Triazolothiadiazole inhibitor of c-met protein kinase
a technology of c-met protein and inhibitor, which is applied in the field of selective inhibitors of c-met, can solve the problems of prolonging the qt interval, causing cardiac qt prolongation, adverse or fatal side effects in many clinical settings, etc., and achieves the effect of treating or lessening the severity of a proliferativ
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example 1
Preparation of 6-((S)-1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)ethyl)quinoline (compound 1)
[0080]As shown in step i of Scheme 1, concentrated sulfuric acid (206 mL, 3.868 mol) was added dropwise to a solution of 2-(quinolin-6-yl)acetic acid (compound 1001, 658.2 g, 3.516 mol, Okeanos Tech Co., Cat. No. OK-J-05024) in 6.5 liters of methanol. During the addition, a slight exotherm was observed. After the addition was complete, the reaction was stirred at reflux for 4 hours. After cooling, the volatiles were removed under reduced pressure, the resulting residue was diluted with 4 liters of ethyl acetate, cooled in an ice bath, treated with 2N NaOH (2.1 liters, 1.2 equiv.) until a pH of 4 was achieved, and then treated with saturated sodium bicarbonate until a pH of 8 was achieved. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, washed with water, ...
example 2
Crystallization of Compound 1 (Free Base)
[0087]To compound 1 (906 mg) was added 40 mL of acetonitrile and 10 mL of methanol. The solid was dissolved on a hot water bath at about 90° C. The solution was filtered off and was allowed to slowly evaporate at room temperature for 4 hours. Crystals gradually precipitated. The mother liquor was decanted and the solid was dried at room temperature under 4 mm Hg vacuum over night.
[0088]About 10 mg of compound 1, crystalline free base (FB), was loaded into a vial with a magnetic stir bar. About 150 μL of solvent were added to each vial. If compound 1 dissolved completely, more solid was added to the vial and stirring of the resulting slurry was continued at room temperature. The 4 day solution was filtered off using centrifuge filters and diluted in methanol to obtain solubility data by HPLC analysis. The results of the solubility study are shown in Table 1. X-ray diffraction data of the crystals in the slurry were collected after 4 and 14 day...
example 3
Salt Formation of Compound 1
[0090]The free base of compound 1 was dissolved in ethanol to make a solution of 0.02 mmol / mL concentration. Base and acid solutions were added to separate vials containing the solution and the solvents were then evaporated at room temperature under vacuum (4 mmHg pressure). 2-Propanol (IPA) and ethanol were individually added to separate vials to re-dissolve the solids and crystallization of the solid in each vial was attempted by slow evaporation at room temperature. The resulted solids were characterized by X-ray diffraction studies. The results are shown in Table 3.
TABLE 3Acid solutionIPA salt formEthanol salt formhydrochloric acidamorphousamorphoussulfuric acid 2:1 molar ratioCrystalline saltCrystalline saltp-toluenesulfonic acidamorphousamorphousFree baseCrystalline FBCrystalline FBmethanesulfonic acidamorphousamorphousbenzenesulfonic acidCrystalline saltamorphousmaleic acidamorphousamorphousL-prolineamorphousamorphousphosphoric acidCrystalline salt...
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