CN103665068B - 一种1-N-乙基庆大霉素C1a的制备方法 - Google Patents
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Abstract
本发明涉及一种1-N-乙基庆大霉素C1a的制备方法，该方法包括以下步骤：在温度18-20℃的情况下，将硼氢化钠缓慢加入装有三氯甲烷及冰醋酸的三口烧瓶中，将3,2’,6’-三-N-乙酰基庆大霉素C1a溶解于三氯甲烷中，通过恒压滴液漏斗缓慢加入上述三口烧瓶中，保持温度为40-50℃，剧烈搅拌反应20小时，降温并加入饱和氢氧化钠水溶液中和该体系，乙醇稀释，用三氯甲烷萃取，真空浓缩，所得油状物，加入1N氢氧化钠水溶液回流24小时。无盐水稀释，进行柱层析分离，收集有效成分，浓缩，冻干得产品1-N-乙基庆大霉素C1a。
Description
技术领域
本发明涉及药物化学领域，具体涉及一种氨基糖苷类抗生素药物庆大霉素C1a的衍生物（1-N-乙基庆大霉素C1a）的制备方法。
背景技术
硫酸依替米星(Etimicinsulfate)是我国科研人员自行研制的，拥有自主知识产权的高效、低毒、抗耐药菌的新一代半制备氨基糖苷类抗生素，是唯一获得国家一类新药证书的抗感染药物。其作用机制是抵制敏感菌的正常蛋白制备，对大肠埃希杆菌、克雷伯氏肺炎杆菌、肠杆菌属、沙雷菌属、奇异变形杆菌、沙门菌属、流感嗜血杆菌及葡萄菌属等有较高的抗菌活性，对部分假单胞杆菌、不动杆菌属等具有一定抗菌活性，对部分庆大霉素、小诺霉素和头孢唑啉耐药的金黄色葡萄球菌、大肠埃希杆菌和克雷伯氏肺炎杆菌，其MIC值仍在该产品治疗剂量的血药浓度范围内。对产生青霉素酶的部分葡萄球菌和部分低水平甲氧西林耐药的葡萄球(MRSA)亦有一定的抗菌活性。
依替米星制备过程中需要用到中间体1-N-乙基庆大霉素C1a，现有技术公开了三种制备方法。
中国专利93112412.3描述了以下方法：
将3，2’，6’-三-N-乙酰基庆大霉素C1a用乙醛进行N-乙基化，在用硼氢化钠还原得到3，2’，6’-三-N-乙酰基-1-N-乙基庆大霉素C1a，再用氢氧化钠于100℃回流水解48小时得到1-N-乙基庆大霉素C1a水解溶液，经过分别732强酸性阳离子树脂柱和YPR-Ⅱ大孔树脂柱纯化，得到1-N-乙基庆大霉素C1a。将解析液减压浓缩后加入硫酸，再于60℃用活性炭脱色，最后冻干得到1-N-乙基庆大霉素C1a硫酸盐，重量收率为30%左右。
中国专利201010132962.4,和中国专利201010132963.9对1-N-乙基庆大霉素C1a的制备进行了改进：先用3，2’，6’-三-N-乙酰基庆大霉素C1a与六甲基二硅胺烷在三氯甲烷溶剂中，在浓硫酸的催化作用下加热至回流而发生生成3，2’，6’-三-N-乙酰基-5，2’’，4’’-三（三甲基硅基）庆大霉素C1a的硅烷化反应，直至反应完全。之后再用乙醛进行乙基化。最后重量收率为45%左右。
现行工艺的弊端在于乙醛的氨化还原反应条件对于pH比较敏感，亚胺的中间体不稳定并且整个反应的副反应较多。因此存在收率较低、后期不易分离纯化，工艺过程繁琐的问题。
本发明的优势在于：避开了使用有毒试剂乙醛来进行乙基化的工艺，并且大幅度的提高了反应的收率。
发明内容
本发明之目的是在现有的基础上，提供了一种操作简便，节能环保并能以较高的收率制备依替米星（1-N-乙基庆大霉素C1a）的方法。
实现本发明的技术方案如下：一种1-N-乙基庆大霉素C1a的制备方法，具有以下步骤：
a、在温度18-20℃的条件下，将硼氢化钠缓慢加入装有三氯甲烷及冰醋酸的三口烧瓶中；
b、将3,2’,6’-三-N-乙酰基庆大霉素C1a溶解于三氯甲烷中，通过恒压滴液漏斗缓慢加入上述三口烧瓶中，控制温度，剧烈搅拌至反应完成；
c、降温至室温，加入饱和氢氧化钠水溶液中和该体系。乙醇稀释，三氯甲烷萃取，真空浓缩。所得油状物加入1N氢氧化钠水溶液回流24小时。用无盐水稀释，通入层析分离柱中上样，收集有效成分，浓缩，冻干得目标化合物1-N-乙基庆大霉素C1a。
