CN105803012B - (s)‑2‑[(1‑苄基磺酰基)吡咯烷‑3‑氨基]‑1‑[4‑(2,4,6‑三甲基苄基)哌嗪]乙酮的用途 - Google Patents
(s)‑2‑[(1‑苄基磺酰基)吡咯烷‑3‑氨基]‑1‑[4‑(2,4,6‑三甲基苄基)哌嗪]乙酮的用途 Download PDFInfo
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Abstract
本发明涉及一种异丁酰胺的制备方法,该方法以异丁腈与去离子水为原料,在腈水合酶催化剂的作用下,异丁腈与去离子水发生水合反应生成异丁酰胺,对获得的异丁酰胺水溶液经过简单的处理就可以获得高纯度的异丁酰胺晶体产品。本发明对获得的异丁酰胺水溶液经过简单的处理就可以获得高纯度的异丁酰胺晶体产品,产品的纯度高达99.95%以上,且产品中不含有机溶剂等有害成分,特别适合在医疗领域中应用。该方法的反应条件温和,操作简单,产品的收率高达99%以上,制备过程简单,易于产业化。
Description
技术领域
本发明涉及化工领域,具体的说,本发明涉及一种异丁酰胺的制备方法。
背景技术
异丁酰胺可以选择性诱导人g-珠蛋白基因转录,加之异丁酰胺的无毒性和在血浆中的半衰期较长的特点,使异丁酰胺在治疗b-地中海贫血和镰刀型贫血中有理想的效果。异丁酰胺也是合成治疗艾滋病治疗药物利托那韦的重要中间体。异丁酰胺在医药领域的广泛应用,目前对其制备过程中使用的各种中间体、以及异丁酰胺的研究正成为本领域的热点。
对异丁酰胺的生产制备方法已有一些报道,主要是以异丁酰氯与氨反应的方法为主,有代表性的方法是Janitschke Lothar等人在美国专利US35528814A中提出的异丁酰胺制备方法。这个方法提出了用物质量过量1至3倍的氨与异丁酰氯在甲苯或二甲苯中于-15~30℃的温度下反应,然后通过加热浓缩反应混合物使生成的产品结晶并通过热过滤的方法获得粗制异丁酰胺,再用溶剂多次洗涤获得高纯度的异丁酰胺产品。这种制备异丁酰胺的方法虽然获得的异丁酰胺的产品纯度达到了99.87%,但是这种方法有以下几方面的缺点:第一是由于使用的异丁酰氯极易与水反应,为避免异丁酰氯接触水等物质而发生分解,需要对溶剂和其他原料进行严格的除水处理,并且反应设备需要严格密封,异丁酰氯与氨反应的过程极为剧烈使对反应条件的控制也要求非常严格,这些增加了制备异丁酰胺的难度。第二是这种方法制备过程中使用过量的氨,过量的氨需要回收处理,否则环境污染严重。同时反应过程中产生的氯化氢对设备腐蚀严重,反应过程中需要对氯化 氢进行控制。这些造成三废处理较多,难于满足环保要求,增加了生产的成本。第三是这种方法过程复杂,产品的收率较低,只有88%左右,并且制备过程中使用了苯类有机溶剂,使产品中含有有害物质的几率增高,就是极其微量的有机溶剂在异丁酰胺中的存在,对产品在医疗领域的应用也有极大的不利影响。
中国专利CN102212566A中公开将腈水合酶生产菌株经过发酵来制备腈水合酶催化剂,在制备催化剂的过程中对于菌株的选择处于研究中,并且在制备后期活性菌株反而会影响收率,因此需要在后期杀灭菌株。
发明内容
本发明的目的在于提供一种异丁酰胺的制备方法。
为了实现本发明的目的,本发明提供一种异丁酰胺的制备方法,该方法包括下列步骤:
(1):腈水合酶催化剂的处理:将腈水合酶生产菌株经过发酵获得的发酵液用1.5mm的烧结金属过滤器进行分离后,再用去离子水清洗2次;
(2):异丁腈水合制备异丁酰胺:将经过清洗的腈水合酶催化剂加入到去离子水中,腈水合酶催化剂的加入量与去离子水的加入量的质量比为0.02:1,异丁腈的加入量与去离子水的加入量的质量比为0.5:1;
相应量的异丁腈应采用连续加入的方式,加入量应该逐渐减小,加入的时间应该控制在2小时,反应过程中反应体系的温度控制在20℃,异丁腈加入完毕后,保持继续反应1小时;
(3):反应液中腈水合酶催化剂的失活:向所述步骤(2)中的得到的每1000毫升反应液中加入0.5克的(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮,搅拌半小时;
(4):异丁酰胺水溶液的精制:将所述步骤(3)中的得到的反应液使用截留分子量能力为2000道尔顿的超滤膜分离掉杂质,然后再经过阴离子交换树脂、阳离子交换树脂进一步精制,最后将溶液的pH调节到7.0;
