硫酸氢氯吡格雷的合成工艺研究

发布时间：2018-03-07 08:06

  本文选题：(RS)-氯吡格雷　切入点：(S)-硫酸氢氯吡格雷　出处：《郑州大学》2014年硕士论文　论文类型：学位论文

【摘要】：氯吡格雷是一种新型的拮抗血小板聚集的药物，属于噻吩并吡啶类化合物。其疗效明显，但是其生产技术有相当的难度。本文对其合成路线以及合成工艺进行了进一步的研究。 (1)本文综合调研了合成硫酸氢氯吡格雷的文献和专利，选择了三条路线合成氯吡格雷。 路线一以(R)-邻氯扁桃酸为原料合成了e.e.值符合欧洲药典标准的硫酸氢氯吡格雷盐，首次使用纤维素柱测定硫酸氢氯吡格雷的e.e.值，收率由51%提高到了60%，得到的（S）-硫酸氢氯吡格雷经分析是Ⅰ晶型。 路线二以(S)-邻氯苯甘氨酸甲酯为原料经Mannich缩合等四步反应合成了(S)-硫酸氢氯吡格雷，在合成关键中间体(S)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯的步骤中，经过合成条件的优化，得到的产物比旋度优于文献数据。 路线三以外消旋的(RS)-邻氯苯甘氨酸为原料，，重点研究了甲酯化、与对甲苯磺酸噻吩-2-乙酯的亲核取代反应、与多聚甲醛发生Mannich缩合、中间体和外消旋(RS)-氯吡格雷进行拆分等反应条件的探索。首次发现以325目的碳酸钾粉末为碱，乙腈为溶剂，过325目的KI作为催化剂，83℃回流30h，以77.34%的收率得到(RS)-(±)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯盐酸盐。摸索了产物(RS)-氯吡格雷的拆分条件，得到了e.e.值98.9%的单一构型硫酸氢氯吡格雷盐。路线三的总收率为25.35%，高于文献报道的收率19.5%。 （2）本论文最后对得到的(S)-硫酸氢氯吡格雷进行了比旋度、干燥失重、有关物质和含量测定等质量检验，符合新药转正标准-硫酸氢氯吡格雷部分的规定。
[Abstract]:Clopidogrel is a new type of anti-platelet aggregation drug, which belongs to thiophene pyridine compounds. Its curative effect is obvious, but its production technology is very difficult. In this paper, the synthesis route and synthetic process of clopidogrel are further studied. In this paper, the literatures and patents on synthesis of clopidogrel sulfate were investigated and three routes were selected to synthesize clopidogrel. Route one synthesized hydroclopidogrel sulfate whose value conforms to the European Pharmacopoeia standard by synthesizing E. E. value from rhamne-o-chloromandelic acid. For the first time, a cellulose column was used to determine the e.e. value of hydroclopidogrel sulfate. The yield was increased from 51% to 60, and the crystal form I was obtained by the analysis of clopidogrel sulfate. In the second route, the synthesis of chlopidogrel was synthesized by Mannich condensation and other four steps, such as Mannich condensation. In the process of synthesis of the key intermediate, Sn-2-thiophene ethylamino-2-thiophene ethylamino-2-chlorobenzyl) methyl acetate, the synthesis conditions were optimized. The specific curl of the product is better than that of the literature. In the third route, the racemic racemic racem-o-chlorophenylglycine was used as the raw material. The reaction of methyl ester, nucleophilic substitution with p-toluenesulfonic thiophene-2-ethyl ester and Mannich condensation with paraformaldehyde were studied. The reaction conditions of the intermediate and racemic racemic RS- clopidogrel were explored. It was first found that 325 object potassium carbonate powder was used as base and acetonitrile as solvent. Ki was used as catalyst for refluxing for 30 h at 83 鈩

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