本发明的有益处在于：避开了使用乙醛乙基化的工艺，并且大幅度的提高了反应的收率。
以下通过比较实验数据进一步说明本发明的有益效果。
具体实施方式
实施例1
在温度18-20℃的情况下，将288g硼氢化钠缓慢加入装有4L三氯甲烷及2L冰醋酸的三口烧瓶中。将575g的3,2’,6’-三-N-乙酰基庆大霉素C1a溶解于6L三氯甲烷中，通过恒压滴液漏斗缓慢加入上述三口烧瓶中，保持温度为40℃，剧烈搅拌反应20小时。降温至25℃，加入饱和氢氧化钠水溶液中和该体系。再加入5L乙醇稀释，用3L三氯甲烷萃取三遍，真空浓缩。所得油状物加入1N氢氧化钠水溶液4L回流24小时。用6L无盐水稀释，通入层析分离柱中上样，无盐水冲洗，乙醇水溶液解析，收集有效成分。浓缩，冻干得产品396g。收率为83%，纯度为94%。
实施例2
在温度18-20℃的情况下，将330g硼氢化钠缓慢加入装有4L三氯甲烷及2L冰醋酸的三口烧瓶中。将575g的3,2’,6’-三-N-乙酰基庆大霉素C1a溶解于6L三氯甲烷中，通过恒压滴液漏斗缓慢加入上述三口烧瓶中，保持温度为50℃，剧烈搅拌反应20小时。降温至25℃，加入饱和氢氧化钠水溶液中和该体系。再加入5L乙醇稀释，用3L三氯甲烷萃取三遍，真空浓缩。所得油状物加入1N氢氧化钠水溶液4L回流24小时。用6L无盐水稀释，通入层析分离柱中上样，无盐水冲洗，乙醇水溶液解析，收集有效成分。浓缩，冻干得产品405g。收率为85%，纯度为95%。
实施例3
在温度18-20℃的情况下，将300g硼氢化钠缓慢加入装有4L三氯甲烷及2L冰醋酸的三口烧瓶中。将575g的3,2’,6’-三-N-乙酰基庆大霉素C1a溶解于6L三氯甲烷中，通过恒压滴液漏斗缓慢加入上述三口烧瓶中，保持温度为45℃，剧烈搅拌反应20小时。降温至25℃，加入饱和氢氧化钠水溶液中和该体系。再加入5L乙醇稀释，用3L三氯甲烷萃取三遍，真空浓缩。所得油状物加入1N氢氧化钠水溶液4L回流24小时。用6L无盐水稀释，通入层析分离柱中上样，无盐水冲洗，乙醇水溶液解析，收集有效成分。浓缩，冻干得产品419g。收率为88%，纯度为96%。
Claims (4)
1.一种1-N-乙基庆大霉素C1a的制备方法，包括以下步骤：
a、在温度18-20℃的条件下，将硼氢化钠缓慢加入装有三氯甲烷及冰醋酸的三口烧瓶中；
b、将3,2’,6’-三-N-乙酰基庆大霉素C1a溶解于三氯甲烷中，通过恒压滴液漏斗缓慢加入上述三口烧瓶中，控制温度，剧烈搅拌至反应完成；
c、降温至室温，加入饱和氢氧化钠水溶液中和该体系，乙醇稀释，三氯甲烷萃取，真空浓缩，所得油状物加入1N氢氧化钠水溶液回流24小时，用无盐水稀释，通入层析分离柱中上样，收集有效成分，浓缩，冻干得目标化合物1-N-乙基庆大霉素C1a。
2.根据权利要求1所述的1-N-乙基庆大霉素C1a的制备方法，其特征是，以3,2’,6’-三-N-乙酰基庆大霉素C1a的量计，硼氢化钠的用量为6-9mol/mol，冰醋酸的用量为25-35mol/mol。
3.根据权利要求1或2所述的1-N-乙基庆大霉素C1a的制备方法，其特征是,滴加3,2’,6’-三-N-乙酰基庆大霉素C1a完毕之后，反应温度控制为0-50℃，反应时间为3-20小时。
4.根据权利要求3所述的1-N-乙基庆大霉素C1a的制备方法，其特征是，反应温度为35-45℃。
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| CN101928312A (zh) * | 2010-03-26 | 2010-12-29 | 常州方圆制药有限公司 | 1-N-乙基庆大霉素C1a硫酸盐的制备方法 |
| CN101928311A (zh) * | 2010-03-26 | 2010-12-29 | 常州方圆制药有限公司 | 1-N-乙基庆大霉素C1a的制备方法 |
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