選擇性COX-1抑制劑莫芬唑酸的合成和工藝研究
發(fā)布時(shí)間：2018-10-15 08:30
【摘要】：非甾體類抗炎藥是全球用量最大的一類抗炎、抗風(fēng)濕藥物,其通過抑制環(huán)氧合酶(COXs)的活性以阻斷花生四烯酸(AA)合成前列環(huán)素(PGI1)、前列腺素(PGE1,PGE2)和血栓素A2(TXA2),從而達(dá)到消炎鎮(zhèn)痛效果。早期研究認(rèn)為,COX-2抑制實(shí)現(xiàn)抗炎作用,COX-1抑制則引發(fā)胃腸道副作用。因此,早期主要針對COX-2抑制劑展開了廣泛研究。近年臨床研究證明,一些Coxibs類選擇性COX-2抑制劑,可以增加心臟病和中風(fēng)等心血管疾病的發(fā)病率。近年Wallace等人報(bào)道單獨(dú)的COX-1抑制幾乎不會形成胃粘膜潰瘍;并且有報(bào)道COX-1還參與疼痛、血栓癥、動脈粥樣硬化、內(nèi)皮功能紊亂、高血壓、癌癥等疾病的病理過程。因此,選擇性COX-1抑制劑成為現(xiàn)代研究的熱點(diǎn)。莫芬唑酸是目前唯一用于臨床的高選擇性COX-1抑制劑,主要用于治療手術(shù)、創(chuàng)傷或拔牙后的炎癥或疼痛,以及用于治療頸椎綜合征和肩肱關(guān)節(jié)炎。其合成方法目前僅有兩篇日本專利報(bào)道。兩條專利路線均存在一定的弊端,不利于工業(yè)化生產(chǎn)。本論文基于兩條已有專利路線,展開了專利路線重現(xiàn)、油狀中間體固化改造、合成路線優(yōu)化三方面研究。根據(jù)調(diào)整過的工藝條件,莫芬唑酸的收率顯著提高,總收率達(dá)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%.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：TQ460.6
本文編號：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%.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：TQ460.6
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