1-叔丁羰基-4-甲基-3-哌啶酮的合成研究  

Synthesis of tert-Butyl-4-Methyl-3-Oxopiperidine-1-Carboxylate

作　　者：郝宝玉[1,2] 张维汉[2] 耿秀丽 赵倩[1] 陈新志[1] 

机构地区：[1]浙江大学化学工程与生物工程学系化学工程联合国家重点实验室,浙江杭州310027 [2]和记黄埔医药有限公司,上海201203 [3]解放军371医院,河南新乡453000

出　　处：《高校化学工程学报》2011年第6期1021-1025,共5页Journal of Chemical Engineering of Chinese Universities

基　　金：国家自然科学基金(21076183);浙江省重点科技创新团队(2009R50002)

摘　　要：1-叔丁羰基-4-甲基-3-哌啶酮是合成新型蛋白酪氨酸激酶Jak3抑制剂CP-690550的重要中间体,今以廉价易得的3-羟基-4-甲基吡啶和氯苄为原料,经过SN2取代反应,再经硼氢化还原生成N-苄基-3-羟基-4-甲基哌啶。过程中考察了溶剂对实验的影响,确定最佳溶剂为3.0 mol·L-1 NaOH水溶液,后经Jones氧化,Pd/C催化脱苄及酰基化反应,得到目标产物1-叔丁羰基-4-甲基-3-哌啶酮,总收率达80.2%。该工艺较现有工艺具有反应原料易得,工艺简单,收率高,较易工业化等优点。tert-Butyl 4-methyl-3-oxopiperidine-1-carboxylate is an important intermediate in the synthesis of the novel protein tyrosine kinase Jak3 inhibitor—CP-690550.In this article,an efficient approach to the synthesis of this interesting compound was proposed.The proposed synthesis process consists of a series of steps： starting from the easy available reagent 4-methylpyridinium,going through the SN2 substitution with benzyl chloride to offer 1-benzyl-3-hydroxy-4-methylpyridium chloride with high yield,and then defining the suitable solvent species and its reasonable concentration for the borohydride reduction with sodium borohydride to provide N-benzyl-3-hydroxy-4-methylpiperidine,consequently,oxidation by Jones reagent under mild temperature to give N-benzyl-3-oxo-4-methylpiperdine,and at last,debenzylation with Pd/C catalyst and acylation to obtain the target product tert-butyl 4-methyl-3-oxopiperidine-1-carboxylate.The total yield can reach 80.2% by using the proposed method.Compared with the existing process,the proposed method has the advantages of easily obtained raw materials,simple in operation and suitable for industrial scale-up.

关 键 词：1-叔丁羰基-4-甲基-3-哌啶酮 3-羟基-4-甲基吡啶 SN2取代 硼氢化还原 Jones氧化 

分 类 号：O641.4[理学—物理化学]