WO2021098847A1 - 一种克林霉素磷酸酯的纯化方法 - Google Patents

一种克林霉素磷酸酯的纯化方法 Download PDF

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WO2021098847A1
WO2021098847A1 PCT/CN2020/130604 CN2020130604W WO2021098847A1 WO 2021098847 A1 WO2021098847 A1 WO 2021098847A1 CN 2020130604 W CN2020130604 W CN 2020130604W WO 2021098847 A1 WO2021098847 A1 WO 2021098847A1
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clindamycin phosphate
reverse micelle
phase
purifying
clindamycin
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French (fr)
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郭佳
于荣
刘鹏
张杭洲
张晓强
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宁夏泰益欣生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof

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  • the invention belongs to the technical field of antibiotic purification, and particularly relates to a method for purifying clindamycin phosphate.
  • Clindamycin phosphate (clindamycin phosphate) is a semi-synthetic derivative of clindamycin. It has the characteristics of good fat solubility and high bioavailability. It can be quickly hydrolyzed into clindamycin in the body to show pharmacological activity. Compared with clindamycin, Clindamycin Phosphate has the characteristics of high antibacterial activity, fast absorption, strong fat solubility and permeability, and less side effects. It has a wide distribution in the body and high tissue concentration, especially in bone tissue; It has strong antibacterial effect on various gram-positive bacteria and has small side effects. It is a broad-spectrum antibiotic with dual broad-spectrum properties of anti-anaerobes and aerobic bacteria. It is mainly used for the treatment of anaerobes and sensitive bacteria. Infections caused by sexual gram-positive bacteria.
  • the traditional method of crystallization of clindamycin phosphate is to dissolve the crude product with ethanol under reflux, decolorization by activated carbon, and gradient cooling and crystallization to obtain the finished product of clindamycin phosphate.
  • the crystallization method in this process requires high equipment and involves a large amount of flammable and explosive organic solvents (ethanol).
  • ethanol flammable and explosive organic solvents
  • the purpose of the present invention is to overcome the above-mentioned defects of the prior art, and provide a clindamycin that greatly reduces the amount of organic solvents, reduces industrial sewage discharge, improves production safety index, reduces equipment requirements, saves energy and reduces consumption, and can improve product quality.
  • Method for the purification of phosphoric acid esters is to overcome the above-mentioned defects of the prior art, and provide a clindamycin that greatly reduces the amount of organic solvents, reduces industrial sewage discharge, improves production safety index, reduces equipment requirements, saves energy and reduces consumption, and can improve product quality.
  • a method for purifying clindamycin phosphate which comprises:
  • TOMAC trioctyl methyl ammonium chloride
  • the surfactant n-octyl- ⁇ -D-glucopyranoside (actyl- ⁇ -D-glucopyranoside, OGP) and crude clindamycin phosphate were dissolved in purified water as the aqueous phase;
  • the reverse micelle extraction system is mixed with the water phase, extracted, left to stand for phase separation to obtain a reverse micelle extraction phase containing clindamycin phosphate, and then inorganic salt is added to make the clindamycin phosphate from the The reverse micelle extraction phase crystallizes out, and the separation is sufficient.
  • TOMAC trioctyl methyl ammonium chloride
  • the concentration of n-octyl- ⁇ -D-glucopyranoside (OGP) is 1-10 mmol/L.
  • the concentration of the crude clindamycin phosphate is 50,000 to 120,000 U/mL.
  • the mixing ratio of the reverse micelle extraction system and the water phase is 1:(1-5), calculated by volume ratio (v:v).
  • the extraction temperature is 20-40°C, and the extraction time is 10-40 min.
  • the added amount of the inorganic salt is 5 mass% to 15 mass% of the crude clindamycin phosphate feed amount.
  • the inorganic salt is NaCl, Na 2 HPO 4 or NaH 2 PO 4 .
  • the present invention adopts reverse micelle extraction method instead of traditional crystallization method, namely adopts trioctyl methyl ammonium chloride (TOMAC)/ethyl acetate as the reverse micelle extraction system, and uses n-octyl- ⁇ -D-glucopyranoside (actyl- ⁇ -D-glucopyranoside, OGP) is used as an affinity cosurfactant to extract the crude clindamycin phosphate.
  • TOMAC trioctyl methyl ammonium chloride
  • OGP n-octyl- ⁇ -D-glucopyranoside
  • OGP n-octyl- ⁇ -D-glucopyranoside
