WO2012152225A1 - 一种米卡芬净钠盐的制备方法 - Google Patents

一种米卡芬净钠盐的制备方法 Download PDF

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WO2012152225A1
WO2012152225A1 PCT/CN2012/075339 CN2012075339W WO2012152225A1 WO 2012152225 A1 WO2012152225 A1 WO 2012152225A1 CN 2012075339 W CN2012075339 W CN 2012075339W WO 2012152225 A1 WO2012152225 A1 WO 2012152225A1
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sodium
solution
compound
formula
weak base
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PCT/CN2012/075339
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English (en)
French (fr)
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焦广俊
刘石东
何兵明
唐志军
季晓铭
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上海天伟生物制药有限公司
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Priority to EP12782012.4A priority Critical patent/EP2708533B1/en
Priority to JP2014509598A priority patent/JP5818974B2/ja
Priority to KR1020137032868A priority patent/KR101604523B1/ko
Priority to US14/116,947 priority patent/US9115177B2/en
Publication of WO2012152225A1 publication Critical patent/WO2012152225A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • This invention relates to the purification of compounds, and more particularly to a process for the preparation of a sodium salt of Micafimgin. Background technique
  • Micafungin is the second clinically used echinocanin after caspofungin, which inhibits the synthesis of 1,3-PD-glucan, the main component of the fungal cell wall, thereby disrupting the synthesis of fungal cell walls. , affecting cell morphology and osmotic pressure, leading to cell lysis and death.
  • Micafungin is mainly used for the treatment of deep fungal infections such as Candida and Aspergillus, especially for the treatment of fungal infections in immunocompromised patients such as chemotherapy and AIDS. Clinically, it is also combined with amphotericin and triazole antifungal drugs.
  • the present invention aims to provide a convenient method for preparing micafungin sodium salt.
  • Another object of the present invention is to provide a process for the preparation of micafungin sodium salt suitable for industrial production.
  • a process for the preparation of a compound of formula II comprising the steps of:
  • the weak base solution has a cation of sodium ions; and the weak base corresponds to a conjugate acid having a pKa value in the range of 4-11, preferably 5-8.
  • the weak base solution is an organic weak base solution, an inorganic weak base solution, or a mixture thereof.
  • the organic weak base is selected from one or more of the following combinations: disodium hydrogen citrate, sodium citrate, sodium acetate, sodium propionate, sodium butyrate, sodium isobutyrate, sodium tartrate, sodium oxalate , sodium benzoate, sodium sorbate, sodium malate, monosodium succinate, sodium succinate; preferably, the organic weak base is selected from one or a combination of the following: disodium hydrogen citrate, Sodium citrate, sodium acetate.
  • the inorganic weak base is selected from one or a combination of the following: sodium hydrogencarbonate, sodium carbonate, disodium hydrogen phosphate, sodium borate, sodium sulfite, sodium hydrogen sulfide; preferably, the inorganic weak base It is sodium bicarbonate.
  • the solution of the weak base solution and the aqueous solution containing the compound of the formula I has a pH of 4.0 to 7.0, preferably a pH of 4.0 to 6.0, more preferably a pH of 4.5 to 5.5.
  • the solution of the weak base solution and the mixed solution of the water and the organic solvent containing the compound of the formula I has a pH of 4.0 to 7.0, preferably a pH of 4.0 to 6.0, more preferably a pH. It is 4.5-5.5.
  • the concentration of the weak base solution is in the range of 0.001 to 1 mol/L; preferably, the concentration of the weak base solution is in the range of 0.01 to 0.5 mol/L.
  • the organic solvent is selected from the group consisting of alcohols or acetonitrile, preferably the alcohols are C1-C4 alcohols, and most preferably one or more of the following combinations: methanol, ethanol, and different Propanol, n-propanol, n-butanol, sec-butanol, tert-butanol.
  • the method for preparing a compound of formula II provided by the present invention comprises Steps:
  • the weak base solution is added to a mixed solution containing the compound of the formula I or a mixed solution of water and an organic solvent at room temperature to adjust the pH to obtain a compound of the formula II; the addition is carried out slowly with stirring. Accordingly, the present invention provides a process for preparing micafungin sodium salt to obtain high purity micafungin sodium salt.
  • FIG. 1 is a HPLC chromatogram of the compound of the formula I of Example 1; the retention time of each peak involved and the area thereof are as follows:
  • Figure 2 is an HPLC chromatogram of the compound of formula II prepared in Comparative Example 2; the retention time and area of each peak involved are as follows:
  • Figure 3 is an HPLC chromatogram of the compound of formula II prepared in Comparative Example 2; the retention time and area of each peak involved are listed in the following table:
  • Figure 4 is an HPLC chromatogram of the compound of formula II prepared in Example 4; the retention time and area of each peak involved are as follows:
  • FIG. 5 is a HPLC chromatogram of the compound of formula II prepared in Example 5; the retention time and area of each peak involved are listed in the following table:
  • Figure 6 shows the pH change of a strong acid (hydrochloric acid) solution titrated with a strong base (sodium hydroxide solution).
  • Figure 7 shows the pH change of a titrated micafungin acid solution in 0.1 M sodium bicarbonate solution.
  • the inventors have found through intensive studies that an inorganic weak base solution, an organic weak base solution or a mixture thereof is added to an aqueous solution of the compound of the formula I or a mixed solution of water and an organic solvent, and the pH of the solution is adjusted to 4.0-7.0, which can be prepared. A solution of high purity micafungin sodium salt is obtained.
  • the method is simple in operation, good in process reproducibility, high in product quality, and suitable for industrial production. Invention process and principle analysis
  • the sodium salt is prepared by adjusting the pH value, which is essentially a process of acid-base neutralization reaction. It includes two ways of reacting a strong acid with a strong base and reacting a strong acid with a weak base. Adding a strong alkali solution to a strong acid solution to adjust the pH value, the pH value of the solution changes, as shown in Figure 6, there is a significant range of pH value, and the instantaneous span of pH reaches 8, so in the actual production process It is difficult to control the pH of the solution. If the pH is slightly inadvertent, the pH of the solution will be adjusted too high.
