选择性COX-1抑制剂莫芬唑酸的合成和工艺研究
发布时间：2018-10-15 08:30
【摘要】：非甾体类抗炎药是全球用量最大的一类抗炎、抗风湿药物,其通过抑制环氧合酶(COXs)的活性以阻断花生四烯酸(AA)合成前列环素(PGI1)、前列腺素(PGE1,PGE2)和血栓素A2(TXA2),从而达到消炎镇痛效果。早期研究认为,COX-2抑制实现抗炎作用,COX-1抑制则引发胃肠道副作用。因此,早期主要针对COX-2抑制剂展开了广泛研究。近年临床研究证明,一些Coxibs类选择性COX-2抑制剂,可以增加心脏病和中风等心血管疾病的发病率。近年Wallace等人报道单独的COX-1抑制几乎不会形成胃粘膜溃疡;并且有报道COX-1还参与疼痛、血栓症、动脉粥样硬化、内皮功能紊乱、高血压、癌症等疾病的病理过程。因此,选择性COX-1抑制剂成为现代研究的热点。莫芬唑酸是目前唯一用于临床的高选择性COX-1抑制剂,主要用于治疗手术、创伤或拔牙后的炎症或疼痛,以及用于治疗颈椎综合征和肩肱关节炎。其合成方法目前仅有两篇日本专利报道。两条专利路线均存在一定的弊端,不利于工业化生产。本论文基于两条已有专利路线,展开了专利路线重现、油状中间体固化改造、合成路线优化三方面研究。根据调整过的工艺条件,莫芬唑酸的收率显著提高,总收率达到18%以上。
[Abstract]:Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used anti-inflammatory and anti-rheumatic drugs in the world. They block the synthesis of prostacyclin (PGI1), prostaglandin (PGE1,PGE2) and thromboxane A2 (TXA2) by inhibiting the activity of cyclooxygenase (COXs). Early studies suggested that inhibition of COX-2 could achieve anti-inflammatory effect, while inhibition of COX-1 could induce gastrointestinal side effects. Therefore, early studies focused on COX-2 inhibitors. Recent clinical studies have shown that some Coxibs selective COX-2 inhibitors can increase the incidence of cardiovascular diseases such as heart disease and stroke. In recent years, Wallace et al reported that the inhibition of COX-1 alone can hardly form gastric mucosal ulcer, and that COX-1 is also involved in the pathological process of pain, thrombus, atherosclerosis, endothelial dysfunction, hypertension, cancer and other diseases. Therefore, selective COX-1 inhibitors have become the focus of modern research. Mofezolic acid is the only highly selective COX-1 inhibitor currently used in the treatment of surgical, traumatic or post-extraction inflammation or pain, as well as in the treatment of cervical syndromes and acromiohumeral arthritis. There are only two Japanese patent reports on the synthetic method. Both patent routes have some drawbacks, which are not conducive to industrial production. In this paper, based on two existing patent routes, three aspects of patent route reappearance, oil-like intermediate solidification and synthesis route optimization are carried out. According to the adjusted technological conditions, the yield of mofezolic acid was improved significantly, and the total yield was over 18%.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.6
本文编号：2271959
[Abstract]:Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used anti-inflammatory and anti-rheumatic drugs in the world. They block the synthesis of prostacyclin (PGI1), prostaglandin (PGE1,PGE2) and thromboxane A2 (TXA2) by inhibiting the activity of cyclooxygenase (COXs). Early studies suggested that inhibition of COX-2 could achieve anti-inflammatory effect, while inhibition of COX-1 could induce gastrointestinal side effects. Therefore, early studies focused on COX-2 inhibitors. Recent clinical studies have shown that some Coxibs selective COX-2 inhibitors can increase the incidence of cardiovascular diseases such as heart disease and stroke. In recent years, Wallace et al reported that the inhibition of COX-1 alone can hardly form gastric mucosal ulcer, and that COX-1 is also involved in the pathological process of pain, thrombus, atherosclerosis, endothelial dysfunction, hypertension, cancer and other diseases. Therefore, selective COX-1 inhibitors have become the focus of modern research. Mofezolic acid is the only highly selective COX-1 inhibitor currently used in the treatment of surgical, traumatic or post-extraction inflammation or pain, as well as in the treatment of cervical syndromes and acromiohumeral arthritis. There are only two Japanese patent reports on the synthetic method. Both patent routes have some drawbacks, which are not conducive to industrial production. In this paper, based on two existing patent routes, three aspects of patent route reappearance, oil-like intermediate solidification and synthesis route optimization are carried out. According to the adjusted technological conditions, the yield of mofezolic acid was improved significantly, and the total yield was over 18%.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.6
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