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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%。
This study reported a low cost, environmentally friendly, suitable for the industrial production of safubicin hemicalcium synthesis route. (R) -3 - ([1,1’-biphenyl] -4-yl was obtained from D-phenylalanine, ) Methyl 2 - [(tert-butoxycarbonyl) amino] propionate was reduced by lithium borohydride and TEMPO catalyzed oxidation and condensation. Lithium hydroxide was hydrolyzed to give (R, Biphenyl] -4-yl) -4 - [(tert-butoxycarbonyl) amino] -2-methyl-2- pentenoic acid followed by catalytic hydrogenation over palladium on charcoal, deprotection, ethyl esterification with succinic anhydride Condensation and into the hemi-calcium salt of the target compound. The process has the advantages of mild reaction conditions and convenient after-treatment; and eliminates the use of reagents that are expensive or have genotoxicity and dangerous reagents such as flammable and explosive reagents. The total yield of 22.8%, product purity of 99.7%, optical purity of 99.8%.