  • Document WO2004014879 uses a 0.1 mol/L NaOH solution to adjust the pH to 6-8 to obtain a compound of formula II, which is in fact a process in which a strong acid reacts with a strong base. Since the compound of formula I contains a benzenesulfonic acid group, the benzenesulfonic acid type compound generally has a pKa value of less than 1, and is a strongly acidic compound, as shown in Table 1 below. Therefore, theoretically, the method of adjusting the pH using sodium hydroxide solution to obtain a sodium salt is not suitable for the preparation of the compound of formula II. Table 1 pKa values of benzenesulfonic acid compounds
  • the inventors conducted in-depth research and surprisingly found that the solution of the compound of the formula I can be obtained by using an inorganic weak base solution, an organic weak base solution or a mixture thereof to adjust the pH value of the compound of the formula I, and Produce new impurities.
  • the inventors conducted an in-depth analysis of the reasons why the above-mentioned weak base solution can achieve good results. First, there is an ionization equilibrium in the weak alkaline solution, the molecule is in an incomplete ionization state, and has a certain buffering capacity. Therefore, in the process of adjusting the pH value, there is no obvious pH sudden range, as shown in FIG.
  • the pH value changes slowly, there is no obvious pH sudden range, and when the pH reaches 7 or so, the pH value is stable, which is extremely beneficial to the actual production process.
  • the pH value is controlled.
  • the weak alkaline solution of the same concentration has a low pH value, and the alkaline solution is not easily caused by the addition of the compound solution of the formula I.
  • the use of a weak base solution to adjust the pH of a solution of a compound of formula I to prepare a sodium salt is more suitable for the preparation of a compound of formula II.
  • the concentration of the weak base solution also has an effect on the pH adjustment to prepare the sodium salt.
  • the concentration of weak alkali is selected to be 0.001-lmol/L, and the effect is best.
  • the inventors conducted in-depth research and discussion, and experimentally defined the pKa value of the conjugate acid corresponding to the weak base. The experimental results show that the pKa value of the weak base corresponding conjugate acid is better at 4-11, 5- 8 best.
  • the pKa value is a specific equilibrium constant, which represents the ability of an acid to dissociate hydrogen ions.
  • pKa the stronger the ability to give protons, the stronger the acidity, and the weaker the basicity of the corresponding conjugate base. The stronger the opposite.
  • the concentration of the weak acid [HA] formed in the solution is calculated to be 100 times the concentration of [H + ] or [A- ] by the above pKa formula,
  • the residual [H + ] concentration is equivalent to the concentration of the remaining [compound of formula I], thus producing a concentration of weak acid [HA] which is 100 times higher than the concentration of the remaining [compound of formula I], ie 99% of the compound of formula I has Conversion to a sodium salt form; when a compound of formula I reacts with a weak base to form a weak acid having a pKa value of 11, the concentration of weak acid [HA] in the solution is calculated to be 3.16 of [H + ] or [A_] concentration by the above formula.
  • the pKa value of the weak base corresponding conjugate acid is selected to be 4-11, which has a better effect.
  • the inventors also studied the stability of micafungin in different pH solutions and found that micafungin has poor stability under high pH solution conditions, usually at a pH of 4.0-7.0. 4.0-6.0 is more stable and most stable at 4.5-5.5. Therefore, when adjusting the pH of micafungin, it is necessary to consider adjusting the pH of the solution. Document WO2004014879 reports that the adjusted pH is 6-8, which is clearly not reasonable.
  • More than % of the compound of formula I has been converted to the compound of formula II, so that when the pH is adjusted to 4, it has been ensured that the compound of formula I is converted to the sodium salt form. Further, in combination with the stability data of the compound of the formula II in a solution of different pH, it is preferred to adjust the pH of the solution to 4.0 to 7.0, more preferably to 4.0 to 6.0, and most preferably to 4.5 to 5.5.
  • the present invention provides a process for the preparation of a compound of formula II, the process comprising the steps of: mixing a weak base solution with an aqueous solution containing a compound of formula I or a mixed solution of water and an organic solvent containing a compound of formula I to provide formula II Compound.
  • the organic solvent is selected from the group consisting of alcohols or acetonitrile, preferably alcohols are C1-C4 alcohols, most preferably selected from one or more of the following combinations: methanol, ethanol, isopropanol, n-propyl Alcohol, n-butanol, sec-butanol, tert-butanol.
  • the pH is from 4.0 to 7.0, preferably from 4.0 to 6.0, more preferably from 4.5 to 5.5.
  • the weak base refers to a base that is not completely ionized in an aqueous solution, that is, the protonation reaction is incomplete, and the corresponding conjugate acid has a pKa value ranging from 4 to 1, preferably from 5 to 8, as shown in Table 2 below.
  • organic weak base is mainly selected from one or more of the following combinations: disodium hydrogen citrate, sodium citrate, sodium acetate, sodium propionate, butyric acid Sodium, sodium isobutyrate, sodium tartrate, sodium oxalate, sodium benzoate, sodium sorbate, sodium malate, monosodium succinate, sodium succinate, preferably selected from one or more of the following: citric acid Sodium hydrogen hydride, sodium citrate, sodium acetate; the inorganic weak base is mainly selected from one or more of the following combinations: sodium hydrogencarbonate, sodium carbonate, disodium hydrogen phosphate, sodium borate, sodium sulfite, sodium hydrosulfide, preferably It is sodium bicarbonate.
  • Citric acid 3. 13 a 4.76 6.40 acetic acid 4.76
  • the concentration of the weak base ranges from 0.001 mol/L to 1 mol/L, preferably from 0.01 to 0.5 mol/L.
  • the method comprises the steps of:
  • the weak base solution is added to a mixed solution containing the compound of the formula I or a mixed solution of water and an organic solvent at room temperature to adjust the pH to obtain a compound of the formula II.
  • relative retention time means that in the HPLC analysis, the retention time of the impurity is compared with the main peak retention time of the main peak micafungin, and the resulting ratio is the relative retention time.
  • room temperature means 0-30 ° C, preferably 5-20 ° C. 00
  • the present invention provides a process for preparing micafungin sodium salt which can effectively avoid the formation of new impurities and simplify the further purification steps.
  • the purification step of the method provided by the invention has the characteristics of mild conditions and easy pH control, which not only requires low equipment but also reduces production cost.
  • the method provided by the invention can obtain the sodium type of micafungin, which is not only beneficial to its quality control, but also beneficial to industrialized large-scale production.
  • the invention is further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used for The invention is illustrated and not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.
