Field of the Invention:

The present invention relates to an improved process for the preparation of clevidipine butyrate. Clevidipine butyrate is chemically known as butyroxymethyl methyl 4-(2',3 '-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and represented by following structural formula-1.

Further the present invention also provides novel crystalline forms of clevidipine butyrate and its intermediates thereof

Clevidipine butyrate (INN, trade name Cleviprex) is a dihydropyridine L-type calcium charmel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Clevidipine butyrate is highly selective for vascular, as opposed to myocardial, smooth muscle and, therefore, has little or no effect on myocardial contractility or cardiac conduction. Clevidipine was approved by the United States Food and Drug Administration on August 1,2008.

Background of the Invention:

Clevidipine butyrate and its process for preparation were first disclosed in US 5856346. The disclosed process involves the condensation of 4-(2',3'-dichlorophenyl)-5- (methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylic acid with chloro methyl butyrate in presence of sodiumbicarbonate in dimethylformamide at 80°C, followed by chromatographic purification provides clevidipine butyrate. Thus obtained clevidipine butyrate was further recrystallized from diisopropylether to provide clevidipine butyrate, having purity around 96%. The said process involves chromatographic technique for purification, which is difficult to carry out in industrial scale. Further the purity of the intermediate and final compound obtained was not satisfactory. Hence this process is commercially not suitable.

us 2003230478 disclosed a process which involve the condensation of 2,3-dichlorobenzaldehyde with methylacetoacetate under microwave irradiation to provide 3,5-dimethyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-carboxyate. The said process involves usage of microwave irradiation which in turn not possible on large scale.

Hence, there is need in the art to develop an improved process for the preparation clevidipine butyrate which avoids chromatographic purification and should be practiced on large scale to produce highly pure clevidipine butyrate in cost efficient manner.

Summary of the Invention:

The first aspect of the present invention provides an improved process for the preparation of clevidipine butyarate compound of formula-1, which comprises of following steps;

a) Condensing the 2,3-dichlorobenzaldehyde compound of formula-2 with methylacetoacetate compound of formula-3 in the presence of an ammonia source in a suitable solvent to provide 3,5-dimethyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4- dihydropyridine-3,5-dicarboxyate compound of fonnula-4,

b) hydrolyzing the compound of formula-4 in the presence of a suitable base in a suitable solvent to provide 4-(2',3'-dichloro phenyl)-5-(methoxycarbonyl)-2,6- dimethyl-l,4-dihydropyridine-3-carboxylic acid compound of formula-5, where in the suitable base used in the mole ratio less than 2.0 molar equivalents w.r.to the compound of formula-4,

c) purifying the compound of formula-5 with a suitable solvent provides highly pure 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylicacid compound of formula-5,

d) reacting the pure compound of formula-5 with chloromethyl butyrate compound of formula-6 in the presence of a suitable base in a suitable solvent to get clevidipine butyrate compound of formula-1,

e) recrystallizing the clevidipine butyrate from a suitable solvent provides highly pure clevidipine butyrate compound of formula-1.

The second aspect of the present invention provides a process for the purification of clevidipine butyrate compound of formula-1, which comprises of

a) Suspending clevidipine butyrate compound of formula-1 in a suitable alcoholic solvent,

b) heating the contents of reaction mixture,

c) filtering the reaction mixture,

d) cooling the obtained filtrate,

e) filtering the precipitated solid, washing with an alcoholic solvent,

f) drying the solid to get highly pure clevidipine butyrate compound of formula-1.

The third aspect of the present invention provides a process for the purification of 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylic acid compound of formula-5, which comprises of following steps;

a) Suspending the compound of formula-5 in a suitable ketone solvent,

b) heating the reaction mixture and then stirred,

c) cooling the reaction mixture,

d) filtering the solid and washing with a suitable ketone solvent,

e) drying the solid to get pure compound of formula-5.

The fourth aspect of the present invention provides a novel crystalline form of clevidipine butyrate compound of formula-1 (herein designated as crystalline form-M) as well as its process for preparation.

The fifth aspect of the present invention provides a novel crystalline form of 3,5- dimethyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxyate compound of formula-4 (herein designated as crystalline form-S) as well as its process for preparation.

The sixth aspect of the present invention provides a novel crystalline form of 4- (2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylic acid compound of formula-5 (herein designated as crystalline form-N) as well as its process for preparation.

Brief Description of the Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form-M of clevidipine butyrate.

Figure 2: Illustrates the IR spectrum of crystalline form-M of clevidipine butyrate.

Figure 3: Illustrates the DSC thermogram of crystalline form-M of clevidipine butyrate.

Figure 4: Illustrates the PXRD pattern of crystalline form-S of 3,5-dimethyl-4-(2',3'- dichlorophenyl)-2,6-dimethyl-l ,4-dihydropyridine-3,5-dicarboxyate compound of formula-4.

Figure 5: Illustrates the IR spectrum of crystalline form-S of 3,5-dimethyl-4-(2',3'- dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyate compound of formula-4.

Figure 6: Illustrates the PXRD pattern of crystalline form-N of 4-(2',3'-dichlorophenyl)-5- (methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-ca^boxylic acid compound of formula-5.

Figure 7: Illustrates the IR spectrum of crystalline form-N of 4-(2',3'-dichlorophenyl)-5- (methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylic acid compound of formula-5.

