本文選題：(RS)-氯吡格雷　切入點：(S)-硫酸氫氯吡格雷　出處：《鄭州大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：氯吡格雷是一種新型的拮抗血小板聚集的藥物，屬于噻吩并吡啶類化合物。其療效明顯，但是其生產(chǎn)技術(shù)有相當(dāng)?shù)碾y度。本文對其合成路線以及合成工藝進行了進一步的研究。 (1)本文綜合調(diào)研了合成硫酸氫氯吡格雷的文獻和專利，選擇了三條路線合成氯吡格雷。 路線一以(R)-鄰氯扁桃酸為原料合成了e.e.值符合歐洲藥典標(biāo)準(zhǔn)的硫酸氫氯吡格雷鹽，首次使用纖維素柱測定硫酸氫氯吡格雷的e.e.值，收率由51%提高到了60%，得到的（S）-硫酸氫氯吡格雷經(jīng)分析是Ⅰ晶型。 路線二以(S)-鄰氯苯甘氨酸甲酯為原料經(jīng)Mannich縮合等四步反應(yīng)合成了(S)-硫酸氫氯吡格雷，在合成關(guān)鍵中間體(S)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯的步驟中，經(jīng)過合成條件的優(yōu)化，得到的產(chǎn)物比旋度優(yōu)于文獻數(shù)據(jù)。 路線三以外消旋的(RS)-鄰氯苯甘氨酸為原料，，重點研究了甲酯化、與對甲苯磺酸噻吩-2-乙酯的親核取代反應(yīng)、與多聚甲醛發(fā)生Mannich縮合、中間體和外消旋(RS)-氯吡格雷進行拆分等反應(yīng)條件的探索。首次發(fā)現(xiàn)以325目的碳酸鉀粉末為堿，乙腈為溶劑，過325目的KI作為催化劑，83℃回流30h，以77.34%的收率得到(RS)-(±)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯鹽酸鹽。摸索了產(chǎn)物(RS)-氯吡格雷的拆分條件，得到了e.e.值98.9%的單一構(gòu)型硫酸氫氯吡格雷鹽。路線三的總收率為25.35%，高于文獻報道的收率19.5%。 （2）本論文最后對得到的(S)-硫酸氫氯吡格雷進行了比旋度、干燥失重、有關(guān)物質(zhì)和含量測定等質(zhì)量檢驗，符合新藥轉(zhuǎn)正標(biāo)準(zhǔn)-硫酸氫氯吡格雷部分的規(guī)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

本文編號：1578590