  • the unit of weight percent by volume in the present invention is well known to those skilled in the art and, for example, refers to the weight of the solute in a 100 ml solution.
  • 0.5g of the compound of the formula I was ion-exchanged with a cation exchange resin 50ml UBK510L according to the micafungin purification process in WO2004014879, and the HPLC purity was 99.54%. Then, 0.1 mol/L of NaOH solution was slowly added dropwise at room temperature under stirring until the pH of the solution reached 4.0, and the sample was analyzed and the HPLC purity was 98.01%, see FIG. The 0.1 mol/L NaOH solution was continuously added until the pH of the solution was 4.5, and the sample was analyzed and the HPLC purity was 97.90%.
  • the NaOH solution of 0.1 mol/L was continuously added dropwise until the pH of the solution was 5.0, and the sample was analyzed and the HPLC purity was 97.81%.
  • the 0.1 mol/L NaOH solution was continuously added dropwise until the pH of the solution was 5.5, and the sample was analyzed and the HPLC purity was 97.75%.
  • a 0.1 mol/L NaOH solution was added dropwise until the pH of the solution was 6.0, and the sample was analyzed and the HPLC purity was 97.67%.
  • the 0.1 mol/L NaOH solution was continuously added until the pH of the solution was 6.5, and the sample was analyzed and the HPLC purity was 97.59%.
  • the dropwise addition of 0.1 mol/L NaOH solution was continued until the pH of the solution was 7.0, and the purity of the sampled analytical HPLC was 97.30%, as shown in FIG. Example 3
  • Example 4 0.2 g of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water, and a 0.01 mol/L sodium hydrogencarbonate solution was slowly added dropwise thereto at room temperature until the pH was 4.5, and the sample was analyzed. The HPLC purity was 99.55%. .
  • Example 4
  • Example 5 The sample of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water, and a solution of 0.001 mol/L of sodium carbonate was slowly added dropwise thereto at room temperature until the pH was 7.0, and the HPLC purity was 99. %, see Figure 4.
  • Example 5 The sample of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water, and a solution of 0.001 mol/L of sodium carbonate was slowly added dropwise thereto at room temperature until the pH was 7.0, and the HPLC purity was 99. %, see Figure 4.
  • Example 5 Example 5
  • Example 6 The 0.25 g of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water, and 0.1 mol/L of disodium hydrogen citrate and sodium citrate (molar ratio of 1:1) were slowly added dropwise with stirring at room temperature. The solution was mixed until the pH reached 4.0, and the sample was analyzed. The HPLC purity was 99.52%, see Figure 5.
  • Example 6 The HPLC purity was 99.52%, see Figure 5.
  • Example 7 Take 0.25 g of the compound of formula I obtained in Example 1, dissolve it in 20 ml of pure water, stir at room temperature A 0.5 mol/L sodium citrate solution was slowly added dropwise until the pH was 5.0, and the sample was analyzed and the HPLC purity was 99.50%.
  • Example 7 Take 0.25 g of the compound of formula I obtained in Example 1, dissolve it in 20 ml of pure water, stir at room temperature A 0.5 mol/L sodium citrate solution was slowly added dropwise until the pH was 5.0, and the sample was analyzed and the HPLC purity was 99.50%.
  • Example 7 Take 0.25 g of the compound of formula I obtained in Example 1, dissolve it in 20 ml of pure water, stir at room temperature A 0.5 mol/L sodium citrate solution was slowly added dropwise until the pH was 5.0, and the sample was analyzed and the HPLC purity was 99.50%.
  • Example 7 Take 0.25 g of the compound of formula I obtained in Example 1, dissolve it in 20 ml of pure water, stir at room temperature A 0.5
  • Example 8 The compound of the formula I obtained in Example 1 was 0.25 g, dissolved in 20 ml of pure water, and a 0.5 mol/L sodium oxalate solution was slowly added dropwise thereto at room temperature until the pH was 4.0, and the HPLC purity was 99.52%.
  • Example 8 The compound of the formula I obtained in Example 1 was 0.25 g, dissolved in 20 ml of pure water, and a 0.5 mol/L sodium oxalate solution was slowly added dropwise thereto at room temperature until the pH was 4.0, and the HPLC purity was 99.52%.
  • Example 8 The compound of the formula I obtained in Example 1 was 0.25 g, dissolved in 20 ml of pure water, and a 0.5 mol/L sodium oxalate solution was slowly added dropwise thereto at room temperature until the pH was 4.0, and the HPLC purity was 99.52%.
  • Example 9 Take 0.25 g of the compound of the formula I obtained in Example 1, dissolved in 20 ml of pure water and 20 ml of methanol, and slowly add 1 mol/L of sodium acetate solution at room temperature until the pH is 4.5, and the sample is analyzed. The HPLC purity is 99.53. %.
  • Example 9 Take 0.25 g of the compound of the formula I obtained in Example 1, dissolved in 20 ml of pure water and 20 ml of methanol, and slowly add 1 mol/L of sodium acetate solution at room temperature until the pH is 4.5, and the sample is analyzed. The HPLC purity is 99.53. %.
  • Example 9 Take 0.25 g of the compound of the formula I obtained in Example 1, dissolved in 20 ml of pure water and 20 ml of methanol, and slowly add 1 mol/L of sodium acetate solution at room temperature until the pH is 4.5, and the sample is analyzed. The HPLC purity is 99.53. %.
  • Example 9 Take 0.25
  • Example 10 Take 0.25 g of the compound of the formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of isopropanol. Slowly add 0.5 mol/L sodium sulfite solution at room temperature until stirring to pH 5.5, sample analysis, HPLC purity. It is 99.48%.
  • Example 10 Take 0.25 g of the compound of the formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of isopropanol. Slowly add 0.5 mol/L sodium sulfite solution at room temperature until stirring to pH 5.5, sample analysis, HPLC purity. It is 99.48%.
  • Example 10 Take 0.25 g of the compound of the formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of isopropanol. Slowly add 0.5 mol/L sodium sulfite solution at room temperature until stirring to pH 5.5, sample analysis, HPLC purity. It is 99.48%.
  • Example 10
  • Example 11 Take 0.25 g of the compound of the formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of n-propanol. At room temperature, a 0.3 mol/L sodium hydrosulfide solution was slowly added dropwise with stirring until the pH was 6.0, and the sample was analyzed. The HPLC purity was 99.38%.
