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具有二芳醚结构的L—左旋甲状腺素钠中间体的合成研究
【作者】 华允宇；
【导师】 夏敏；
【作者基本信息】 浙江理工大学 ， 有机化学， 2010， 硕士
【摘要】 目前,合成L-左旋甲状腺素钠的难点在于具有二芳醚结构的关键中间体的制备。采用Ullmann反应制备二芳醚中间体突破了L-左旋甲状腺素钠合成中存在的这一瓶颈。本文对该合成过程进行了详细研究。本论文的前期工作主要集中在以磷酸钾为缚酸剂、CuI为催化剂、N,N-甲基甘氨酸为配体的反应体系中,L-酪氨酸及其衍生物同对溴苯甲醚的偶联反应,结果只有N-乙酰-L-酪氨酸乙酯能得到相应的二芳醚结构的产物。进一步研究发现尽管该底物能获得中等的产率,但所得的二芳醚中间体的比旋光值为零。我们推测手性传递失败的原因可能是由含有强吸电子能力的乙酰基促使氨基酸手性中心发生互变异构所致。于是我们采用具有给电子能力的苄基对氨基进行保护,希望能使手性得以保持,最终我们获得了光学活性保持、产率适中的预想产物。初步的研究结果告诉我们,该方法是可行的,因此我们进一步考察了各种影响转化率及产物e.e.值的因素。我们使用普通液相色谱柱及手性色谱柱,通过峰面积积分的方法分别定量分析了反应体系中产物的含量和其e.e.%值。考察了碱、催化剂及反应溶剂的种类;配体、对溴苯甲醚、碱及催化剂的用量;此外还包括温度和时间等各种影响因素。结果发现,使用有机碱作为缚酸剂的反应体系无法获得目标产物,采用无机碱为反应的缚酸剂,其中以价廉且缚酸能力强的磷酸钾为最佳选择,但其用量与值密切相关。时间对e.e%值的影响较小,而达到最优产率的条件为8小时。相比之下,温度的影响较为复杂,较为合理的反应温度为90℃,在100～110e.e%产率达到最高,但e.e.%值显著下降。对于配体而言,虽然其用量达到一定时,产率不再提高,但继续增加用量可以获得更高的e.e.%值。尽管碘化亚铜的催化活性最高,但并不是最好的选择,因为它不仅价格昂贵且使反应产物的e.e.%下降。在考察了一系列溶剂后发现,醇溶剂效果最差,偶联反应在其中不发生,而DMF及NMP最为出色,两者在产率及产物e.e.%值方面均表现出近似结果。在优化后的反应条件下,我们以47%产率和94.7%的e.e.值获得了目标产物O-对甲氧苯基-N,N-二苄基酪氨酸乙酯。这表明通过Ullmann反应来制得二芳醚中间体可以进一步开辟新的合成L-左旋甲状腺素钠的有效途径。
【Abstract】 It has been elucidated by the literature that the difficulty in the multi-step synthesis of L-Thyroxine lies in the preparation of the key intermediate with diaryl ether structure. In order to break through such bottle neck, Ullmann coupling reaction is utilized to obtain the diaryl ether. The thesis has studied in detail the process in access to such compound.The primary research is focused on the coupling of 4-bromoanisole and L- tyrosine and its derivatives under the conditions that N, N-dimethylglycine, potassium phosphate and cuprous iodide are to be as the ligand, base and catalyst, respectively. It is found that L-tyrosine without protections of its amino and carboxyl groups is hardly the effective candidate for the Ullmann coupling, only its derivative with double protections on amino and carboxyl groups can be carried out the desired reaction. Therefore, we adopt the strategy to turn amino and carboxyl into corresponding acetamide and ester. However, the extraordinarily low specific rotating value of the product demonstrates that the derivative of L-tyrosine with the above double protective groups has lost its potential as the substrate in route to L-Thyroxine, despite of the reasonable chemical yield involved with it.We has attributed the above failure to the strong electron-withdrawing capacity of acetyl, which leads to the facilitation of the tautomerism at theα-carbon on amino acid and the resulting racemization of the substrate. Hence, we design the alternative candidate derivative of L-tyrosine with double benzyls at the N atom, and it is hoped their electron-donating effect will contribute to the maintenance of optical activity for the coupling product. The primary result is in our expectation that not only the chemical yield is acceptable, but also the e.e% value is high enough. Then the detailed survey of those factors influencing the reaction conversion and the product’s e.e% value are executed.We use the common and chiral HPLC analysis of peak integrals to quantitatively detect the product content in reaction system and the e.e% value of the product mixture, respectively. Various effecting factors have been investigated such as the species of bases, catalysts and solvents, the amounts of ligand, 4-bromoanisole, base and catalyst, the reaction time and temperature. It is found that organic bases are ineffective for the coupling, only inorganic ones can be useful. Among them, potassium phosphate is the suitable one due to its cost and performance, but its amount is closely linked with the e.e% value of the product. Moreover, it is determined that the optimal reaction time for the coupling is around 8h, and there is little relationship with the e.e% value and the reaction time. However, the case is not the same for reaction temperature, although the best yield can be gained at about 100~110oC, the e.e% value at this temperature is dropped dramatically. The compromised temperature of the reaction is decided to be at 90oC. Although the yield is stabilized when the amount of the ligand is used at low percentage, the pretty good e.e% value can only be achieved for high percentage usage of the ligand. Despite of its good reaction conversion, CuI is not selected as our optimal catalyst owning to its high cost and poor performance on the product’s e.e% value. Among the screened solvents, it is found that alcohols are the poor ones without any target compound while DMF and NMP are both the best with the approximately the same reaction yield and product’s e.e% value.Under the optimal conditions, the product of O-anisoly-N, N-dibenzyltyrosine ethyl ester can be isolated in 47% yield and XXXX e.e% value. It is exhibited that the approach to the significant intermediate for the synthesis of L-Thyroxine has been established via the Ullmann coupling. The further work based on such method to explore the novel route to L-Thyroxine is under the due course.