RE-CRYSTALLIZATION METHOD OF 2-METHYL-6-OXO-1, 6-DIHYDRO-3, 4'-BIPYRIDINE-5-CARBONITRILE (MILRINONE)

Priority

This application claims the benefit to the provisional application No. 5636/CHE/2013. filed on December 6.2013 entitled "re-crystallization method of 2-methyl-6-oxo-l,6-dihydro-B^'-bipyridine-S-carbonitrile^ilrinone)" the contents of which incorporated by reference herein
Field of the Invention

The present invention relates to a method of purifying crude milrinone by recrystallization. More particularly, the invention relates to novel method of recrystallization to produce pure 2-methyl-6-oxo-l, 6-dihydro-3, 4'-bipyridine-5-carbonitrile (milrinone).
Background of the Invention

Milrinone, commonly known and marketed as the drug Primacor, is a medication used in patients suffering from heart failure.

Milrinone is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility. Milrinone also works to vasodilate vessels which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. Milrinone has been used in those suffering from heart failure for many years.

Recrystallization in the prior art methods by using single solvent need to have complex operation and the pollution is relatively large. Purification of such compounds to meet pharmaceutical specifications requiring exceptionally high purity is difficult even in the laboratory and more so in manufacture of commercial quantities. Indeed, even prior successful purification procedures require numerous time and yield-consuming cycles of recrystallization.

Illustrative some of the recrystallized methods in the prior art have used many times to achieve recrystallization purification requirements, such as Zheng Takaaki etc., Chinese Journal of Pharmaceuticals 1990 volume 21 (11) The page 486-487) discloses using dimethylformamide ( DMF) was recrystallized, but the product as a pale yellow granular crystals, the color cannot reach medical requirements, and dimethylformamide (DMF) relatively expensive (compared to other commonly used), thus the use of the multiple recrystallization gives higher cost.

Liu Qiming, etc., Huazhong University (Medical Sciences) 34 No. 1, No. 74, February 2005), the use of ethanol recrystallization, the experiment confirmed that a large amount of solvent used is 20 times more, and then in the refining process using activated charcoal (filtering may cause the product to precipitate, the adsorption of the activated carbon, resulting in reduced yield of the product), and recrystallized three times to reach through the purification requirements to get the purity 99.63%.

In Chinese Patent CN102558044, method of recrystallization of crude milrinone is carried out by using DMF and water at the temperature from 80-95 ° C as mentioned.

In Chinese patent CN 101143844, the final purification method of crude milrinone is carried out by acetone and ether treatment, as the solvent acetone is highly expensive and the ether is highly flammable, this acetone and ether treatment is not suitable for bulk industrial production.

In U.S. Patent No. 6118002, the purification of l,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)-nicotinonitrile (milrinone) is mentioned where the emphasis of the invention is more on the removal of the amide impurity from the crude milrinone.

Patent CN1629141 in China, the use of "one-pot" was obtained as milrinone is still crude. The process of purification or recrystallization methods of Milrinone described in the prior art procedure are complex and cumbersome. Therefore, a need is felt to develop a simplified and industrially applicable method of purification of crude milrinone.
The present invention involves novel method for recrystallization of milirinone, using mixed solvent system. According to the present invention using of using mixed solvent system for the recrystallization method of milrinone has advantage of cost reduction in terms of solvents, reduce production costs and is environmentally friendly; also seen in the invention the satisfactory appearance and color of the crystal, where the color appears to be white, rather than the yellow or yellowish colored crystals obtained in the conventional method of crystallization.

Summary of the Invention

Taking into consideration the above mentioned shortcomings of the known prior art processes for the purification of milrinone of the formula I, our aim was directed towards developing an improved environmentally safe and industrially applicable purification process, which is devoid of the above-mentioned insufficiencies.

The present invention provides the melhod of re-crystallizing milrinone. More particularly the present invention provides novel method of re-crystallization of milrinone used in the synthesis of milrinone final purification step of the reaction.

One of the embodiments of the present invention provides method for re-crystallization of the crude milrinone from mixture of organic solvents. The process comprising crude milrinone was dissolved in first solvent and addition of second solvent followed by isolation of the white crystals of pure milrinone.

Detailed Description of the Invention

The present invention related to the novel method of re-crystallization of milrinone. The process for preparing milrinone is prepared as the process known in the art.

The main objective of the present invention is to provide an improved process for the preparation of highly pure (> 99.8%) milrinone overcoming the drawbacks of the hitherto known prior art processes.

Another objective of the present invention is to provide an improved process for the preparation of highly pure (> 99.8%) milrinone of the formula (1) avoiding the multiple recrystallizations, contamination of solvents, complicated operation thereby making the process simple.

Yet another objective of the present process is to provide an improved process for the preparation of highly pure (> 99.8%) milrinone by isolating crude milrinone by recrystallizing from mixed solvents.

Yet another objective of the present process is to provide an improved process for the preparation of highly pure (> 99.8%) milrinone by crystallization with polar aprotic solvents and a polar protic solvents.

Still another objective of the present invention is to provide an improved purification process for the preparation of highly pure (> 99.8%) milrinone of the formula (I) by using polar solvent comprising dimethylformarnide. dimethyl sulfoxide and acetonitrile and an alcoholic solvent as a second crystallization solvent.

The inventive step of present invention is on the recrystallization of milrinone crude to produce pure white colored milrinone crystals.

The present invention involves novel recrystallization method for the purification of milrinone. Milrinone crude used as a starting material can be obtained by the known prior art methods.

