Studies On The Synthetic Process Of Cyanoethyl Tetraisopropyl Phosphodimide And Its Analogues

Trivalent organophosphorus compounds exibits unique nucleophilic properties due to the presence of unequal sp~3hybrid lone pair electrons in the phosphorus centers,which were widely used as organometallic ligands and nucleophilic organic catalysts.In addition to nucleophilicity,its inherent reducibility is also the basis for many important reactions in organic synthesis,such as Michaelis-Arbuzov reaction,Mitsunobu reaction,Staudinger reaction,etc.Phosphosamide compounds are an important class of trivalent phosphorus compounds.In recent years,with the rise of research on nucleic acid drugs,the market demand for phosphamide compounds has gradually increased,especially cyanoethyl tetraisopropyl phosphide diamine,which is the preferred reagent for the phosphorylation of nucleic acid drugs due to its unique reactivity.However,due to its production process technology being mastered by foreign countries,this product is in a monopolistic state and severely undersupplied.This paper mainly studies the synthesis process of cyanoethyl tetraisopropyl phosphoridene diamine and its analogues.The research content mainly includes two parts:(1)Studies on the synthetic process of cyanoethyl tetraisopropyl phosphoridene diamine;(2)Studies on the synthetic process of hexaethyl phosphorous triamine and cyanoethyldiisopropyl chlorophosphorous amide.In the first part,the synthetic process of cyanoethyl tetraisopropyl phosphide diamine was studied.Firstly,the synthetic process of 3-hydroxypropiononitrile was investigated,which was a key raw material for the synthesis of cyanoethyl tetraisopropyl phosphorous diamine.Under the conditions of using methyl cyanoacetate as the raw material,sodium borohydride as the reducing agent,and tetrahydrofuran as the solvent,3-hydroxypropiononitrile was obtained in a stable yield of over 80%and purity of 99%.Subsequently,we explored the synthetic process of cyanoethyl tetraisopropyl phosphoridene diamine using the 3-hydroxypropionic nitrile we synthesized as the raw material.A one pot reaction method was used,using cyclohexane as the reaction solvent.To begin with,phosphorus trichloride reacted with diisopropylamine for 1.5 hours at low temperature to produce the intermediate of di(diisopropylamine)phosphorus chloride,and then 3-hydroxypropionic nitrile was added for 3 hours,Cyanoethyl tetraisopropyl phosphoridediamine can be synthesized with a phosphorus spectrum yield of about 88%.After DMF washing,concentration,and vacuum distillation of the crude product,cyanoethyl tetraisopropyl phosphorous diamine was finally obtained with a yield of 63%and a purity of over 99%.This synthetic process provides a potential industrialized production method for the preparation of high-purity cyanoethyl tetraisopropyl phosphide diamine.In the second part,the synthetic process of hexaethyl phosphorous triamine and cyanethyl diisopropyl chlorophosphorous amide,which are analogues of cyanoethyl tetraisopropyl phosphorous triamine,was studied.Through the exploration of process conditions,using cyclohexane as a solvent and reacting phosphorus trichloride with 6.5equivalents of diethylamine for 1.5 hours at low temperature,hexaethyl phosphorous triamine can be synthesized with a phosphorus spectrum yield of about 90%.The crude product can be purified to over 98%with a yield of 84%after post-treatment.Subsequently,research was conducted on the synthesis of cyanoethyl diisopropyl chlorophosphamide.Using phosphorus trichloride,3-hydroxypropiononitrile,and diisopropylamine as raw materials,cyanoethyldiisopropyl chlorophosphamide was synthesized at low temperature in cyclohexane solvent with a phosphorus spectrum yield of about 88%.After post-treatment,the crude product had a phosphorus spectrum purity of over 99%and a yield of 68%.This part of the work provides a feasible method for the industrial production and application of hexaethyl phosphoryl triamine and cyanoethyl diisopropyl chlorophosphoramide.