Preparation method of 2-arylnitrile-thiazole derivative

[0083] Reference Example 1 5-iodo-2-isobutoxybenzonitrile

[0084] 2-Methyl-1-propanol (1.11g, 15.1mmol) was dissolved in N,N-dimethylformamide (20mL), cooled to 0°C, and sodium hydride (0.6g, 15.1mmol, 60% dispersed in mineral oil). After the mixture was stirred at 0°C for 30 minutes, 2-fluoro-5-iodobenzonitrile (2.5 g, 10.1 mmol) was added thereto, returned to room temperature, and stirred overnight. After the reaction was completed, it was quenched with water (30 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v)=40:1) to obtain the title compound as a yellow liquid (2.7g, 90%) .

[0085] 1 H NMR (400MHz, CDCl 3 )δ(ppm):1.05(d,6H,J=6.7Hz),2.12-2.19(m,1H),3.80(d,2H,J=6.5Hz),6.72(d,1H,J=8.9Hz) ,7.77(dd,1H,J=2.2,8.9Hz),7.80(d,1H,J=2.2Hz).

[0086] Example 1 2-zinc bromide-4-methylthiazole-5-ethyl carboxylate

[0087] Under anhydrous and oxygen-free conditions, zinc powder (325mg, 5mmol) and 1,2-dibromoethane (94mg, 0.5mmol) were mixed, and N,N-dimethylformamide (10mL) was added thereto . After the mixture was stirred at reflux for 0.5 hours, it was cooled to room temperature, and trimethylchlorosilane (65 mg, 0.6 mmol) and 5-iodo-2-isobutoxybenzonitrile (602 mg, 2 mmol) were sequentially added thereto. The reaction solution was heated up to 85°C, stirred for 7 hours, cooled, and used directly for the next reaction.

[0088] Example 2 Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

[0089]Under anhydrous and oxygen-free conditions, the above-prepared mixture was added to ethyl 2-bromo-4-methylthiazole-5-carboxylate (249mg, 1mmol) and Pd(PPh 3 ) 4 (116mg, 0.1mmol) in the mixture. Stir at room temperature and monitor the reaction by TLC. After the reaction, brine (20 mL) was added, and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate (v / v)=10:1) to give the title compound as a white solid (0.21g, 61%) .

[0090] 1 H NMR (400MHz, CDCl 3 )δ(ppm):1.09(d,6H,J=6.7Hz),1.39(t,3H,J=7.2Hz),2.17-2.24(m,1H),2.76(s,3H),3.90(d, 2H,J=6.5Hz),4.35(q,2H,J=7.2Hz),7.00(d,1H,J=8.9Hz),8.09(dd,1H,J=2.2,8.9Hz),8,17( d,1H,J=2.2Hz).