(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮的合成（英文）

Asymmetric synthesis of N-protected 3-methylpiperidin-2-one and its diastereoisomer

目的:探索合成(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮的新方法。创新点:以常规化工原料D-苯苷氨醇为主要原料,在比较温和的条件下合成重要的药物中间体(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮及其同系物。该方法中的甲基化步骤较常规甲基化步骤减少1当量s-Bu Li的用量,更环保和安全。方法:利用D-苯苷氨醇的空间位阻作用,在六元环内酰胺中引入具有特定光学纯度的手性甲基。在甲基化过程中,用叔丁基二甲基氯硅烷对羟基进行保护,以减少仲丁基锂的用量。结论:以工业易得的δ-戊内酯及D-苯苷氨醇为初始原料,探索合成3-甲基-2-哌啶酮类物质的新方法。新方法中对仲丁基锂的消耗量与常规方法有所不同。当羟基受保护时,甲基化1当量六元环内酰胺(化合物7)消耗1.5当量而非2.5当量仲丁基锂,甲基化产物脱掉醇羟基保护基,得到(3S)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮(化合物1)及其非对映异构体(3R)-1-[(R)-2-羟基-1-苯乙基]-3-甲基-2-哌啶酮(化合物8),二者摩尔比为1:2.5。通过重结晶或柱层析的方法可对二者进行完全分离。

This paper reports the asymmetric synthesis of an important pharmaceutical intermediate （3S）-1-[（1R）-2-hydroxy-1- phenylethyl]-3-methylpiperidin-2-one （compound 1） from commercially available D-plenylglycinol and delta-valerolactone. During the alkylation process, the hydroxyl group can be protected or unprotected, resulting in a different consumption of s-BuLi, and leading to a different diastereomeric excess （de） of compound 1. When 1-[（lR）-2-hydroxy-t-phenylethyl]-piperidin- 2-one （compound 2） was alkylated with 2.5 eq. of s-BuLi, compound 1 was obtained as a single isomer detected by chiral high performance liquid chromatography （HPLC） columns with an overall yield of 91%. With the hydroxyl group protected, （R）-1 （2-[（tert-butyldimethylsil） oxy]-1-phenylethyl） piperidine-2-one （compound 6） could be alkylated with 1.5 eq. of s-BuLi, giving compound 1 and its diastereoisomer 8 in a ratio of 1：2.5 and a yield of methylation of 90%. Compounds 1 and 8 could be sepa- rated completely and easily by flash chromatography. The absolute configuration of compound 8 was determined by singlecrystal X-ray analysis. The mechanism of the alkylation process is discussed based on experimental results.