Process for preparing levosimendan and intermediates for use in the process

Patent metadata

Field	Value
Publication number	US-9000158-B2
Application number	US-201013384211-A
Country	US
Kind code	B2
Filing date	Jul 12, 2010
Priority date	Jul 14, 2009
Publication date	Apr 7, 2015
Grant date	Apr 7, 2015

Abstract

In an embodiment, the present invention provides a process for preparing (−)-6-(4-aminophenyl)-5-methylpyridazin-3-(2H)-one, 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 to obtain a diastereomeric salt of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and the chiral tartaric acid derivative; and b) reacting the diastereomeric salt with a base to obtain (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone. The (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone may be used to prepare levosimendan.

First claim

The invention claimed is:

1. A process for preparing (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone, 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 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; and
b) isolating (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone from the first diastereomer salt, wherein the chiral tartaric acid derivative is selected from the D- or L-isomer of di-p-anisoyl-tartaric acid, di-p-tolyl-tartaric acid or O,O′-dibenzoyl-tartaric acid.

2. The process according to claim 1 , wherein step b) comprises separating the first diastereomer salt from the second diastereomer salt and reacting the first diastereomer salt with an organic or inorganic base to obtain (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone.

3. The process according to claim 2 , wherein the base is selected from the group consisting of ammonia, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, potassium carbonate and sodium bicarbonate.

4. The process according to claim 2 , wherein the first diastereomer salt is a salt of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and di-p-anisoyl-D-tartaric acid having the formula VI

or a salt of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone and di-p-anisoyl-L-tartaric acid having the formula VII

5. The process according to claim 1 , wherein step a) is carried out in the presence of a solvent, wherein the solvent is a mixture of water and a polar solvent.

6. The process according to claim 5 , wherein the polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone and acetonitrile.

7. The process according to claim 5 , wherein the solvent is a mixture of water and ethanol.

8. The process according to claim 1 , wherein the chiral tartaric acid derivative is the D-isomer of the tartaric acid derivative.

9. The process according to claim 1 , wherein the chiral tartaric acid derivative is di-p-anisoyl-D-tartaric acid.

10. 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.

11. 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.

12. The process according to claim 11 , wherein the step (ii) comprises reacting the (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone of the second diastereomeric salt with sodium hydroxide.

Assignees

• Rao Dharmaraj Ramachandra
• Kankan Rajendra Narayanrao
• Phull Manjinder Singh
• Sawant Ashwini Amol
• Cipla Ltd

Inventors

• Rao Dharmaraj Ramachandra
• Kankan Rajendra Narayanrao
• Phull Manjinder Singh
• Sawant Ashwini Amol

Classifications

• C07D237/04 Primary

  having less than three double bonds between ring members or between ring members and non-ring members · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C07D237/06

  having three double bonds between ring members or between ring members and non-ring members · CPC title