埃索美拉唑钠的合成

Synthesis of esomeprazole sodium

目的制备埃索美拉唑钠。方法以4-甲氧基-3,5-二甲基-2-羟甲基吡啶为原料,经氯化后与5-甲氧基-2-巯基苯并咪唑反应合成奥美拉唑硫醚物,奥美拉唑硫醚物在以(1S,2S)-(-)-1,2-环己二胺-D-酒石酸盐为手性配体、环烷酸钴为催化剂、过氧化钠为氧化剂的条件下进行不对称氧化合成高光学纯度埃索美拉唑钠。结果与结论目标化合物的结构经IR、1H-NMR、13C-NMR和MS确证。该法操作简便,收率较高(45%),产品光学纯度≥99%,含量≥98%,适于工业化生产。

Esomeprazole is the first optical isomer proton pump inhibitor, and its sodium salt is applied to the patients who are in need of PPI but not capable of oral dosing. At present, there are three methods to synthesize esomeprazole such as omeprazole racemic resolution, omeprazole sulfide complexes asymmetric cataly tic oxidation and biochemical oxidation. However, the omeprazole racemic resolution is limited industrially due to its high cost and low yield. The aim of this study is to propose a modified asymmetric oxidation meth- od to prepare esomeprazole for industrialized production. Compared with the traditional method, this new method has three advantages. Firstly, the（ 1S, 2S）-（ -）-1,2-diaminocyclohexane D-tartrate was used as chiral ligands, which avoids the addition of organic alkali in the traditional route. Secondly, cobalt naphthenate was applied as the catalyst to solve the problem of water-contacting over traditional titanium catalyst. Lastly, sodium peroxide is not only the oxidant to lower the cost of asymmetric oxidizing the omeprazole sulfide compounds but also the source of sodium for no more addition of other sodium source.