4-(5-iodo-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine synthesis

Yield:1111637-86-5 54.6%

Reaction Conditions:

Stage #1: 4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-5-aminewith sulfuric acid;iodine;acetic acid;potassium iodide;sodium nitrite in water at -3 - 50; for 2 h;
Stage #2: with ammonia;water

Steps:

A-1

Preparation of 4-(5-iodo-1 H-pyrazol-4-yl)-2-(methylthio)pyrimidine (A)A solution of NaNO₂ (20.0 g, 0.29 mol) in water (150 mL) was poured into a solution of 4-(2- (methylthio)pyrimidin-4-yl)-1 H-pyrazol-5-amine 6 (50.0 g, 0.24 mol) in a mixture of glacial acetic acid (400 mL) and water (100 mL) at -3 ⁰C. The temperature increased to -1 ⁰C. Concentrated H₂SO₄ (10 mL) was added to the obtained solution, and a solution of potassium iodide (120.0 g, 1.2 mol.) and I₂ (123.0 g, 10.48 mol) in water (200 mL) was added dropwise. The obtained solution was heated to 50 ⁰C for 2 h, and the mixture was neutralized with aqueous ammonia. Excess iodine was treated with Na₂S₂O₃. The precipitate was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was evaporated, and the residue was purified by chromatography (THF: EtOAc = 4:1 ) to give 4-(5-iodo-1 H- pyrazol-4-yl)-2-(methylthio)pyrimidine (A) (42.2 g, 54.6%) as a yellow solid. ¹H NMR (400 MHz, DMSO): δ 8.55 (d, 1 H), 8.35 (s, 1H), 7.55 (d, 1 H), 2.55 (s, 3H).

References:

WO2009/16460,2009,A2 Location in patent:Page/Page column 40; 59