利奈唑酮及其类似物的合成研究

【作者】 焦军平；

【导师】 刘毅锋；

【作者基本信息】 西北大学 ， 有机化学， 2008， 硕士

【摘要】 利奈唑酮是一种新型噁唑烷酮类抗菌药物,其结构新颖、作用机制独特,无交叉耐药性。对革兰氏阳性菌具有很好的抗菌作用。本文采用两条不同的合成路线合成出了利奈唑酮及其2个类似物,并用IR、¹H NMR、¹³C NMR和MS进行了表征。路线一采用苯甲醛作保护剂,使S-环氧氯丙烷氨解、酸化生成S-1-氨基-3-氯-2-丙醇盐酸盐,然后经乙酰化反应后,生成中间体（S）-N-[2-乙酰氧基-3-氯丙基]乙酰胺,再用N-（3-氟-4-吗啉苯基）氨基甲酸苄酯和中间体在催化剂叔丁醇锂存在下25℃反应生成利奈唑酮,总产率达到43.6%。通过正交实验对该方法噁唑烷酮环形成反应的条件进行了优化。路线二使S-1-氨基-3-氯-2-丙醇盐酸盐酰化后,进行脱氯反应,生成中间体S-3-乙酰胺基-1,2-环氧丙烷,然后中间体再和N-（3-氟-4-吗啉苯基）氨基甲酸乙酯反应生成利奈唑酮。文献报道该步反应要在-78℃进行,我们对其进行适当的改进,避免了采用低温条件下合成噁唑烷酮环,用二丁基二月桂酸锡作为催化剂,使S-3-乙酰胺基-1,2-环氧丙烷和N-（3-氟-4-吗啉苯基）氨基甲酸乙酯在150～160℃反应合成利奈唑酮,产率:65～70%。并根据实验结果,提出用该催化剂合成利奈唑酮的反应机理。在S-3-乙酰胺基-1,2-环氧丙烷的合成中,对脱氯剂的选择我们做了筛选实验,证明用有机碱叔丁醇钠脱氯,可以保证反应物的空间构型保持不变,能够顺利生成目标产物。更多还原

【Abstract】 Linezolid is a new type of oxazolidinone antibacterial agent with a novel structure and a unique effect mechanism,and without the character of cross drug-resistant.It also has a good antibacterial effect to gram-positive bacterial.Two different methods used in synthesis of linezolid and its analogous.The products were characterized by IR,¹HNMR、¹³C NMR and MS techniques.Bezaldehyde was used as protective agent in first method.S-Epichloeohydrin was aminated and acidulated to give（2S）-1-Amino-3-chloro-propanol Salts.The acetylation of （2S）-1-Amino-3-chloro-propanol by acetic anhydride produced the intermediate （S）-N-[2-（acetyloxy）-3-chloropropyl]acetamide.And then at 20℃,in the presence of lithium tert-butoxide,benzyl 3-fluoro-4-morpholinophenyl carbamate react with（S）-N-[2-（acetyloxy）-3-chloropropyl]acetamide to give linezolid in total yield of 43.6%.The second method dealt with the acylation of（2S）-1-amino-3-chloro-propanol Salts in the presence of triethylamine.And（2S）-1-acetamino-3-chloro-propanol was cyclized by remove of chlorine with sodium tert-butoxide to get S-glycidylacetamid,which reacted with benzyl 3-fluoro-4-morpholinophenylcarbamate to give linezolid.According to the previous documents,this reaction happens in nitrogen gas at-78℃.However we have made some appropriate improvement to avoid the synthesis of oxazolidnone ring at very low temperature. Using dibutyltin dilaurate as catalyst,S-glycidylacetamide reacted with ethyl 3-fluoro-4-morpholonophenylcarbamate at 150-160℃to form linezolid in yield of 65-70%. The mechanism of oxazolidnone ring-forming reaction was also described.In the synthesis of S-glycidylacetamide,we used organic alkali sodium tert-butoxide as dechlorination agent,not only to keep the space frame of the reactant unchanged,but also to obtain successfully the aim product.更多还原