New Strategy for the Synthesis of N-[4-(4-Aryloxy-2,6-dimethylphenyl)thiazol-2-yl]isonicotinamides

• Main Author: 簡培修
• Other Authors: Huang, Jiann-Jyh
• Language: zh-TW
• Online Access: http://ndltd.ncl.edu.tw/handle/81831312539373765618

碩士 === 國立嘉義大學 === 應用化學系研究所 === 103 === In this thesis, I explored a new synthetic strategy for the preparation of N-[4-(4-aryloxy-2,6-dimethylphenyl)thiazol-2-yl]isonicotinamides 12–15 which were known as Hec1/Nek2 inhibitors. For the synthesis of compounds 12–14, 1-(4-iodo-2,6-dimethylphenyl)ethanone (33) served as the starting material to react with TBABr3. The reaction provided the desired 2-bromo-1-(4-iodo-2,6-dimethylphenyl)ethanone (34) in 99% yield. Compound 34 was allowed to react with thiourea to construct the 2-aminothiazole scaffold, providing 4-(4-iodo-2,6-dimethylphenyl)thiazol-2-amine (35) in 83% yield. After reacted with isonicotinoyl chloride hydrochloride, 35 was converted to N-[5-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl]isonicotinamide (36) in 99% yield. The iodo atom in 36 was transformed into a hydroxyl group by use of CuI/KOH/PEG-400/H2O catalytic system to generate the key intermediate N-[5-(4-hydroxy-2,6-dimethylphenyl)thiazol-2-yl]isonicotinamide (21) in 43% yield. O-Arylation of 21 by aryl halides 22 and 23, or heteroaryl halide 24 using CuI and Fe(acac)3 as the catalysts provided the desired 12–14 in 46–54% yields. This strategy, however, was not feasible for 15 possessing a methoxypropoxy group. As a result, its preparation was acomplished by linear syntheic method in four steps with 20% yield.