【作者】 骆浩；

【导师】 付玉杰；

【作者基本信息】 东北林业大学 ， 生药学， 2010， 硕士

【摘要】 溃疡性结肠炎(Ulecrative Coltiis, UC)是一种慢性炎性疾病,局限于结肠粘膜及粘膜下层的炎症过程。这种病迄今为止尚不能治愈,而且在世界各国普遍发病率较高,被世界卫生组织列为现代难治病之一。近年来我国溃疡性结肠炎的发病率呈上升趋势,近十年患病人数较前50年增加10倍左右。巴柳氮钠是一种新型的“非特异性”水杨酸类抗炎药物,它可用于治疗溃疡性结肠炎,它与同类相比具有起效快、疗效好、副作用小的特点。目前已有相关合成巴柳氮钠的报道,但是其工艺存在不足之处,本文的目的就是对巴柳氮钠进行合成工艺研究,改进原有的合成方法,优化反应条件并提高收率。最后获得合成巴柳氮钠最佳工艺条件：第一步合成对硝基苯甲酰基-β-丙氨酸的最佳工艺条件：反应溶剂水的体积50mL,反应时间10 s,温度为52℃,摩尔比(对硝基苯甲酰氯：β-丙氨酸)为1：3.5,功率为420 W,产物收率96.8%。第二步合成对氨基苯甲酰基-β-丙氨酸的最佳工艺条件：反应溶剂为乙酸乙酯,催化剂钯碳用量为5%,反应时间3.8 h,温度为39℃,产物收率94.2%。第三步合成巴柳氮酸的最佳工艺条件：摩尔比(盐酸：对氨基苯甲酰基-β-丙氨酸)为1.46：1,摩尔比(对氨基苯甲酰基-β-丙氨酸：水杨酸)为0.952：1,结晶溶剂为70%醋酸,产物收率78.2%。第四步通过巴柳氮酸的成盐反应,合成巴柳氮钠,产物收率96.5%。该路线以对硝基苯甲酰氯和β-丙氨酸为起始原料,经N-酰化、氢化还原、重氮化、偶合和成盐四步反应合成巴柳氮钠,并通过核磁及红外确定了结构,得到目标化合物的总收率为68.8%。该反应路线的独特之处在于运用微波辅助合成法合成巴柳氮钠,整个反应时间缩短2 h,并且通过响应面分析法得到最佳工艺,节约生产成本,以及在反应过程中采用绿色溶剂,减少对环境的污染。总的来说,本工艺路线合理、可靠,适合工业化生产。更多还原

【Abstract】 Ulcerative colitis is a chronic inflammatory disease, confined to mucosa and submucosa of the inflammatory process. The disease still can not cure, and is in higher incidence in the world. Ulcerative colitis was considered as one of disease which was difficult to cure. In recent years, the incidence of ulcerative colitis in China was upward, and the number of patients compared with 50 years the previous century increased 10 times.Balsalazide disodium is a new type of "non-specific" salicylic acid anti-inflammatory drugs, which can be used to treat ulcerative colitis. It has advantages of rapid onset, better efficacy, side effects compared with other similar drugs. At present, there are some reports about synthesis of balsalazide disodium, but their technology wasn’t very good.The purpose of this paper is on synthesis of balsalazide disodium and improve previous synthesis method, optimize reaction conditions to improve the yield of balsalazide disodium.The optimum synthesis conditions of balsalazide disodium were got:The optimal reaction conditions of synthesis of N-p-nitorbenzoyl-β-alnaine were:solvent volume H2O 50 mL, reaction time 10 s, temperature 52℃, molar ratio (nitrobenzoyl chloride:β-alanine) of 1:3.5, microwave power 420 W. The yield of N-p-nitorbenzoyl-p-alnaine was 96.8%..The optimal reaction conditions of synthesis of N-p-aminobenzoyl-β-alnaine were: reaction solvent ethyl acetate,5% Pd/Ccatalyst, reaction time 3.8 h, temperature 39℃.The yield of N-p-aminobenzoyl-β-alnaine was 94.2%.The optimal reaction conditions of synthesis of balsalazide acid were:molar ratio(HCl: amino-benzoyl-β-alanine) 1.46:1,molar ratio(p-aminobenzoyl-β-alanine:SA)0.952:1, crystalli-zation solvent 70% acetic acid. The yield of balsalazide acid was 78.2%.At last, balsalazide disodium was synthesized by balsalazide acid salt formation, and the yield of it was 96.5%.Balsalazide disodium was synthesiezd fom 4-nitrobenzyl chloride andβ-alnaine via acylation, reduction, diazotization, coupling and salt formation, and the structure was confirmed by NMR and IR. The total yield of the target compound was 68.8%, and it was higher than the yield which was reported in other literature.The reaction route is unique in that microwave-assisted synthesize sodium balsalazide disodium, and two hours were shorten in the whole reaction time, save production costs by response surface methodology and use green solvents to reduce environmental pollution in the all reaction process. Overall, this process route is reasonable and reliable, and suitable for industrial production.更多还原