Study On Synthesis Of Pyridine Derivatives With CF₃-Bearing Building Block

Fluorine-the most xenobiotic element has gained a status of a privileged element in the design of biologically active compounds.Thus,according to the relatively recent data,more than 10%of newly registered pharmaceuticals and about 40%of agrochemicals contain fluorine.Among these fluorine-containing and biologically active compounds nitrogen heterocycles has received a great deal of attention.In particular, trifluoromethyl-containing pyridine derivatives were found to act as anticancer agents, vanilloid receptor-1 antagonists,antimalarial agents,cytokine production inhibitors, immunosuppressants and antiallergics.We succeed in preparation of 2-chloro-6-(trifluoromethyl)nocotinic acid and a series of intermediate.It is an important intermediate for preparate(Vanilloid Receptor-1)antagonists.This paper is divided into three parts:(1)We first synthesized 2-chloro-6-(trifluoromethyl)nocotinic acid with halogenate and hydrolyze.As reported,2-chloro-6-(trifluoromethyl)pyridine was deprotonated by lithium diisopropylamide(LIDA)concomitantly at the 3- and 4-positions.However, after the reaction mixture had been stored for 4 h at -75℃,the more basic 4-lithio species was found to have been completely converted into the less basic 3-lithio isomer. Upon trapping with iodine,only 2-chloro-3-iodo-6-(trifluoromethyl)pyridine was obtained.Equilibration of the organometallic intermediates at -75℃followed by carboxylation and neutralization provided the 2-chloro-6-(trifluoromethyl) pyridine-3-carboxylic acid.It is rigorous condition and fussy operation.middling yield However,It was prepared by 2-hydroxy-6-(trifluoromethyl)nocotinic acid and phosphorus pentachloride under 110-160 degree in this paper,purity:95%,yield:40%. In order to improve yield,use by-product as reactant to hydrolyze to 2-chloro-6-(trifluoromethyl)nocotinic acid,under different degree,different equivalent and different concentration of sulfuric acid,and then find optimize reaction condition, purity:99%,yield:95%,this reaction is easy to operate and adapt to manufacture.(2).2-chloro-6-(trifluoromethyl)nicotinonitrile was prepared by 2-hydroxy-6-(trifluoromethyl)nicotinonitrile and phosphorus pentachloride,phosphoric trichloride.2-chloro-6-(trifluoromethyl)nocotinic acid is also synthesized by hydrolysis of 2-chloro-6-(trifluoromethyl)nicotinonitrile under different degree,different equivalent and different concentration of sulfuric acid. (3)We first synthesized 2-substituted amino-3-amide-6-(trifluoromethyl)pyridine with 2-chloro-3-(trichloromethyl)-6-(trifluoromethyl)pyridine and nucleophilic reagent such as morpholine,piperidine,pyrrole etc.We synthesized 2-substituted amino-6-(trifluoromethyl)nicotinonitrile with a new method.As reported.It was prepared by trifluoroacetylvinyl ether and 3-amide-3-pyrrole(morpholine)-1-propylene cyanogen in dry acetonitrile was heated at reflux 2 hours.Give 2-pyrrole-6-(trifluoromethyl)nicotinonitrile.Yield:79%.Give 2-morpholine-6-(trifluoromethyl)nicotinonitrile.Yield:77%.But solvent is toxicity and pollute environment.yield moderate.It was prepared by 2-chloro-6-(trifluoromethyl) nicotinonitrile with a series of amine in this paper.2-substituted amino-3-amide-6-(trifluoromethyl)nocotinic acid was prepared by hydrolyze 2-substituted amino-6-(trifluoromethyl)nicotinonitrile.It is a convenient method and easy to operate.