US 9,115,177 B2  1  2  PREPARATION METHOD OF MICAFUNGIN  SODIUM  CROSS-REFERENCE TO RELATED  APPLICATIONS  FIELD OF INVENTION  BACKGROUND  SUMMARY OF INVENTION  This application is a 371 National Phase of PCT/CN2012/  075339, filed on May 11, 2012, which claims benefit of and  priority to CN 201110121705.5, filed on May 12, 2011,  which is incorporated herein by reference in its entirety for all  purposes.  The invention involves purification of compounds, particu- larly a preparation method for Micafungin sodium.  Micafungin is a second clinically applied pneumocandins  drug after caspofungin.  It  mostly inhibits the synthesis of the  main ingredient of fungi cell walls, i.e. 1,3-~-D-dextran, and  therefore disrupts the formation of fungi cell walls and influ› ences cell morphology and osmotic pressure thereof, thus  leading to cytolysis and cell death. Micafungin is mainly used  for treating deep fungi infections such as that from  Monilia,  Aspergillus,  etc. In particular, it is used for treating fungi  infections in patients with low immunity, such as chemo› therapy patients, AIDS patients, etc. Clinically, it is also used  in combination with amphotericin and triazole anti-fungi  drugs.  Micafungin is developed by Fujisawa Pharmaceutical,  under the trade name of Mycamine. Micafungin is on the  market as sodium form, the formula of which is shown as  follows.  WO9611210 and WO2004014879 have reported processes  for synthesis and purification of micafungin.  WO9611210 has reported a method for obtaining the  sodium salt by using cation exchange resin (DOWEX- 50WX4).  It  is impossible to control the pH value of the  product using said method. In addition, this method only  applies to small-scale preparation.  It  is hardly suited for  expanded scale of production and quality of products thereof  is unmanageable.  WO2004014879 has reported a method using 0.1 mol/L  NaOH solution to adjust pH value to 6-8. The Inventors have  performed multiple experiments using methods reported in  the literature and have discovered that adjusting the pH value  mixing a weak base solution with a water solution contain› ing the compound of formula I or a mixture solution of water  and organic solvent( s) containing the compound of formula I,  and thereby obtaining the compound of formula II;  In the first aspect of the Invention, a preparation method for  the compound of formula II is provided, comprising steps as  follows:  The Invention aims at providing a convenient method for  the preparation of micafungin sodium.  Another objective of the Invention is to provide a prepara› tion method of micafungin sodium which is adapted for the  industrial production.  Therefore, it is urgent to develop a method for the prepa› ration of micafungin sodium in order to obtain micafungin  sodium of high purity.  according to said method leads to a significant rise in the  content ofimpurity from micafungin degradation, as is shown  in FIGS.  2  and  3,  thereby considerably increasing the diffi› culty in the subsequent separation and purification and it is  difficult to prepare micafungin sodium of high purity. Hence,  the method can not fulfil the requirements for industrialized  manufacture.  II  -N  \  0  0  OH  i1  0~ 8 ’0  HO  II  -N  \  0. 