【作者】 刘田春；

【导师】 吴平东；

【作者基本信息】 浙江大学 ， 化学工程与技术， 2002， 博士

【摘要】 奥美拉唑(?)是一种新型的抗消化性溃疡药，本论文在综述了其合成方法文献资料的基础上，选择以2,3,5-三甲基吡啶(?)为起始原料，经氮氧化，硝化，甲氧基化，重排，水解，氯化，硫醚化，硫醚氧化八步有机反应合成得到奥美拉唑(?)。对各步单元有机反应及相关中间体化合物的分离方法进行了系统研究，合成总收率为45.5％，含量＞99.5％，产品质量指标达到美国药典24(USP 24)要求。 选择30％过氧化氢和冰醋酸反应形成过氧醋酸作为氧化剂与2,3,5-三甲基吡啶(?)进行氧化反应，最佳的原料配比为2,3,5-三甲基吡啶(?)：30％过氧化氢=1：1.55～1.70，过氧化氢的滴加时间＞6h。研究了反应温度对转化率，选择性和收率的影响。优选出最佳反应温度95～100℃，时间9～10h，得到2,3,5-三甲基吡啶-N-氧化物(?)粗品收率＞98.0％，纯度≥98.0％，与文献报道的收率96.5％，纯度94％比较有一定的提高。由于简化处理后粗品纯度高，不须经过文献采用的高真空精馏方法，可直接用于下步反应。 对2,3,5-三甲基吡啶-N-氧化物(?)的硝化反应进行了理论探讨，提出了硝化剂活性是影响硝化定位选择性的主要因素，为实验的设计和工艺条件的筛选提供了理论依据。分别采用65％硝酸和文献方法的发烟硝酸作为硝化剂，对反应温度和时间对选择性，收率的影响进行了研究和对比，实验结果表明，与文献方法使用的发烟硝酸作为硝化剂相比，使用65％硝酸，由于硝化活性降低，4-位硝化的选择性明显提高，有效地控制了6-位硝化和4,6-位二硝化副产物的生成，酸性强度降低后，避免了硝化反应过程中产物脱氧形成4-硝基-2,3,5-三甲基吡啶。最佳反应温度80℃，时间6h，硝化产物4-硝基-2,3,5-三甲基吡啶-N-氧化物(?)粗品收率97.8～98.5％，纯度＞98.0％。粗品可不经纯化直接用于下步反应，反应周期缩短，同时减少了使用发烟硝酸在生产过程中对环境和设备的严重污染。 研究了工业级甲醇钠作为甲氧基化试剂与4-硝基-2,3,5-三甲基吡啶N-氧化物(?)进行甲氧基化反应，其物料配比为硝化物(?)：甲醇钠=1：1.5～1.8(mol)。在反应体系中加入5％催化量季铵盐三乙基苄基氯化铵，降低了反应温度，缩短了反应时间，反应温度55℃，时间5h，得到4-甲氧基-2,3,5-三甲基吡啶N-氧化 浙江大学博士学位论文物（旦）粗品收率95刀％，纯度297．5％，与文献报道的硝化和甲氧基化二步收率68，5 k，纯度仅为89．0％比较，本文上述H步收率93．l％，纯度397．5％，收率和纯度明显提高，粗品不需纯化可直接用于下步反应，简化了工艺操作。研究了一种合成个甲氧基毛，3，5－三甲基毗唆的简便新方法，以价廉的2，3，5－三甲基毗陡（，为原料，经氧化，硝化，甲氧基化，脱氧四步反应合成得到4－甲氧基毛，3，5－三甲基毗陡，总收率高达82．0％。 从理论上探讨了个甲氧基工，3，5－三甲基毗陡N氧化物旧）在醋卧中重排反应的机理以及在重排反应过程中可能形成的副产物。研究结果表明，反应温度是形成副产物的主要因素，按照文献的反应温度90—130℃，经过对照品比较，4甲氧基E，3，S－H甲基毗陡－N－氧化物坦）脱氧副产物增加，降低了反应的选择性。重排反应温度降低至70～80℃，可得到最佳的反应收率。将重排反应和酸性水解二步反应合并成一步进行，简化了成盐步骤，其收率＞乃刀％，纯度＞99刀％。通过各步单元有机反应的研究，有效地控制了各步副产物的生成，提高了反应的选择性，由于备中间体粗品纯度高，因此，在合成过程中氮氧化，硝化，甲氧基化，重排，水解五步反应可采用“一锅合成法”，中间体不需分离纯化，简化了设备和操作，提高了效益，其收率以入3，5－三甲基毗陡堕）计，得到2－羟甲基习，5－二甲基＊甲氧基毗咤盐酸盐（担）总收率达到刀％，纯度乃9．0％，与文献总收率41．7％比较提高了28．3％。 以2－羟甲基刁，5－二甲基4甲氧基毗唆盐酸盐（担）为原料，于二氯甲烷溶剂中与过量的氯化亚枫进行亲核取代反应，低温滴加，反应温度25～300C，时间3h，得到收率高达98刀％的2－氯甲基I，5－二甲基A甲氧基D比陡盐酸盐回，纯度＞9＊刀％，合成工艺简单，反应条件易于控制，操作方便。 首先研究了2－氯甲基上，5－二甲基＊甲氧基毗陡盐酸盐①与5－甲氧基上－硫基苯并咪哩（0在甲醇／水／氢氧化钠体系中进行亲核取代反应制备5－甲氧基盯Q，5－二甲基＊甲氧基毛毗陡基）甲硫基卜1 苯并咪哇Q）的方法。实验结果表明，反应温度降低，选择性好，但反应速度慢；反应温度升至回馏，互与氢氧化钠发生水解生成羟甲基物（丛）的竟争副反应速度加快，对收率影响明显，其该反应体系中最佳收率为85—89％，操作条件难以控制。利用相转移催化作用原理，使用甲苯／水两相反应体系，采用价廉易得的季镣盐四正丁基涣化铰作为催化剂， 互正 浙江大学博士学位论文降低反应温度至50～55’C，反应速度加快，缩短了反应时间，?更多还原

