Field of the Invention:
The present invention relates to the process for preparation of" Milrinone" and its structurally related analogs. Milrinone is chemically known as l,6-Dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile, whose structure is depicted below.

(i) R= CH3 (Milrinone) Milrinone is known to be useful as cardiotonic agent. It is available in the form of injectable as the lactate salt.
Background of the Invention:
US Patent 4,413,127 discloses a process for preparation of Milrinone comprising the reaction of l-Ethoxy-2-(4-pyridinyl) ethenyl methyl ketone with malononitrile in ethanol. US Patent 4,313, 951 also discloses a process for preparation of Milrinone in which l-(4-pyridinyl)-2-(dimethylamine) ethenyl methyl ketone reacts with a-cyanoacetamide in DMF in presence of sodium methoxide. The other US Patents 4, 347, 363 and 4, 469, 871 also discloses the process for preparation of Milrinone.
According to the US Patent 6,118,002 all prior art processes for preparation of Milrinone are often burdened by co-production of impurities that require unusual measures to achieve purity levels suitable for pharmaceutical applications. US Patent 6,118,002 discloses a process for purification of Milrinone, in which the corresponding amide impurity (l,6-Dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carboxamide) is

derivatised by acylation and the derivatised impurity was separated by recrystallisation techniques due to it's differentiated solubility.
The prior art does not discloses a process for separation of impurit(y)ies including amide impurity except US Patent 6,118,002, which involves an additional chemical reaction utilizing an acylating agent. The process disclosed in the US Patent 6,118,002, as described above is not suitable for commercial scale production of Milrinone, since it involves an additional reagents, solvents and operations.
Hence it is required to develop a cost-effective, eco-friendly and a simple process, which gives a pharmaceutically acceptable pure Milrinone. The present invention is directed towards highly pure Milrinone having HPLC purity not less than 99.5 % with an amide impurity less than 0.3%, preferably less than 0.1%.
Summary of the Invention:
The present invention is directed to a process for the preparation of highly pure Milrinone a cardiotonic agent and it's structurally related analogs of formula (I).

The process comprises reaction of l-(lower-alkoxy)-2-(4-pyridinyl) ethenyl lower-alkyl ketone of formula (II)


in a suitable solvent in the presence of base to result a highly pure Milrinone and it's analogs.
Detailed Description of the Invention:
The present invention provides a process for preparation of highly pure Milrinone and it's analogs.
The process of present invention comprises:
a) Dissolving l-(lower-alkoxy)-2-(4-pyridinyl) ethenyl lower-alkyl ketone of
formula (II) in an alkanol;
b) addition of malononitrile of formula (III);
c) followed by addition of a base;
d) heating the resulting mixture to a sufficient time for completion of the reaction;
e) cooling the reaction mass;

f) isolating of the separated solid in a conventional manner.
g) drying the wet solid to s constant weight.
The process of the present invention is schematically depicted below.

The term lower alkyl or lower alkoxy means C1-C4 carbons in straight or branched chain. For example the lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl and tert-butyl. Similarly lower the alkoxy groups represents methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy and tert-butoxy.
Step a) of the present invention involves the dissolution of l-(lower-alkoxy)-2-(4-pyridinyl) ethenyl lower-alkyl ketone of formula (II) in an alkanol having carbon atoms 1 to 4, illustrated by methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and alike. The dissolution of the compound of formula (II) in alkanol can be performed between 25°C to reflux temperature of the alkanol being used, but the preferred dissolution temperature is 25 - 40°C.
Step b) is the addition of malononitrile after dissolution of l-(lower-alkoxy)-2-(4-pyridinyl) ethenyl lower-alkyl ketone of formula (II) at 25°C to reflux temperature of the alkanol being used, but the preferred addition temperature of Milrinone is 25 - 40°C. The

addition of malononitrile can be performed in small portions if required at commercial scale production.
Step c) is the addition of base after addition of malononitrile of formula (III) at 25°C to reflux temperature of the alkanol being used, but the preferred addition temperature of the base is 25 - 40°C. The addition of base can be performed in small portions if required at commercial scale production.
Step d) involves the heating of reaction mass after addition of base slowly to an elevated temperature particularly reflux temperature of the solvent being used in the reaction. In general the reflux temperature is continued for about 10 to 30 hours, preferably to 20 hours for completion of the reaction. Optionally the reaction can be monitored by Chromatographic techniques preferably Thin Layer Chromatographic technique.
Step e) involves cooling of the reaction mass to 0 - 40°C, preferably 25 - 30°C
Step f) is the separation of solid by conventional techniques such as centrifuge or filtration.
Step g) involves drying of the wet solid at 30 - 80°C, preferably at 65 - 70°C. The drying can also be done under vacuum till the weight attains.
Milrinone obtained in the present invention is having above 99.5% purity on HPLC analysis. The related amide impurity is well below the pharmacopoeial limits (less than 0.3%) and in most of the times the level of amide impurity is less than 0.1%.
The compound of the formula (II), can be prepared by the processes described known in the art. Malononitrile of the formula (III) is available in commercial quantities.

