泰利霉素重要中间体3-氧代-6-O-甲基红霉素的合成

Synthesis of 3-Oxo-6-O-methylerythromycin,an Important Intermediate of Telithromycin

由克拉霉素的前体6-O-甲基-2′,4″-二(三甲基硅)-红霉素A9-(1-异丙氧基环己基)肟(Ⅰ)出发,常温下以φ(HC l)=10%的盐酸催化水解得3-羟基-6-O-甲基红霉素A9肟(Ⅱ);然后一锅煮进行化合物Ⅱ的2′-羟基乙酰化、3-羟基氧化,得2′-乙酰基-3-氧代-6-O-甲基红霉素A9-(O-乙酰基)肟(Ⅳ);最后脱乙酰基、还原9-肟基再次应用一锅煮法合成,得到目的化合物3-氧代-6-O-甲基红霉素(Ⅵ),总收率为57.0%,经HPLC测定w(Ⅵ)=98.5%。通过1HNMR1、3CNMR和MS,表征了各中间体及目标化合物的结构。

Hydrolysis of 6-O-methyl-2＇ ,4＂-bis （ trimethylsilyl ） -erythromycin A9- （ isopropoxycyclohexyl ） oxime ,a precursor of clarithromycin, was conducted under φ （HCI） = 10% hydrochloric acid as a catalyst at room temperature for 2 h to yield 3-hydroxy-6-O-methylerythromycin A9-oxime. Then 2＇-OH was protected with acetyl group and 3-OH was oxidized in one-pot synthesis to yield 2＇-O-acetyl-3-oxo- 6-O-methylerythromycin A9-acetyloxime. Finally two acetyl groups were removed and 9-oxime was reduced in one-pot synthesis. 3-Oxo-6-O-methylerythromycin was obtained in 57.0% overall yield with 98.5% purity. Structures of the target compound and all intermediates were identified by ^1HNMR, ^13CNMR and MS.