本文選題：頭孢菌素 + 鹽酸頭孢吡肟��； 參考：《蘇州大學(xué)》2014年碩士論文

【摘要】：鹽酸頭孢吡肟（Cefepime Hydrochloride）是20世紀(jì)90年代由美國(guó)Bristol-MyersSquibb公司研發(fā)，1993年上市，作為第一個(gè)上市的第四代頭孢菌素，具有抗菌譜廣，活性高的特點(diǎn)。文獻(xiàn)報(bào)道的合成方法很多，從起始原料來(lái)看，主要有兩種：第一種以GCLE（7-苯乙酰胺基-3-氯甲基頭孢烷酸對(duì)甲氧基芐酯）為原料；第二種以7-ACA（7氨基頭孢烷酸）為原料。以GCLE開始合成路線長(zhǎng)，需要取代、脫保護(hù)等多步反應(yīng)。以7-ACA為原料，，為了防止△-異構(gòu)化的產(chǎn)生，需要使用極性小的氟利昂或環(huán)戊烷作為硅烷化和碘代化試劑，收率低，后處理麻煩，溶劑回收困難。本文對(duì)合成方法進(jìn)行了優(yōu)化，選擇單一的二氯甲烷作為溶劑，控制特定的反應(yīng)條件和控制體系水分的方法，保證在完成硅烷化保護(hù)和碘代反應(yīng)后，加入N-甲基吡咯烷取代，不至于發(fā)生△-異構(gòu)化。一步得到鹽酸頭孢吡肟關(guān)鍵中間體7-氨基-3-(1-甲基1--四氫吡咯)甲基-3-頭孢-4-羧酸鹽酸鹽(7-MPCA),然后與AE-活性酯縮合得到鹽酸頭孢吡肟粗品，產(chǎn)品經(jīng)重結(jié)晶得到鹽酸頭孢吡肟。高效液相色譜檢測(cè)純度大于99.5%，總收率可達(dá)70%以上。最后采用元素分析（EA）、紅外色譜（IR）、核磁共振分析（1HNMR）和質(zhì)譜分析（MS）等手段，確定了所得產(chǎn)物結(jié)構(gòu)，證實(shí)了所得產(chǎn)品為鹽酸頭孢吡肟。所合成的產(chǎn)品通過質(zhì)量研究，穩(wěn)定性研究表明：工藝所得產(chǎn)品穩(wěn)定，與對(duì)照品一致。
[Abstract]:Cefepime Hydrochloride (Cefepime Hydrochloride) was developed by Bristol-MyersSquibb Company in 1990s and listed in 1993. Cefepime Hydrochloride (Cefepime Hydrochloride) is the first fourth generation cephalosporin to be listed on the market with wide antibacterial spectrum and high activity. There are many synthesis methods reported in the literature. There are two kinds of raw materials: the first is GCLE7-phenylacetamide-3-chloromethyl-cephalosporic acid (p-methoxybenzyl ester) and the second is 7-ACA(7 amino-cephalosporic acid). The synthesis route is long with GCLE, which needs to replace, deprotect and other multistep reactions. In order to prevent the isomerization of 7-ACA, it is necessary to use low polarity freon or cyclopentane as silanization and iodination reagents. The yield is low, the post-treatment is troublesome and the solvent recovery is difficult. In this paper, the synthesis method has been optimized by selecting a single dichloromethane as the solvent, controlling the specific reaction conditions and controlling the water content of the system, so as to ensure the addition of N-methylpyrrolidine after the silane protection and the iodination reaction have been completed. Do not occur-isomerization. The key intermediates of cefepime hydrochloride (7- amino-3-methyl-1-methyl-tetrahydropyrrole) methyl -3-cef-4-carboxylate 7-MPCAN were obtained in one step, and then condensed with AE-active ester to obtain the crude product of cefepime hydrochloride. The product was recrystallized to obtain cefepime hydrochloride. The purity of HPLC was more than 99.5, and the total yield was over 70%. Finally, the structure of the product was determined by elemental analysis, IR, 1H NMR and MS, and the product was confirmed to be cefepime hydrochloride. Through the quality research and stability study, the synthesized product is stable and consistent with the reference substance.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.3

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 宮平,趙燕芳,馮潤(rùn)良,張占濤;鹽酸頭孢吡肟的合成[J];中國(guó)藥物化學(xué)雜志;2002年06期

本文編號(hào)：1920212