CN101550152B - 一种头孢克洛化合物及其制法 - Google Patents
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Abstract
本发明涉及一种头孢克洛化合物及其制法，该方法是将现有技术制备的头孢克洛粗品，经过以下步骤制备得到相对纯的头孢克洛化合物：向头孢克洛粗品中加入碱性溶液，调节pH值至8-10，充分反应至澄清，得头孢克洛盐溶液，然后经大孔吸附树脂吸附，吸附完全后，用洗脱剂洗脱头孢克洛盐，收集洗脱液，加活性炭吸附，过滤，滤液加入酸性溶液，调节pH值至3-4，析出结晶，过滤，洗涤，干燥，得头孢克洛晶体。
Description
技术领域
本发明涉及一种头孢克洛化合物的精制方法，属于医药技术领域。
背景技术
头孢克洛，其化学名称为：(6R，7R)-7-[(R)-2-氨基-2-苯乙酰氨基]-3-氯-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-甲酸一水合物，分子式为：C15H14ClN3O4S·H2O，分子量：385.83，结构式为：
为半合成第二代β-内酰胺类抗生素，对于革兰氏阳性菌有较强的抗菌活性，对产青霉素酶金黄色葡萄球菌、A组溶血性链球菌、草绿色链球菌和表皮葡萄球菌的活性与头孢羟氨苄相同，对不产酶金黄色葡萄球菌和肺炎球菌的抗菌作用较头孢羟氨苄强2～4倍。对革兰阴性杆菌包括对大肠埃希菌和肺炎克雷伯菌等的活性较头孢氨苄强，与头孢羟氨苄相仿，对奇异变形杆菌、沙门菌属和志贺菌属的活性较头孢羟氨苄强。临床上主要用于由敏感菌所致呼吸系统、泌尿系统、耳鼻喉科及皮肤、软组织感染等。
在美国专利US3925372中公开介绍了头孢克洛的制备方法，将7-ACCA经N，O-双-三甲硅基乙酰胺保护，与苯甘氨酸甲基钠盐和氯甲酸甲酯形成的混酐反应制得。J.Med.Chem.，18：403，1975.中头孢克洛的合成，使用7-ACCA的对硝基苄基酯为起始原料，最后需要通过头孢克洛酯的水解得到头孢克洛产品，总收率约50％。在美国专利US5608055中公开了头孢克洛的合成工艺，采用7-ACCA为原料，经过酰化缩合、水解得到头孢克洛的盐酸盐水溶液，在此溶液中加入DMF制得头孢克洛DMF复合物，头孢克洛DMF复合物经转化得到头孢克洛原料药。上述专利合成的头孢克洛通常含有高于头孢克洛重量0.5％的苯甘氨酸，和高于头孢克洛重量0.3％的7-ACCA，获得的头孢克洛纯度较差，杂质较多，采用普通的介质吸附的方法，例如活性炭吸附法，并不能从根本上除去上述杂质，而且还会吸附头孢克洛原料。
发明内容
本发明的目的在于克服现有技术存在的缺点，提供一种头孢克洛化合物的精制纯化方法，从根本上大大提高了头孢克洛的纯度，保证了制剂的质量。
本发明提供的头孢克洛化合物的精制方法，该方法是将现有技术制备的头孢克洛粗品，经过以下步骤制备得到相对纯的头孢克洛化合物：向头孢克洛粗品中加入碱性溶液，调节pH值至8-10，充分反应至澄清，得头孢克洛盐溶液，然后经大孔吸附树脂吸附，吸附完全后，用洗脱剂洗脱头孢克洛盐，收集洗脱液，加活性炭吸附，过滤，滤液加入酸性溶液，调节pH值至3-4，析出结晶，过滤，洗涤，干燥，得头孢克洛晶体。
上述所述的精制方法，碱性溶液为能和酸发生反应的有机碱、固体碱式盐或无机碱的水溶液，可以为氨水、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、乙酸钠、乙酸钾、乙基己酸钠、三乙胺、二异丙基乙基胺、三丁胺、三乙醇胺、二甲基苄基胺。
上述所述的精制方法，大孔吸附树脂为聚苯乙烯吸附树脂及其衍生树脂，优选为Hz816吸附树脂或AmberliteXAD-4吸附树脂。
上述所述的精制方法，洗脱剂为低碳有机溶剂-水混合液，选自甲醇-水混合液、乙腈-水混合液、丙酮-水混合液、乙醇-水混合液或异丙醇-水混合液，优选为体积比为1∶1的异丙醇-水混合液。
上述所述的精制方法，酸性溶液为能和碱发生反应的有机酸或无机酸的水溶液，选自盐酸、磷酸、硝酸、硫酸、柠檬酸、甲酸、乙酸溶液。
上述所述的精制方法，析出结晶过滤后用乙醇洗涤，40-50℃减压干燥。
本发明提供的头孢克洛化合物的精制方法，解决了目前技术合成的头孢克洛纯度低、杂质高的缺点，提高了临床制剂的质量，保障了用药的安全性；该方法工艺简单，操作方便，成本低，适合于规模化生产。
具体实施方式
以下通过具体实施方式进一步解释或说明本发明内容，但实施例不应被理解为对本发明保护范围的限制。
实施例1