  • the clindamycin phosphate is crystallized out by adding inorganic salt (sodium salt) So that it is separated from the reverse micelle system; the affinity co-surfactant is introduced in order to improve the extraction efficiency of clindamycin phosphate.
  • the present invention has the following advantages: 1 Safety: Compared with the cooling crystallization method, reverse micelle extraction does not involve organic solvents, and the process is relatively safe; 2 Cost: The cost of surfactant consumed by a single batch of clindamycin phosphate is far It is much lower than the cost of organic solvents. In addition, reverse micelle extraction does not produce crystallization mother liquor, so there is no need to consume steam to recover ethanol; 3Product quality: general impurities have higher solubility in reverse micelles, which is beneficial to improve the product 4In terms of equipment: the requirements for equipment are not high, and the discharge of industrial sewage is small, which reduces the pressure on environmental protection.
  • the purification method of clindamycin phosphate of the present invention is beneficial to improve the purity of the product, avoids the use of flammable and explosive organic solvents, reduces sewage discharge, reduces environmental protection pressure, and reduces production The cost also reduces the safety risk of the production environment.
  • the crude clindamycin phosphate used in the present invention is prepared by the currently disclosed synthetic method, or can be prepared according to the following method: adding clindamycin hydrochloride alcoholate and acetone into a dry enamel glass reactor, and cooling the temperature to ⁇ Phosphorus oxychloride was added dropwise after -5°C; after keeping the temperature at 0 ⁇ -5°C and reacting for 0.5 ⁇ 1h, thin-plate chromatography showed that the propylene protection reaction was complete, add phosphorus oxychloride at a temperature of ⁇ -10°C, and then Add pyridine dropwise at ⁇ -10°C. Then react at 0 ⁇ -5°C for at least 2h, until the thin-plate chromatography shows that the reaction is complete.
  • the flow rates of water washing and analysis are both 400-600L/h.
  • the methanol solution is transferred to a concentration kettle, and the methanol is recovered to dryness by distillation under reduced pressure. Add ethanol, stir at 5-10°C for 0.5-1.0h, and centrifuge to obtain crude clindamycin phosphate. The yield is 70.0%-85.0%.
  • the crude clindamycin phosphate mentioned in the following examples and comparative examples are all crude clindamycin hydrochloride hydrate prepared by this method.
  • TOMAC trioctyl methyl ammonium chloride
  • OGP n-octyl- ⁇ -D-glucopyranoside
  • the crude clindamycin phosphate and OGP are dissolved in purified water to prepare a mixed solution with a concentration of about 50000U/mL and 3mmol/L as the water phase.
  • the TOMAC reverse micelle extraction system and the water phase were mixed in a volume ratio of 1:2, and the crude clindamycin phosphate was stirred and extracted at 25°C for 15 minutes, and then left to stand for phase separation.
  • Reverse micellar extraction phase of mycin phosphate After the extraction is completed, 15% (weight) NaCl of the crude clindamycin phosphate feed is added to crystallize the clindamycin phosphate from the reverse micelle, thereby separating the clindamycin phosphate from the reverse micelle system. Filter and dry to obtain the finished product.
  • the extraction yield was 93.43%, and the clindamycin B phosphate was 0.89%.
  • the TOMAC reverse micellar extraction system and the water phase were mixed in a volume ratio of 1:3, and the crude clindamycin phosphate was stirred and extracted at 30°C for 25 minutes, and then left to stand for phase separation.
  • Reverse micellar extraction phase of mycin phosphate After the extraction is completed, 12% (weight) NaCl of the crude clindamycin phosphate feed is added to crystallize the clindamycin phosphate from the reverse micelle, thereby separating the clindamycin phosphate from the reverse micelle system. Filter and dry to obtain the finished product.
  • the extraction yield was 94.12%, and the clindamycin B phosphate was 0.85%.
  • the TOMAC reverse micelle extraction system and the water phase were mixed in a volume ratio of 1:5, and the crude clindamycin phosphate was stirred and extracted at 20°C for 40 minutes, and then the phases were separated by standing to obtain the content of clindamycin.
  • Reverse micellar extraction phase of mycin phosphate After the extraction is completed, adding 5% (weight) NaCl of the crude clindamycin phosphate feed amount to crystallize the clindamycin phosphate from the reverse micelles, thereby separating the clindamycin phosphate from the reverse micelle system. Filter and dry to obtain the finished product.
  • the extraction yield was 94.81%, and the clindamycin B phosphate was 0.87%.

