The Synthetic Process Research On 3,5-Disubstituted 2-Thioxo-Imidazolidin-4-One Chiral Drug Nec-1 And Its Derivatives

2-thioxo-imidazolidin-4-one (2-thiohydantoin) derivatives are very important structural motifs featuring five-membered hetereocyclic stem nucleus. These kinds of compounds were first discovered in 1890 and have been used in a wide range of scientific and societal fields. Specifically, they can be used as chiral auxiliary, metal ligand and kinetic resolution reagent in synthetic chemistry, herbicide in agricultural research and protein sequence analysis in biological sciences. Most importantly, they are being widely used for the purpose of medicine and pharmaceutical sciences, including antiepileptic, antifungal, antiviral, antitumor (treatments of leukemia, melanoma, lung cancer, colon cancer, ovarian cancer, breast cancer and prostate cancer), lead compounds and building blocks of the drug intermediates. Since the year of 2005, Nec-1 derivatives, such as Nec-1 and O-Nec-1, have been proved to be potent RIP1 kinase inhibitors, which might be potential for the treatments of many diseases, including ischemic injury and stroke. As the previous methods could not solve the racemic problem of thiohydantoins, Nec-1 derivatives could not be synthesized with satisfactory enantiopurities. As a result, before the biological evaluation or SAR research of Nec-1 derivatives, resolution by chiral colomn or other time-consuming procedures were indispensbale for obtaining the enantiopure products. As for the SAR analysis of Nec-1 derivatives, previous studies demonstrated that the R-enantiomers are more potent than their counterparts. Therefore, it is paramount and highly applicable to develop a novel synthetic process research on enantioselective synthesis of 2-thioxo-imidazolidin-4-one derivatives, especially chiral 3,5- disubstituted thiohydantoins.A wide range of synthetic methods have been reported in the literature, including Ammonium Thiocyanate Method, PEG Method, TEA Method, A12O3 Method, Ethyl Chloroacetate Method, Functionalized Ionic Liquid Method, etc. However, these methods generally involve harsh conditions, low yields or toxic reagents. Moreover, only racemic thiohydantoins could be obtained through traditional methods, which has become the obstacle regarding in-depth evaluation of the pharmacological activity of these compounds. Therefore, we were trying to slove these issues mentioned above. The NaH-Mediated Method was developed by analysing the racemic mechanism reported in the previous literature, and then exploring the synthetic routes and reaction conditions, this method can solve the racemic problem with satisfactory enantiopurities.In this dissertation,12 thiohydantoin derivatives as well as four Nec-1 derivatives ((S)Nec-1, (R)Nec-1, (S)-O-Nec-1 and (R)-O-Nec-1) have been enantioselectively synthesized with good to high yields and enantiomerical purity. All of target molecules were identified by melting points, exterior,’H-NMR,13C-NMR, HRMS and chiral-HPLC.In the succeeding research, we will further design and synthesize more chirally novel thiohydantoin derivatives and conduct the biological activity evaluation.