【作者】 王瑞廷；

【导师】 张嫡群；

【作者基本信息】 河北医科大学 ， 药物化学， 2003， 硕士

【摘要】 非甾体抗炎药(NSAIDs)是一类目前临床广泛应用的解热、镇痛、抗炎药。其作用机制主要是通过抑制环氧化酶(COX),从而阻断花生四烯酸合成前列腺素(PG)。而PG在体内又具有广泛的生理功能。对神经系统可导致炎症与疼痛，对心血管系统可扩张肾血管，增加肾血流，尿及钠排出增加，对消化系统可抑制胃酸分泌，保护胃粘膜作用。因此，常用的NSAIDs在发挥治疗作用的同时也会引起胃肠道的刺激，从而致消化性溃疡以及产生肾毒性。90年代后国外学者发现COX存在两种形式，即COX-1 和COX-2。COX-1存在于大多数人体组织中(尤其是胃、肾和血小板), 通过合成生理需要的PG来调节细胞正常生理活性，如抑制胃酸分泌、保护胃粘膜，维持肾血流通畅及调节血小板聚集；而COX-2的特点为存在于炎症组织，参与炎症反应，催化合成致炎的PG，从而导致组织炎症和损伤。因此，最理想的NSAIDs应该具有选择性抑制COX-2，目前大多数临床常用的NSAIDs对COX-1和COX-2的抑制作用选择性差，因此在发挥治疗作用的同时常致胃肠道不良反应的出现。为了克服目前常用NSAIDs的不足，国内外相继研究开发了具有选择性抑制COX-2的药物。 在目前研究的选择性COX-2抑制剂中，戊地昔布<WP=4>(Valdecoxib, Bextra，SC-65872)，化学名：4-(5-甲基-3-苯基-异噁唑基)苯磺酰胺, 属于第二代COX-2抑制剂，由美国Pharmacia公司研制开发，于2002年4月首次在美国上市，适应症为缓解骨关节炎(OA)和成人类风湿性关节炎(RA)的体征和症状。治疗原发性痛经。戊地昔布用于治疗与口腔外科有关的疼痛时较第一代COX-2抑制剂罗非昔布(Rofecoxib , Vioxx),塞来昔布(Celecoxib,Celebrex)更有效。有203例病人参与的研究结果显示，与服用罗非昔布50mg相比，服用戊地昔布40mg止痛起效明显较快，疼痛缓解显著改善，疼痛程度较轻。此外，与罗非昔布组相比，戊地昔布组需要解救药物或治疗无效的病人较少。戊地昔布能强效选择性抑制重组人COX-2异构体，而对重组人COX-1的抑制作用较弱，其IC50(COX-1)/ IC50(COX-2)的比值为28000, Celecoxib和Rofecoxib的IC50(COX-1)/ IC50(COX-2)比值分别为375和800。帕瑞昔布(Parecoxib)，化学名：N-[4-(5-甲基-3-苯基异噁唑-4-)苯磺酰基]丙酸胺钠盐。它是戊地昔布的酰胺化前体药物，而且是一种注射剂，静注后在体内可迅速完全的转化为戊地昔布。因此特别适用于那些不宜口服给药的患者。此外，帕瑞昔布还可以代替吗啡类镇痛药而没有其成隐性、耐受性等副作用。所以帕瑞昔布和戊地昔布是非常具有应用前景的药物，相信在不久的将来它们会在抗炎药市场上占主导地位。国内目前未见戊地昔布合成的文献报道，为此我们开展对该药的研制。目的：①合成4-(5-甲基-3-苯基异噁唑-4-基)苯磺酰胺(Vaidecoxib, Bextra)并对其结构进行光谱鉴定。②对合成<WP=5>方法进行改进并优化。③合成一定量的戊地昔布，作为帕瑞昔布及其他衍生物的原料。方法：该化合物经六步合成。第一步制备苯乙酰氯，以苯乙酸为原料，用氯化亚砜酰化生成苯乙酰氯；第二步制备二苯乙酮，上步产品苯乙酰氯与苯在路易斯酸无水AlCl3存在下发生Fredel-Crafts酰化反应得到化合物二苯乙酮;第三步制备二苯乙酮肟， 二苯乙酮与盐酸羟胺在乙酸钠作用下生成二苯乙酮肟;第四步制备5-甲基-5-羟基-3,4-二苯基异噁唑啉，二苯乙酮肟与两倍摩尔量的正丁基锂反应产生一个双阴离子,该双阴离子与酰化试剂乙酸乙酯发生酰化反应得到氢化的异噁唑,即5-甲基-5-羟基-3,4-二苯基异噁唑啉;第五步制备4-(5-甲基-3-苯基异噁唑-4-基)苯磺酰胺，上步产品与氯磺酸形成磺酰氯,磺酰氯用浓氨水处理得到磺酰胺衍生物戊地昔布；第六步精制戊地昔布，得到的戊地昔布粗品，用2-丁酮和10%异丙醇重结晶得纯品戊地昔布。结果：①合成的4-(5-甲基-3-苯基异噁唑-4-基)苯磺酰胺，经熔点测定、光谱鉴定与文献结构一致。②改进优化关键步骤地合成方法。③合成一定量的戊地昔布，作为帕瑞昔布及其他衍生物的原料。结论：1. 文献制备二苯乙酮时，反应完后蒸馏出二苯乙酮粗品，再用甲醇重结晶得纯品。我们直接用重结晶的方法取代其蒸馏操作，简化了操作，并且改用95%乙醇重结晶，毒性减小，价格便宜。2. 合成5-甲基-5-羟基-3，4-二苯基异噁唑啉是关键的步骤，因为无水操作要求严格，所以对两种合成方法进行了<WP=6>对比。实验以乙酸乙酯为酰化剂进行的合成法优于以乙酸酐为酰化剂的合成法，后一种方法反应时间长，收率低，产品需用硅胶柱分离纯化，而前者反应时间短，收率高，产品用重结晶的方法纯化，简化了操作，且节省了大量的溶剂。此外，在实验过程中，我们用薄层色谱监测反应进行的程度，反应时间以1h为宜，比文献缩短了1h。3. 合成4-（5-甲基-3-苯基异噁唑-4-基）苯磺酰胺是重要的步骤，对其合成方法进行了对比。采用反应5h的方法进行合成。该方法反应时间短，操作简单，收率也较高。4. 对4-（5-甲基-3-苯基异噁唑-4-基）苯磺酰胺合成中的氨化反应进行了考察。氨化反应完后，对其后处理的两种方法进行了对比，过滤法操作简单且收率高，提取法易造成产品的丢失，并且麻烦。更多还原