  • Example 11 Take 0.25 g of the compound of the formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of n-propanol. At room temperature, a 0.3 mol/L sodium hydrosulfide solution was slowly added dropwise with stirring until the pH was 6.0, and the sample was analyzed. The HPLC purity was 99.38%.
  • Example 11 Take 0.25 g of the compound of the formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of n-propanol. At room temperature, a 0.3 mol/L sodium hydrosulfide solution was slowly
  • Example 12 The 0.25 g of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water and 5 ml of sec-butanol, and slowly stirred at room temperature with stirring. O. lmol/L sodium butyrate and sodium isobutyrate (molar ratio 1) : 1 ) Mixed The solution was sampled until pH 4, and the HPLC purity was 99.53%.
  • Example 12
  • Example 13 Take 0.25 g of the compound of formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of t-butanol. Slowly add 0.5 mol/L of disodium hydrogen phosphate solution to the pH to 6.0 after stirring at room temperature. The HPLC purity was 99.40%.
  • Example 13 Take 0.25 g of the compound of formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of t-butanol. Slowly add 0.5 mol/L of disodium hydrogen phosphate solution to the pH to 6.0 after stirring at room temperature. The HPLC purity was 99.40%.
  • Example 14 Take 0.25 g of the compound of formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of n-butanol. Slowly add 0.5 mol/L sodium borate solution at room temperature with stirring until pH 6.5, sample analysis, HPLC The purity is 99.30%.
  • Example 14 Take 0.25 g of the compound of formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of n-butanol. Slowly add 0.5 mol/L sodium borate solution at room temperature with stirring until pH 6.5, sample analysis, HPLC The purity is 99.30%.
  • Example 14 Take 0.25 g of the compound of formula I obtained in Example 1, and dissolve it in 20 ml of pure water and 20 ml of n-butanol. Slowly add 0.5 mol/L sodium borate solution at room temperature with stirring until pH 6.5, sample analysis, HPLC The purity is 99.30%.
  • Example 14 Take 0.25 g of the compound of formula I obtained
  • Example 15 Take 0.22 g of the compound of the formula I obtained in Example 1, dissolved in 20 ml of pure water and 20 ml of ethanol, and slowly add 0.4 mol/L of monosodium succinate, sodium succinate and sodium tartrate at room temperature with stirring (molar ratio is The mixed solution of 1 : 1 : 1) was sampled and analyzed until the pH reached 4.0, and the HPLC purity was 99.53%.
  • Example 15
  • Example 16 0.22 g of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water and 20 ml of methanol, and 0.05 mol/L of sodium hydrogencarbonate and sodium acetate (molar ratio of 1:1) were slowly added dropwise with stirring at room temperature. The solution was mixed until the pH was 4.5, and the sample was analyzed and the HPLC purity was 99.54%.
  • Example 16
