Synthesis
1. Preparation of 5-methoxy-benzothiazol-2-ylamine: To a suspension of (3-methoxyphenyl)thiourea (1.822 g, 10 mmol) in dichloromethane (20 mL) was slowly added dropwise a solution of bromine (1.76 g, 11 mmol) in 10 mL of trichloromethane at 0 °C for 30 min. The reaction mixture was stirred at room temperature for 3 hours and then heated to reflux for 1 hour. After completion of the reaction, the precipitate was collected by filtration and washed with dichloromethane. The solid was suspended in saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, dried with magnesium sulfate and concentrated to give a white solid product (1.716 g, 95% yield).
2. Preparation of 2-amino-benzothiazol-5-ol: 5-methoxy-benzothiazol-2-ylamine (1.716g) obtained in the previous step was suspended in 16mL of 48% aqueous hydrobromic acid, and the reaction was heated in an oil bath at 105°C for 10 hours. After the reaction was cooled to room temperature, the precipitate was collected by filtration and washed with acetone. The solid in the filtrate was suspended in saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate and concentrated to give a white solid product (0.986 g, 63% yield).
3. Synthesis of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[6-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea hydrochloride [Compound B12]: 2-amino-benzothiazol-5-ol obtained from the previous step was used as a raw material, and the reaction was carried out according to the literature method. The product was characterized by nuclear magnetic resonance hydrogen spectroscopy (DMSO-d6) and liquid chromatography-mass spectrometry (LC-MS): 1H NMR (DMSO-d6) δ 11.1 (br, 1H), 9.69 (br, 1H), 9.28 (br, 1H), 8.71 (s, 1H), 7.97 (d, 1H), 7.79 (d and s, 3H), 7.56 (d, 2H), 7.56 (d, 2H), 7.13 (d, 2H). 2H), 7.13 (dd, 1H), 6.53 (s, 1H), 4.56 (t, 2H), 3.98 (m, 2H), 3.82 (t, 2H), 3.65 (m, 2H), 3.55 (m, 2H), 3.25 (m, 2H), 1.31 (s, 9H); LC-MS: ESI 561 (M + H)+.
References
[1] Patent: US2007/232604, 2007, A1. Location in patent: Page/Page column 40
[2] Medicinal Chemistry Research, 2012, vol. 21, # 7, p. 1136 - 1148
[3] Ukrainskii Khimicheskii Zhurnal (Russian Edition), 1956, vol. 22, p. 363,365
[4] Chem.Abstr., 1957, p. 4358
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
