Study On Synthesis Of The Intermediate Derivatives Of Antitumor Drug TNBG

The derivatives containing the structure of THIQ presented a variety of pharmacological action, such as anti-fungal, anti-tumor, inhibitor of iNOS, nerve block and so on. In addition, the derivatives containing 1-Aminomethyl-1, 2, 3, 4-tetrahydroisoquinoline(AMTIQ) were important intermediate of antischistosomal medicine praziquantel, and they were also intermediate for the innovative antitumor drug TNBG. Therefore, making in-depth research on synthesis of the intermediate AMTIQ and its derivatives had an important theory significance and practical merit in developing innovative antitumor drug TNBG's derivatives.For the present, the intermediate AMTIQ was commonly synthesized through catalytic hydrogenation reaction, hydrolytic reaction from Reissert compounds which served as starting materials. The overall yield of the route was about 15%.when using the methord, there exist the following problem concerning lack of raw materials, high temperature and high pressure, catalytic hydrogenation and requiring a long time to heat. In a very environmentally friendly modern society,the shortcomings were in urgent need of developing a synthesis route of environmental protection and wide application prospect in the industrial production. Therefore, we designed a AMTIQ synthetic route which was prepared from phenethylamine by acylation, alkylation, cyclization, hydrazinolysis and hydrogenation. Via experiment, the overall yield of AMTIQ is 26%. The synthesis route was environmentally friendly, with the prospect of industrial production and avoiding the high pressure and high temperature ,while there was yet a chance for increasing the yield. With the above as base, we expected to develop a route with cheap and readily available raw materials, easy operation, high overall yield, high quality, environmental-friendly and good prospects for industrial production.During the synthesis of AMTIQ derivatives, we mainly made the following innovative improvements.1. In the acylation reaction, generated HCl between the reaction of acyl chloride and amine is extremely violent. In order to solve the problem, we took measures to change the dropping method of acyl chloride. The chloride first diluted with solvent then droped. The measure made the reaction become mild and controllable. The reaction conditions was optimized by orthogonal experiment. The yield of acylation reaction were all maintained at about 90%.2. During the cyclization of DIQA intermediate and its derivatives MIQA, DMQA and MDQA.,P₂O₅ was added in two steps so as to aviod the common agglomeration. The amount of P₂O₅ can be reduced by nearly 30%. In the meantime, the reaction conditions was optimized and the yield is up to 90.6%.3. In this paper, the original hydrogenation(46%) and hydrazinolysis reaction(90%) was processed by the means of"one-pot". The total yield was increased from 41.4% to 78.7% and doubled the total yield of original two-steps reaction.In the hydrazinolysis reaction, the ratio of raw materials and hydrazine hydrate was 1:1.2 and the amount of hydrazine hydrate was reduced by 20%.Meanwhile,avoiding the protection of nitrogen is conducive to environmental protection.In the hydrogenation reaction, the reduction is more moderate and controllable by changing the way of dropwising KBH4. The amount of KBH₄ is reduced 10% by optimizing the experimental conditions through orthogonal experiments.4. According to the improved synthesis, AMTIQ was prepared from phenethylamine by acylation, alkylation, cyclization, hydrazinolysis and hydrogenation. The total yield could reach 62.4%. The yield was 2.4 times as much as that of original. The overall yield of the three AMTIQ derivatives MTIQ, DMIQ and MDIQ were respectively reach 62.4%,62.0%,69.2%.5. Four target products AMTIQ,MTIQ, DMIQ and MDIQ were synthesized in the research. MTIQ, DMIQ and MDIQ were new compounds among the new products. The four target poducts were all confirmed by IR, Ms and ¹HNMR.In summary, the obtained AMTIQ synthetic route is facility and controllable. On the premise of upgrading the products'quality and yield, we also taked into account the cost of production and environmental protection. The acquired synthetic route of AMTIQ derivatives possessed the prospect of access to the industrialized production.