  • Example 17 0.22 g of the compound of the formula I obtained in Example 1 was dissolved in 20 ml of pure water and 20 ml of methanol, and 0.2 mol/L of sodium sorbate and sodium malate were slowly added dropwise with stirring at room temperature; the molar ratio was 1:1. The mixed solution was sampled and analyzed until the pH reached 4.0, and the HPLC purity was 99.49%.
  • Example 17

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Description

一种米卡芬净钠盐的制备方法
技术领域
本发明涉及化合物纯化， 尤其涉及一种米卡芬净（Micafimgin) 钠盐的制 备方法。 背景技术
米卡芬净是继卡泊芬净之后第 2 个用于临床的棘白菌素类药物， 它主 要抑制真菌细胞壁的主要成分 1,3-P-D-葡聚糖合成,从而破坏真菌细胞壁的合 成,影响细胞形态和渗透压,导致细胞溶解死亡。 米卡芬净主要用于治疗念珠 菌、 曲霉菌等深部真菌感染， 特别是用于治疗化疗、 AIDS 等免疫力低下患 者的真菌感染。 临床还与两性霉素和三唑类抗真菌药物进行联合用药。
米卡芬净由日本藤泽公司开发， 其商品名为米开民 （Mycamine ) 上市 药物是其钠
Figure imgf000003_0001
文献 WO9611210和 WO2004014879报道了有关米卡芬净的合成以及纯 化工艺。
文献 WO9611210 报道采用阳离子交换树脂 (DOWEX-50WX4)交换成钠 盐， 该方法所得产品的 pH值无法控制， 而且该方法只适合小规模制备， 不 易放大生产， 产品的质量不易控制。
文献 WO2004014879报道采用 0.1mol/L的 NaOH溶液调节 pH值至 6-8。 发明人多次按该文献报道的方法进行实验， 发现该方法调节 pH值导致米卡 芬净降解的杂质含量显著升高， 见附图 2和 3所示， 明显增加后续分离纯化 的难度， 最终难以制备得到高纯度米卡芬净钠盐， 因此该方法无法满足工业 化生产的要求。
因此， 本领域迫切需要开发出一种制备米卡芬净钠盐的方法， 以得到高 纯度的米卡芬净钠盐。 发明内容
本发明旨在提供一种便捷的米卡芬净钠盐制备方法。
本发明的另一目的是提供一种适合工业化生产的米卡芬净钠盐制备方 法。 在本发明的第一方面， 提供了一种如式 II所示化合物的制备方法， 所述的 方法包括步骤：
将弱碱溶液和含有式 I化合物的水溶液或含有式 I化合物的水和有机溶剂的 混合溶液混合， 得到式 II化合物；
HO H
Figure imgf000005_0001
在上述的制备方法中， 所述的弱碱溶液， 其阳离子为钠离子； 所述的弱 碱对应的共轭酸 pKa值范围为 4-11， 优选 5-8。
在上述的制备方法中，所述的弱碱溶液为有机弱碱溶液、无机弱碱溶液、 或其混合。 所述的有机弱碱选自以下的一种或一种以上的组合： 柠檬酸氢二 钠、 柠檬酸钠、 醋酸钠、 丙酸钠、 丁酸钠、 异丁酸钠、 酒石酸钠、 草酸钠、 苯甲酸钠、 山梨酸钠、 苹果酸钠、 琥珀酸一钠、 琥珀酸钠； 较佳地， 所述的 有机弱碱选自以下的一种或一种以上的组合： 柠檬酸氢二钠、 柠檬酸钠、 醋 酸钠。所述的无机弱碱选自以下的一种或一种以上的组合:碳酸氢钠、碳酸钠、 磷酸氢二钠、 硼酸钠、 亚硫酸钠、 硫氢化钠； 较佳地， 所述的无机弱碱为碳 酸氢钠。
在上述的制备方法中， 弱碱溶液和含有式 I化合物的水溶液混合后的溶 液的 pH值为 4.0-7.0， 较佳地 pH值为 4.0-6.0， 更佳地 pH值为 4.5-5.5。
在上述的制备方法中， 弱碱溶液和含有式 I化合物的水和有机溶剂的混 合溶液混合后的溶液的 pH值为 4.0-7.0， 较佳地 pH值为 4.0-6.0， 更佳地 pH 值为 4.5-5.5。
在上述的制备方法中， 所述弱碱溶液的浓度范围为 0.001-lmol/L; 较佳 地， 所述弱碱溶液的浓度范围为 0.01-0.5mol/L。
在上述的制备方法中， 所述的有机溶剂选自醇类或乙腈， 优选醇类为 C1-C4 的醇， 最佳地选自以下的一种或一种以上的组合： 甲醇、 乙醇、 异丙 醇、 正丙醇、 正丁醇、 仲丁醇、 叔丁醇。
在另一个实施方式中， 本发明提供的如式 II所示化合物的制备方法包括 步骤：
室温下， 将弱碱溶液加入到含有式 I化合物的水溶液或水和有机溶剂的 混合溶液中， 调节 pH值， 得到式 II化合物； 所述的加入是在搅拌下缓慢加 入。 据此， 本发明提供了一种制备米卡芬净钠盐的方法， 以得到高纯度的米 卡芬净钠盐。 附图说明
图 1是实施例 1式 I化合物 HPLC图谱； 其中涉及的各峰的保留时间及 其面积等数据如下表所列：
Figure imgf000006_0001
图 2是对比例 2制备的式 II化合物 HPLC图谱； 其中涉及的各峰的保留 时间及其面积等数据如下表所列：
保留时间 面积 高度 面积百分比
13.112 21149 1395 0.06
16.581 61878 3000 0.18
17.318 21882 1309 0.06
18.479 33290939 1423115 98.01
19.365 38294 2451 0.11
20.599 289113 6553 0.85
22.127 28987 1280 0.09
23.124 17974 976 0.05
23.791 140287 6104 0.41
25.357 15057 439 0.04
26.618 9618 399 0.03 28.392 31413 1013 0.09 图 3是对比例 2制备的式 II化合物 HPLC图谱； 其中涉及的各峰的保留 时间及其面积等数据如下表所列：
Figure imgf000007_0001
图 4是实施例 4制备的式 II化合物 HPLC图谱； 其中涉及的各峰的保留 时间及其面积等数据如下表所列：
保留时间 面积 高度 面积百分比
16.490 26352 1220 0.20
17.214 8971 547 0.07
18.227 13 1621 10 614407 99. 17 19.255 8117 545 0.06
20.468 56926 2842 0.43
23.620 9839 512 0.07 图 5是实施例 5制备的式 II化合物 HPLC图谱； 其中涉及的各峰的保留 时间及其面积等数据如下表所列：
Figure imgf000008_0001
图 6显示了强碱 （氢氧化钠溶液） 滴定强酸 （盐酸） 溶液的 pH值变化 图。
图 7显示了 0.1M碳酸氢钠溶液滴定米卡芬净酸溶液的 pH值变化图。 具体实施方式