向头孢克洛粗品100g中加入1mol/L的氢氧化钠溶液，调节pH值至9.1，充分反应至澄清，得头孢克洛钠盐溶液，然后经Hz816吸附树脂吸附，吸附完全后，用体积比为1∶1的异丙醇-水混合液洗脱头孢克洛钠盐，收集洗脱液，加入4g活性炭室温吸附30分钟，过滤脱碳，滤液加入1mol/L盐酸溶液，调节pH值至3.2，析出结晶，过滤，用乙醇洗涤，50℃减压干燥，得头孢克洛晶体94.2g，收率94.2％，HPLC检测纯度为99.8％。
实施例2
向头孢克洛粗品100g中加入2mol/L的氢氧化钾溶液，调节pH值至8.7，充分反应至澄清，得头孢克洛钾盐溶液，然后经AmberliteXAD-4吸附树脂吸附，吸附完全后，用体积比为1∶1的甲醇-水混合液洗脱头孢克洛钾盐，收集洗脱液，加入6g活性炭室温吸附20分钟，过滤脱碳，滤液加入2mol/L甲酸溶液，调节pH值至3.8，析出结晶，过滤，用乙醇洗涤，40℃减压干燥，得头孢克洛晶体92.5g，收率92.5％，HPLC检测纯度为99.9％。
实施例3
向头孢克洛粗品100g中加入5mol/L的乙酸钠溶液，调节pH值至8.8，充分反应至澄清，得头孢克洛钠盐溶液，然后经AmberliteXAD-4吸附树脂吸附，吸附完全后，用体积比为1∶1的乙腈-水混合液洗脱头孢克洛钠盐，收集洗脱液，加入10g活性炭室温吸附30分钟，过滤脱碳，滤液加入2mol/L硫酸溶液，调节pH值至3.5，析出结晶，过滤，用乙醇洗涤，45℃减压干燥，得头孢克洛晶体93.0g，收率93.0％，HPLC检测纯度为99.7％。
实施例4
向头孢克洛粗品100g中加入10％的碳酸氢钾溶液，调节pH值至8.6，充分反应至澄清，得头孢克洛钾盐溶液，然后经Hz816吸附树脂吸附，吸附完全后，用体积比为1∶1的丙酮-水混合液洗脱头孢克洛钾盐，收集洗脱液，加入5g活性炭室温吸附20分钟，过滤脱碳，滤液加入8mol/L乙酸溶液，调节pH值至3.6，析出结晶，过滤，用乙醇洗涤，47℃减压干燥，得头孢克洛晶体91.9g，收率91.9％，HPLC检测纯度为99.8％。
Claims (5)
1.一种式(I)所示结构的头孢克洛化合物的制法，
其特征在于包括如下步骤：向头孢克洛粗品中加入碱性溶液，调节pH值至8-10，充分反应至澄清，得头孢克洛盐溶液，然后经大孔吸附树脂吸附，吸附完全后，用洗脱剂洗脱头孢克洛盐，收集洗脱液，加活性炭吸附，过滤，滤液加入酸性溶液，调节pH值至3-4，析出结晶，过滤，洗涤，干燥，得头孢克洛晶体；其中所述碱性溶液为氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、乙酸钠、或乙酸钾溶液；其中所述酸性溶液选自盐酸、硫酸、甲酸、或乙酸溶液。
2.如权利要求1所述的头孢克洛化合物的制法，其特征在于大孔吸附树脂为Hz816吸附树脂或AmberliteXAD-4吸附树脂。
3.如权利要求1所述的头孢克洛化合物的制法，其特征在于洗脱剂为低碳有机溶剂-水混合液，并选自甲醇-水混合液、乙腈-水混合液、丙酮-水混合液、乙醇-水混合液或异丙醇-水混合液。
4.如权利要求3所述的头孢克洛化合物的制法，其特征在于洗脱剂为体积比为1∶1的异丙醇-水混合液。
5.如权利要求1所述的头孢克洛化合物的制法，其特征在于析出结晶过滤后用乙醇洗涤，40-50℃减压干燥。
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| CN111057072A (zh) * | 2019-12-16 | 2020-04-24 | 广州维奥康药业科技有限公司 | 一种头孢克洛杂质去除方法 |
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| US5693790A (en) * | 1991-11-11 | 1997-12-02 | Biochimica Opos Spa | Crystalline form of a cephalosporin antibiotic |
| CN101314605A (zh) * | 2008-06-12 | 2008-12-03 | 华东理工大学 | 从头孢克洛萘酚复合物中提纯头孢克洛的方法 |
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| US5693790A (en) * | 1991-11-11 | 1997-12-02 | Biochimica Opos Spa | Crystalline form of a cephalosporin antibiotic |
| CN101314605A (zh) * | 2008-06-12 | 2008-12-03 | 华东理工大学 | 从头孢克洛萘酚复合物中提纯头孢克洛的方法 |
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