Study On The Synthesis Of (3S)-1-[(R) -2-hydroxy-1-phenylethyl]-3-methylpiperidin -2-one And Its Diastereomer

Piperidin-2-one is a versatile synthetic building block for the synthesis of piperidine alkaloids. Piperidine alkaloids are one of the most wildly used alkaloids in the pharmaceutical and chemical industries. It is undoubted that the series of products greatly benefit sub-health people to adjust the lipid of blood, prevent hypertension, tumor and so on.Piperidin-2-one and piperidine alkaloids can be extracted in nature. But the multiple operationsmake the cost of production stay at a relatively high level. And what’s worse, natural piperidin-2-one alkaloid is not sufficient enough to meet the need of pharmaceutical and chemical industries. Thus, synthesis of these materials attracts lots of scholars and pharmaceutical industries.(3S)-1-[(R)-2-hydroxy-1-phenylethyl]-3-meth.ylpiperidin-2-one and its analogs and derivatives are significant medical intermediates in the treatment of mental illness and other disease. Since (3S)-1-[(R)-2-hydioxy-1-phenylethyl]-3-methylpiperidin-2-one and its derivatives are alkaloids, and they enjoy many obvious advantages such as its weak toxic and side effects. Because of the huge potential, many researchers spared no efforts to optimize related synthesis route.This project put forward an improved synthetic method of (3S)-1-[(R)-2-bydroxy-1-phenylethyl]-3-methylpiperidin-2-one and made some optimizations of a few experiment procedure to make the route more economical and environmentally friendly and can be carried on under mild reaction conditions. D-phenylglycinol and delta-valerolactone are the key raw material. Then treatment of delta-valerolactone with thionyl chloride gave rise to 5-chlorovaleryl chtoride.Meanwhile, Ter-butyldimethylsilyl chloride (TBDMS-Cl) was introduced to protect the hydroxyl group of D-phenylglycinol. The product of the two reactions above was combined together and gave rise to (R)-1-(2-[(tert-butyldimethylsflyl)oxy]-1-pheny--lethyl) piperidin-2-one. Then (R)-1-(2-[(tert-butyldimethylsilyl) oxy]-1-phenylethyl) piperidin-2-one could be aikcylated directly by 1.5eq of s-BuLi, ultimately giving (3S)-1-[(R)-2-hydroxy-1-phenytethyl]-3-methylpiperidin-2-one and its diastereoisomer (3R)-1-[(R) -2-hydroxy-1-phenylethyl]-3-methylpiperidin-2-one in a ratio of 12.5 which could be separated by flash chromatography or recrystallization. On the other hand, (R)-1-(2-[(tert-burykidimethylsi--lyl) oxy]-1-phenylethyl) piperidin-2-one could transfer into 1-[(1R)-2-hydroxy-1-phenyle-thyl]-piperidin-2-one by deprotection and then methylated with 2.5eq of s-BuLi, giving (3S)-1-[(R)-2-hy-droxy-1-phenylethyl]-3-methylpiperidin-2-one as a single isomer.In this synthetic route, the raw material is easy to get, the reaction condition is relatively mild with no pyroreaction and microwave energy. This proposed synthetic process is much of industrial value because of the high yield, cheap and easily gained material.The structures of some important intermediates and products were comfirmed by melting-point apparatus, high-resolution mass spectroscope (HRMS), HPLC, 1H-NMR, IR and MS.