The present invention involves purification of crude milrinone by recrystallization method involving mixture of solvents. The crude milrinone as obtained by any known prior art methods dissolved in a first solvent at an ambient temperature then a second solvent added to the reaction solution followed by isolation of the separated solid. The volume of the first solvent used for the dissolution of milrinone crude comprises from 2 to 10 times of the crude material. Preferably the volume of the first solvent used for the dissolution of milrinone crude comprises from 5-8 times, more preferably the volume of the first solvent comprises 5-10 times. Milrinone crude dissolved in first solvent at a suitable temperature. Preferably, milrinone crude dissolved in the first solvent at 25 C to 90°C. Preferably, the temperature comprises from 40°C to 80°C. More preferably, the temperature comprises from 55°C to 70°C. A second solvent added to the solution of milrinone crude at a suitable temperature, preferably, the second solvent can be added at 25°C to 70°C. Most preferably, the second solvent can be added at 40°C to 60°C. Finally, the solid of the purified milrinone can be isolated from the mixture of solvents by the conventional methods.

The process of purification of milrinone crude by recrystallization method of the present invention comprises,
a) addition of first solvent to the crude milrinone under stirring in a reaction vessel;
b) heating the reaction solution of step a) to 35°C to 90°C;
c) stirring the reaction solution of step b) for about 10 to 50 minutes;
d) addition of a second solvent to the reaction solution of step c) at 30 C to 65°C for
about 25 to 50 minutes;
e) stirring the contents of step d) at about 35°C to 55°C for about 25 to 45 minutes;
f) cooling the reaction solution of step e) to 5 to 20°C and stirring for about 10 to 40
minutes;
g) filtering the separated solid of step 0 by conventional method and washing the solid with second solvent, and h) drying the obtained solid of step g) at about 40 to 80°C for about 3-10 hours. The first solvent of step a) is an organic solvents preferably, a polar aprotic solvent selected from the group comprising tetrahydrofuran, acetonitrile, dimethyl formamide, dimethyl sulfoxide, ethyl acetate and acetone.

Most preferably, the first solvent is dimethyl formamide.

The second solvent of step d) is preferably an organic solvent, more preferably a polar protic solvent selected from an alcohol, formic acid, hydrogen fluoride and ammonia. Most preferably the second solvent is an alcoholic solvent such as methanol, ethanol, propanol and isopropanol.

The addition of second solvent of step d) is preferably carried out at temperature 35 to 60°C. More preferably, the addition of second solvent is carried out at 40-55 C.

The drying of the solid at step h) is carried out under vacuum at about 50 to 75°C, more preferably, the solid is dried at 55 to 70°C under vacuum.

Optionally, the solid compound of step g) can be taken back and the steps of a) to g) separated for better quality of the product.

Optionally, the dried compound of step h) is subjected to micronization followed by drying at about 55 to 75°C under vacuum.

Milrinone obtained by the process of the present invention comprises white crystals with purity above 99.80%. Accordingly, the present invention provides a process of purification of milrinone which is simple and convenient with high yield and purity. This is well suitable for industrial production and drug injection preparation.

The details of the invention are given in the Example, which is provided for illustration only and therefore the Example should not be construed to limit the scope of the invention.

Examples

Preparation of (1, e-Dihydro-l-methyl^-oxo-P^'-bipyridinel-S-carbonitrile) (Milrinone pure) 50 grams of the milrinone crude product as obtained by the prior art methods was dissolved in 500 ml dimethyl formamide at 65-75°C and stirred for 30 minutes. The reaction solution was filtered through watmann filter paper at hot condition. To the filtrate 500 ml of methanol was slowly added at 45-55°C for about 40 minutes. The reaction solution was stirred at 45-55°Cs for about 30 minutes. Cooled the reaction solution to 10-15°C and stirred for about 30 minutes. Filtered the solid and washed with methanol (25 ml). Dried the obtained solid under vacuum at 65-70°C for about 6 hours.

We Claim

1. An improved process for the purification of Milrinone (I) comprises the following steps of

a) dissolving the crude milrinone in a first solvent at a suitable temperature;
b) stirring the reaction solution of step a) at an ambient temperature for about 1 to 5 hours;
c) adding a second solvent to the reaction solution of step b);
d) cooling the reaction contents of step c) to 0-3 5°C;
e) stirring the contents for about 1-3 hours at 0-25°C;
f) filtering the separated solid of step e) by a suitable method;
g) washing the solid of step f) with the second solvents and
h) drying the solid at a suitable temperature for about 3 hours to get the pure milrinone.

2. An improved process according to claim 1 wherein the first solvent of step a) is a polar aprotic solvent selected from the group comprising tetrahydrofuran, acetonitrile, dimethyl formamide, dimethyl sulfoxide, ethyl acetate and acetone.

3. An improved process according to claim 1 wherein the second solvent of step c) is a polar protic solvents selected from the group comprising an alcohol, formic acid, hydrogen fluoride and ammonia.

4. An improved process according to claim 3 wherein the solvent is an alcoholic solvent such as methanol, ethanol, propanol and isopropanol.

5. An improved process according to claim 1 in step c) wherein the addition of the second
solvent is carried out at temperature 35 to 60°C.

6. An improved process according to claim 5 wherein the addition of the second
solvent is carried out at temperature 40 to 55°C.

7. An improved process according to claim ] further comprises micronization of the
solid of step h) by conventional methods.

8. An improved process according to claims 1-7 wherein a milrinone is
obtained as a crystalline compound.

Recrystallization method of 2-methyl-6-oxo-l,6-dihydro-3,4*-bipyridine-5-carbonitrile(milrinone)