奈韦拉平及其吡啶并二氮杂卓类似物的合成研究

【作者】 曾伟；

【导师】 赵伟杰； 孟庆伟；

【作者基本信息】 大连理工大学 ， 应用化学， 2004， 硕士

【摘要】 艾滋病(Acquired Immune Deficiency Syndrome，AIDS)已经成为严重危害人类身体健康的疾病。中国目前有艾滋病病毒感染者约84万，艾滋病感染人数正高速增长，预计到2010年中国的艾滋病感染者将达到1000万。因此，研发价格低廉的抗HIV药物，已经成为摆在中国政府和科研工作者面前一个十分迫切和重要的课题。 本论文以氰基乙酰胺和乙酰乙酸乙酯为起始原料，经环合、氯化、氰基水解、霍夫曼重排、催化加氢脱氯、选择性氯化、酰化、芳香氯的胺解和胺的N-芳基化反应，合成了5，11-二氢-6H-二吡啶[3，2-b∶2’，3’-e][1，4]二氮杂卓-6-酮类的5个化合物和非核苷类逆转录酶抑制剂奈韦拉平(nevirapine)，其中合成奈韦拉平的九步反应总收率为30.9％。目标化合物结构运用IR、MS、~1H-NMR进行了表征。重点对中间体2-氯-3-胺基-4-甲基吡啶的合成工艺进行了优化，中间体总收率比文献值提高了9个百分点；在加氢脱氯反应中，加入助催化剂W后，Pd／C催化剂用量、溶剂用量分别降低为文献用量的30％和50％，反应收率90.5％，与文献值相同。首次采用醋酸成盐法对奈韦拉平进行精制研究，优化提纯工艺可使产品纯度达到99％以上。另外选用极性溶剂S水溶液重结晶法对奈韦拉平进行精制研究，极性溶剂S浓度为40％时，精制产品的纯度高于99.0％，回收率高于70％，母液可回收套用，样品质量达到德国伯明翰公司产品指标。对奈韦拉平中主要杂质的分离进行了研究，发现主要杂质是2-(2-环丙胺基-3-吡啶)-7-甲基-恶唑[5，4-b]吡啶，其结构运用IR、MS、~1H-NMR进行了表征。探讨了Cu催化二吡啶[3，2-b∶2’，3’-e][1，4]二氮杂卓-6-酮类化合物的合成，未见文献报道。更多还原

【Abstract】 Acquired Immune Deficiency Syndrome (AIDS) has become one of the most serious diseases in the world. There are about 840, 000 people infected with HIV in China reported by the government on Dec. 1st, 2003. The number of people infected with HIV is increasing rapidly nowadays and will be 10,000,000 by the end of 2010 if no effective measures would be taken right now. Drugs used to treat AIDS in China mostly depend on importation. Most patients cannot afford for their high price. Therefore, researching anti~HIV drugs with low price has become a vital task to be accomplished by the government and researchers as soon as possible.From cyanoacetamide and ethyl acetoacetate, non-nucleoside reverse transcriptase inhibitor nevirapine and five other compounds, as 5, ll-dihydro-6H-dipyrido[2, 3-b:2 ,3 -e][1, 4]diazepin-6-one analogues, are prepared via ring closure reactions chlorinations hydrolyzation Hoffmann rearrangement catalytic hydrogenation regioselective chlorination acylation aryl amination. The total yield of nevirapine synthesis is 30. 9%. The structures are confirmed by IR, MS 1H-NMR. Much stress is laid on the synthesis of the intermediate 2-chloro-3-amino-4-methylpyridine (CAPIC), and 9 percent is increased in the total yield of CAPIC. Nevirapine is purified through two different methods, and the quality of the sample meets the demand of the company Boehriger-Ingelheim. The primary impurity in nevirapine is separated and it is 2-(2-cyclopropylamino-3-pyridyl)-7-methyl-oxazolo[5,4-b]pyridine, whose structure is confirmed by IR MS 1H-NMR. It is the first time applying CuI as catalyst to form C-N bond in the synthesis of 5, 11-dihydro-6H-dipyrido[2, 3-b: 2 , 3’-e][1, 4]diazepin-6-ones.更多还原