发明人通过深入研究， 发现将无机弱碱溶液、 有机弱碱溶液或其混合加 入到式 I化合物的水溶液或水和有机溶剂的混合溶液中， 调节溶液的 pH值 到 4.0-7.0， 均能够制备得到高纯度米卡芬净钠盐的溶液。 该方法操作简便， 工艺重现性好， 产品质量高， 适合工业化生产。 发明过程及原理分析
将酸制备成钠盐主要有两种方式， 一种是采用阳离子树脂交换， 另一种 是调节 pH值。 调节 pH值的方式制备钠盐， 实质为酸碱中和反应的过程。 它 包括强酸与强碱反应和强酸与弱碱反应的两种方式。 采用强碱溶液加入到强 酸溶液调节 pH值， 溶液 pH值的变化情况， 如附图 6所示， pH值存在一明 显的突越范围， pH值的瞬间跨度达到 8， 因而在生产实际过程中， 难以控制 溶液的 pH值， 稍有不慎， 溶液 pH值就会调节过高。 文献 WO2004014879 采用 0.1mol/L的 NaOH溶液调节 pH值至 6-8得到式 II化合物， 实则为强酸 与强碱反应的过程。 因为式 I化合物含有苯磺酸基， 苯磺酸型化合物的 pKa 值一般小于 1， 为强酸性化合物， 见下表 1所示。 因而从理论上分析， 采用 氢氧化钠溶液调节 pH值获得钠盐的方法不适合用于制备式 II化合物。 表 1苯磺酸类化合 的 pKa值
苯磺酸类化合物 pKa
苯磺酸 0.70
甲苯磺酸 -2.58
4-羟基苯磺酸 -2.19
1-萘磺酸 0.57
本发明人对文献 WO2004014879报道的方法进行了多次重复， 然后又从 局部 pH值过高的角度再次对文献方法进行了分析和验证，发现在调节 pH值 的过程中， 相对于整个溶液体系而言， O. lmol/L的氢氧化钠溶液在体系中浓 度相对较低，能控制溶液整体 pH值为 6-8，但是在滴加氢氧化钠溶液过程中， 局部的碱浓度过高， 即局部溶液的 pH值过高， 导致局部的米卡芬净发生降 解， 从而导致杂质含量过高， 见附图 1、 2和 3所示， 其中附图 1 为调节前 式 I化合物的 HPLC纯度， 附图 2和 3是 O. lmol/L的氢氧化钠溶液调节式 I 化合物 pH值后的 HPLC纯度， 降解相当明显。
为了避免上述存在的显著缺陷， 发明人又进行了深入研究， 惊喜地发现 采用无机弱碱溶液、 有机弱碱溶液或其混合调节式 I化合物的溶液 pH值， 均能够得到式 II化合物， 且不产生新的杂质。 发明人对上述弱碱溶液能够取 得良好结果的原因进行了深入分析。 首先弱碱溶液存在一电离平衡， 分子处 于不完全电离状态， 具有一定的缓冲能力， 因而在调节 pH值过程中， 不存 在明显的 pH突越范围， 见附图 7所示。 采用 0.1M碳酸酸氢钠溶液滴定米卡 芬净酸的溶液时， pH值变化缓慢， 不存在明显的 pH突越范围， 并且 pH值 达到 7左右时， pH值稳定， 极其有利于实际生产过程中的 pH值控制； 其次， 同浓度的弱碱溶液本身 pH值较强碱溶液低， 在加入到式 I化合物溶液过程 中， 不易造成局部 pH值过高。 因此， 采用弱碱溶液调节式 I化合物溶液的 pH值制备钠盐的方法更适合用于式 II化合物的制备。 此外， 发明人进一步 深入研究， 惊喜地发现弱碱溶液的浓度对调节 pH制备钠盐也存在影响。 理 论上说弱碱浓度越低越好， 但是浓度过低， 显然不符合实际生产的要求， 结 合实验数据发现弱碱浓度选定为 0.001-lmol/L， 效果最佳。 发明人又进行了深入研究与探讨， 经过实验对弱碱对应的共轭酸的 pKa 值进行了限定， 实验结果表明弱碱对应的共轭酸的 pKa值在 4-11效果较佳， 5-8最佳。 pKa值是一个特定的平衡常数， 代表一种酸离解氢离子的能力， pKa值越小给出质子的能力越强， 酸性就越强， 其所对应的共轭碱的碱性就 越弱， 反之就越强。 其计算公式为 pKa= -lg[H+][A— ]/[HA] ( HA代表弱酸， H+为弱酸 HA电离的氢离子， A—为弱酸 HA电离的负离子） 。 式 I化合物 为强酸型磺酸化合物， 在溶液当中， 几乎处于完全电离状态， 其 pKa值一般 小于 1， 因而遇到弱碱 (；共轭酸 pKa=4)时能够促进反应进行。 当式 I化合物与 其弱碱反应后生成 pKa值为 4的弱酸时，通过上述 pKa值公式计算得到溶液 中生成弱酸 [HA]的浓度为 [H+]或 [A— ]浓度的 100 倍， 由于残留的 [H+]浓度与 残留的 [式 I化合物]的浓度相当， 因而生成弱酸 [HA]的浓度的高于残留 [式 I 化合物]的浓度的 100倍， 即 99 %的式 I化合物已经转变成钠盐形式； 当式 I 化合物与其弱碱反应后生成 pKa值为 11 的弱酸时， 通过上述公式计算得到 溶液中生成弱酸 [HA]的浓度为 [H+]或 [A_]浓度的 3.16 X 105倍， 同理， 99.99% 的式 I化合物转变成钠盐形式； 最后根据实验结果确证， 弱碱对应的共轭酸 的 pKa值选定为 4-11， 具有较佳的效果。 发明人又通过米卡芬净在不同 pH 的溶液中的稳定性实验研究， 发现米 卡芬净在高 pH值的溶液条件下稳定性差， 通常在 pH值 4.0-7.0的稳定性较 好，在 4.0-6.0更为稳定，在 4.5-5.5最为稳定。因而调节米卡芬净的 pH值时， 势必需要考虑调节溶液的 pH值。文献 WO2004014879报道调节的 pH为 6-8， 显然不具有合理性。发明人通过实验发现溶液的 pH值调节到 7， 稳定性相对 较好， 未发生明显的降解。 再由 pH 值计算公式 (pH = -lg[H]+)计算， 若式 I 化合物的起始浓度为 0.01mol/L时， 当 pH值为 4时， 即溶液中的 H+浓度残 留低于 0.0001mol/L， 又由于式 I化合物为强酸型磺酸化合物， 在溶液当中， 几乎处于完全电离状态， 故当 pH 调节到 4 时， 残留的式 I 化合物低于 0.0001mol/L, 也就是 99 %以上的式 I化合物已经转变成式 II化合物， 因此 pH值调节到 4时， 已经确保式 I化合物转变成钠盐形式。又结合式 II化合物 在不同 pH的溶液中的的稳定性数据， 将溶液的 pH值调节到 4.0-7.0较佳， 更佳的是调节到 4.0-6.0， 最佳的是调节到 4.5-5.5。
综上所述， 发明人经过对酸碱原理的仔细研究， 并经过大量实验筛选， 惊喜地发现使用弱碱溶液调节米卡芬净酸溶液的 pH值时， 可以有效地避免 米卡芬净发生降解生成新的杂质， 顺利实现米卡芬净酸型到钠型的转化， 大 大减轻了后续纯化步骤的压力， 有效提高了终产品米卡芬净的收率和纯度。 式 II化合物的制备方法
本发明提供了如式 II所示化合物的制备方法， 所述的方法包括步骤： 将弱碱溶液和含有式 I化合物的水溶液或含有式 I化合物的水和有机溶剂的 混合溶液混合， 得到式 II化合物。
其中， 所述的有机溶剂选自醇类或乙腈， 优选醇类为 C 1-C4 的醇， 最 佳地选自以下的一种或一种以上组合： 甲醇、 乙醇、 异丙醇、 正丙醇、 正丁 醇、 仲丁醇、 叔丁醇。
