Process for the preparation of high purity Levosimendan
Inventors
BHATT, Chiragkumar Anilkumar • Pandya, Keyurkumar Amrutla • Parmar, Pankaj Vasudev • Jeyakumar, John Muthiah Raja
Assignees
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Publication Number
US-11760730-B2
Publication Date
2023-09-19
Expiration Date
Abstract
An improved process for the preparation of high purity Levosimendan includes treatment of Levosimendan crude with an organic acid, adding an organic acid to precipitate Levosimendan and isolating pure Levosimendan from the precipitate. Levosimendan obtained by the improved process is pharmaceutically acceptable with no impurity higher than 0.2 percent.
Core Innovation
The process relates to the preparation of pharmaceutically acceptable Levosimendan by chirally resolving a racemic mixture of (±)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one to yield (−)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one, followed by converting the (−)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one to Levosimendan crude. The Levosimendan crude is then dissolved in an organic solvent, water, or a mixture thereof, and an organic acid is added to precipitate Levosimendan.
The described purification focuses on precipitating Levosimendan from the dissolved crude by adding an organic acid, with precipitation optionally carried out with cooling and then isolated by filtration of the precipitate, with optional washing steps and drying. The purified Levosimendan has no impurity above 0.2% and is free of an unknown impurity attributed to prior reflux degradation (MW ~561.55).
The broader described preparation route includes chirally resolving a racemic intermediate, converting the resolved intermediate to Levosimendan crude, and applying the organic-acid precipitation purification. Organic acids are listed as suitable for the precipitation step, and the partial content further reports avoidance of reflux of crude/water as part of the improved approach.
Claims Coverage
The document contains one independent claim (clm-00001) directed to a purification process framework for preparing pharmaceutically acceptable Levosimendan, with multiple dependent claims that refine solvent choice, acid/precipitation conditions, and isolation/washing details. Across the claim set, the inventive features center on chirally resolving a racemic intermediate, converting it to Levosimendan crude, dissolving the crude, precipitating with an organic acid, and isolating pure Levosimendan, with additional constraints for precipitation conditions and optional downstream washing/isolation refinements.
Chiral resolution of a racemic intermediate
Chirally resolving a racemic mixture of (±)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one to yield (−)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one.
Conversion to Levosimendan crude
Converting the (−)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one to Levosimendan crude.
Dissolving Levosimendan crude in an appropriate medium
Dissolving the Levosimendan crude in organic solvent, water, or a mixture thereof.
Organic-acid precipitation of Levosimendan
Adding an organic acid to the dissolved crude to precipitate Levosimendan.
Isolation of pure Levosimendan
Isolating pure Levosimendan.
Acid addition conditions for precipitation
Adding an organic acid solution at 0–5°C until the reaction mixture reaches a pH of about 2–4.
Cooling-induced precipitation followed by filtration
Precipitating through cooling and then filtering the resulting precipitate.
Acetone as an organic solvent
Using acetone as the organic solvent.
Weak-base washing using selected weak bases
Using a weak base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, potassium acetate, ammonium acetate, and basic salts of an organic acid.
Overall claim coverage emphasizes preparing pharmaceutically acceptable Levosimendan by resolving a racemic intermediate to the (−) enantiomer, converting to Levosimendan crude, dissolving the crude, precipitating Levosimendan by adding an organic acid, and isolating pure Levosimendan. Dependent refinements further specify precipitation conditions (temperature and pH), isolation by cooling precipitation and filtration, concrete solvent selection (acetone), and optional washing using defined weak-base salts.
Stated Advantages
Purified Levosimendan has no impurity above 0.2%.
Purified Levosimendan is free of an unknown impurity (MW ~561.55) attributed to prior reflux degradation.
Comparative HPLC purity data versus EP0894087 (reflux) is provided to support improved purity.
Documented Applications
Preparation of pharmaceutically acceptable Levosimendan, including a purification approach based on organic-acid precipitation to isolate pure Levosimendan from Levosimendan crude.
Heart failure context is mentioned via 'calcium sensitizer' and 'heart failure (ADHF)' in the partial content key entities.
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