【Abstract】 Nonsteroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents widely used in the treatment of pain, fever and inflammation. The mechanism of NSAIDs is mainly inhibiting cyclooxygenase(COX),which is the key enzyme required for the conversion of arachidonic acid into prostagladins(PGs). While PGs have many physiological functions. It can lead to inflammation and pains in the nervous system. Besides, PGs are responsible for nomal renal function, and they are cytoprotective in the gastrointestinal tract. Thus, the therapeutic effects and side effects of this class exist at the same time. As a consequence, NSAIDs users suffer from a high incidence of gastrointestinal irritation, including the development of life-threatening gastrointestinal ulcers. In 1990, Fu et al. discovered the existence of two isoforms of COX: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and, particularly, in the gastrointestinal tract and kidneys, where it is mainly responsible for the synthesis of cytoprotective PGs. COX-2 is selectively induced by proinflammatory cytokines(IL-1) and growth factors(TNFα) and facilitates the release of PGs involved in the inflammatory process. Therefore, the ideal NSAIDs should selectively inhibit COX-2, the clinically<WP=8>useful NSAIDs inhibit both COX-1 and COX-2, so the therapeutic effects and side effects of this class of drug exist at the same time . Selective inhibition of COX-2 provided a new class of anti-inflammatory, analgesic, and antipyretic drugs with significantly reduced side effects. In the present selective COX-2 inhibitors, Valdecoxib (Bextra),(4-(5-methyl-3-phenyl-isoxazol-4-yl)benzenesulfonamide). It belongs to the second generation of COX-2 inhibitors. It came onto the markets first in America in April,2002. Valdecoxib has been investigated for the treatment of chronic pain associated with osteoarthritis(OA), rheumatoid arthritis(RA) and pain associated with dysmenorrhoea. Its treatment of pain about oral surgery is better than the first generation of COX-2 inhibitors- Rofecoxib (Voixx) and Celecoxib (Celebrex) . A number of studies show that valdecoxib 40mg was significantly more effective than rofecoxib 50mg. Valdecoxib showed a 28000-fold selectively for COX-2 using isolated recombinant human COX-isoenzymes. Under the same experimental conditions the values found for celecoxib, rofecoxib were 375 and 800, respectively. Parecoxib(N-[[4-(5-methyl-3-phenyl-4-isoxazoly)-phenyl]sulfonyl]propanamide) is the water-soluble inactive prodrug of valdecoxib. Intravenous administration of pareco-xib sodium to all animal species resulted in complete and rapid conversion to valdecoxib. Besides, parecoxib can<WP=9>replace the kind of analgesic drugs such as Morphine and it has no side effects of endurance and so on. Thus , parecoxib and valdecoxib can be widely used in clinical practice. There were no reports on the preperation of valdecoxib in our country. In this paper, we report the synthesis of valdecoxib. Objective:①The aim is to synthesize 4- (5- methyl -3- phenyl- isoxazol- 4- yl) benzenesulfonamide and identify its structure by spectrum.②to improve the synthetic procedures.③to synthesize a good many Valdecoxib in order to synthesize Parecoxib and other compounds.Methods: Valdecoxib is synthesized by six steps. The first step is to synthesize phenylacid chloride. Phenylacetic acid is converted to phenylacid chloride with thionyl chloride. The second step is to synthesize desoxybenzoins. phenylacid chloride in the presence of a Leuis acid such as aluminum chloride to provide the desired compound desoxybenzoins by Friedel-Crafts in high yield. The third step is to synthesize desoxybenzoin keto-oxime. Desoxybenzoins with hydroxylamine hydrochloride by sodium acetate in ethanol, provide the desired compound desoxybenzoin keto-oxime. The forth step is to synthesize 5- hydroxy -5- methyl- 3,4- diphenylisoxazoline. desoxybenzoin keto-oxime is treated with two equivalents of a base such as n-butyllithium in cyclohexane to produce a dianion whic更多还原