Study On Synthesis Technology Of Diaminopyrimidine Oxide Derivatives

Diaminopyrimidines are a very important class of fine chemicals with a wide range of applications in the fields of pharmaceuticals,pesticides and daily chemicals.The idea of using diaminopyrimidines as the parent structure and introducing different N heterocyclic monomers is currently the mainstay of the development of this class of compounds.Amongst others,direct N-oxidation of pyrimidine rings using catalysts,hydrogen peroxide or peroxy acids has the disadvantages of long reaction times,large amounts of waste acid and complex processes.Therefore,catalytic oxidation using catalysts is a novel and challenging task with important research significance.In this paper,two different experimental route schemes were designed to synthesize three diaminopyrimidine oxide derivatives,6-pyrrolidinyl-2,4-diaminopyr imidine-3-oxide（4a）,6-（1-piperidinyl）-2,4-pyrimidinediamine-3-oxide（4b）and1-（6-amino-1-hydroxy-2-iminopyrimidin-4-yl）piperidin-4-ol（4c）,to explore and optimize their process conditions,to analyse and finalise the structural characterisation of the raw materials,intermediates and target products in the experiments by GC,HPLC-MS,NMR and FTIR.All three compounds,6-pyrrolidinyl-2,4-diaminopyrimidine-3-oxide（4a）,6-（1-piperidinyl）-2,4-pyrimidinediamine-3-oxide（4b）and 1-（6-amino-1-hydroxy-2-i-minopyrimidin-4-yl）piperidin-4-ol（4c）,were synthesized using experimental route one.The effects of material ratio,catalyst dosage,reaction time,reaction temperature and solvent on the reaction were investigated for the synthesis process.The results showed that the better conditions for the synthesis of 2,4-diamino-6-hydroxypyrimidine（1）were 75℃,2h,with a molar ratio of ethyl cyanoacetate to guanidine hydrochloride of1:1.12 and a yield of 82.3%;the better conditions for the synthesis of2,4-diamino-6-chloropyrimidine（2）were 95～100℃,2h,with a molar ratio of 1:1.5:3.5with triethylamine and trichloroxapyrimidine and a yield of 86.2%;The synthesis of2,6-diamino-4-chloropyrimidine-1-oxide（3）by pyrimidine ring N-oxidation was optimized using a home-made nano-Co Cr₂O₄ catalyst,where the Co Cr₂O₄ catalyst was analyzed by TG-DSC,XRD.TEM and FT-IR characterization,and the better conditions were 5%of the raw material,50℃,90min,in 95.6%yield;the better conditions for the synthesis of 2,6-diamino-4-NR₁R₂ pyrimidine oxides（4a-c）were80～85℃,2～3h,with a molar ratio of 1:1.15～1.20 between2,6-diamino-4-chyrimidine-1-oxide（3）and HNR₁R₂,and the yields were above 85%.6-Pyrrolidinyl-2,4-diaminopyrimidine-3-oxide（4a）,6-（1-piperidinyl）-2,4-pyrim-idinediamine-3-oxide（4b）were synthesized using experimental route II,which is two different methods from the conventional experimental route I.The effects of the synthesis process material ratio,reaction time and reaction temperature on the reaction were investigated.The results showed that the better conditions for the synthesis of ethyl N-cyanoacetimidate hydrochloride（5）were 0～5℃,1.5h,with a molar ratio of malononitrile to anhydrous ethanol of 1:1.1 and a yield of 90.10%;the better conditions for the synthesis of ethyl（Z）-N-cyano-2-isocyanoacetimidate（6）were 25℃,12h,with a molar ratio of intermediate（5）to monocyanamide of 1:1.3 and a yield of82.1%The synthesis of（Z）-N-（2-isocyano-1-（NR₁R₂-1-yl）ethylidene）cyanamide（7a-b）was carried out under the optimum conditions of 1:2.5～3.0 molar ratio of intermediate（6）to N heterocyclic structure,25～30℃,6h,in 78.3-81.5%yield;finally,the target product 2,6-diamino-4-NR₁R₂pyrimidine-N oxide（4a-b）was obtained by condensation using hydroxylamine.The preferred process conditions were a molar ratio of 1:1.6 between intermediate（7）and hydroxylamine hydrochloride,25℃,16h,and a yield of 84～86%.