Study On Synthesis Of Diaryl Ether Structure Of L-l-thyroxine Sodium Intermediates

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.