Synthesis And Biological Activity Of 2-(4-aryloxyphenoxy) Propionamide Derivatives

China is a large country of grain production and consumption.Currently,grain has risen to the national strategic material,of which improving the unit area yield is a very important way to ensure food security.The pesticide is essential in ensuring high and stable yields.As an pesticide with high efficiency,low toxicity and low residue,2-(4-aryloxyphenoxy)propionic acid(APP)herbicides inhibiting acetyl-CoA carboxylase(ACCase)have been identified as one of the most important herbicides.At present,our country doesn’t have commercial APP herbicide variety with self-owned intellectual property in gramineous crop fields,and in foreign varieties there are only Cyhalofop butyl and Metamifop for rice field,Clodinafop propargyl for wheat field,which have developed resistance in varying degrees in a range of important graminaceous weed.So researching new herbicide of high efficiency,low toxicity and low residue applied in rice,wheat and corn field with self-owned intellectual property is important to break the monopoly,improve grain production and replace the existing resistant varieties.Novel 2-(4-aryloxyphenoxy)propionamide compounds with latent activity were designed by choosing commercial APP herbicides Clodinafop propargyl and Metamifop as lead compounds based on pesticide molecular design technologies,such as principle of active groups of stitching and principle of combination of bioactive sub-structures.N-alkoxy-2-(4-aryloxyphenoxy)propionamide(Al～A40)and N-arylmethyl-2-(4-arylxoy-phenoxy)propionamide(F1～F17)were designed by the replacement of the ester moiety in Clodinafop propargyl with N-alkoxy amide moiety and N-arylmethyl.N-pyridyl-2-(4-arylxoyphenoxy)propionamide(J1～J73)were designed by the replacement of N-phenylamide with N-pyridyl-amide and N-pyridyl hydrazide.3 series,130 novel 2-(4-arylxoyphenoxy)propionamide compounds above were prepared by multistep synthetic procedures starting from(R)-2-(4-hydroxyphenoxy)propanoic acid by various reaction types such as etherification,acylation,gabriel reaction,nitration,ammoniation,aromatic cyanide,amidation.At the same time,the racemic compounds(±)-Al,(±)-A34,(±)-F2 of high activity compounds Al,A34,F2 and R chiral isomers(R)-Jl of J1 were synthesized and the configuration of which were determined by rotation and chiral column chromatography.The influence of electron-withdrawing group on etherification reactions and aryl amination were studied and the reaction occurred more easily when electron withdrawing ability of electron-withdrawing group on aromatic ring was stronger.The effect of pyridine intermediates with different substituent to reaction activity of amide was researched and the stronger electron withdrawing ability of electron-withdrawing group and the greater steric hindrance on pyridine ring,the worse was the reaction activity.The effects of different reaction conditions on the yield and steric configuration were studied and the temperature was the primary factor for racemization of chiral compounds,the compounds A1～A40,F1～F1 7,J54～J67 synthesised at room temperature may be all R configuration compounds and the compounds J1～J53 and J68～J73 prepared under reflux conditions may be all racemic compounds.The structures and steric configuration of compound(A1～A40,F1～F17,J1～J73)were characterized by a variety of characterization methods such as 1H NMR,13C NMR,IR,LC-MS,specific rotation,elemental analysis and chiral column liquid chromatography.The configuration of the chiral compounds had some effect on 1H NMR spectra.The bioassays of insecticidal activity,bactericidal activity,herbicidal activity and Anti-tumor activity in vitro were carried out according to the standard operation procedure of pesticide bioassay and the MTT assay separately.On the basis of the biological result,herbicidal activity,crop security and the structure-activity relationship were discussed mainly.The results showed that compound A1 to Mythimna sepatara(1000 mg/L),J21 and J66 to Aphis fabac(500 mg/L)exhibited>90%activity.Compounds J9,J16,J46 and J63 exhibited excellent inhibitory activity(IC50<50 mg/L)on Rhizoctonia solani.Most of compounds A1～A40,F1～F17,J1～J73 exhibited>90%herbicidal efficiency to monocotyledonous herbs(Digitaria sanguinalis,Echinochloa crus-galli and Setaria viridis)at dosage of 2250 g ai/ha,showing no or low activity against dicotyledonous weeds,and exhibited better herbicidal efficacy in posternergence treatments than in pre-emergence treatments.Further activity and crop safety indicated that the activity of compounds A1,A2,A6,A8,A12,A15,A18,A28,A34,A40,F2,J1,J14,J21,J26,J27,J49,J54,J55,J59,J62,J64 and J67 was higher than commercial APP herbicide clodinafop propargyl,metamifop or cyhalofop butyl.In particular,compounds A6,A12,A15,A28 and A34 were much more effective than clodinafop-propargyl.Compound A1,A8,A12,A15 and A28 exhibit safety on broadleaf crops soybeans,cotton,canola,and can be used for herbicide applied on broadleaf crop fields.With gramineous crops security,high activity compounds A1,F2,J1,J21,J54,J60,J62 and J64 were safe to Wheat or rice,and further safety testing found that selectivity index of compound J1 to Zhengmai 9023,Zhenginai 3166 and Jinsui 8145 were all greater than 5,so J1 showed high crops security to Wheat of different varieties.Qualitative structure-activity relationship studies found that herbicidal activity was related to steric configuration,the compounds of R configuration had more effective activity,and different substituent had great influence on the activity and crops security in which Ar group had the most influence.Anti-tumor activity results showed that most of compounds have good inhibitory activity on A549 and Hela cell lines.The results also showed that different series of compounds were of different activity and showed higher activity on A549 than on Hela cell line.IC50 values of Compounds A14,F13,F15,F16 were comparative to that of control drug cis-platinum.