FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARING LEVO ISOMER OF [[4-(l,4,5,6-
TETRAHYDRO-4-METHYL-6-OXO-3-
PYRIDAZINYL)PHENYL]HYDRAZONO]PROPANEDINITRILE"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956

(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Technical field:
The present invention describes a process for preparing pure (-) enantiomer of [[4-(l,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (levosimendan) (Formula I).

Background and prior art:
Levosimendan is a highly potent cardiotonic that increases the sensitivity of heart to calcium without causing a rise in intracellular calcium. The drug is marketed by Abbott under the trade name Simdax. It was first disclosed in US5569657.
The prior art indicates that pure levosimendan can be obtained by passing the racemic mixture over a chiral phase chromatography column. But the process becomes tedious and industrially unacceptable when large quantity of material is involved.
The other technique involves using optically pure (-) enantiomer of 6-(4-aminophenyl)-5-methyl pyridazin-3(2H)-one as starting material. The method of obtaining (-)6-(4-aminophenyl)-5-methyl pyridazin-3(2H)-one are given in EP208518, which describes the separation of pure enantiomers of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone using chiral HPLC column.
CN1616437 describes treating (+)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone with 50% alkali or 50% acid.
JP10109977 discloses use of 1-propanol/ethyl acetate as resolving solvent and L- or D-tartaric acid as resolving agent.
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US5569657 discloses preparation of levosimendan and its salts. (±)6-(4-aminophenyl)-5-methyl pyridazin-3(2H)-one is dissolved in 2-propanol on heating. L-tartaric acid is gradually added to the solution and stirred on heating to obtain a clear solution. The solution is cooled slowly to room temperature and then stirred over night at 20°C to obtain crystalline product. On filtering the wet salt is dissolved in water and to it potassium carbonate solution is added with stirring. The free base obtained is filtered, washed with water and dried. The product is further dissolved in dioxane on heating and allowed to cool to room temperature. The contents are filtered and dried under vacuum to obtain (-)6-(4-aminophenyI)-5-methyl pyridazin-3(2H)one crystalline solid. The pure (-)6-(4-aminophenyl)-5-methyl pyridazin-3(2H)-one compound is then treated with sodium nitrite and malononitrile under acidic condition to obtain levosimendan. The disadvantage of the resolution process disclosed is that to obtain a high optical purity (99.5%) of pyridazinone compound recrystallisation with dioxane is required. Also the process involves multiple steps and is time consuming.
US6180789 describes preparation of levosimendan by treating (-) enantiomer of 6-(4-
amino phenyl)-5-methyl pyridazin-3(2H)-one, resolved using D- or L-tartaric acid in
aqueous ethyl acetate, with sodium nitrite and malononitrile and further crystallizing with
aqueous acetone.
The patent also discloses other resolving agents like benzoic acid, sulphuric acid and
resolving solvents like isopropanol, isobutanol, isopropyl acetate, butyl acetate, acetone
and acetonitrile; but they are said to cause partial resolution only.
There are certain drawbacks of the process disclosed in US6180789 -
When D-tartaric acid is the resolving agent -
Excess amount of resolving agent is required to achieve complete resolution.
Seeding with D-tartaric acid salt of (-)6-(4-amino phenyl)-5-methyl pyridazin-3(2H)-one
is also needed in the process.
Hot filtration of the precipitate is to be done; which is not at all workable when dealing
with large batches at industrial scale.
The temperature of reaction is to be maintained at 0°C.
The enantiomeric purity of the product is low, even after giving a number of washings.
In order to get desired enantiomeric excess recrystallisation with acetonitrile in presence
of absorbent followed by washing with excess acetonitrile is needed. Treatment with
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large amount of solvent increases the cost of the process and also reduces the yield due to
wastage.
When L-tartaric acid is the resolving agent -
For the precipitation of salt, cooling upto - 10°C is required.
Also the enantiomeric purity of the desired (-)6-(4-amino phenyl)-5-methyl pyridazin-
3(2H)-one product is quite low (78.7%).
Due to the problems with the prior art there is felt a need to develop a new process for resolving Ievosimendan that is simple, economical, eco-friendly and good yielding.
Objects of the invention:
The object of the present invention is to provide a process for resolving (-) enantiomer of 6-(4-aminophenyl)-5-methyI pyridazin-3(2H)-one from its racemic mixture.
Another object of the present invention is to provide an improved process for preparing optically pure Ievosimendan.
Yet another object of the present invention is to provide a process that produces Ievosimendan in high yield and enantiomeric purity without any additional means of purification.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The process of present invention relates to the preparation of Ievosimendan in high optical purity without any recrystallisation or purification.
According to the present invention there is provided a process for preparing optically pure Ievosimendan by resolving (±)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-
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pyridazinone with a resolving agent to obtain diastereomeric salt of (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and resolving agent, converting the salt into enantiomerically pure (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and then treating the free base with sodium nitrite and malononitrile.
In an embodiment the process of present invention involves reaction of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone of formula II with a resolving agent which is preferably a chiral tartaric acid derivative of formula III in the presence of a solvent to obtain corresponding diastereomeric salt of formula IV.

The chiral tartaric acid derivative is selected from D- or L- isomers of di-p-anisoyl-tartaric acid, di-p-tolyl-tartaric acid or O, O'-dibenzoyl-tartaric acid. Preferably the chiral acid for the process of present invention is D-isomer of the tartaric acid derivative but most preferably di-p-anisoyl-D-tartaric acid of formula III is used.

