3,5-二取代-2-硫代咪唑啉-4-酮类手性药物Nec-1及其衍生物的合成工艺研究

发布时间：2018-04-06 00:28

本文选题：2-硫代咪唑啉-4-酮　切入点：Nec-1　出处：《山东大学》2016年硕士论文

【摘要】：2-硫代咪唑啉-4-酮(2-硫海妥英、2-乙内酰硫脲)衍生物是一类重要的五元杂环化合物。自从1890年被发现后,广泛应用于化学合成、农学研究与生命医药领域。例如,该类化合物可作为有机合成制备的手性辅基、金属配体或动力学拆分试剂,此外还广泛用于农业生产的除草剂及生命科学的蛋白质测序分析等。近年来,2-硫代咪唑啉-4-酮类化合物广泛应用于医药领域,常作为某些先导化合物或药物的中间体,且被报道具有抗癫痫、抗真菌、抗病毒、抗肿瘤(白血病、黑素瘤、肺癌、结肠癌、卵巢癌、乳腺癌、前列腺癌等)等生物活性。2005年,3,5-二取代-2-硫代咪唑啉-4-酮类化合物首次被报道具有RIP1激酶抑制活性,典型的药物如Nec-1和O-Nec-1已被证实具有针对缺血性损伤和中风等疾病的潜在治疗用途。然而受限于早期合成方法,Nec-1和O-Nec-1一直未能找到有效的手性合成方法,因此只能通过手性制备柱或化学拆分等方法获得光学异构体后再进行活性研究。由于前期研究已证实该类化合物的R构型的活性明显高于其对映异构的S构型,因此发展新型手性制备3,5-二取代-2-硫代咪唑啉-4-酮类衍生物的方法在当前药学领域具有重要的理论意义及应用前景。据文献报道,合成2-硫代咪唑啉-4-酮类化合物的主要方法有硫氰酸铵法、聚乙二醇法、三乙胺介导法、氧化铝介导法、氯乙酸乙酯法以及功能化离子液体法。然而文献所报道的2-硫代咪唑啉-4-酮类化合物的合成方法均涉及反应条件苛刻、存在后处理麻烦及收率低等主要问题。最关键的问题上述方法只能得到2-硫代咪唑啉-4-酮的消旋体,这已成为阻碍深入评价该类化合物药理活性的瓶颈因素。本论文围绕上述关键问题,通过对产物消旋机理的调研分析以及反应条件(碱、溶剂及反应温度)和反应路线进行初步摸索,发展了新型NaH介导法合成工艺,并实现了12个2-硫代咪唑啉-4-酮类化合物的手性合成。该工艺不仅得到光学纯度较高目标化合物,而且可应用于(S)-Nec-1、(R)-Nec-1、(S)-O-Nec-1和(R)-O-Nec-1等活性药物的手性合成,并得到了光学纯度极高的O-Nec-1光学异构体和一定光学纯度的Nec-1光学异构体。本论文中,所有目标化合物都测定了熔点等物理常数,并对其外观进行了描述,所有目标化合物均经1H-NMR,13C-NMR,HRMS以及Chiral-HPLC确证。后期工作中,我们还将继续设计并合成更多结构新颖的2-硫代咪唑啉-4-酮类手性衍生物,然后进行相关活性研究。
[Abstract]:2-thioimidazoline-4-ketone-2-thiotoin-2-ethyl thiourea) derivatives are a class of important quaternary heterocyclic compounds.Since its discovery in 1890, it has been widely used in chemical synthesis, agronomy and life medicine.For example, these compounds can be used as chiral auxiliary groups, metal ligands or kinetic resolution reagents for organic synthesis, in addition, they are widely used in herbicides in agricultural production and protein sequencing analysis in life sciences, etc.In recent years, 2-thio-imidazoline-4-one compounds have been widely used in the field of medicine. They are often used as intermediates of some leading compounds or drugs, and have been reported to have antiepileptic, antifungal, antiviral, anti-tumor (leukemia, melanoma, lung cancer).In 2005, 5-disubstituted -2-thio-imidazoline-4-one compounds were first reported to have RIP1 kinase inhibitory activity.Typical drugs such as Nec-1 and O-Nec-1 have been shown to have potential therapeutic uses for diseases such as ischemic injury and stroke.However, limited by the early synthesis methods, Nec-1 and O-Nec-1 have not been able to find an effective chiral synthesis method, so they can only obtain optical isomers by chiral preparation column or chemical resolution method, and then study their activity.The activity of R configuration of this kind of compound is obviously higher than that of its isomerization S configuration.Therefore, the development of a novel chiral method for the preparation of 3o 5-disubstituted -2-thio-imidazoline-4-one derivatives has important theoretical significance and application prospect in the field of pharmaceutical science.According to the literature, the main methods of synthesizing 2-thio-imidazoline-4-ketones include ammonium thiocyanate, polyethylene glycol, triethylamine, alumina, ethyl chloroacetate and functionalized ionic liquid.However, the synthesis methods of 2-thio-imidazoline-4-one compounds reported in the literature are all related to the harsh reaction conditions, the problems of post-treatment and low yield.The most important problem mentioned above is that the racemates of 2-thio-imidazoline-4-one can only be obtained, which has become the bottleneck factor that hinders the further evaluation of the pharmacological activities of these compounds.Based on the investigation and analysis of the racemic mechanism of the product, the reaction conditions (alkali, solvent and reaction temperature) and the reaction route, a new process of NaH mediated synthesis was developed in this paper.The chiral synthesis of 12 2-thioimidazoline-4-ketones was achieved.This process not only gives high optical purity target compounds, but also can be applied to the chiral synthesis of active drugs, such as Snec-Nec-1r-Nec-1 and Rnc-O-Nec-1, etc. O-Nec-1 optical isomers with high optical purity and Nec-1 optical isomers with certain optical purity have been obtained.In this thesis, the melting point and other physical constants of all the target compounds were determined and their appearance were described. All the target compounds were confirmed by 1H-NMR-13C-NMR-HRMS and Chiral-HPLC.In the later work, we will continue to design and synthesize more novel 2-thioimidazoline-4-one chiral derivatives, and then study the related activities.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R914

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