METHOD OF PRODUCING (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1-4-DIHYDRO-1,6-NAPHTHYRIDINE-3-CARBOXAMIDE AND ITS PURIFICATION FOR USE AS PHARMACEUTICAL ACTIVE INGREDIENT Russian patent published in 2020 - IPC C07D471/04 

FIELD: organic chemistry.

SUBSTANCE: invention relates to a method of producing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I), which comprises reacting a compound of formula (XIV) or (XIVa) with dimethyl sulphate to obtain a compound of formula (XV) or (XVa), which without recovery is directed to reduction using 1.21 eqv. REDAL (sodium bis(2-methoxyethoxy)aluminum dihydride) and 1.28 eqv. N-methylpiperazine to obtain an aldehyde of formula (XVI) or (XVIa), which is further added to the reaction without separation to obtain a nitrile of formula (VI), which is dissolved in 3–7-fold amount of isopropanol, 5–10 mol % piperidine and 5–10 mol % glacial acetic acid at 30 °C, is further reacted with a compound of formula (VII) to obtain a compound (VIIIa+b) which then reacts with 4-amino-5-methylpyridone to obtain compound (X), which is added to the reaction while stirring with 2.5–5 eqv. triethyl orthoacetate in dimethylacetamide at 100–120 °C for 1.5–3 hours to obtain a compound of formula (XI), which is saponified in 9-fold amount of a mixture of THF/water, having ratio of 2:1, aqueous sodium hydroxide solution to obtain a compound of formula (XII), which is then, without isolation of intermediate compounds, is first reacted in THF with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, at the second stage is heated with reflux together with hexamethyldisilazane for 16–24 hours, and at the third stage is hydrolysed in water using THF or water to obtain a compound of formula (XIII), which is used at a step for chiral chromatography to obtain a compound of formula (I) in form of a solution in an inert solvent. Invention also relates to a method of producing a crystalline form of the compound of formula (I) and a method for preparing a medicinal agent based on the compound of formula (I) in crystalline form.

EFFECT: disclosed is an improved method of producing, which gives compound of formula (I) in 9 stages with total output of 27_7 % of theoretical without chromatographic purification of intermediate products.

3 cl, 10 dwg, 8 ex