第八章-甾体激素生产工艺

第八章甾体激素生产工艺•第一节概述•第二节氢化可的松生产工艺•第三节生产工艺原理及其过程•第四节原辅材料的制备、综合利用与三废治理1第一节概述一、甾体类药物的结构与临床应用•甾体化合物又称类固醇，是一类含有环戊烷多氢菲核的化合物。2•由于甾体母核上取代基、双键位置或立体构型等的不同，形成了一系列具有独特生理功能的化合物。•甾体化合物广泛存在于动物、植物组织或某些微生物的细胞中，比较常见的甾体化合物有动物组织中的胆固醇、胆酸、脱氧胆酸、皮质醇和皮质酮等肾上腺皮质激素，睾丸酮、雄酮、孕酮和雌二醇等性激素，植物中的薯芋皂素、豆葫醇等；酵母细胞中的麦角固醇等。3甾体激素性激素肾上腺皮质激素雌性激素雄性激素孕激素蛋白同化激素糖代谢皮质激素盐代谢皮质激素雌甾烷甾体激素分类雄甾烷孕甾烷孕甾烷雄甾烷二、甾体化合物的生产工艺路线研究•从自然界获取的天然结构的化合物活性极低，必须对其进行结构改造，以增强其治疗活性，并克服不良反应。•常用的方法主要是利用化学合成和微生物转化相结合的工艺路线。56第二节氢化可的松的生产工艺一、氢化可的松（Hydrocortisone)的结构化学名：11,17,21-三羟基孕甾-4-烯-3,20二酮HOCOCH2OHHOHHO8-17氢化可的松又称皮质醇。主要药理作用：能影响糖代谢，并具有抗炎、抗病毒、抗休克及抗过敏作用，临床用途广泛，主要用于肾上腺皮质功能不足，自身免疫性疾病（如肾病性慢性肾炎、系统性红斑狼疮、类风湿性关节炎），变态反应性疾病（如支气管哮喘、药物性皮炎），以及急性白血病、眼炎及何杰金氏病，也用于某些严重感染所致的高热综合治疗。8副作用：对充血性心力衰竭、糖尿病等患者慎用；对重症高血压、精神病、消化道溃疡、骨质疏松症忌用。氢化可的松作为天然皮质激素，疗效确切，在临床上一直不减其重要作用。二、原料的选择•甾体药物半合成法的起始原料都是甾醇的衍生物。•如从薯芋科植物得到薯芋皂素，从剑麻中得到剑麻皂素，从龙舌竺中得到番麻皂素，从油脂废气物中获得豆甾醇和β-谷甾醇，从羊毛脂中得到胆甾醇。这些都可以作为合成甾体药物半合成原料。910OOOHOOOHHHOOOHHOOHOHOH8-28-38-48-58-68-7薯芋皂素剑麻皂素番麻皂素豆甾醇β－谷甾醇胆甾醇1160%的甾体药物的生产原料是薯芋皂素，近年来，由于薯芋皂素资源迅速减少，以及C-17边链微生物氧化降解成功，国外以豆甾醇、β-谷甾醇作原料的比例已上升。12全合成需要30多步化学反应，工艺工程复杂，总收率太低，无工业化生产价值。目前国内外制备氢化可的松都采用半合成方法。三、半合成路线研究13薯芋皂素立体构型与氢化可的松的一致，A环带有羟基，B环带有双键，易于转化为Δ4-3-酮的活性结构，合成工艺相当成熟。我国主要以薯芋皂素为半合成原料。剑麻皂素和番麻皂素的资源在我国也很丰富，但尚未得到充分利用。比较薯芋皂素与氢化可的松的化学结构，可知必须去掉薯芋皂素中的E、F环，而薯芋皂素经开环裂解去掉E、F环后，可得到关键中间体－双烯醇酮醋酸酯（8-8）。从8-8到氢化可的松，除将C－3羟基转化为酮基，C－5,6双键移到C－4,5位，还需引入三个特定的羟基。1415这些基团的转化和引入，有的较易进行。如C-3位的羟基经直接氧化可直接得到酮基，同时还伴有Δ5双键的转位。C-21上有活泼氢，可通过卤代之后再转化为羟基；利用Δ16双键存在，开经过环氧化反应转为C-17位羟基，并且由于甾环的立体效应使得C-17位羟基刚好为α－构型。最关键一步是C-11β-羟基的引入。由于C-11位周围没有活性功能基团的影响，采用化学法很困难。应用微生物氧化法完美地解决了这一难题。黑根霉菌和犁头霉菌：前者专一性的在C-11位引入α羟基，而后者引入β羟基。16OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO犁头霉菌黑根霉菌工艺路线17OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO黑根霉菌氧化溴代脱溴碘化置换梨头霉菌氧化醋酸化合物S18（一）经醋酸可的松的合成路线OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO19OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO20OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO21（二）经化合物S的合成路线OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO22OOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOOOOOHCOCH2OHOHOHOCOAcOCH3COOHCH3OCOOCH3OCOOCH3OHBrCOOCH3OHCOOCH2IOHCOOCH2OAcOHCOOCH3OOHCOOCH3OOCOOCH3OBrOHCOOCH3OOHCOOCH2IOOHCOOCH2OAcOOHH2NCNHNCH2OAcOOHNNHCNH2OOH2NCNHNCH2OAcOHNNHCNH2OHOO23第三节生产工艺原理及其过程以犁头霉菌氧化工艺路线研究生产工艺。一、Δ5,16-孕甾二烯-3β-醇-20-酮-3-醋酸酯的制备1.工艺原理氧化开环，水解，消除等过程（1）加压消除开环在薯芋皂素结构中，边链是一个特殊的螺环系统，其中E、F两环相连，且以螺环缩酮的形式相连，当缩酮的α位含有活泼氢时，能在酸碱的协同催化下发生消除而形成双键，其过程如下：24OOHOHOOHOOHOAcOOAcA+B-25（2）铬酐氧化氧化开环指Δ20双键被氧化断链打开E环，氧化剂是铬酸。OAcOOAcOCOOAcO26OAcOOCROOHAcOOCROOAcOH2O,HOAcAcO-（3）水解－1,4-消除在酸性质子的作用下，C－20酮发生烯醇化，当其回复为酮时，则发生消除。2.工艺过程将薯芋皂素、醋酐、冰醋酸投入反应罐中，然