Study On A Novel Chloromethylation And Its Application In Drug Synthesis

Chloromethyl substituted aromatics are a class of very useful intermediate in drug synthesis,it is commonly used in the synthesis of unnatural amino acids.Blanc chloromethylation is a classical organic chemical reaction in which chloromethyl groups are introduced into aromatic compounds.In this thesis,a novel Blanc chloromethylation reaction was studied and the method was applied to the ?-opioid receptor antagonist dipeptide H-Dmt-Tic-OH.It mainly includes the following contents.In the first chapter,the research progress of chloromethylation reaction was reviewed.A brief overview of the type,use and reaction mechanism of chloromethyl reaction was given,and the application of chloromethylation reaction in drug synthesis was also listed.The Blanc chloromethylation was systematically introduced around chloromethylation reagents and catalysts:chloromethylation reagents mainly included formaldehyde and concentrated hydrochloric acid,chloromethyl ether or dichloromethyl ether,chloromethyl alkyl ether,etc;catalysts included protonic acid,Lewis acid,ionic liquids,micelles,and phase transfer catalysts.In drug synthesis,formaldehyde and concentrated hydrochloric acid are used as chloromethylation reagents and acid-catalyzed classical Blanc reaction is used to realize the introduction of chloromethyl.Because of the conditions of heating with concentrated hydrochloric acid,there are some disadvantages,such as harsh reaction conditions,low yield,environmental pollution serious equipment corrosion,etc.Therefore,it is particularly urgent to develop a new method of chloromethylation with mild reaction conditions,high yield,environmental friendliness and safe operation.In the second chapter,a new chloromethylation method and it's applications in the preparation of unnatural amino acid 2,6-d imethyl-D,L-tyro s ine were systematically studied.In this thesis,chloromethylation reaction was effectively realized under solvent-free conditions using dimethoxymethane and c hloro sulfonic acid as chloromethylation reagents and Lewis acid as catalyst.By investigating different catalysts and their dosage,the ratio of dimethoxymethane and chlorosulfonic acid and reaction temperature,the optimum reaction conditions were selected:the ratio of d ime tho xy me thane and chloro sulfonic acid to aromatics:n(aroma tics):n(dimethoxymethane):n(chlorosulfonic acid)=1.0:1.2:1.2;10 mol%anhydrous zinc chloride as catalyst;reaction temperature was 5-10?.The yield was 65%-90%,and the main product was mo no substituted chloromethyl,which had excellent reaction selectivity.The catalytic mechanism was proposed.In addition,the new chloro me thy la tio n reaction was successfully applied to the synthesis of 2,6-dimethyl-D,L-tyrosine,a unnatural amino acid.In the third chapter,a new asymmetric synthesis method of 2,6-dime thyl-L-tyro s ine was studied.L-camphor sulfonamide was used as chiral auxiliary to condensate with diphenylmethylene glycine ethyl ester,alkylate with O-Carbethoxy-3,5-dimethyl-4-chloromethyl phenol under alkaline conditions,remove chiral auxiliary,and hydrolyze to optically pure 2,6-dimethyl-L-tyros ine,which laid an experimental foundation for the synthesis of dipeptide H-Dmt-Tic-OH,a ?-opioid receptor antagonist.