Formula III
The solvent employed for the preparation of diastereomeric salt in the process of present invention is a mixture of water and polar solvent. The polar solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone and acetonitrile. Most preferably the solvent used in the process of present invention is a mixture of water and ethanol.
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In another embodiment the process of present invention further involves treating the diastereomeric salt of formula IV with a base in presence of solvent to obtain (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone of formula V.

The solvent for this reaction is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, water and acetonitrile. Preferably the solvent used for the preparation of free base in the process of present invention is water.
Further the (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (V), prepared by process of present invention, is treated with sodium nitrite and malononitrile to obtain levosimendan (I).
The particularly preferred process of present invention for preparing levosimendan (formula I) comprises;
(a) reacting (±)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone of Formula II,

Formula II
with di-p-anisoyl-D-tartaric acid of formula III in the presence of water and ethanol solvent mixture to form diastereomeric (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone di-p-anisoyl-D-tartaric acid salt of formula IV,
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Formula IV
at a temperature ranging from 55°C to 70°C. The salt may further be optionally recrystallised using water and ethanol solvent mixture.
(b) treating the diastereomeric salt of formula IV with an organic or inorganic base
selected from sodium methoxide, sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium bicarbonate, potassium carbonate or sodium bicarbonate in
presence of water to obtain pure (-) enantiomer of 6-(4-aminophenyl)-4,5-dihydro-5-
methyl-3(2H)-pyridazinone of formula V.

Formula V
(c) reacting (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)~pyridazinone of formula
V with sodium nitrite and malononitrile under acidic condition to obtain levosimendan of
formula I.
The mother liquor from the resolution step (a) is enriched with (+)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone which may be converted into (±)6-(4-aminophenyl)-4,5-dihydro-5-rnethyl-3(2H)-pyridazinone and used again in the process of present invention.
The process of present invention yields levosimendan in substantially pure enantiomeric form. The ratio of levosimendan : dextrosimendan as prepared by process of present invention is about 99 : 1, as compared to the 96:4 ratio obtained by prior art process. Also
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the levosimendan prepared from the present process has a purity of about 99.9%, as determined by chiral HPLC.
In another embodiment, the (±)6-(4-aminophenyl)-4,5-dihydro-5-rnethyl-3(2H)-pyridazinone is reacted with di-p-anisoyl-L-tartaric acid in the presence of water and ethanol solvent mixture to form diastereomeric (+)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone di-p-anisoyl-L-tartaric acid salt. The mother liquor obtained on resolution contains (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone which acts as starting material for the preparation of levosimendan.
Further in the process of present invention highly pure (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone is obtained without any recrystallisation or purification. Thus preventing the wastage of solvent and corresponding decrease in yield of product; in turn making the process economical, high yielding and industrially viable. Also the use of di-p-anisoyl-D-tartaric acid as resolving agent causes rapid precipitation of the diastereomeric salt which in turn in a single step gives levosimendan in high yield. The solvent employed in process of present invention is a mixture with water which makes the process environment friendly.
The details of the invention are given in the examples which are provided below for illustration only and therefore these examples should not be construed to limit the scope of the invention.
Examples:
Example 1
Step 1: 50 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 500 ml ethanol was added to a flask and stirred at 65°C for 30 min. Further di-p-anisoyl-D-tartaric acid (113.3 g) and 500 ml water was added and stirring was continued for 1 hr. The reaction mass was cooled to 15°C and stirred for another 30 min. Then the mass was filtered, washed with water and dried under vacuum at 55°C to obtain corresponding diastereomeric salt (yield - 110 g, purity - 99.5%). Step 2: The obtained salt and water (500 ml) was added to a reaction vessel and stirred at 25 - 30°C for 30 min. The pH of the resulting solution was adjusted to 8-9 by adding
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10% potassium carbonate solution and stirring was continued for 30 min. After completion of reaction, the contents was filtered and dried under vacuum at 55°C to obtain solid (-)6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (yield - 24 g, purity - 99.6%).
Step 3: To a solution of (-)6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one (20 g) and dilute hydrochloric acid (52 ml of concentrated hydrochloric acid in 789 ml of water), 8 g of dilute sodium nitrite (8 g of sodium nitrite in 52 ml of water) was added and stirred. After 10 min malononitrile solution (6.3 g malononitrile in 52 ml of water) was added. The solution was stirred for 1 hr at room temperature. The pH of suspension was adjusted to 6.0 with sodium acetate solution. The suspension was filtered, washed with water followed by ethanol and then dried to obtain solid levosimendan (yield -22 g, purity -99.9%).
Example 2
10 g of racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 100 ml ethanol were added and stirred at 65°C for 30 min. Di-p-anisoyl-L-tartaric acid (22.6 g) and 100 ml water were added and stirring continued for 1 hr. After completion of reaction, the mass was cooled to 15°C to get a solid and then filtered. The mother liquor obtained was treated with sodium nitrite and malononitrile as described above to obtain solid levosimendan (yield - 4 g, purity - 99.6%).
Example 3
The filtrate obtained from step 1 of Example 1 was further treated with 50% sodium hydroxide solution as described above to obtain racemic 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone
Dated this 14th day of July 2009

Dr. Gopakumar G. Nair Agent for the Applicant
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