Process for the preparation of 2-cyanoethyl (4s)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by resolution of racemates by means of diastereomeric tartaric acid esters

A process for preparing 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IVa)

• comprising steps (i) and (iii):
• (i) resolving by optical resolution racemic 2-cyanoethyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV)
• with a chiral substituted tartaric ester of the formula (IIIa) or (IIIb)
• to obtain one or more of the diastereomeric salts
• where Ar is unsubstituted or substituted aryl or heteroaryl, and
• (iii) converting the diastereomeric salt obtained in step (i) to the compound of formula (IVa).

A 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 (Ia),

• comprising steps (i), (iii), (v) and (vi):
• (i) resolving by optical resolution racemic 2-cyanoethyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV)
• with a chiral substituted tartaric ester of the formula (IIIa) or (IIIb)
• to obtain one or more of the diastereomeric salts
• where Ar is unsubstituted or substituted aryl or heteroaryl,
• (iii) converting the diastereomeric salt obtained in step (i) to the compound of formula (IVa)
• (v) hydrolysing the compound of formula (IVa) with sodium hydroxide solution in a THF/water mixture (2:1) to give the compound of the formula (VIIa)
• (vi) reacting the compound of the formula (VIIa), in THF as solvent, firstly with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, adding hexamethyldisilazane and then heating the mixture under reflux for 16-24 hours, and then adding a THF/water mixture, so as to obtain the compound of formula (Ia).