公斤级沙库必曲半钙盐的合成

发布时间：2018-06-30 16:40

本文选题：沙库必曲 + 抗心衰　；参考：《中国医药工业杂志》2017年09期

【摘要】：本研究报道了一条成本低、环境友好、适合产业化的沙库必曲半钙盐合成路线。以价廉易得的D-苯丙氨酸为原料,经碘代、甲酯化、氨基保护和Negishi偶联得(R)-3-([1,1'-联苯]-4-基)-2-[(叔丁氧羰基)氨基]丙酸甲酯,经硼氢化锂还原、TEMPO催化氧化、缩合、氢氧化锂水解得(R,E)-5-([1,1'-联苯]-4-基)-4-[(叔丁氧羰基)氨基]-2-甲基-2-戊烯酸,再经钯炭催化氢化、脱保护、乙酯化、与丁二酸酐缩合并成半钙盐得目标化合物。本工艺反应条件温和,后处理操作简便;革除了价昂或有基因毒性的试剂以及易燃易爆等危险试剂的使用。总收率22.8%,产品纯度99.7%,光学纯度99.8%。
[Abstract]:In this study, a low cost, environmental friendly, suitable for industrial synthesis of sarcomycinec semicalcium salt was reported. Methyl (R) -3- ([1 (1) (1) (1) (1) (1) (1) -4-phenyl] -4-yl] -2- [(tert-butyloxycarbonyl) amino] propionate was synthesized from cheap and readily available D- phenylalanine by iodination, methylation, amino protection and Negishi coupling. Methyl propionate was oxidized and condensed by lithium borohydride reductive TEMPO. Lithium-hydroxide was hydrolyzed to (RNE) -5- ([1tbutoxycarbonyl] -4-yl) -4- [(tert-butyloxycarbonyl) amino] -2-methyl-2-penteneic acid, then hydrogenated by palladium charcoal, deprotected, ethylated and condensed with succinic anhydride to form a target compound of semicalcium salt. The reaction conditions are mild, the post-treatment is simple, and the use of such dangerous reagents as combustible and explosive is removed. The total yield was 22. 8%, the purity of the product was 99. 7%, and the optical purity was 99. 8%.
【作者单位】：浙江大学化学系;上药集团-常州制药厂有限公司;
【分类号】：R914

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