Process for preparing levosimendan and intermediates for use in the process

A process for preparing levosimendan, which process comprises:

• a) reacting racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone of formula II
• with a chiral tartaric acid derivative selected from the D- or L-isomer or di-p-anisoyl-tartaric acid, di-p-tolyl-tartaric acid or O,O′-dibenzoyl-tartaric acid to form a first diastereomer salt and a second diastereomer salt, wherein the first diastereomer salt is a salt of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the chiral tartaric acid derivative, and wherein the second diastereomer salt is a salt of (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the chiral tartaric acid derivative;
• b) isolating (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone from the first diastereomer salt;
• c) and converting (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone to levosimendan by reacting (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone with sodium nitrite and malononitrile.

A process for preparing (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone, which process comprises:

• (i) reacting racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone of formula II
• with a first chiral tartaric acid derivative selected from the D- or L-isomer of di-p-anisoyl-tartaric acid, di-p-tolyl-tartaric acid or O,O′-dibenzoyl-tartaric acid to obtain a first diastereomeric salt and a second diastereomeric salt, wherein the first diastereomeric salt is a salt of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the first chiral tartaric acid derivative and wherein the second diastereomeric salt is a salt of a (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the first chiral tartaric acid derivative, and separating the first and second diastereomeric salts;
• (ii) converting the (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone of the second diastereomeric salt obtained from step (i) to racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone;
• and
• (iii) reacting the racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone obtained from step (ii) with a second chiral tartaric acid derivative selected from the D- or L-isomer of di-p-anisoyl-tartaric acid, di-p-tolyl-tartaric acid or O,O′-dibenzoyl-tartaric acid to form a third diastereomeric salt and a fourth diastereomeric salt, wherein the third diastereomeric salt is a salt of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the second chiral tartaric acid derivative, and wherein the fourth diastereomeric salt is a salt of (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the second chiral tartaric acid derivative;
• and
• (iv) isolating (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone from the third diastereomeric salt.