Preparation of N-(3-methylphenyl)-4-(4-pyridine)-2-thiazolamine_Kain Industrial Additive

Background and overview^[1]

N-(3-methylphenyl)-4-(4-pyridine)-2-thiazolamine belongs to the 4-pyridyl-2-anilinothiazole (PAT) class of compounds and is effective against renal cell carcinoma (RCC). Cells are cytotoxic. Advanced kidney cancer has a poor prognosis, and renal cell carcinoma (RCC) is often refractory to standard treatments. Therefore, treatment of advanced RCC has unmet clinical needs. The VHL tumor suppressor gene is mutated or inactivated in most RCC. Michael P. Hay et al. discovered that 4-pyridyl-2-anilinothiazole (PAT) is selectively cytotoxic to VHL-deficient RCC by inducing autophagy and increasing autolysosomal acidification.

Preparation^[2]

A mixture of bromoketone hydrobromide (1.13 g, 4.03 mmol) and 3-methylphenylthiourea (0.67 g, 4.03 mmol) in EtOH (20 mL) was stirred at reflux temperature for 3 h. . The mixture was cooled to 20 °C, diluted with water (50 mL), and pH adjusted to approximately 3. This was mixed with aqueous NH3 solution at 8 °C, and the mixture was stirred at 20 °C for 2 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography eluting with a gradient of EtOAc/pet (50-100%) to give N-(3-methylphenyl)-4-(4-pyridine)-2-thiazolamine (0.94 g, 87%), as milky white powder. mp (EtOAc/pet. ether) 158-160 °C; ¹H NMR δ 10.27 (br s, 1 H, NH), 8.62 (dd, J = 4.6, 1.6 Hz, 2 H, H-2′, H-6′), 7.84 (dd, J = 4.6, 1.6 Hz, 2 H, H-3′, H-5′), 7.69 (s, 1 H, H-5), 7.57 ( br d, J = 7.9 Hz, 1 H, H-6″), 7.47 (br s, 1 H, H-2″), 7.24 (dd, J = 7.8, 7.5 Hz, 1 H, H-5″) , 6.81 (br d, J = 7.5 Hz, 1 H, H-4″), 2.33 (s, 3 H, CH3); ¹³C NMR δ 163.5, 150.1 (2), 147.6, 140.9, 140.8, 138.1, 128.8, 122.2, 119.8(2), 117.5, 114.1, 107.2, 21.2; MS m/z 268.4 (MH+, 100%). Anal, calcd for C15H13N3S.bul..1/4.H2O: 5 C, 66.27; H, 5.01; N, 15.46. Found: C, 64.48; H, 5.08; N, 15.08%.

References

[1] Hay M P , Turcotte S , Flanagan J U , et al. 4-Pyridylanilinothiazoles That Selectively Target von Hippel?Lindau Deficient Renal Cell Carcinoma Cells by Inducing Autophagic Cell Death[J]. Journal of Medicinal Chemistry, 2010, 53 (2):787-797.

[2] From PCT Int. Appl., 2009114552, 17 Sep 2009