Improved Process For The Synthesis Of 1,4,7,10-Tetraazacyclododecane And It's N-selective Substisution Derivatives

Aza macrocyclic compounds and their N-substituted derivatives have attracted much attention because of their susceptibility to complexation with metal cations.Selective N-functionalization of the tetraazamacrocycles,can modulate the properties of the complex by adjusting the properties of the coordination subunit.Previously,the synthesis of various asymmetric azamacrocyclic compounds(influenced by nitrogen heterocycles and alkylating agents)was studied,but the synthesis of symmetrically tetraazamacrocycles was less.The Pyridine Containing Tri Aza-macrocyclic can be further N-alkylated by increasing the thermodynamic stability and having seven possible donor sites to obtain a large amount of complexes.However,the synthesis of tetraazamacrocycles is the most critical step in the study above.Based on this paper,the synthesis of cyclen,symmetrically tetraazamacrocycles and PCTA suitable for industrial production were studied.Cyclen:(1)using diethylenetriamine(DIEN)and diethanolamine as raw materials,respectively,after sulfonylation,ring-forming reaction,and finally under the action of 98%H2SO4 to obtain cyclen;(2)to TETA as raw material,first with Glyoxal condensed into a double imidazole ring compound,in the base catalyzed with the binuclear nucleophiles 1,2-dibromoethane ring into a tetracyclic compound,and finally with bromine or hydroxylamine hydrochloride open loop to get cyclen.Synthesis of two types of cyclen derivatives:(1)cyclen via oxamides to protect two adjacent N atoms,and then SN2 reaction occurs with the alkylation reagent:benzyl chloride,BrCH2COOC(CH3)3,deprotection obtained symmetric 1N,4N-dialkylated cyclen;(2)2,6-dichloromethylpyridine and 3Ts-diethylenetriamine through SN2 reaction loop,98%H2SO4 deprotection to obtain PCTA.In this paper,based on the literature method,combined with the reaction mechanism of each step,through the selection of raw materials,reaction conditions screening(including catalyst,solvent,reaction time and temperature,destructive exploration,etc.),post-processing optimization and other aspects of the high Rate,high purity and simple operation of the synthetic route.