三百八十二章 酰氯路线(1 / 1)

前面都很顺利,到了最后关头却以失败而告终,这种感觉有如足球场上,一路带球带到对方球门,抬脚猛射,却被守门员扑住一般,那种失望,无以言表。

没有控制这杂质的方法,再不死心也得放弃。课题组讨论之下,决定主攻以三碘异酞酰氯为出发原料,经乙酰氧基乙酰氯对苯环上的氨基进行进攻,这样的话,就从源头上解决了氯乙酰化杂质,工艺上与质量研究上都不需考虑它,至少这一只拦路虎是不存在的。

以DMAC为溶剂,在低温条件下让三碘异酞酰氯与乙酰氧基乙酰氯反应。第一步反应很顺利,转化率接近理论水平,只少量的杂质,可中间体怎么从偶极非质子溶剂DMAC中拿出来呢?拿常见的与酰氯不发生反应的有机溶剂一种一种地尝试下去吧,经过讨论,课题组列出了乙酸乙酯,甲苯,苯,氯仿等多种溶剂进行析料试验,结果显示氯仿析料能得到颗粒状结晶,并且容易过滤,收率也最高,乙酸乙酯不析料,甲苯与苯析出的产物又细又粘,很难过滤。

中间体得到了,下一步的反应是在三乙胺的催化下与氨基甘油在DMAC溶剂中低温反应,反应与第一步一样十分顺利,可反应结束后的析料却没这么简单了,同样的四种溶剂完全全溶。

料液析不出来,得不到想要的中间体,怎么办呢?扩大溶剂范围再选再试。二氯甲烷,甲基叔丁基醚,异丙醚,正已烷,环已烷等等一种一种的试过去,几乎同一种结果,或是全溶,或是只析出一团粘乎乎的杂质,根本无法过滤。

既然无法过滤,干脆就直接往下醇解,不结晶了。百般无奈的条件下,王近之与李均森想出了这么个笨办法,……l加甲醇回流醇解。回流几小时后,发现有固体物料慢慢地析了出来,极可能是碘佛醇水解物,液体越来越稠,即将下班了,王近之吩咐先停止反应,过滤出部分固体送检。

赵定岳很配合,连夜按排杨靓青给课题组分析。第二天早上刚上班,王近之李均森宋俊文等三人就集中在分析室。

“不会是某人看中我们部门的小杨,集体替他过来提亲了吧。”赵定岳边打趣边打开电脑,屏幕显示碘佛醇水解物液相纯度百分之九十九点二,基本上没什么后峰。

奇怪了,色泽呈灰色的,色谱纯度有这么高?三人感到有些不可思议,管它呢,放大实验做一批,往下做到碘佛醇再说。

烷基化反应原来就很顺利,所以,条件也没什么变更就往下进行下去了,反应液显示的结果与之前的相同,虽然色泽较深,可经过阴树脂处理后,得到接近无色的料液,再经过一系列的后处理,统于得到了碘佛醇粗品,经过乙醇重结晶,液相检测结果,除了因热敏性差而引起的杂质B偏高外,其它指标都达标。

虽然小试不合格,可上一轮的中试已证实,杂质B在中试时是不会明显升高的,希望的曙光又一次出现在眼前。

“还是保守些,把除了液相之外的其它指标全部按药典标准检测后再决定是否中试吧?”吴总召集的讨论会上,王近之与李均森建议道。太多的参数没有优化,急忙投入中试说不定会出现什么新的问题。

“我们可以等,市场不会等我们,大不了收率低一些,也得先试出几十千克产品,给客户以希望,中试与优化同步进行,试成功后再进一步优化工艺。”吴总以不容致异的口气下了结论。

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