US 9,115,177 B2  6  5  MODES FOR CARRYING OUT THE INVENTION  1brough intensive research, the inventors have discovered  that by adding inorganic weak base solution, organic weak  base solution or combination thereof into a water solution  containing the compound of formula I or a mixture solution of  water and organic solvent containing the compound of for› mula I, and adjusting pH value of the solution to 4.0-7 .0, a  solution of micafungin sodium ofhigh purity can be prepared.  The method is easily operated and ofhighreproducibility, and  the quality of product is high, therefore, the method is well  suited for industrial production.  Process of Invention and Analysis of the Principle  The inventors have repeated the method reported in  WO2004014879 for multiple times and analyzed and vali› dated the reported method from the point of view oflocal pH  value. The inventors have found that during the course of pH  adjusting, regarding the whole solution system, 0.1 mol/L  NaOH solution has a relatively low concentration and the  overall pH value can be managed at 6-8, however, during the  course of adding NaOH solution dropwise, the local base  concentration gets too high, i.e. local pH value in the solution  gets overly high, therefore, partial degradation occurred in  micafungin, hence the impurity content is much too high. See  FIGS.  1, 2  and  3.  FIG.  1  shows the HPLC purity of formula I  compound before pH adjustment. FIGS.  2  and  3  show HPLC  purities after formula I compound is adjusted in pH value with  0.1 mol/L NaOH solution, in which obvious degradation can  be found.  In order to avoid the aforesaid prominent defects, the  inventors have conducted further and intensive researches  and have unexpectedly found that by using inorganic weak  base solution, organic weak base solution or combinations  The inventors have also discovered via experiments on  stability of micafungin in solutions with different pH that  The inventors have also conducted further researches and  discussions for determining the pKa values of the conjugate  acid corresponding to the weak base. The test results showed  that the pKa value of the conjugate acid corresponding to the  weak base is preferably at 4-11, most preferably 5-8. ThepKa  value is a particular balance constant which represents the  capacity of an acid to dissociate hydrogen ion. The lower the  pKa value, the strong its capacity to offer proton, hence a  stronger acidity, a smaller alkalinity ofits corresponding con› jugate base has, and vice versa. The equation to calculate pKa  is: pKa=-1 g[H+][A-]/[HA] (HA stands for weak acid, H+ is  the hydrogen ion ionized from the weak acid HA, A- is an  anion ionized from the weak acid HA). The compound of  Formula I is a sulfonic acid compound of strong acid type. In  a solution, it is almost completely ionized, and the pKa  thereof is generally lower than 1. Therefore, it can facilitate  the reaction to take place when encounter a weak base ( con› jugate acid pKa=4). When the compound of formula I reacts  with the weak base and generates a weak acid with the pKa  value of 4, via the aforesaid equation of pK, it can be calcu- lated that the concentration of weak acid [HA] generated in  the solution is 100 times the concentration of [H+] or [A-].  Since the concentration of residue [H+] is comparable with  that of the residue formula I compound, the concentration of  generated weak acid [HA] is 100 times higher than that of the  residue [formula I compound], that is, 99% of the formula I  compound has been transformed into the form of sodium salt.  When formula I compound reacted with the weak base and  generates a weak acid with pKa of 11, it can be calculated via  the aforesaid equation that the concentration of the weak acid  [HA] generated in the solution is 3.16xl0 $^{5 }$times that of [H+]  or [A-]. Likewise, 99 .99% of formula I compound has trans› formed into a sodium salt form. Lastly, based on the experi› ment results, it is verified that pKa value of the conjugate acid  of the weak base should be chosen at 4-11, for achieving the  optimum effects.  thereof to adjust pH value of solution of formula I compound,  compound of formula II can be obtained without generating  extra impurities. The inventors have conducted in-depth  analysis on the cause of the sound result from the aforesaid  weak base solution. First of all, there exists within the weak  base solution an ionization equilibrium. The molecules are in  a state of incomplete ionization and possess a certain degree  of buffer capacity. Therefore, when adjusting the pH value,  there is not an obvious pH surge, as is shown in FIG.  7.  While  using 0.1 M NaHCO$_{3 }$ solution to titrate the solution of micaf› ungin, the pH changes slowly and there is not an obvious pH  surge, and the pH value can be stably remained at 7, thus  facilitating the pH control during the practical production.  Secondly, compared with the strong base solution, weak base  solutions of the same concentration per se have lower pH  values. During the course of adding the weak base solution  into the solution of formula I compound, the local pH value  won’t readily rise. Therefore, using weak base solution to  adjust the pH of the solution of formula I compound for  preparing sodium salt is a method much suited for the prepa› ration of formula II compound. In addition, the inventors, via  further in-depth studies, further unexpectedly found that the  concentration of weak base solution will also influence the  sodium salt preparation via adjustment of pH. In theory, the  lower the concentrations of weak bases, the better the results,  however, overly low concentration obviously does not con- form to the practical requirements in the production. Based on  the experiment data, the concentration of the weak base is  preferably at 0.001-1 mol/L, for achieving the best effects.  Generally, there are two ways for preparing acid into  sodium salt. One is exchange using cationic resin; the other is  via adjusting pH value. Virtually, preparing sodium salt by  adjusting pH value is a process of neutralization reaction  between acid and base.  It  includes two types of reactions, i.e.  the reaction between strong acid and strong base, and the  reaction between strong acid and weak base. If strong base  solution is added into strong acid solution for adjusting pH  value, there is a sharp change in the pH value of the solution  (the change of pH value is illustrated in FIG.  6),  and the pH  value will be instantly altered by 8. Therefore in the practical  production, it is hard to control the pH value and a slightest  mistake could lead to an overregulated pH value. In  WO2004014879, a 0.1 mol/L NaOH solution was used to  adjust pH value to 6-8 for obtaining formula II compound.  It  was actually a reaction between strong acid and strong base.  The compound of formula I contains benzene sulfonic acid  groups and pKa values of benzene sulfonic acid compounds  are generally less than 1, therefore the compound is strong  acid compound (See FIG.  1).  Therefore, theoretically, the  method using NaOH solution to adjust pH values for obtain› ing sodium salt is unsuitable for preparation of formula II  compound.  TABLE 1  pKa values of Compounds of Benzene SulfonicAcid  Compounds of Benzene Sulfonic Acid  benzene sulfonic acid  toluene sulfonic acid  4-hydroxy benzene sulfonic acid  1-naphthalene sulfonic acid  pKa  0.70  -2.58  -2.19  0.57 