Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient
AssigneeBayer Pharma Aktiengesellschaft
InventorsJohannes Platzek, Gunnar Garke, Alfons Grunenberg
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Abstract
The present invention relates to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I) and also the preparation and use of the crystalline polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I).
Claims24
A process for preparing a compound of formula (VI)
- comprising reacting a compound of formula (XIV) or formula (XlVa)
- with dimethyl sulphate to give a compound of formula (XV) or (XVa)
- reducing the non-isolated methyl esters of the formula (XV) or (XVa) with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminium dihydride) and 1.28 equivalents of N-methylpiperazine to give an aldehyde of formula (XVI) or (XVIa)
- and reacting the aldehyde of formula (XVI) or (XVIa) without isolation to give the compound of formula (VI)
A process for preparing compounds of formulae (Villa+b) (VIIIa+b)
- comprising dissolving a compound of formula (VI)
- in isopropanol (3-7 fold) 3-7 fold, 5-10 mol % of piperidine and 5-10 mol % of glacial acetic acid at 30° C. and reacting the dissolved compound of formula (VI) with a compound of formula (VII)
- to give the compounds of formulae (VIII a+b)
A process for preparing a compound of formula (XI)
- comprising stirring a compound of formula (X)
- with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give the compound of formula (XI)
A process for preparing a compound of formula (XII)
- comprising saponifying a compound of formula (XI)
- in a THF/water mixture (2:1, 9-fold) 2:1, 9-fold, with aqueous sodium hydroxide solution to give the compound of formula (XII)
A process for preparing a compound of formula (XIII)
- comprising reacting a compound of formula (XII)
- in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII)
Dependencies are inferred from the claim text.