â… .Research On Synthesis Of Key Intermediate 1-Methyl-3-Phenylpiperazine Of Antidepressant-Mirtazapine â…¡.Research On Aminohalogenation Reaction Of Alkenes

The first part of the dissertation was based on the synthesis of 1-methyl-3-phenylpiperazine, which is an important preparation intermediate for a novel antidepressant mirtazapine.The synthetic route consisted of several steps starting from styrene oxide and N-methylethanolamine and went through nucleophilic ring-oping reaction, chlorination, cyclization and hydrolysis. Styrene oxide was treated with N-methylethanolamine in toluene to afford intermediate N-（2-hydrox-yethyl）-N-methyl-α-hydroxy-β-phenylethylamine which was then chloride-zed directly with thionylchloride to afford hydrochloride of N -（2-chloroet-hyl）-N-methyl-α-chloro-β-phenylethylamine, and polit-plant enlargement was successfully done in 500 L reaction vessel, the yield was up to 69.2%. Compared with solvent DMF in other literature, this route has advantages of simple process, reuse of solvent, high yield and high quality of product. Emphasis was placed on the cyclization, ammonia and p-toluenesulfonamide were used as cyclizing agent. By comparison, p-toluenesulfonamide is superior than ammonia. Then, effects of reaction temperature, feed ratio and dosage of solvent were studied, finally the condition of hydrolysis was optimized carefully. In the optimum reaction condition, the yield of cyclization was up to 91.5%, the intermediate was characterized by X-Ray diffraction. The yield of hydrolysis was 88-92%, the total yield of 1-Methyl-3-Phenylpiperazine reached 60.1% （based on N-methylethanolamine）, The final product was characterized by X-Ray diffraction.This route has advantages of easily available materials, mildly reacting-conditions, simple process and high yields, so it becomes more suitable for large-scale preparation.In the second part of the dissertation, the aminohalogenation reaction of alkenes with N,N-dibromo-4-methylbenzenesulfonamide was studied.In this section the aminohalogenation reaction of alkenes using N,N-dibromo-4-methylbenzenesulfonamide as the halogen and nitrogen source was chiefly studied. Meanwhile, we had succeeded in extending this reaction to aliphatic alkenes. First, the mixture of p-toluenesulfonamide and bromine was treated with sodium hydroxide to afford N,N-dibromo-4-meth- ylbenzenesulfonamide, then addition reaction occurred with three kinds of alkenes（ph-CH=CH₂,CH₂=CH-COR, ph-CH=CH-CO₂R） to afford haloamine products, we found solvents had significant effect on this reaction. Aminohalogenation reaction can smoothly proceed in chloroform, good yields（46.7%-95.8%） and excellent regioselectivities were obtained, for styrene, Br atom bonded toβcarbon atom of phenyl, for another two kinds of substrates, Br atom bonded toαcarbon atom of carbonyl. In order to elucidate their structures, N-（2-br-omo-1-phenylethyl）-4-methyl-benzenes-ulfonamide was characterized by X-Ray diffraction.Finally, a potential mechanism of the reaction was proposed on the basis of the experiment data.