其中， 所述的 pH值为 4.0-7.0， 优选 4.0-6.0， 更优选为 4.5-5.5。 . 其中， 所述弱碱是指在水溶液中不完全电离的碱， 即指质子化反应不完 全， 其对应的共轭酸 pKa值范围为 4- 1 1， 优选 5— 8， 见下表 2所示； 主要 包括： 有机弱碱或无机弱碱； 有机弱碱主要选自以下的一种或一种以上的组 合： 柠檬酸氢二钠、 柠檬酸钠、 醋酸钠、 丙酸钠、 丁酸钠、 异丁酸钠、 酒石 酸钠、 草酸钠、 苯甲酸钠、 山梨酸钠、 苹果酸钠、 琥珀酸一钠、 琥珀酸钠， 较佳地选自以下的一种或一种以上组合： 柠檬酸氢二钠、 柠檬酸钠、 醋酸钠； 无机弱碱主要选自以下的一种或一种以上组合： 碳酸氢钠、 碳酸钠、 磷酸氢 二钠、 硼酸钠、 亚硫酸钠、 硫氢化钠， 较佳为碳酸氢钠。
表 2 上述弱碱所对应的共轭酸的 pKa值
共轭酸的名称 pKal pKa2 pKa3
柠檬酸 3. 13 a 4.76 6.40 醋酸 4.76
丙酸 4.87
丁酸 4.82
异丁酸 4.69
酒石酸 3.04 a 4.37
草酸 1.27a 4.27
苯甲酸 4.20 山梨酸 4.76
苹果酸 3.40 a 5.13
琥珀酸 4.21 5.64
碳酸 6.38 10.25
磷酸 2.12a 7.2 12.36a
硼酸 9.24 12.74a
亚硫酸 1.90a 7.20
氢硫酸 6.88 14.15a
注： 标注 a的 pKa值不在本文要求的范围内。
其中， 所述弱碱的浓度范围为 0.001mol/L-lmol/L， 优选 0.01-0.5mol/L。 在另一优选例中， 所述方法包含以下步骤：
室温下，将弱碱溶液加入到含有式 I化合物的水溶液或水和有机溶剂的混合 溶液中， 调节 pH值， 得到式 II化合物。
如本文所用， "相对保留时间" 是指在 HPLC分析中， 将杂质的保留时 间与主峰米卡芬净的主峰保留时间相比， 所得的比值即相对保留时间。
如本文所用， 室温是指 0-30°C， 优选 5-20°C . 00
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本发明提到的上述特征， 或实施例提到的特征可以任意组合。 本案说明书所 揭示的所有特征可与任何组合物形式并用， 说明书中所揭示的各个特征， 可以 任何可提供相同、 均等或相似目的的替代性特征取代。 因此除有特别说明， 所 揭示的特征仅为均等或相似特征的一般性例子。 本发明的主要优点在于：
1、 本发明提供了一种制备米卡芬净钠盐的方法， 可以有效地避免生成 新杂质， 简化进一步纯化的操作步骤。
2、 本发明提供的方法所经过的纯化步骤具有条件温和、 pH值易于控制 等特点， 既对设备要求不高， 又降低了生产成本。
3、 本发明提供的方法能得到米卡芬净的钠型， 不但有利于其质量控制， 而且有利于工业化大生产。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于 说明本发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实 验方法， 通常按照常规条件或按照制造厂商所建议的条件。 除非另外说明， 否则所有的百分数、 比率、 比例、 或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的， 例如 是指在 100毫升的溶液中溶质的重量。
除非另行定义， 文中所使用的所有专业与科学用语与本领域熟练人员所 熟悉的意义相同。 此外， 任何与所记载内容相似或均等的方法及材料皆可应 用于本发明方法中。 文中所述的较佳实施方法与材料仅作示范之用。 式 I化合物的 HPLC纯度测定方法为：
HPLC分析柱： YMC-ODS 250 X 4.6mm, 5 μ m
流动相： 乙腈： 磷酸盐缓冲液 （pH 3.0 ) =70:45
流速： 1.15ml/min
柱温: 35±5 °C
运行时间： 50min
稀释液： 水的磷酸盐缓冲液
检测波长： 210nm
进样量： ΙΟμΙ
主峰保留时间： 18分钟左右。 实施例 1
米卡芬净 （式 I化合物） 的制备
参照 WO2004014879中的米卡芬净合成工艺， 制备得到米卡芬净二异丙 基乙胺盐约 10.00g， 经阳离子交换树脂 UBK510L进行离子交换除去二异丙 基乙胺， 收集产品馏分， 浓缩得到式 I化合物， HPLC纯度为 99.55 %， 见附 图 1。 对比例 2
米卡芬净钠 （式 II化合物） 的制备
参照 WO2004014879中的米卡芬净纯化工艺将式 I化合物 0.5g经阳离子 交换树脂 50ml UBK510L进行离子交换， 取样分析， HPLC纯度为 99.54 %， 然后在室温和搅拌的条件下， 缓慢滴加 0. 1mol/L 的 NaOH 溶液， 直至溶液 pH至 4.0， 取样分析， HPLC纯度为 98.01%， 见附图 2。 继续滴加 0. 1mol/L 的 NaOH溶液， 直至溶液 pH至 4.5， 取样分析， HPLC纯度为 97.90%。 继续 滴加 0. 1mol/L的 NaOH溶液， 直至溶液 pH至 5.0， 取样分析， HPLC纯度为 97.81%。 继续滴加 0. 1mol/L的 NaOH溶液， 直至溶液 pH至 5.5， 取样分析， HPLC纯度为 97.75%。 滴加 0. 1mol/L的 NaOH溶液， 直至溶液 pH至 6.0， 取 样分析， HPLC纯度为 97.67 %。 继续滴加 0. 1mol/L的 NaOH溶液， 直至溶液 pH至 6.5， 取样分析， HPLC纯度为 97.59%。 继续滴加 0. 1mol/L的 NaOH溶 液， 直至溶液 pH至 7.0， 取样分析 HPLC纯度为 97.30 %， 同附图 3。 实施例 3
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.2g， 将其溶于 20ml纯水， 室温下， 搅拌 下缓慢滴加 0.01mol/L 的碳酸氢钠溶液， 直至 pH至 4.5， 取样分析， HPLC 纯度为 99.55%。 实施例 4
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.2g， 将其溶于 20ml纯水， 室温下， 搅拌 下缓慢滴加 0.001mol/L的碳酸钠溶液， 直至 pH至 7.0， 取样分析， HPLC纯 度为 99. 17%， 见附图 4。 实施例 5
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水， 室温下， 搅拌 下缓慢滴加 O. lmol/L的柠檬酸氢二钠和柠檬酸钠 （摩尔比 1 : 1 ) 的混合溶液， 直至 pH至 4.0， 取样分析， HPLC纯度为 99.52%， 见附图 5。 实施例 6
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水， 室温下， 搅拌 下缓慢滴加 0.5mol/L的柠檬酸钠溶液， 直至 pH至 5.0， 取样分析， HPLC纯 度为 99.50%。 实施例 7