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Abstract

涉及一种克林霉素磷酸酯的纯化方法，其包括：将表面活性剂三辛基甲基氯化铵(TOMAC)溶于有机溶剂乙酸乙酯中制成反胶束萃取系统；将表面活性剂正辛基-β-D-吡喃葡萄糖苷(actyl-β-D-glucopyranoside，OGP)和克林霉素磷酸酯粗品溶解在纯化水中作为水相；将上述反胶束萃取系统与水相混合、萃取，静置分相，得到含有克林霉素磷酸酯的反胶束萃取相，然后加入无机盐使克林霉素磷酸酯从反胶束萃取相中结晶析出，分离即可。其有利于提高产品的纯度，且避免了易燃易爆类有机溶剂的使用，减少了污水的排放从而减轻环保压力，降低了生产成本同时也降低了生产环境的安全风险。

Description

一种克林霉素磷酸酯的纯化方法 技术领域
本发明属于抗生素提纯技术领域，特别涉及一种克林霉素磷酸酯的纯化方法。
背景技术
克林霉素磷酸酯(clindamycin phosphate)，是克林霉素的半合成衍生物，具有脂溶性好，生物利用度高等特点，它能在体内迅速水解成克林霉素而显示药理活性。克林霉素磷酸酯与克林霉素相比，具有抗菌活性高、吸收快、脂溶性及渗透性强、副作用少等特点，体内分布广，组织浓度高，尤其在骨组织中为甚；对各种革兰氏阳性菌均有较强的抗菌作用，副作用小，是一种兼有具有抗厌氧菌和需氧菌的双重广谱特性的广谱抗生素，临床主要用于治疗厌氧菌和敏感性革兰阳性菌引起的感染。
传统克林霉素磷酸酯的结晶方法是将其粗品用乙醇加热回流溶解，活性炭脱色处理，梯度降温结晶得到克林霉素磷酸酯成品。该工艺中结晶方法对设备要求高，涉及大量易燃易爆的有机溶剂(乙醇)，结晶过程存在一定的安全风险；且污水排放量多不利于环保。
发明内容
本发明的目的就在于克服上述现有技术的缺陷，提供一种大大减少有机溶剂用量，减少工业污水排放，提高生产安全指数，降低设备要求，节能降耗，且可提升产品质量的克林霉素磷酸酯的纯化方法。
为实现上述发明目的所采取的技术方案为：
一种克林霉素磷酸酯的纯化方法，其包括：
将表面活性剂三辛基甲基氯化铵(TOMAC)溶于有机溶剂乙酸乙酯中制成反胶束萃取系统；
将表面活性剂正辛基-β-D-吡喃葡萄糖苷(actyl-β-D-glucopyranoside，OGP)和克林霉素磷酸酯粗品溶解在纯化水中作为水相；
将所述反胶束萃取系统与所述水相混合、萃取，静置分相，得到含有克林霉素磷酸酯的反胶束萃取相，然后加入无机盐使克林霉素磷酸酯从所述反胶束萃取相中结晶析出，分离即可。
所述反胶束萃取系统中，三辛基甲基氯化铵(TOMAC)浓度为10～50mmol/L；
所述水相中，正辛基-β-D-吡喃葡萄糖苷(actyl-β-D-glucopyranoside，OGP)浓度为1～10mmol/L。
所述水相中，克林霉素磷酸酯粗品的浓度为50000～120000U/mL。
所述反胶束萃取系统与所述水相的混合比例为1:(1～5)，以体积比计(v:v)。
所述萃取温度为20～40℃，萃取时间为10～40min。
所述无机盐的加量为克林霉素磷酸酯粗品投料量的5质量％～15质量％。
所述无机盐为NaCl、Na 2HPO 4或NaH 2PO 4。
本发明采用反胶束萃取法替代传统结晶法，即采用三辛基甲基氯化铵(TOMAC)/乙酸乙酯作为反胶束萃取系统，以正辛基-β-D-吡喃葡萄糖苷(actyl-β-D-glucopyranoside，OGP)作为亲和助表面活性剂，对克林霉素磷酸酯粗品进行萃取，萃取完毕后通过加入无机盐(钠盐)使克林霉素磷酸酯结晶析出从而使其与反胶团体系得到分离；其中引入的亲和助表面活性剂为了提高克林霉素磷酸酯的萃取效率。本发明具有以下优势：①安全方面：与降温结晶法相比，反胶束萃取不涉及有机溶剂，过程相对较为安全；②成本方面：单批克林霉素磷酸酯所消耗表面活性剂的费用远远低于有机溶剂的费用，此外，反胶束萃取不产生结晶母液，故不需要消耗蒸汽来回收乙醇；③产品质量方面：一般杂质在反胶团中有较高的溶解度，有利于提高产品的纯度；④设备方面：对设备要求不高，工业污水排放少，减轻环保压力。
综上所述，本发明的克林霉素磷酸酯的纯化方法有利于提高产品的纯度，且避免了易燃易爆类有机溶剂的使用，减少了污水的排放从而减轻环保压力，降低了生产成本同时也降低了生产环境的安全风险。
具体实施方式
下面用实例，对本技术方案进行具体的描述，应该理解的是，实例是用于说明本发明而不是对本发明的限制。本发明的范围与核心内容依据权利要求书加以确定。
