摘要
目的探索新的合成DPP-Ⅳ抑制剂沙格列汀重要中间体N-叔丁氧羰基-3-羟基-1-金刚烷基甘氨酸的方法,以降低沙格列汀的生产成本。方法以金刚烷甲酸(1)为起始原料,经过羟酸的氯化,取代,脱羧3步反应一锅法制得金刚烷甲基酮(2),然后分步氧化得到2-(3-羟基-1-金刚烷基)-2-1-羰基乙酸(3),将3与盐酸羟氨反应得到2-(3-羟基-1-金刚烷基)-2-乙醛酸肟(4)并还原得到3-羟基-1-金刚烷甘氨酸;然后用BOC酸酐保护氨基得到DPP-Ⅳ抑制剂沙格列汀重要中间体N-叔丁氧羰基-3-羟基-1-金刚烷基甘氨酸(5)。结果得到一个未经报道的新化合物2-(3-羟基-1-金刚烷基)-2-乙醛酸肟(4),以金刚烷甲酸(1)为原料计算总收率可达36%。结论本方法所用原料价廉易得,反应条件温和,操作简便,收率高,适合工业化生产。
OBJECTIVE To explore a new synthesis method of the saxagliptin intermediate of the dipeptidyl peptidase Ⅳ （ DPP- Ⅳ ） inhibitor saxagliptin, N-BOC-3-hydroxy-1-adamantylglycine, to reduce the synthesis cost of saxagliptin. METHODS The synthesis used 1-adamantane carhoxylic acid （ 1 ） as the starting material. Through achlorination, substitution, and decarboxylation afford 1- adamantyl methyl ketone （2） was obtained, which was then converted into 2-（3-hydroxy-l-adamantyl）-2-oxoacetic acid （3）by oxidation with potassium permanganate in aqueous NaOH. Compound 3 reacted with hydroxylamine hydrochloride to give the 2-（3-hydrox-1- adalnantyl）-2-hydroxyimino acetic acid（4） , and then oxime 4 was reduced, and got the amino with BOC20 to afford dipeptidyl peptidase Ⅳ （DPP-Ⅳ）inhibitor saxagliptin intermediate N-BOC-3-hydroxyadamanty- lglycine（5 ）. RESULTS We got a new compound 4 which had not been reported. The 36% overall yield was reached. CONCLUSION This synthetic route is simple, its reaction conditions are mild, and the raw materials are cheap and readily available, so it is suitable for manufacturing purposes.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2014年第11期931-934,共4页
Chinese Pharmaceutical Journal
基金
重庆市自然科学基金资助项目(CSTC 2006BB5286)
作者简介
王安民，男，硕士研究生研究方向：药物设计与合成
通讯作者：胡湘南，男，教授研究方向：药物化学研究Tel／Fax：（023）68485161E-mail：huxiangnan62@163．com