【Abstract】 Omeprazole(l) is a specific drug for the treatment of gastric ulcer. Based on the review of the literatures, a synthesis process of OmeprazoleQJ with an overall yield of 45.5%(assay^99.5%) from cheap and easily available 2,3,5-trimethylpyridine (5) has been studied and developed. The synthetic route comprises eight reaction steps: N-oxidation, nitration, methoxylation, acetoxylation rearrangement, hydrolysis, chloration, etherification and S-oxidation. The quality of the product conforms to USP 24.N-Oxidation of 2,3,5-trimethylpyridine(5) was carried out by using peracetic acid formed in situ with 30% hydrogen peroxide and acetic acid as the oxidizing agent. The effect of the reaction temperature and time on the conversion, selectivity and yield was studied. The experimental results showed that the yield of 2,3,5-trimethylpyridine-N-oxide(6) reached 98.0% with a purity greater than 98.0%. The optimum reaction conditions are as follows: 2,3,5-trimethylpyridine(5):30% hydrogen peroxide=l: 1.55-1.70, the dropwise addition time of 30% hydrogen peroxide ^6 h, the reaction temperature is 95-100 癈 and the reaction time is 10 h. The crude N-oxide was directly nitrated without the purification by high vacuum distillation.The nitration mechanism of 2,3,5-trimethylpyridine-N-oxide(6) was discussed and it was revealed that the activity of nitrating agent was the key factor affecting the orientation selectivity of nitration. By substituting 65% nitric acid for fuming nitric acid, the selectivity of 4-position nitration was increased and the formation of 6-NOa and 4,6-(NC>2)2 by-products was controlled. The optimum reaction temperature and time were found to be 80 癈 and 6 h respectively. The yield of crude 4-nitro-2,3,5-trimethylpyridine-N-oxide(7) was 98.5% with a purity greater than 98.0%.Nucleophilic substitution of the - NO: radical by the -OCH3 radical was carried out by sodium methoxide of technical grade. By using benzyltriethylammonium chloride as catalyst, the reaction temperature was decreased from reflux to 55"C under 5 h of reaction time. The yield of raw 4-methoxyl-2,3,5-trimethylpyridine-N-oxide(8) was enhanced up to 95% with a purity of 97.5% compared to the yield of 68.5% (purity of 89.0%) reported in the literature. Meanwhile, a novel method for the synthesis of 4-methoxyl-2,3,5-trimethylpyridine with an overall yield of 82.0% from 2,3,5-trimethylpyridine(5) was developed via N-oxidation, nitration, methoxylation and deoxygenation.Based on exploring the mechanism of the rearrangement reaction of 4-methoxyl-2,3,5-trimethylpyridine-N-oxide(8) with acetic anhydride, O-acylation and subsequent acetoxylation of the 2-position methyl group and acid hydrolysis of the aceloxyl group were studied. The results showed that the optimum rearrangement reaction temperature was 70-80癈, while the literature reported temperature was 90-130 癈 . The yield of 2-hydroxymethyl-3,5-dimethyl-4-methoxylpyridine hydrochloride(lO) was 75.0% with purity ^99.0%. Through study on each reaction, the by-products in each step were controlled effectively and the purity of each intermediate was enhanced. Therefore, the five-step reaction could be conducted in "one pot", thus simplifying the equipment and operation. The overall yield of 10 from 2,3,5-trimethylpyride(5) was as high as 70% with purity^99.0%, compared with an overall yield 41.7% in the literature.Nucleophilic substitution of -OH radical by the -Cl radical of 10 of thionyl chloride was carried out in methylene chloride as solvent under 25~30癈 and 3 h of reaction time. The yield of 2-chloromethyl-4methoxyl-3,5-dimethylpyridine hydrochloride(3) was 98.0% with purity^99.0%.A study has been made on etherification of 2-chloromethyl-4methoxyl-3,5-dimethylpyridine hydrochloride(3) and5-methoxy-2mercaptobenzimidazole(4) with NaOH to synthesize 5-methoxyl-2((3,5-dimethyl-4-methoxyl-2-pyridinyl)-methylthio)-benzimidazole (2).According to the method in the literature, the reaction was carried out in water/更多还原