The Application Of [3+2] Cycloaddition Key Technolony In The Synthesis Of Arylhydantoin Derivatives

Nitrogen-containing heterocyclic compounds have a very wide range of biological activities and occupy an important position in the field of pharmaceutical research and organic synthesis.Hydantoin and its derivatives are one of many nitrogen-containing heterocyclic compounds.They are extremely rare in natural compounds and have significant activities in anti-cancer,anti-inflammatory,anti-diabetes,anti-microbial,adrenergic receptor regulation,anti-convulsion,anti-platelet and anti-HIV.Because of its special activity,it has attracted numerous scientific researchers to study.For the acquisition of such compounds,the commonly used method is chemical synthesis.When studying nitrogen-containing heterocyclic compounds,it is found that the 1,3-dipolar cycloaddition reaction is an efficient and concise method for constructing nitrogen-containing heterocyclic compounds.Generally,this kind of reaction is a multi-component reaction,and its raw materials have many advantages such as low price,easy availability,and safe operation.Therefore,when designing the reaction route,the key technology of[3+2]cycloaddition was introduced to synthesize five-membered nitrogen heterocyclic compounds,and finally achieved good results.The main contents of this paper are as follows:（1）Firstly,the two excipients required in the reaction route were synthesized.According to the method shown in the literature,DL-α-aminoisobutyric acid was used as the starting material to synthesize 2-aminoisobutyric acid methyl ester hydrochloride with methanol under the action of thionyl chloride.4-chloro-1-butanol reacted with TBSCl under the action of imidazole and DMF to protect the hydroxyl group and synthesize chlorinated ether.Then,4-amino-2-（trifluoromethyl）benzonitrile was used as the starting material to react with triphosgene to synthesize3-trifluoromethyl-4-cyanophenyl isocyanate,and the best solvent and acid binding agent were selected.The second step is the[3+2]cycloaddition reaction of phenyl isocyanate and amino acid methyl ester to prepare arylhydantoin,and the conditions of solvent and alkali were screened.The third step is the Ullmann C-N coupling reaction of arylhydantoin and chlorinated ether to explore the best catalyst,ligand,alkali and temperature.In the fourth step,RU58841 was prepared by hydroxyl deprotection with an overall yield of 44%.Then,on the basis of the synthesis of RU58841,RU58642 was prepared by Ullmann CN coupling reaction with bromoacetonitrile using arylhydantoin,the key intermediate in the second step,as the starting material,with a single step yield of 87.2%.The reaction mechanism of each step was introduced,and the structure of each step was confirmed by ¹H NMR,¹³C NMR and HR-MS.（2）Based on the research of the first work,3-trifluoromethyl-4-cyanophenyl thioisocyanate was synthesized by the reaction of 4-amino-2-（trifluoromethyl）benzonitrile with thiophosgene,and then 3-trifluoromethyl-4-cyanophenyl thioisocyanate was subjected to[3+2]cycloaddition reaction with methyl2-aminoisobutyrate hydrochloride to construct an aryl thiohydantoin ring,which was then subjected to Ullmann C-N coupling with a chlorinated ether.Finally,the hydroxyl group was deprotected with TBAF to obtain RU 59063.The total yield of this route reached 61.5%.The structure of each step was confirmed by ¹H NMR,¹³C NMR and HR-MS.In this paper,the hydantoin ring was constructed by[3+2]cycloaddition technology,and three final products were synthesized through a series of reactions:RU 58841,RU 58642 and RU 59063.The innovation of this paper lies in:firstly,the phosgene in the original route is replaced by solid triphosgene,which improves the safety of the reaction;in the[3+2]cycloaddition,the cyanide was replaced by amino acid ester,and the reaction conditions became milder,and the waste liquid did not need to be specially treated.In the C-N coupling,the form of Ullmann C-N coupling catalyst and ligand was used to accelerate the reaction time and improve the yield.The route is relatively simple,safe and effective.