Synthesis Of Adamantane Derivatives Containing N-heterocycles

With their good liposolubility and low toxicity, adamantane and its derivatives have demonstrated their unique pharmacological effects, and are usually used to design drugs and biologically active compounds such as antivirus, anti-Parkinson’s disease, anti-diabetic and anti-depressant agents. The antiviral action of1-adamantanamine hydrochloride has been detected, which brings about an impetus to the wide pharmacological study of adamantane derivatives such as Rimantadine, Tromantadine, Somantadine, Memantine, Saxagliptin, etc. This has aroused extensive interest to the development and research of new drugs and clinical pharmacology.In this paper, the application of adamantane derivatives in the field of medicine is reviewed. With the retrosynthetic principle, two adamantane derivatives as effective drugs:(2S)-1-{[(3-hydroxy-l-adamantanyl)amino]acetyl}-2-pyrrolidine carbonitrile (Vildagliptin) and N-{2-[4-(2-pyrimidinyl)-1-piperazinyl] ethyl} adamantane-1-carboxamide (Adatanserin) have been synthesized and the synthetic conditions have been optimized respectively.With linear synthetic route, Adatanserin has been synthesized via twice N-alkylation, Gabriel hydrolysis and amidation reactions using2-chloropyrimidine and piperazine as the starting material and the overall yield is43.4%. The optimal conclusions are as follows:molar ratio of2-chloropyrimidine and piperazine is1:3in the fist step; reaction time is12h and reaction temperature is80℃in second step of alkylation reaction; adamantanecarbonyl chloride as active acylation agent is used to prepare Adatanserin in high yield of91%and molar ratio of adamantanecarbonyl chloride and2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamine is1.3:1.With new convergent synthetic route, Adatanserin has been synthesized by amidation reactions, N-alkylation using2-pyrimidine and adamantanecarbonyl chloride as the starting material and the overall yield is57%. The optimal conclusions are as follows:chloroethylamine hydrochloride is not acylated with adamantanecarbonyl chloride directly; After chloroethylamine hydrochloride is neutralized by sodium hydroxide, it can easily reacted with adamantanecarbonyl chloride; in alkylation reaction the optimal solvent is DMF, the temperature is110℃and the reaction time is48h.In our strategy, Vildagliptin has been prepared from inexpensive L-proline by twice amidation, Von Braun amide dehydration and N-alkylation reactions in overall yield of44.2%and one-pot synthesis was used in the last step. The optimal conclusions are as follows:molar ratio of L-proline and chloroacetyl chloride is1:1.8and reaction time is3h in first amidation reaction; the inexpensive dehydrant of N,N’-dicyclohexylcarbodiimide and instable ammonium carbamate are used in second amidation reaction; One-pot synthesis is adopted in the third step which include two conversion procedures of amide dehydration and N-alkylation; the optimal temperature and reaction time are:the first-stage reaction temperatue:35℃reaction time2hours; the second stage reaction temperature:65℃, reaction time:5hours.