加米霉素合成工艺优化

Synthesis Improvement of Gamithromycin

对加米霉素合成工艺进行了优化。(E)-红霉素A肟在氢氧化锂存在下于异丙醇中经异构化得(Z)-红霉素A肟,以THF作溶剂,在冰水浴条件下与对甲苯磺酰氯的丙酮溶液反应,然后经异丙醇重结晶得重排产物9-脱氧-12-脱氧-9,12-亚胺醚-8a,9-二脱氢-8a-氮杂-8a-红霉素A,纯度90%。在甲醇-水中经硼氢化钠还原得9-脱氧-8a-氮杂-8a-同型红霉素A,纯度94%。最后在钯炭催化下与丙醛经还原烃化得目标化合物,纯度99.6%,总收率30.7%。优化后的工艺反应条件温和、操作便捷,且各中间体均采用重结晶精制,质量便于控制,适合工业化生产。

The synthetic process of gamithromycin was optimized.(E)-Erythromycin A oxime was isomerized in isopropanol in the presence of lithium hydroxide to(Z)-erythromycin A oxime, which was subjected to a Beckmann rearrangement in THF/acetone at 0 ℃ with p-toluene sulfonyl chloride to produce 9-deoxy-12-deoxy-9,12-iminoether-8a,9-didehydro-8a-aza-8a-erythromycin A with a purity of 90%. After a reduction with sodium borohydride in methanol/water, 9-deoxy-8a-aza-8a-homoerythromycin A was synthesized with a purity of 94%. Then the latter was subjected to a reductive alkylation with propanal in the presence of palladium-carbon to afford the target compound with a purity of 99.6% and an overall yield of 30.7%. The optimized process has mild reaction conditions and convenient operation, and all of the intermediates can be refined by recrystallization, which makes it easy for quality control. This process is more suitable for industrial production.