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

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.