,R1、R3为F,R2、R4 为H,R5为CH3。
优选的是,其中,R1、R3为F,R2、R4 为H,R5为CD3。
优选的是,其中,R1、R2、R3为F, R4 为H,R5为CH3。
本发明的目的还可以进一步由吲哚类化合物的制备方法来实现,包括如下步骤:
步骤一、以4, 6-二卤-1H-吲哚-2-甲酸或多卤取代的1H-吲哚-2-甲酸为原料在催化剂作用下发生酯化反应得到4, 6-二卤-1H-吲哚-2-羧酸甲酯或多卤取代的1H-吲哚-2-羧酸甲酯;
步骤二、所述步骤一得到的产物通过甲基化反应得到4, 6-二卤-1-甲基-1H-吲哚-2-羧酸甲酯或多卤取代的1-甲基-1H-吲哚-2-羧酸甲酯;
步骤三、所述步骤二得到的产物与水合肼反应得到式(I)化合物。
优选的是,其中,所述步骤一具体包括:将4, 6-二卤-1H-吲哚-2-甲酸或多卤取代的1H-吲哚-2-甲酸溶于无水甲醇中,搅拌下加入催化量的浓硫酸,升温回流,反应3 h,冷却、过滤,石油醚洗涤。
优选的是,其中,所述步骤二具体包括:将步骤一所得产物溶于N, N-二甲基甲酰胺中,冰水浴下搅拌,加入氢化钠和碘甲烷或氘代碘甲烷,冰水浴至室温下反应2 h,加入冰水淬灭反应,饱和食盐水洗涤,干燥,柱层析得甲基化产物或氘代甲基化产物。
优选的是,其中,所述步骤三具体包括:将步骤二所得产物溶于无水乙醇中,加入水合肼,回流反应5 h,冷却至室温,抽滤除去溶剂,石油醚洗涤。
本发明的目的还可以进一步由吲哚类化合物作为醛酮衍生化试剂在水环境中醛酮检测中的应用。
本发明至少包括以下有益效果:
1、本发明吲哚类化合物含有酰肼基团,可快速与醛酮类化合物发生反应,通过在N原子上引入甲基或氘代甲基,提高三级胺的离子化能力,进而提高了质谱检测灵敏度。
2、本发明的吲哚类化合物的制备方法,反应原料易得,合成条件简单,制备产率高,所得产物易于离子化。
3、本发明的吲哚类化合物可用于水环境中醛酮的检测,质谱响应灵敏、重现性好、检出限低。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为本发明实施例1中化合物1的核磁共振氢谱图;
图2为本发明实施例1中化合物1的核磁共振碳谱图;
图3为本发明实施例1中化合物2的核磁共振氢谱图;
图4为本发明实施例1中化合物2的核磁共振碳谱图;
图5为本发明实施例1中目标化合物DFICH的核磁共振氢谱图;
图6为本发明实施例1中目标化合物DFICH的核磁共振碳谱图;
图7为本发明实施例1中目标化合物DFICH与苯甲醛反应产物的核磁共振氢谱图;
图8为本发明实施例1中目标化合物DFICH与苯甲醛反应产物的核磁共振碳谱图;
图9为本发明实施例1中目标化合物DFICH检测醛酮类化合物的超高效液相色谱-三重四级杆质谱图。
具体实施方式
下面结合附图对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
应当理解,本文所使用的诸如“具有”、“包含”以及“包括”术语并不配出一个或多个其它元件或其组合的存在或添加。
需要说明的是,下述实施方案中所述实验方法,如无特殊说明,均为常规方法,所述试剂和材料,如无特殊说明,均可从商业途径获得。
<实施例1>
吲哚类化合物DFICH,其结构式如下:
具体合成路线如下:
具体合成步骤如下:
步骤一、化合物1(4, 6-二氟-1H-吲哚-2-羧酸甲酯)的合成
将4, 6-二氟-1H-吲哚-2-甲酸 (0.79 g, 4.00 mmol) 溶于无水甲醇 (15 mL)中充分搅拌,加入催化量的浓硫酸,升温回流。TLC检测反应。3 h后停止反应,静置冷却,白色固体析出。过滤,加少量石油醚洗涤,干燥得白色固体化合物1(0.80 g),产率94.7%;化合物1的核磁共振氢谱图见图1,核磁共振碳谱图见图2。
MS (ESI) m/z: 212 (M+H+, 100); 1H NMR (300 MHz, DMSO) δ 12.39 (s, 1H),7.18 (d, J = 1.4 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.95 (td, J = 10.4, 1.7Hz, 1H), 3.88 (s, 3H). 13C NMR (75 MHz, DMSO) δ 162.14, 161.98, 161.46,158.96, 158.80, 158.16, 157.95, 154.84, 154.63, 139.08, 138.90, 138.71,128.67, 128.63, 113.65, 113.35, 103.85, 96.36, 96.27, 95.96, 95.44, 95.38,95.10, 95.03, 52.47.
