Synthetic Of Stable Isotope Labeled Of Cimbuterol-D₉ And Mabuterol-D₉

With the economic development of our country,people's various demands are unceasingly increased.Especially in term of diet,people need healthier and safer foods.In the "Healthy China" strategy that China is advancing,food safety is one of the important construction contents.However,the news is continually broken in some big food-safty problems,which makes 'food security' become into 'food crisis'.That is a matter of general anxiety.Recently there appeared many poisoning events in pork foods due to the high clenbuterol content.Other similar compounds are Ractopamine,Cimbuterol,Mabuterol etc which are part of ? agonist.Since 1997,our government has issued a series of regulations and laws to prohibit use of ?agonist to ensure food safety.There are many detection methods for ? agonist.Isotope dilution mass spectrometry(IDMS)are most accurate.But detection reagents used in IDMS are mainly imported and very expensive.The project researches on the preparation technologies for Cimbuterol and Mabuterol compounds labeled by deuterium isotope.In process of experiment,resonable synthetic route is designed and proper refining process is seleted based on the synthetic route of natural abandunce ? agonist and synthetic features of stable isotope-labelling.At first,a new synthetic route is designed by using raw material of natural abandunce in exploring test.Then,key raw material of deuterium tert-butylamine is used instead in the route and its basic reaction condition is studied.After that,the stability of total synthesis test is studied on this basis.And abundance experiments are carried out finally.Thus,the new synthesis routes of Cimbuterol-D9 and Mabuterol-D9 are developed,by which isotope abundance and chemical purity of products can meet the requirements of expected isotope-labelling reagents.The results are as follows:(1)The p-Aminoacetophenone is brominated,cyanated,brominated,aminated and reduced to give Cimbuterol-D9.Through the exploration of conditions,it was determined that the feed ratio was 1.5 times,the highest utilization of tert-butylamine,the total yield of the product was 28%.The product was characterized by HPLC,LC-MS and NMR.The chemical purity was 98.30%.the isotopic abundance was greater than 98.00 atom%D.The product can be used as an isotope internal standard reagent for detection.(2)3-chloro-4-amino-5-trifluoromethyl-Acetophenone is brominated,aminated,and reduced,then get Mabuterol-D9.Start to find the best experimental conditions.When the molar ratio of 3-chloro-4-amino-5-trifluoromethyl-?-Bromoacetophenone to tert-butylamine is 1:1.5,the reaction temperature is 70?,and the reaction time is 2 hours,the yield based on the tert-butylamine consumed is 22.0%.The product was characterized by HPLC,LC-MS and NMR.The chemical purity was 98.19%.Isotope abundance was greater than 98.00 atom%D.The product can be used as an isotope internal standard reagent for detection.