本发明所用克林霉素磷酸酯粗品采用目前公开的合成方法制备，也可以按照下述方法制备：将盐酸克林霉素醇化物和丙酮加入到干燥的搪瓷玻璃反应釜中，温度冷却到≤-5℃后滴加三氯氧磷；保持温度在0～-5℃反应0.5～1h后，薄板 层析显示丙叉保护反应完全后，在温度≤-10℃加入三氯氧磷，然后在≤-10℃滴加吡啶。然后在0～-5℃反应至少2h，直至薄板层析显示反应完全。将定量纯化水加入水解釜中并用夹套盐水降温至0～-5℃待用。将反应液吸入已降温的水解釜中，控制釜内温度在25～30℃水解至少4h，经薄板层析显示反应完全。加入Na 2CO 3调节釜内pH至3～4，调完后，在温度＜50℃条件下真空回收残留在水中的丙酮，在浓缩液中加入活性炭脱色后压滤，滤液用工艺用水稀释，上大孔吸附树脂柱进行分离，然后用纯化水洗涤、甲醇解析，水洗和解析流速均为400～600L/h。甲醇解析液转移至浓缩釜中，减压蒸馏回收甲醇至干。加乙醇，5～10℃条件下搅拌0.5～1.0h后，离心得到克林霉素磷酸酯粗品。其收率为70.0％～85.0％。
以下实施例和比较例中所提到的克林霉素磷酸酯粗品均为采用此法制备得到的盐酸克林霉素水化物粗品。
实施例1
将三辛基甲基氯化铵(TOMAC)溶于乙酸乙酯中制成15mmol/L的TOMAC乙酸乙酯溶液作为反胶束萃取系统；以正辛基-β-D-吡喃葡萄糖苷(OGP)为亲和助表面活性剂，将克林霉素磷酸酯粗品和OGP溶解在纯化水中配制成浓度分别为约50000U/mL和3mmol/L的混合溶液作为水相，克林霉素磷酸酯溶液与OGP溶液比例为，克林霉素磷酸酯溶液：OGP溶液＝33:1(C：C)。将TOMAC反胶束萃取系统与水相按照体积比为1:2的比例混合，在25℃条件下，对克林霉素磷酸酯粗品进行搅拌萃取15min后，静置分相，得到含有克林霉素磷酸酯的反胶束萃取相。萃取完毕后加入克林霉素磷酸酯粗品投料量15％(重量)NaCl使克林霉素磷酸酯从反胶团中结晶析出从而使克林霉素磷酸酯与反胶团体系得到分离。过滤、干燥得到成品。萃取收率为93.43％，克林霉素B磷酸酯为0.89％。
实施例2
将TOMAC溶于乙酸乙酯中制成30mmol/L的TOMAC乙酸乙酯溶液作为反胶束萃取系统；以OGP为亲和助表面活性剂，将克林霉素磷酸酯粗品和OGP溶解在纯化水中配制成浓度分别为约80000U/mL和6mmol/L的混合溶液作为水相，克林霉素磷酸酯溶液与OGP溶液比例为，克林霉素磷酸酯溶液：OGP溶液＝26:1(C：C)。将TOMAC反胶束萃取系统与水相按照体积比为1:3的比例混合，在30℃条件下，对克林霉素磷酸酯粗品进行搅拌萃取25min后，静置分相，得到含有克林霉 素磷酸酯的反胶束萃取相。萃取完毕后加入克林霉素磷酸酯粗品投料量12％(重量)NaCl使克林霉素磷酸酯从反胶团中结晶析出从而使克林霉素磷酸酯与反胶团体系得到分离。过滤、干燥得到成品。萃取收率为94.12％，克林霉素B磷酸酯为0.85％。
实施例3
将TOMAC溶于乙酸乙酯中制成45mmol/L的TOMAC乙酸乙酯溶液作为反胶束萃取系统；以OGP为亲和助表面活性剂，将克林霉素磷酸酯粗品和OGP溶解在纯化水中配制成浓度分别为约110000U/mL和10mmol/L的混合溶液作为水相，克林霉素磷酸酯溶液与OGP溶液比例为，克林霉素磷酸酯溶液：OGP溶液＝22:1(C：C)。将TOMAC反胶束萃取系统与水相按照体积比为1:5的比例混合，在20℃条件下，对克林霉素磷酸酯粗品进行搅拌萃取40min后，静置分相，得到含有克林霉素磷酸酯的反胶束萃取相。萃取完毕后加入克林霉素磷酸酯粗品投料量5％(重量)NaCl使克林霉素磷酸酯从反胶团中结晶析出从而使克林霉素磷酸酯与反胶团体系得到分离。过滤、干燥得到成品。萃取收率为94.81％，克林霉素B磷酸酯为0.87％。
比较例1
向克林霉素磷酸酯粗品中按照1:8(m:v)的比例加入乙醇，升温回流溶解并缓慢加水直至获得澄清溶液。然后加入3kg活性炭进行脱色处理30min，脱色液转移至结晶釜中，以自由降温速率降至25℃，保温3h；再降温至0℃，保温2h。离心，用10kg乙醇漂洗后，干燥得到成品。结晶收率为80.30％，克林霉素B磷酸酯为1.27％。
比较例2
向克林霉素磷酸酯粗品中按照1:9(m:v)的比例加入乙醇，升温回流溶解并缓慢加水直至获得澄清溶液。然后加入4.2kg活性炭进行脱色处理40min，脱色液转移至结晶釜中，以自由降温速率降至30℃，保温3h；再降温至3℃，保温3h。离心，用13kg乙醇漂洗后，干燥得到成品。结晶收率为82.14％，克林霉素B磷酸酯为1.15％。