步骤二、化合物2(4, 6-二氟-1-甲基-1H-吲哚-2-羧酸甲酯)的合成
在 0℃下,将化合物 1 (0.64 g, 3.00 mmol) 溶于DMF (10 mL),充分搅拌,加入NaH (0.22 g, 9.00 mmol) 和碘甲烷 (1.27 g, 9.00 mmol)。冰浴至室温反应,TLC检测,2h后完全反应。加入少量冰水淬灭反应,将反应液用饱和食盐水(20 mL×4)洗涤,干燥,浓缩后快速柱层析,纯化得白色固体化合物2 (0.63 g),产率93.4%;化合物1的核磁共振氢谱图见图3,核磁共振碳谱图见图4。
MS (ESI) m/z: 226 (M+H+, 100); 1H NMR (300 MHz, DMSO) δ 7.43 (d, J =9.3 Hz, 1H), 7.27 (s, 1H), 7.00 (td, J = 10.3, 1.9 Hz, 1H), 3.99 (s, 3H),3.86 (s, 3H). 13C NMR (75 MHz, DMSO) δ 162.43, 162.27, 161.46, 159.25, 159.08,158.06, 157.85, 157.74, 154.74, 154.53, 141.05, 140.85, 140.68, 128.89,128.85, 112.01, 111.71, 105.53, 96.92, 96.61, 96.52, 96.21, 94.62, 94.56,94.26, 94.20, 52.33, 32.74.
步骤三、化合物DFICH(4, 6-二氟-1-甲基-1H-吲哚-2-甲酰肼)的合成
将化合物2 (0.45 g, 2 mmol)溶于无水乙醇中,加入过量水合肼升温回流。反应5h后原料完全反应。停止反应后,冷却至室温析出白色沉淀,抽滤,加少量石油醚洗涤,得产品DFICH,为白色絮状固体0.37 g,产率82.2%;化合物DFICH的核磁共振氢谱图见图5,核磁共振碳谱图见图6。
MS (ESI) m/z: 226 (M+H+, 100); 熔点: 153.7℃-155.1℃; 1H NMR (300 MHz,DMSO) δ 9.85 (s, 1H), 7.35 (d, J = 9.4 Hz, 1H), 7.08 (s, 1H), 6.95 (s, 1H),4.58 (s, 2H), 3.96 (s, 3H). 13C NMR (75 MHz, DMSO) δ 161.46, 161.32, 158.30,158.13, 157.63, 157.42, 154.33, 154.13, 140.28, 140.09, 139.91, 132.45,112.06, 111.77, 99.89, 96.01, 95.92, 95.61, 94.30, 94.24, 93.94, 93.88,32.47. HRMS (ES+) calcd for C10H10F2N3O (M+H)+: 226.1988, found 226.1984。
<实施例2>
化合物DFICH用于水中醛酮类化合物的检测(以检测苯甲醛为例)
DFICH与苯甲醛反应所得标准物质为Z/E-N'-亚苄基-4, 6-二氟-1-甲基-1H-吲哚-2-甲酰肼,其结构式如下:
具体检测原理:
检测过程步骤(以检测苯甲醛为例):
步骤一、制备DFICH与苯甲醛反应所得标准物质:
将DFICH (0.06 g, 0.25 mmol)溶于无水乙醇中,加入过量苯甲醛,升温40 ℃。反应0.5 h后原料完全反应。停止反应后,旋除溶剂柱分离,得白色固体标准物质0.07 g,产率90.0%;DFICH与苯甲醛反应产物的核磁共振氢谱图见图7,DFICH与苯甲醛反应产物的核磁共振碳谱图见图8。
MS (ESI) m/z: 314 (M+H+, 100); 熔点: 142.2℃-143.5℃; 1H NMR (300 MHz,DMSO) δ 11.97 (s, 1H), 8.43 (s, 1H), 7.73 (s, 2H), 7.57 – 7.25 (m, 5H), 7.00(t, J = 9.8 Hz, 1H), 4.00 (s, 3H). 13C NMR (75 MHz, DMSO) δ 161.91, 157.90,148.20, 141.29, 134.70, 131.99, 130.60, 129.34, 127.55, 101.66, 96.26, 94.51,94.16, 56.48, 32.68, 19.01. HRMS (ES+) calcd for C17H14F2N3O (M+H)+:313.1027, found 313.1025。
制备DFICH与其他醛酮类化合物反应所得标准物质的步骤同上,在此不再赘述。
步骤二、DFICH检测水中的醛酮类化合物:
DFICH作为衍生化试剂,使用UHPLC-MS/MS检测水中的醛酮类化合物。
2.1、醛酮-DFICH标准溶液配制
将5 mg DFICH加入5% HCl水溶液中,定容至10 mL,配制成500 μg/mL的DFICH衍生溶液。取1 mL的10 、20、50、100、200、500、1000 μg/L的醛酮标准水溶液,加入100 μL 500 μg/mL的DFICH衍生溶液,在40℃条件下静置1 h,配制成醛酮-DFICH标准溶液。
2.2 DFICH检测水中的醛酮类化合物的前处理反应
取1 mL的水样,加入100 μL 的500 μg/mL DFICH衍生溶液,40℃条件下静置1 h。
2.3 仪器条件
2.3.1 超高效液相色谱条件
