【摘要】：隨著癌癥患者的逐漸增加，各種抗癌藥物相繼問世進(jìn)行臨床研究，多韋替尼現(xiàn)階段正進(jìn)行臨床研究。 多韋替尼屬于苯并咪唑喹啉酮的一種衍生物，根據(jù)研究和科學(xué)實(shí)驗(yàn)，證明這種藥物對于肝癌晚期患者具有明顯的治療效果。 本文通過查閱相關(guān)文獻(xiàn)，總結(jié)多韋替尼乳酸鹽的合成路線的優(yōu)缺點(diǎn)，最終選擇以5-氯-2-硝基苯胺和N-甲基哌嗪回流反應(yīng),可以得到5-(4-甲基哌嗪基-1-基)-2-硝基苯胺,然后由5-(4-甲基哌嗪基-1-基)-2-硝基苯胺經(jīng)過催化加氫還原硝基可以形成4-(4-甲基哌嗪基-1-基)鄰苯二胺,再與β-乙氧基-β-亞胺基丙酸乙酯鹽酸鹽在酸性條件下回流成環(huán),得到6-（4-甲基哌嗪）-1-氫-苯并咪唑-2-乙酸乙酯,接下來6-（4-甲基哌嗪）-1-氫-苯并咪唑-2-乙酸乙酯與2-氨基-6-氟苯腈在堿性條件下環(huán)合得多韋替尼，最后多韋替尼與乳酸成鹽得到對位替尼乳酸鹽。該方法避免了氨基易氧化的缺點(diǎn)，簡化了操作步驟。 通過對各步反應(yīng)條件的優(yōu)化，最終我們選擇了5-氯-2-硝基苯胺與N-甲基哌嗪的摩爾比為1：3，，不需要溶劑；在乙醇做溶劑在75℃下用鈀碳加氫還原，在2-氨基-6-氟苯腈制備過程中選擇溫度為90℃，最后用六甲基二硅基氨基鋰作為堿，成鹽用乙醇作為溶劑，在整個(gè)過程中反應(yīng)產(chǎn)率提高了，產(chǎn)物更加容易處理。整個(gè)合成路線最終的產(chǎn)率達(dá)到44.5%。 對合成過程的中間體進(jìn)行了熔點(diǎn)、紅外、高效液相、核磁等相關(guān)的分析和結(jié)構(gòu)表征。根據(jù)實(shí)驗(yàn)結(jié)果表明得到的產(chǎn)物圖譜與目標(biāo)產(chǎn)物相符合，最終合成的化合物達(dá)到了預(yù)期要求，其性能指標(biāo)、結(jié)構(gòu)與目標(biāo)需求一致。 可以預(yù)測以5-氯-2-硝基苯胺為初始原料合成多韋替尼乳酸鹽的路線是切實(shí)可行的。
[Abstract]:With the increasing number of cancer patients, various anticancer drugs have been published to carry out clinical research. Dovetinib is a derivative of benzimidazole quinolinone, which has been proved to be effective in the treatment of advanced liver cancer. In this paper, the advantages and disadvantages of the synthesis route of dovetinib lactate were summarized, and the reflux reaction of 5-chloro-2-nitroaniline and N-methylpiperazine was selected. 5- (4-methylpiperazino-1-yl) -2-nitroaniline was obtained. Then 4- (4-methylpiperazinyl-1-yl) -2-nitroaniline was hydrogenated to form 4- (4-methylpiperazinyl-1-yl) o-phenylenediamine by catalytic hydrogenation of nitroaniline. Ethyl 6- (4-methylpiperazine) -1-hydrobenzimidazole-2-acetate was obtained by refluxing with ethyl 尾 -ethoxy- 尾 -iminolpropionate under acidic conditions. Then 6- (4-methylpiperazine) -1-hydrobenzimidazole-2-acetate ethyl ester and 2-amino-6-fluorobenzonitrile were cyclized to obtain dovetinib under alkaline conditions. Finally, dovetinib was salted with lactic acid to obtain paratinib lactate. This method avoids the disadvantage that amino is easy to oxidize and simplifies the operation steps. By optimizing the reaction conditions, the molar ratio of 5-chloro-2-nitroaniline to N-methylpiperazine is 1: 3, and no solvent is needed. In the solvent of ethanol, palladium carbon was hydrogenated at 75 鈩

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