| Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the clinical treatment of fever, pain and inflammation. The mechanism of NSAIDs is mainly inhibiting cyclooxygenase (COX), which is the key enzyme required for the conversion of arachidonic acid to prostagladins (PGs). PGs have many physiological functions. It can lead to inflammation and pains in nervous system, dilate renal blood vessels and increase renal blood flux in cardiovascular system. On the other hand, PGs can restrain gastric acid excretion and protect gastric mucosa in the digestive system. Traditional NSAIDs have therapeutical effects accompanied by restraining the normal function of PGs, which result in gastrointestinal ulcer and renal toxicity, etc. In 1980s, Endothelium-derived Relaxing Facter (EDRF) was confirmed as NO. Then scholars began to study the biological effects of NO and found its wide physiological functions in many systems. For example, NO has expanding blood vessels and anti-thrombotic activities in cardiovascular system; NO participates in study and memory of animals in central nervous system and adjusts gastrointestinal moving in peripheral nervous system. In addition, NO can also increase gastric mucosal blood flow by dilatalting gastric mucosal blood vessels, protect gastric mucosa through accelerating gastric mucus exereting and mucosa repairing following injury. So abroad researchers synthesized a series of NO-NSAIDs, such as NO-Aspirin, NO-Napoxen, NO-Ketoprofen and so on. They hope this kind of drugs can not only perform the therapeutical effects of NSAIDs, but also avoid their gastrointestinal side effects.NCX-4016, 2-(acetyloxy) benzoic acid 3-(nitroxymethyl) phenyl ester, is a excellent representation of NO-Aspirin among the synthetic NO-NSAIDs. It has higher anti-inflammatory, anti-thrombotic activities and obviously decreased side effects on gastrointestinal tract compared with ASA. It contributes to curing pro-ulcer, treats gastric ulcer which induced by HCl or ethanol without developing gastric ulcer. This drug can notably increase gastric mucosal blood flow, accelerate mucous excretion and protect mucosal cell. It posseses anti-trombotic activity, can also inhibit blood vessel inflammatory and promot apoptosis. In addition, NCX-4016 still has analgesic and heart-protecting activity. At present, NCX-4016 is in clinical trial and will have wide application after going on sale.Objective: To synthesize 2-(acetyloxy) benzoic acid 3-(nitr-oxymethyl) phenyl ester (NCX-4016). To improve the synthetic procedures. To seek a new synthetic route which is suitable for industrialization with gentle reaction condition, cheap raw material that is easy to get. Methods: NCX-4016(5)was synthesized through five steps. 2-(acetyloxy) benzoic acid (1) was synthesized by the esterification of 2-(hydroxy) benzoic acid and acetic anhydride. Heating (1) and thionyl chloride in hexane obtained 2-(acetyloxy) benzoyl chloride (2). 2-(acetyloxy) benzoic acid 3-(methyl) phenyl ester (3) was prepared through the acylation of (2) and m-methyl phenol as raw material. Halogenation of (3) with N-bromosuccinimide (NBS) in carbon tetrachloride gived 2-(acetyloxy) benzoic acid 3-(bromomethyl) phenyl ester (4). Silver Nitrate and (4) reacted in acetonitrile at room temperature for 4 hours and converted to 2-(acetyloxy) benzoic acid 3-(nitroxymethyl) phenyl ester (5) in good yield. This synthetic route was not reported previously.Results2-(acetyloxy)benzoic acid 3-(nitroxymethyl) phenyl ester (5), IR(cm-1):3452.92, 3081.27, 2998.89, 2891.54, 1280.41, 1592.22, 1485.33, 1446.74, 1376.07, 1237.55, 1201.83, 1151.32, 1050.32, 869.30, 789.83, 697.08, 753.87. 1HNMR(():7.18(8.24(8H, Ar), 5.45(2H, s, -CH2ONO2), 2.32 (3H, s, OCOCH3). MS(m/z):332.07 (M+1), 290.06, 269.08, 163.03, 121.02, 93.05. Anal. Calcd for C16H13NO7:C, 58.01; H, 3.96; N, 4.23; Found: C, 58.02; H, 3.93; N, 4.21. The melting point, IR, 1HNMR, MS, elementary analysis are in accord with references.2-(acetyloxy)benzoic acid 3-(methyl) phenyl ester(3), mp: 7... |
