Synthesis Of N'-(4-methoxybiphenyl-3-yl) Hydrazine Carboxylic Acid, Isopropyl Ester

The synthesis routes of N ' -(4-methoxybiphenyl-3-yl)hydrazinecarboxylic acid, isopropyl ester (bifenazate) were studied. An efficient route was accomplished in six steps starting from 4-hydroxybiphenyl and following the sequence of nitration, methylation, catalytic hydrogenation, diazotization, reduction of diazonium salt and acylation.The synthesis focused on the replacement of dimethyl sulfate by methyl-carbonate for methylation. Whether nitration first or methylation first was compared on the synthesis of 3-nitro-4-methoxybiphenyl, and the results showed that nitration-first, methylation-second was the best approach and the total yield of the two steps can be reached to 89.5%. In addition, the influence of different amounts of potassium carbonate, tetrabutyl ammonium bromide(TBAB) and dimethyl carbonate (DMC) on the methylation reaction were studied. The amount of potassium carbonate showed no obvious effect on the reaction. The best molar ratio of TBAB: DMC: 3-nitro-4-methoxybiphenyl was 1: 8: 1. The best reaction time was 18h on the temperature of 138℃with 93.8% yield.A variety of reduction systems on the synthesis of 3-amino4-methoxybiphenyl were investigated and catalytic hydrogenation was the best method for industry. The yield(95.1%) of 3-amino-4-methoxybiphenyl was given under the optimum conditions that 0.5% Raney Ni (weight percent of 3-nitro-4-methoxybiphenyl) as catalyst, 1.5MPa for the pressure of autoclave and 1.5h for the reaction time at 80℃.Different conditions of acylation were studied, and the optimal condition was achieved using acetonitrile as solvent and pyridine as deacid reagent. The molar ratio of pyridine: isopropyl chloroformate: 3- hydrazine-4-methoxybiphenyl was 2: 1.1: 1. The yield was 62%.