Synthesis Of Nomegestrol Acetate, Calixarene Applications In Catalytic Synthesis Of S(Se)-aryl Phosphonates

Nomegestrol Acetate is a novel and effective oral progestin. In the knownsteroidal oral contraceptives, oral contraceptive effect of Nomegestrol Acetate isalmost one hundred percent, which is a strong inhibitor of ovulation by suppressingpituitary gonad. The results of the clinical trials show it has the feature of a highcontraceptive efficacy, almost no side effects in clinical trial and easy to secure use.Because the preparation of the Nomegestrol Acetate is very difficult, it did not comeinto the market in our country and many countries at present. Thus, study on asynthesis route of nomegestrol acetate, which is suitable for industrial production, isvery meaningful. According to reports in the literature, the synthesis of Nomegestrolacetate mainly included the key step about double bond transposition reaction, whichused cyclohexene as a hydrogen source. However, transitional byproduct hydride wasgenerated and Nomegestrol Acetate had the almost same Rf value as byproduct, so thatit was very hard to separate and purify. Therefore, this paper will explore the last stepof this double bond transposition reaction. We try to isolate the Nomegestrol acetateand the by-products and culture their single crystals. Meanwhile, we selected hydrogensource with large space steric and systematicly investigated the influence of thesolvents, reaction temperature, different hydrogen sources and its dosage, the dosageof catalyst to the double bond transfer reaction. Moreover, we reduced the formation ofby-products, which solved the difficult problems of low yield and difficult separation.The ultimate yield of the Nomegestrol Acetate was70%and purity could be up to99.89%, while the yield was only42%according to literature methods.In our preliminary work, we used CsOH as a catalyst to synthesizeO,O-dialkyl-S(Se)-aryl phosphate esters. However, duo to be expensive price of CsOHthis method was limitted in the industrial production. On the basis of literatureresearch, we learned calyx [4] arene-crown-5(A) have good complexing ability on K+.Thus, we used this calixarene A for activating KOH, which is cheap and available.Moreover, we investigated the reaction of dialkyl phosphites with diaryldisulfides(diselenides) to the synthesis of O,O-dialkyl-S(Se)-aryl phosphates. As the reaction ofdiethyl phosphite and diphenyldisulfides (diselenides) an example, we systematiclyinvestigated the influence of the solvents, reaction time, temperature, different phasetransfer catalyst and its dosage, the dosage of calix[4]arene-crown-5(A) and KOH tothis reaction. By optimizing reaction conditions, the best conditions for preparation of O,O-diethyl-S-aryl phosphonates as follows: in the presence of10mol%calixareneA and30mol%of potassium hydroxide at40℃under atmosphere in THF for9hours.The yield of O,O-diethyl-S-aryl phosphonate was88%. The best conditions forpreparation of O,O-diethyl-Se-aryl phosphonate was in the presence of10mol%calixarene A and20mol%of potassium hydroxide at25℃under atmosphere in THFfor9hours. The yield O,O-diethyl-Se-aryl phosphonate was89%. Under the bestcondition, we synthesized a series of O,O-dialkyl-S(Se)-aryl phosphates. As theexperimental results shown, the length of alkyl chain and the electronegativity of arylfunctional group have little effect on the yield of O,O-dialkyl-S(Se)-aryl phosphates.All above yields were more than85%. Thus, a new route to preparation S(Se)-arylphosphonates was developed.