头孢地尔侧链酸的合成

Synthesis of the Side Chain of Cefiderocol Acid

本研究以"一锅法"合成头孢地尔侧链酸(Z)-2-[[(1-叔丁氧羰基-1-甲基)乙氧]亚胺基]-2-[2-[(叔丁氧羰基)-氨基]噻唑-4-基]乙酸。(Z)-2-(2-氨基噻唑-4-基)-2-[[(1-叔丁氧羰基-1-甲基)乙氧]亚胺基]乙酸乙酯(2)在4-二甲胺基吡啶(DMAP)存在下与二碳酸二叔丁酯(Boc2O)反应生成单Boc保护的(Z)-2-[[(1-叔丁氧羰基-1-甲基)乙氧]-亚胺基]-2-[2-[(叔丁氧羰基)氨基]噻唑-4-基]乙酸乙酯(3)和双Boc保护的(Z)-2-[[(1-叔丁氧羰基-1-甲基)乙氧]亚胺基]-2-[2-[二(叔丁氧羰基)氨基]噻唑-4-基]乙酸乙酯(4)的混合物,然后该混合物不经纯化直接在氢氧化钠溶液中"一锅"发生两步水解得目标化合物,总收率74%,纯度99.2%。本工艺收率高、操作简便、易于放大。本研究还首次报道了化合物4的单晶衍射图。

In this study, the side chain of cefiderocol acid, （Z）-2-[[ [ （1-（tert-butoxycarbonyl）-1-methyl]-ethyoxy] iminol-2- E2- E （tert-butoxycarbonyl） aminol thiazol-4-yl] acetic acid, was synthesized by a ＂one-pot＂ method. Ethyl （Z） -2- （2-aminothiazol-4-yl） -2- [ [ [1- （tert-butoxycarbonyl） - l-methyl] ethyoxy] imino] acetate （2） reacted with di-tert butyl dicarbonate in the presence of DMAP to give a mixture of ethyl （Z） -2- [ [ [ l- （tert-butoxycarbonyl） - 1- methyl] ethyoxy] imino]-2- [2- E （tert-butoxycarbonyl） amino] thiazol-4-yl] acetate （3） and ethyl （Z） -2- [ [ [ 1 - （tert- butoxycarbonyl） - 1-methyl] ethyoxy] imino] -2- [2- [di （tert-butoxycarbonyl） amino] thiazol-4-yl] acetate （4）. Then without further purification, the mixture was treated with NaOH aqueous solution to afford the target compound with an overall yield of 74 % and a purity of 99.2 % via the one-pot two steps hydrolysis. This process has some advantages such as simple operation and high yield, which make it easy to scale up. In addition, the single crystal diffraction pattern of compound 4 was also reported for the first time.