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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。
Objective: To explore a new method for the synthesis of (3S) -1 - [(R) -2-hydroxy-1-phenylethyl] -3-methyl-2-piperidone. Innovative point: Taking the conventional chemical raw material D-phenylethanolamine as the main raw material, the important intermediate 3S-1 - [(R) -2-hydroxy-1-phenylethyl] -3-methyl-2-piperidone and homologs thereof. The methylation step in this method can reduce the amount of s-Bu Li by 1 equivalent than the conventional methylation step and is more environmentally friendly and safe. Methods: With the steric hindrance of D-phenylethanolamine, a chiral methyl group with specific optical purity was introduced into 6-membered ring lactam. In the methylation process, with tert-butyldimethylchlorosilane hydroxyl protection, in order to reduce the amount of sec-butyl lithium. CONCLUSION: A new method for the synthesis of 3-methyl-2-piperidones was explored using readily available δ-valerolactone and D-phenetidinol as starting materials. The new method of sec-butyl lithium consumption and the conventional method is different. When the hydroxyl group is protected, methylated one equivalent six-membered ring lactam (compound 7) consumes 1.5 equivalents instead of 2.5 equivalents of sec-butyllithium and the methylated product detaches the alcoholic hydroxyl protecting group to give (3S) -1- [(R) -2-hydroxy-1-phenylethyl] -3-methyl-2-piperidone (Compound 1) and its diastereomer (3R) Hydroxy-1-phenylethyl] -3-methyl-2-piperidone (compound 8) in a molar ratio of 1: 2.5. The two can be completely separated by recrystallization or column chromatography.