Synthesis, Process, Structure And Properties Of Bisphosphonates And 5 - Ethoxycarbonyl - 1,2,4 - Triazole Schiff Bases

Bisphosphonates, as effective bone resorption inhibitors, can effectively treat hypercalcemia, multiple myeloma, solid tumor bone metastasis and Paget caused by malignant tumors and osteoporosis. They are thought to be one of the strongest bone resorption inhibitors with their effect and low toxicity. Zoledronic acid is the strongest one in similar drugs of bisphosphonates. So synthesis and process of zoledronic acid and new bisphosphonates were studied in the part one of this paper.1,2,4-triazole Schiff base derivatives, showing better fungicidal activities, have been attracting more and more attention of chemists and pharmacologists for recent years. In order to screen the new biological activity of Schiff bases for the solubility and permeability change of lead compound, new 5-ethoxycarbony-11,2,4-triazole Shiff bases were mainly studied in the part two of this paper.Part one:A reasonable synthetic route of zoledronic acid, from imidazole with ethyl chloroacetate by the promoters KI/K2CO3 and the phase transfer catalyst Bu4NBr, salification by hydrochloride, hydrolysis by phosphoric acid with phosphorus oxychloride, was proposed; Solvents including methylbenzene, ethanol (95%) and orthophosphoric acid (85%), were emphasized and the conditions of N-alkylation were disclosed through orthodox experiments. Under the aforementioned conditions, A novel process presented lower poisonousness, simple operation,51% higher yield and suitable for pharmaceutical; The crystal structure of 1H-imidazole-1-acetic acid hydrochloride was determinated and calculated. The crystal belongs to orthorhombic system with space group P 2(1)2(1)2(1)/n. The whole molecule consists of imidazole acetic acid cation and chloride ion. A one-dimensional chain structure involved in hydrogen bond and the three-dimensional structure by the formation of Fan De hua gravitational and electrostatic attraction. The Infrared spectra of quantum chemistry calculation are in good agreement with the experimental data. The HOMO orbital of compound is caused by the chloride ion while the LOMO orbital mainly comes from the acetic acid; The bisphosphonates of 1,2,4-triazole acetic acid and amino acids were synthesized by the process of zoledronic acid.Part two:Thirty-six new 1,2,4-triazole Shiff bases were synthesized and the structures were confirmed by melting point, elemental analysis, IR,1H NMR,13C NMR, HRMS, DSC/ TG techniques. Using ethanol as solvent without acetic acid, the process presented simple operation, higher yield and cheaper energy; Shiff bases are solid and insoluble in water. Compared with the 1,2,4-thiazole Shiff bases without 5-ethoxycarbonyl, 5-ethoxycarbonyl-1,2,4-thiazole Shiff bases presented better solubility in organic solvent and lower melting point. The crystal structers of 3-methyl-4-(3-nitrobenzylideneamino)-5-ethoxy carbonyl-methylsulfanyl-1,2,4-triazole (h) and 3-methyl-4-(4-hydroxybenzylideneamino)-5-et hoxycarbonyl-methylsulfanyl-1,2,4-triazole (k) were detected and analyzed. The crystal of h belongs to monoclinic system with space group F1 (1)/c and the crystal of k belongs to orthorhombic system with space group P2(1)2(1)2(1)/n. The triazole ring and benzene ring of h and k are almost coplanar in the molecular structure. Six hydrogen bonds, including C-H…N and C-N…O, contribute to the stability and packing of the structure h while seven hydrogen bonds, including C-H…S, C-H…N, C-H…O, C-H…S, N-H…O hydrogen bonds, contribute to the stability and packing of the structure k; The biological activities to four vegetable pathogens of thirty-eight compounds have been tested.5-ethoxycarbonyl-1,2,4-thiazole Shiff bases exhibited the better biological activity to four vegetable pathogens compared with the Schiff bases without 5-ethoxycarbonyl. Aromatic ring substituents of 5-ethoxycarbonyl-1,2,4-thiazole Shiff bases for halogens exhibited the better biological activity and for 2,4-dinitro is better than or equivalent to triadimefon.