Claims (8)

  1. 一种克林霉素磷酸酯的纯化方法，其特征在于，其包括：
    将表面活性剂三辛基甲基氯化铵溶于有机溶剂乙酸乙酯中制成反胶束萃取系统；
    将表面活性剂正辛基-β-D-吡喃葡萄糖苷和克林霉素磷酸酯粗品溶解在纯化水中作为水相；
    将所述反胶束萃取系统与所述水相混合、萃取，静置分相，得到含有克林霉素磷酸酯的反胶束萃取相，然后加入无机盐使克林霉素磷酸酯从所述反胶束萃取相中结晶析出，分离即可。
  2. 根据权利要求1所述的克林霉素磷酸酯的纯化方法，其特征在于，所述反胶束萃取系统中，所述三辛基甲基氯化铵浓度为10～50mmol/L。
  3. 根据权利要求1所述的克林霉素磷酸酯的纯化方法，其特征在于，所述水相中，所述正辛基-β-D-吡喃葡萄糖苷浓度为1～10mmol/L。
  4. 根据权利要求1所述的克林霉素磷酸酯的纯化方法，其特征在于，所述水相中，所述克林霉素磷酸酯粗品的浓度为50000～120000U/mL。
  5. 根据权利要求1所述的克林霉素磷酸酯的纯化方法，其特征在于，所述反胶束萃取系统与所述水相的混合比例为1:(1～5)，以体积比计。
  6. 根据权利要求1所述的克林霉素磷酸酯的纯化方法，其特征在于，所述萃取温度为20～40℃，萃取时间为10～40min。
  7. 根据权利要求1所述的克林霉素磷酸酯的纯化方法，其特征在于，所述无机盐的加量为所述克林霉素磷酸酯粗品投料量的5质量％～15质量％。
  8. 根据权利要求1或7所述的克林霉素磷酸酯的纯化方法，其特征在于，所述无机盐为NaCl、Na 2HPO 4或NaH 2PO 4。
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