Thienopyridinone compounds
A technology of compound and stereochemistry, applied in the direction of drug combination, organic chemistry, organic active ingredients, etc., can solve the problem of reducing the sensitivity of FGFR inhibitors
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[0400] Solvates can be important for methods of preparation of substances (e.g., with respect to their purification, storage of substances (e.g., their stability), and ease of handling substances, and are often used as part of the isolation stage or purification stage of chemical syntheses Formed. Those skilled in the art can determine whether a hydrate or other solvate has been formed by the isolation conditions or purification conditions used to prepare a given compound by means of standard and long-established techniques. Examples of such techniques include thermogravimetric Analytical (TGA), differential scanning calorimetry (DSC), X-ray crystallography (such as single crystal X-ray crystallography or X-ray powder diffraction) and solid-state NMR (SS-NMR, also known as magic-angle spinning NMR or MAS -NMR). Such techniques, like NMR, IR, HPLC, and MS, are part of the skilled chemist's standard analytical toolkit. Alternatively, the skilled person can intentionally form solv...
example 1
[0629]
[0630] a) Preparation of intermediate 1
[0631] 7-Hydroxythieno[3,2-b]pyridin-5(4H)-one
[0632]
[0633] Intermediate 1 was synthesized as described in Journal of Chemical Research, Miniprint, 1980, #1 pp. 113-126.
[0634] General procedure A: 1 H NMR (400MHz, DMSO-d 6 ) (Varian) 7.94 (d, J=5.3Hz, 1H), 7.12 (d, J=5.5Hz, 1H), 6.00 (s, 1H).
[0635] b) Preparation of Intermediate 2
[0636] 6-((phenylamino)methylene)thieno[3,2-b]pyridine-5,7(4H,6H)-dione
[0637]
[0638] A stir bar, Intermediate 1 (7-hydroxythieno[3,2-b]pyridin-5(4H)-one) (65.0 g, 389 mmol) and ethylene glycol (600 mL) were added to a 1 L round bottom flask. The resulting mixture was stirred at 135°C and treated with trimethoxymethane (61.9 g, 583 mmol) and aniline (36.2 g, 389 mmol) in one portion. The resulting mixture was stirred at 135°C for 16 hours. The mixture was cooled to 25°C and filtered. The filter cake was washed with ethanol (100 mL). The solid was dried at 50 °C to g...
example 2
[0668]
[0669] a) Preparation of Intermediate 9
[0670] 2-(cis-2,6-dimethylmorpholino)-5-nitropyridin-4-amine
[0671]
[0672] A stir bar, intermediate 7 (2-chloro-5-nitropyridin-4-amine) (1.00g, 5.76mmol), intermediate 8 (cis-2,6-dimethylmorpholine) (800mg , 6.95mmol), N,N-diisopropylethylamine (2.24g, 17.3mmol) and n-butanol (10mL) were added to a 40mL glass bottle, which was stirred at 110°C for 16 hours. The mixture was cooled to room temperature with the formation of a yellow solid. The precipitate was filtered and washed with ethanol (5 mL x 3) to give Intermediate 9 (1.50 g, 90.0% purity, 92.9% yield) as a yellow powder.
[0673] b) Preparation of Intermediate 10
[0674] 6-(cis-2,6-dimethylmorpholino)pyridine-3,4-diamine
[0675]
[0676] A stir bar, intermediate 9 (2-(cis-2,6-dimethylmorpholino)-5-nitropyridin-4-amine) (1.50 g, 5.95 mmol) and methanol (50 mL) were added to 75 mL of hydrogenated glass, then wet palladium on carbon (400 mg, 50% aqueous ...
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