The following examples will further illustrate the invention without, however, limiting it thereto.
Experimental Section:
Reference example:
Preparation of l-Ethoxy-2- (4-pyridinyI) ethenyl methyl ketone (Formula (II),
R=CH3: Rx = C2H5):
To a mixture containing 55.5 ml (49.5 grams, 0.3345 moles) of triethylorthoformate, 52.5 ml (56.7 grams, 0.5564 moles) of acetic anhydride and 60.0 ml of acetic acid was added 30.0 grams (0.2222 moles) of l-(4-Pyridinyl) propan-2-one, with stirring at room temperature whereupon an exothermic reaction took place raising the reaction temperature from 30° C to 43° C. Stirring of the reaction mixture was continued while allowing the temperature to cool to room temperature and then continued for 22 hours. The reaction mixture was then concentrated on a rotary evaporator at about 60 - 74° C under vacuum and diluted with 300.0 ml of ethyl acetate. Reaction mixture was washed with a solution of 14.0 grams sodium carbonate dissolved in 140.0 ml of water. The reaction mixture was treated with 1.5 grams of carbon followed by drying over 10.0 grams of sodium sulphate. Solvent was distilled off under vacuum at below 55°C and 30.0 ml of heptane was added. Heptane distilled of under vacuum at below 55°C to get the residual mass. 150.0 ml of Heptane was added to the resulting residual mass and stirred at room temperature for 1 hour. Separated solid was filtered and washed with 30.0 ml of Heptane and dried under vacuum at 30 °C for 2 hours to yield 35.8 grams (84%) of l-Ethoxy-2-(4-pyridinyl)-ethenyl methyl ketone, which was used in the next step without further purification.
The same process is adopted in preparation of other analogues of compound of formula (II).

Example 1
Preparation of l,6-Dihydro-2-methyl-6-oxo-[3,4,-bipyridine]-5-carbonitriIe (Milrinone):
30.0 grams (0.1571 moles) of l-Ethoxy-2- (4-pyridinyl) ethenyl methyl ketone (Obtained in reference example) was dissolved in 300 ml of methanol, 10.4 grams (0.1576 moles) of malononitrile and 1.8 ml (1.3 grams, 0.0129 moles) triethyl amine were added sequentially at 30°C. The resulting mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature; and the precipitate of fine needle type crystals were filtered, washed with 60.0ml of methanol, dried at 68°C till the constant weight to yield 24.8 grams (75%) of l,6-Dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile. HPLC purity is 99.85%, with a single maximum impurity of 0.07%.
It can be further purified from methanol.

We Claim:
1. A process for preparation of highly pure l,6-Dihydro-2-alkyl-6-oxo-[3,4'-bipyridine]-
5-carbonitrile of the formula (I):

wherein R is a lower alkyl group,
which comprises reaction of l-(lower-alkoxy)-2-(4-pyridinyl)ethenyl lower-alkyl ketone of the formula (II)

wherein R and Ri is a lower alkyl group, with malononitrile in a solvent, in presence of base.
2. The process according to claim 1, wherein R is C1-C4 straight or branched chain alkyl
groups.

3. The process according to claim 2, wherein R is methyl and R1 ethyl.
4. The process according to claim 1, wherein the said solvent is C1-C4 alkanol.
5. The process according to claim 4, wherein the said C1-C4 alkanol is a methanol.
6. The process according to claim 1, wherein the base is an organic or inorganic.
7. The process according to claim 6, wherein the organic base is trialkylamine.
8. The process according to claim 7, wherein the trialkyl amine is triethyl amine.
9. The process according to claim 1, wherein the reaction is carried out at elevated
temperatures.
lO.The process according to claim 95 wherein the reaction is carried out at a temperature of 40°C to reflux temperature of the alkanol.
11. The process according to claim 10, wherein the reaction temperature is reflux
temperature of the alkanol.
12. A process as claimed in claim 1 for the preparation of l,6-Dihydro-2-alkyl-6-oxo-
[3,4'-bipyridine]-5-carbonitrile is substantially as herein before exemplified.