流速:0.5 mL/min。柱温:40℃。进样体积:5 μL。流动相:50%乙腈、50%水。
2.3.2 质谱条件
模式:正离子模式;毛细管电压:2.8 kV;离子源温度:120℃;雾化温度:350℃;雾化气流速:800 L/h;反吹气流速:10 L/h;碰撞气流速:0.10 mL/min;醛酮类衍生物的质谱多反应监测模式特征离子见表1。
表1 醛酮类衍生物的保留时间、特征离子和线性参数
2.4 超高效液相色谱-三重四级杆质谱图
醛酮类-DFICH衍生物的保留时间、特征离子和线性参数如表1所示。由表1所知,在10~1000 μg/L(质量浓度以醛酮计)浓度范围内,醛酮类-DFICH衍生物线性关系良好,相关系数>0.999。醛酮类-DFICH衍生物的总离子流谱图见图9,按照保留时间顺序,依次是丁烯醛-DFICH、丁酮-DFICH、戊醛-DFICH、苯甲醛-DFICH、甲基苯甲醛-DFICH、己醛-DFICH的谱图。
适合水样中醛酮类化合物的高通量快速检测,本发明的吲哚类化合物DFICH与醛酮反应得到的衍生产物,质谱响应高、基质干扰小、重现性好、所有物质均达到基线分离,7min内即可完成醛酮类化合物的分析。因此本发明的新型化合物DFICH可用于超高效液相色谱质谱法检测水中的醛酮类化合物。
<对比例1>
现有技术中用于水中醛酮检测的DNPH(2,4-二硝基苯肼),衍生化产物的质谱响应灵敏度相对较低,其检测方法一般采用液相色谱-紫外检测法。尽管液相色谱检测方法具有定量准确,重现性好的优点,但是由于紫外检测器的灵敏度较低,因而只适于检测水环境中浓度相对较高的醛酮类化合物;同时前处理过程需萃取并浓缩醛酮-DNPH衍生化合物,此过程中易造成目标物损失,回收率差;此外,使用DNPH衍生、液相色谱紫外检测器测定水中的醛酮类化合物,具有检出限较低,前处理繁琐,需要的水样以及衍生溶液多,分析时间长,溶剂用量大的特点,不利于低浓度样品、大批量样品的检测。
现有技术中用于水中醛酮检测的化合物DNPH(2, 4-二硝基苯肼)与本发明的DFICH化合物用于水中醛酮检测的对比数据如下表2。
表2 DNPH与DFICH检测水中醛酮的对比
超高效液相-质谱联用分析法结合了液相色谱和质谱的优势,具有更高的选择性和灵敏度,定性、定量能力强。由图9可以看出,本发明设计的衍生化试剂DFICH,对醛酮检测化合物的质谱响应灵敏度高、检出限低、分析时间短、前处理简便、需要的水样以及衍生溶液少、可被应用于水环境中低含量醛酮类化合物的高通量快速检测。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用。它完全可以被适用于各种适合本发明的领域。对于熟悉本领域的人员而言,可容易地实现另外的修改。因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节和这里示出与描述的图例。
Claims (6)
2.一种制备权利要求1所述的吲哚类化合物的方法,包括如下步骤:
步骤一、将4, 6-二氟-1H-吲哚-2-甲酸溶于无水甲醇中,搅拌下加入催化量的浓硫酸,升温回流,反应3 h,冷却、过滤,石油醚洗涤得到4, 6-二氟-1H-吲哚-2-羧酸甲酯;
步骤二、所述步骤一得到的产物通过甲基化反应得到4, 6-二氟-1-甲基-1H-吲哚-2-羧酸甲酯;
步骤三、所述步骤二得到的产物与水合肼反应得到式(I)化合物。
3.如权利要求2所述的方法,其中,所述步骤二具体包括:将步骤一所得产物溶于N, N-二甲基甲酰胺中,冰水浴下搅拌,加入氢化钠和碘甲烷,冰水浴至室温下反应2 h,加入冰水淬灭反应,饱和食盐水洗涤,干燥,柱层析得甲基化产物。
4.如权利要求2所述的方法,其中,所述步骤三具体包括:将步骤二所得产物溶于无水乙醇中,加入水合肼,回流反应5 h,冷却至室温,抽滤除去溶剂,石油醚洗涤。
5.如权利要求3所述的方法,其中,步骤一所得产物、氢化钠、碘甲烷的摩尔比为1:3:3。
6.权利要求1所述的吲哚类化合物作为醛酮衍生化试剂在水环境中的醛酮检测中的应用。
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Derivatizing assay for the determination of aldehydes using micellar electrokinetic chromatography;Donegatti, Tiago Augusto 等;《Electrophoresis》;20171231;第38卷(第7期);第1068-1074页 * |
Fast determination of total aldehydes in rainwaters in the presence of interfering compounds;Sergii Sukharev 等;《Environmental Chemistry Letters》;20190322;第17卷;第1405-1411页 * |
Sergii Sukharev 等.Fast determination of total aldehydes in rainwaters in the presence of interfering compounds.《Environmental Chemistry Letters》.2019,第17卷第1405-1411页. * |
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