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水， 室温下， 搅拌 下缓慢滴加 0.5mol/L的草酸钠溶液， 直至 pH至 4.0， 取样分析， HPLC纯度 为 99.52%。 实施例 8
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水和 20ml 甲醇， 室温下， 搅拌下缓慢滴加 lmol/L的醋酸钠溶液， 直至 pH至 4.5， 取样分析， HPLC纯度为 99.53%。 实施例 9
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水和 20ml异丙醇， 室温下， 搅拌下缓慢滴加 0.5mol/L的亚硫酸钠溶液， 直至 pH至 5.5， 取样分 析， HPLC纯度为 99.48%。 实施例 10
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水和 20ml正丙醇， 室温下， 搅拌下缓慢滴加 0.3mol/L的硫氢化钠溶液， 直至 pH至 6.0， 取样分 析， HPLC纯度为 99.38%。 实施例 11
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水和 5ml仲丁醇， 室温下， 搅拌下缓慢滴加 O. lmol/L的丁酸钠和异丁酸钠 （摩尔比 1 : 1 ) 的混 合溶液， 直至 pH至 4， 取样分析， HPLC纯度为 99.53%。 实施例 12
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水和 20ml叔丁醇， 室温下， 搅拌下缓慢滴加 0.5mol/L的磷酸氢二钠溶液， 直至 pH至 6.0， 取样 分析， HPLC纯度为 99.40%。 实施例 13
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.25g， 将其溶于 20ml纯水和 20ml正丁醇， 室温下，搅拌下缓慢滴加 0.5mol/L的硼酸钠溶液，直至 pH至 6.5，取样分析， HPLC纯度为 99.30%。 实施例 14
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.22g， 将其溶于 20ml纯水和 20ml乙醇， 室温下， 搅拌下缓慢滴加 0.4mol/L 的琥珀酸一钠、 琥珀酸钠和酒石酸钠 (摩 尔比为 1 : 1 : 1)的混合溶液， 直至 pH至 4.0， 取样分析， HPLC纯度为 99.53%。 实施例 15
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.22g， 将其溶于 20ml纯水和 20ml 甲醇， 室温下， 搅拌下缓慢滴加 0.05mol/L的碳酸氢钠和醋酸钠 (摩尔比为 1 : 1)的混 合溶液， 直至 pH至 4.5， 取样分析， HPLC纯度为 99.54%。 实施例 16
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.22g， 将其溶于 20ml纯水和 20ml 甲醇， 室温下，搅拌下缓慢滴加 0.2mol/L的山梨酸钠和苹果酸钠 (；摩尔比为 1 : 1)的混 合溶液， 直至 pH至 4.0， 取样分析， HPLC纯度为 99.49%。 实施例 17
米卡芬净钠 （式 II化合物） 的制备
取实施例 1所得式 I化合物 0.22g， 将其溶于 20ml纯水和 20ml 甲醇， 室温下，搅拌下缓慢滴加 0.2mol/L的丙酸钠和苯甲酸钠 (摩尔比为 1 : 1)的混合 溶液， 直至 pH至 4.0， 取样分析， HPLC纯度为 99.52%。 以上所述仅为本发明的较佳实施例而已， 并非用以限定本发明的实质技 术内容范围， 本发明的实质技术内容是广义地定义于申请的权利要求范围 中， 任何他人完成的技术实体或方法， 若是与申请的权利要求范围所定义的 完全相同， 也或是一种等效的变更， 均将被视为涵盖于该权利要求范围之中。

Claims

权 利 要 求
1.一种如式 II所示化合物的制备方法， 其特征在于， 所述的方法包括步骤： 将弱碱溶液和含有式 I化合物的水溶液或含有式 I化合物的水和有机溶剂的 混合溶液混合 得到式 Π化合物；
Figure imgf000018_0001
2.如权利要求 1 所述的制备方法， 其特征在于， 所述的弱碱溶液， 其阳 离子为钠离子。
3.如权利要求 2所述的制备方法， 其特征在于， 所述的弱碱对应的共轭 酸 pKa值范围为 4-1 1， 优选 5-8。
4.如权利要求 1 所述的制备方法， 其特征在于， 所述的弱碱溶液为有机 弱碱溶液、 无机弱碱溶液、 或其混合。
5.如权利要求 4所述的制备方法， 其特征在于， 所述的有机弱碱选自以 下的一种或一种以上的组合： 柠檬酸氢二钠、 柠檬酸钠、 醋酸钠、 丙酸钠、 丁酸钠、 异丁酸钠、 酒石酸钠、 草酸钠、 苯甲酸钠、 山梨酸钠、 苹果酸钠、 琥珀酸一钠、 琥珀酸钠。
6. 如权利要求 5 所述的制备方法， 其特征在于， 所述的有机弱碱选自 以下的一种或一种以上的组合： 柠檬酸氢二钠、 柠檬酸钠、 醋酸钠。
7. 如权利要求 4 所述的制备方法， 其特征在于， 所述的无机弱碱选自 以下的一种或一种以上的组合:碳酸氢钠、 碳酸钠、 磷酸氢二钠、 硼酸钠、 亚 硫酸钠、 硫氢化钠。
8. 如权利要求 7 所述的制备方法， 其特征在于， 所述的无机弱碱为碳 酸氢钠。
9.如权利要求 1 所述的制备方法， 其特征在于， 所述混合后溶液的 pH 值为 4.0-7.0。
10.如权利要求 9所述的制备方法，其特征在于，所述的 pH值为 4.0-6.0。
11.如权利要求 10所述的制备方法，其特征在于，所述的 pH值为 4.5-5.5。
12. 如权利要求 1所述的制备方法， 其特征在于， 所述弱碱溶液的浓度 范围为 0.001-lmol/L o
13. 如权利要求 12 所述的制备方法， 其特征在于， 所述弱碱溶液的浓 度范围为 0.01-0.5mol/L。
14.如权利要求 1所述的制备方法， 其特征在于， 所述的有机溶剂选自醇 类或乙腈， 优选醇类为 C 1-C4的醇， 最佳地选自以下的一种或一种以上的组 合： 甲醇、 乙醇、 异丙醇、 正丙醇、 正丁醇、 仲丁醇、 叔丁醇。
15.如权利要求 1-14 任一所述的制备方法， 其特征在于， 所述方法包括 步骤：
室温下， 将弱碱溶液加入到含有式 I化合物的水溶液或水和有机溶剂的 混合溶液中， 调节 pH值， 得到式 II化合物。
16.如权利要求 15所述的制备方法， 其特征在于， 所述的加入是在搅拌 下缓慢加入。
PCT/CN2012/075339 2011-05-12 2012-05-11 一种米卡芬净钠盐的制备方法 WO2012152225A1 (zh)

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