(5):异丁酰胺晶体的制备:将精制后的异丁酰胺水溶液在温度80℃、压力0.08Mpa条件下直接蒸发后干燥,或者将异丁酰胺水溶液的浓度浓缩到90%后进行喷雾干燥或冷冻结晶后再进行真空干燥,这即获得高纯度的异丁酰胺晶体。
优选地,在所述步骤(1)中所述菌株为星状诺卡氏菌ATCC 19247。
本发明还提供(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮在制备杀灭星状诺卡氏菌ATCC 19247的中间体中的用途。
本发明所述的方法以异丁腈与去离子水为原料,在腈水合酶催化剂的作用下,异丁腈与去离子水发生水合反应生成异丁酰胺,对获得的异丁酰胺水溶液经过简单的处理就可以获得高纯度的异丁酰胺晶体产品。本发明对获得的异丁酰胺水溶液经过简单的处理就可以获得高纯度的异丁酰胺晶体产品,产品的纯度高达99.95%以上,且产品中不含有机溶剂等有害成分,特别适合在医疗领域中应用。该方法的反应条件温和,操作简单,产品的收率高达99%以上,制备过程简单,易于产业化。
具体实施方式
以下通过具体实施方式的描述对本发明作进一步说明,但这并非是对本发明的限制,本领域技术人员根据本发明的基本思想,可以做出各种修改或改进,但是只要不脱离本发明的基本思想,均在本发明的范围之内。
实施例1异丁酰胺的制备
(1):腈水合酶催化剂的处理:将腈水合酶生产菌株经过发酵获得的发酵液用1.5mm的烧结金属过滤器进行分离后,再用去离子水清洗2次;
(2):异丁腈水合制备异丁酰胺:将经过清洗的腈水合酶催化剂加入到去离子水中,腈水合酶催化剂的加入量与去离子水的加入量的质量比为0.02:1,异丁腈的加入量与去离子水的加入量的质量比为0.5:1;
相应量的异丁腈应采用连续加入的方式,加入量应该逐渐减小,加入的时间应该控制在2小时,反应过程中反应体系的温度控制在20℃,异丁腈加入完毕后,保持继续反应1小时;
(3):反应液中腈水合酶催化剂的失活:向所述步骤(2)中的得到的每1000毫升反应液中加入0.5克的(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮,搅拌半小时;
(4):异丁酰胺水溶液的精制:将所述步骤(3)中的得到的反应液使用截留分子量能力为2000道尔顿的超滤膜分离掉杂质,然后再经过阴离子交换树脂、阳离子交换树脂进一步精制,最后将溶液的pH调节到7.0;
(5):异丁酰胺晶体的制备:将精制后的异丁酰胺水溶液在温度80℃、压力0.08Mpa条件下直接蒸发后干燥,或者将异丁酰胺水溶液的浓度浓缩到90%后进行喷雾干燥或冷冻结晶后再进行真空干燥,这即获得高纯度的异丁酰胺晶体。
实施例2(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮在制备杀灭星状诺卡氏菌ATCC 19247的中间体中的用途
抑菌试验
采用本领域中经典的滤纸片法来进行抑菌试验,其中星状诺卡氏菌ATCC 19247购自上海笃玛生物科技有限公司。
培养液
营养琼脂和营养肉汤,购自北京中科晨宇实验设备有限公司。
试验方法
将星状诺卡氏菌ATCC 19247接种于琼脂平板营养液平面上,接种时均匀密布。
称取0.02克的(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮,加入9000毫升无菌水,超声30分钟,然后0.22μm的微孔滤膜过滤,得到溶液。镊取无菌圆形滤纸片,喷洒上述溶液至完全润湿,贴在已接种细菌的琼脂平板营养液平面上。将琼脂平板置于37℃的培养箱内,温育18小时。测量抑菌环的直径。测定3次取平均值。
结果
星状诺卡氏菌ATCC 19247的抑菌环的平均直径为13.68mm,这表明(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮具有极强杀灭星状诺卡氏菌ATCC 19247的效果。
Claims (1)
1.(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮在制备杀灭星状诺卡氏菌ATCC 19247的药物中的用途,所述药物通过下列方法制得:称取0.02克的(S)-2-[(1-苄基磺酰基)吡咯烷-3-氨基]-1-[4-(2,4,6-三甲基苄基)哌嗪]乙酮,加入9000毫升无菌水,超声30分钟,然后0.22μm的微孔滤膜过滤。
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