Study On Synthesis Of The Intermediate Of Antitumor Drug TNBG

1-Aminomethyl-1,2,3,4-tetrahydroisoquinoline (ATIQ) is the important intermediate of non-cytotoxicity antitumor drug TNBG, and it's the intermediate of antischistosomal agent praziquantel, too. Moreover, A few compounds which mother nuclide is ATIQ possess noticeable analgesic effect, Some tetrahydroisoquinoline compounds (THIQs) which containing ATIQ exhibit manifold bioactivities. For instance, 1-aminomethyl-4- phenyl-1,2,3,4-tetrahydroisoquinolines manifest variform pharmacological properties such as anti-depressant, antihistaminic and cholinergic agonist or antagonist activity and so on. Therefore, the efficient synthesis of the intermediate ATIQ is very important in the theory significance and practical value.The common procedure with which ATIQ was prepared, is that ATIQ came from Reissert compound via catalysis hydrogenation and hydrolization. However,owing to the stuff hardly obtained, essential high temperature and high pressure as well as longer time taken to heat and reflux, the approach was gravely restricted to be industrialized.According to the principle which requests starting material easily found, cheaper cost, convenient manipulate, environment friendly and available to the industrialization, linking to the related literatures,β-phenethylamine and chloroacetyl chloride were determined as starting material after retro-synthetic analysis. Six potential synthetic routes were obtained through retro-addition, interchange, removal functional groups. The fundamental researching consequence is described as the following:1. A synthetic route was established via five steps reactions including acylation, alkylation, cyclization, reduction and hydrazinolysis. In the route, the reaction condition is mild and controllable, the materials and reagents are inexpensive and easily got, and the manipulation is convenient.2.When the molar ratio ofβ-phenethylamine to chloroacetyl chloride was 1:1.2, chloride hydrogen was neutralized with pyridine under 0℃, the yield of amide could been gone up to 94%, which was enhanced 10% compared with related literature.3. When"two steps method"was adopted in cyclization, That is, at first, adding Lewis acid SnCl4 crystallization, then dehydrator P2O5 added, and increasing the dosage of P2O5 (the molar ratio of P2O5 to amide was 7:1), The yield of 1-chloromethyl-3,4-dihydroisoquinoline(CDIQ)could reach 79%, which of the related literature was mere a half.4. When carrying out the reaction of N-(N-acetylphenethylamine) phthalimide (PAPA) obtained, postprocessing was simplified, not repeatedly extracting with chloroform, but directly washing the products with water, then recrystallization with methanol. The white fibriform crystal was gained, and the yield can be kept steadily at about 83%. Moreover, the reagent could be reused after that DMF was reclaimed, not only environment protection and pollution decrease, but also the cost reduced.5. As preparing N-[(1-methylene)-3,4-dihydroisoquinoline] phthalimide (DIQA) with Bischler-Napieralski cyclization reaction, the inertia high boiling point solvent like xylene was abolished, and it was replaced with acetonitrile. The powder production could be directly obtained with water and alkaline water treatment after finishing the reaction, and the yield was 82%.6. The cost had been obviously cut down scince cheaper and steadier potassium borohydride was used to all the reduction reactions through taking the place of sodium borohydride.7. When DIQA was reduced, the selectivity was higher with KBH3OAc than with KBH4.8. Twelve compounds have been synthesized in this thesis, six of them are new compounds. The desired production ATIQ has been authenticated by IR, MS, 1H NMR and HRMS.In conclusion, an efficient and facile route of synthesis of ATIQ has been developed via five steps reactions including acylation, alkylation, cyclization, reduction and hydrazinolysis withβ-phenethylamine and chloroacetyl chloride as starting material. With lower cost, mild condition, convenient operation, the route has established the foundation for the industrialization and possesses the prospect of access to the industrialized production.