Synthesis of 3-bromo-4-isobutyloxyphenyl carbothioamide

3-bromo-4-isobutyloxyphenyl carbothioamide 1 is an important intermediate in many biologically active compounds such as febuxostat. In this work, a rapid synthetic method for compound 1 was established. The compound 1 was synthesized from the commercially available 4-hydroxybenzonitrile 2 through three steps including bromination, oxyalkylation and thioamidation. The structure was confirmed by MS and HNMR. Furthermore, the synthetic method was optimized. The total yield of the three steps was 49.2%. Introduction Febuxostat is a new urate lowering therapy drugs which exhibited significant therapeutic effect on gout[1-12]. As more and more people have been plagued by gout, developing gout inhibitors is one of the research hotspots for the treatment of gout. Konda S et al reported a synthetic route of febuxostat. It was synthesized throught eight steps, using 4-hydroxy-3-nitrobenzaldehyde as a starting material, febuxostat was prepared by dehydration, thioformylation, cyclization, oxygen alkylation, catalytic hydrogenation, followed by diazotized, hydrolysis, acidification. On the other hand , used p-hydroxy thiobenzamide as a starting material, febuxostat was obtained after cyclization, formylation, etherification, oximation dehydration and hydrolysis[14-15]. Chen Y et al established a synthetic route of febuxostat using methyl 4-hydroxybenzoate as raw material, through bromintion, oxyalkylation, cyanide, hydrolysis, chlorination and aminolysis reaction, thioamidation, cyclization, hydrolysis and acidification to give the title compound[16]. Most of the synthetic methods of 3-bromo-4-isobutyloxyphenyl carbothioamide which reported in the literature have the drawbacks such as longer synthetic route, lower yield and harmful to environment. 3-bromo-4-isobutyloxyphenyl carbothioamide 1 is a key intermediate for synthesizing Febuxostat. Therefore, the optimization of the synthetic route and methods of 3-bromo-4-isobutyloxyphenyl carbothioamide 1 is necessary. In this study, we designed and optimized the synthetic methods for 3-bromo-4-isobutyloxyphenyl carbothioamide 1 and make it more suitable for industrial production. The structure of febuxostat was shown in Fig. 1 Fig. 1 Sructure of febuxostat Materials and methods NMR spectra were performed using Bruker 300 MHz spectrometers (Bruker Bioscience, Billerica, MA, USA) with TMS as an internal standard. Mass spectra (MS) were taken in ESI mode on Agilent 1100 LC–MS (Agilent, Palo Alto, CA, USA). Elemental analysis was determined on a 2nd International Conference on Machinery, Materials Engineering, Chemical Engineering and Biotechnology (MMECEB 2015) © 2016. The authors Published by Atlantis Press 794 Carlo-Erba 1106 Elemental analysis instrument (Carlo Erba, Milan, Italy). All the materials were obtained from commercial suppliers and used without purification, unless otherwise specified. Yields were not optimized. TLC analysis was carried out on silica gel plates GF254 (Qindao Haiyang Chemical, China). Synthesis of compounds The structures and the synthetic route were shown in Scheme 1.