【摘要】：石杉?jí)A甲是一種高效的乙酰膽堿酯酶抑制劑。2-甲氧基-6-羥基-7,8-二氫-5-喹啉羧酸甲酯是合成石杉?jí)A甲的關(guān)鍵中間體，本文綜述了該中間體已有的合成方法，在此基礎(chǔ)上提出并驗(yàn)證了自己的新合成方法。 (1):以1,4-環(huán)己二酮縮乙二醇為起始原料，用N,N-二甲基甲酰胺二甲基縮醛在羰基的α位進(jìn)行取代。取代產(chǎn)物在氰基乙酸甲酯的作用下關(guān)環(huán)，，此反應(yīng)為本路線的創(chuàng)新點(diǎn)。關(guān)環(huán)產(chǎn)物通過(guò)已知的方法得到中間體化合物1。 (2):以2-甲氧基-6-甲基吡啶為原料，與1,3-二溴-5,5-二甲基海因反應(yīng)，得到3-溴代吡啶衍生物。吡啶衍生物再進(jìn)一步與N-溴代丁二酰亞胺（NBS）反應(yīng)，得到多溴代的混合物。通過(guò)與亞磷酸二乙酯還原生成3-溴-2-(溴甲基)-6-甲氧基吡啶。乙酰乙酸甲酯與堿作用生成雙負(fù)離子，端基碳上的負(fù)離子優(yōu)先與3-溴-2-(溴甲基)-6-甲氧基吡啶反應(yīng)得到化合物(3-溴-6-甲氧基吡啶-2-基)-3-羰基戊酸甲酯，這步反應(yīng)是本路線的創(chuàng)新點(diǎn)�；衔�(3-溴-6-甲氧基吡啶-2-基)-3-羰基戊酸甲酯經(jīng)鈀或CuI/氨基酸催化關(guān)環(huán)得到所需的化合物1。這步反應(yīng)是本路線的另一創(chuàng)新之處。 總之，兩種新的合成方法都避免了易致敏試劑丙炔酰胺的使用；相對(duì)于方法一,方法二避免了碳酸銀等貴試劑的使用，且路線較短，收率穩(wěn)定，總收率為46%。
[Abstract]:Huperzine A is a highly effective inhibitor of acetylcholinesterase. Methyl 2-methoxy-6-hydroxy-7-dihydro-5-quinoline carboxylate is the key intermediate for the synthesis of Huperzine A. On this basis, a new synthetic method is proposed and validated. The results are as follows: (1) using 1-hexamethylene glycol as starting material, N-dimethylformamide dimethyl acetal was substituted at the 偽 -site of carbonyl group. The substitution product under the action of methyl cyanoacetate, this reaction is the innovation point of this route. Intermediate 1 was obtained by the known method. (2) 3-bromopyridine derivatives were synthesized by the reaction of 2-methoxy-6-methylpyridine with 1-dibromo-5-dimethyl hydantoin. Pyridine derivatives further reacted with N-bromosuccinimide (NBS) to obtain a polybrominated mixture. 3-bromo-2-(bromomethyl)-6-methoxy pyridine was synthesized by reduction with diethyl phosphite. Methyl acetoacetate reacted with alkali to form dianion, and the anion on the terminal carbon preferentially reacted with 3-bromo-2- (bromomethyl) -6-methoxy pyridine to form a compound (3-bromo-6-methoxypyridyl-2-yl) -3-carbonyl valerate. This reaction is the innovation of this route. The compound (3-bromo-6-methoxy pyridine-2-yl) -3-carbonyl valerate was synthesized by palladium or CuI/ amino acid catalyzed ring closure. This reaction is another innovation in this route. In a word, the two new synthetic methods have avoided the use of propylidene, a sensitive reagent, and the second method has avoided the use of expensive reagents such as silver carbonate in comparison with the first method, and the route is relatively short, the yield is stable, and the total yield is 46%.
【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(lèi)號(hào)】：R914

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本文編號(hào)：2261182