Figure 8: Illustrates the PXRD pattern of crystalline clevidipine butyrate obtained as per example-3 of US 5856346 after purification by chromatography using 45% ethylacetate in isooctane.

Figure 9: Illustrates the DSC thermogram of crytsalline clevidipine butyrate obtained as per example-3 of US 5856346 after purification by chromatography using 45% ethylacetate in isooctane.

Figure 10: Illustrates the PXRD diffractogram of crystalline clevidipine butyrate obtained as per example-3 of US 5856346 after recrystallisation from diisopropylether.

Figure 11: Illustrates the DSC thermogram of crystalline clevidipine butyrate obtained as per example-3 of US 5856346 after recrystallization from diisopropylether.

Detailed Description of the Invention:

As used herein the term "suitable solvents" refers to the solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, petroleum ether;

"hydrocarbon solvents" like toluene, xylene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutaol; "chloro solvents" like methylene chloride, chloroform and ethylene chloride; polar solvents like water; and also mixtures there of

As used herein the term "suitable base" refers to hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and etc.

As used herein the term "ammonia source" refers to ammoniimi acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, ammoniimi sulphate and ammonium nitrate etc.

Accordingly, the first aspect of the present invention provides an improved process for the preparation of clevidipine butyrate compound of formula-1, which comprises of following steps;

a) Condensing the 2,3-dichlorobenzaldehyde compound of formula-2

in the presence of an ammonia source in a suitable solvent to provide 3,5-dimethyl-4- (2',3'-dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxyate compound of formula-4.

b) hydrolyzing the compound of formula-4 in the presence of a suitable base in a suitable solvent provides 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6- dimethyl-l,4-dihydropyridine-3-carboxylic acid compound of formula-5, where in the suitable base used in the mole ratio less than 2.0 molar equivalents w.r.to compound of formula-4,

c) purifying the compound of formula-5 with a suitable ketone solvent provides highly pure 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine -3-carboxylicacid compound of formula-5,

d) reacting the pure compound of formula-5 with chloromethyl butyrate compound of fonnula-6 in the presence of a suitable base in a suitable solvent to provide clevidipine butyrate,

e) recrystallizing the clevidipine butyrate from a suitable alcoholic alcoholic solvent provides highly pure clevidipine butyrate compound of formula-1.

In a preferred embodiment, improved process for the preparation of clevidipine
butyrate compound of formula-1 comprises of following steps;

a) Condensing the 2,3-dichlorobenzaldehyde compound of formula-2 with methylacetoacetate compound of formula-3 in the presence of ammonium acetate in isopropanol provides 3,5-dimethyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4- dihydropyridine-3,5-dicarboxyate compound of formula-4,

b) hydrolyzing the compound of formula-4 in the presence of potassium hydroxide in aqueous isopropanol provides 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6- dimethyl-l,4-dihydro pyridine-3-carboxylic acid compound of formula-5, where in potassium hydroxide used in the mole ratio less than 2.0 molar equivalents w.r.to compound of formula-4,

c) purifying the compound of formula-5 with acetone to provide highly pure 4-(2',3'- dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- arboxylicacid compound of formula-5,

d) reacting the pure compound of formula-5 with chloromethyl butyrate compound of formula-6 in the presence of sodiirai bicarbonate in dimethylformamide at 80-85°C to provide clevidipine butyrate,

e) recrystallizing the clevidipine butyarte from isopropanol provides highly pure clevidipine butyrate compound of formula-1.

The second aspect of the present invention provides a process for the purification of clevidipine butyrate compound of formula-1, which comprises of the following steps;

a) Suspending clevidipine butyrate compound of formula-1 in 2-propanol or n-propanol,

b) heating the contents of reaction mixture,

c) filtering the reaction mixture,

d) cooling the obtained filtrate,

e) filtering the precipitated solid and washing with 2-propanol or n-propanol,

f) drying the solid to get the highly pure clevidipine butyrate compound of formula-1.

Clevidipine butyrate obtained as per the prior art processes, for example US 5856346 obtained after recrystallization from diisopropyl ether having purity only about 98%. The following are the details of impurities mentioned in terms of their RRT in HPLC along with its % area, which are observed in the clevidipine butyrate obtained from the process disclosed in example-3 of US 5856346.

S.No. Relative retention time(RRT in Min) Area %
1. 1.09 0.05
2. 094 0.15
3. 0.79 0.48
4 0.71 0.1

Clevidipine butyrate obtained after purification by the present invention is having purity grater than 99.8% by HPLC. Hence the present invention process is highly advantages than the prior art process.

The third aspect of the present invention provides process for the purification of 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylic acid compound of formula-5, which comprises of following steps;

a) Suspending the compound of formula-5 in a suitable ketone solvent,

b) heating the reaction mixture and then stirred,

c) cooling the reaction mixture,

d) filtering the solid and washing with a suitable ketone solvent,

e) drying the solid to get highly pure compound of formula-5.

Compound of formula-5 obtained as per the prior art process is having purity only about 97% and the same has been utilized further for the preparation of clevidipine butyrate leads to high levels of impurity in final stages.

The following are the details of impurities mentioned in terms of their RRT in HPLC along with its % area, observed in 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)- 2,6-dimethyl-l,4-dihydro pyridine-3-carboxylicacid compound of formula-5 by the prior art process.

We the present inventor surprisingly found that the purification of compound of formula-5 using acetone washed out the impurities present in that and having purity grater than 99%. When utilizing the same in the preparation of clevidipine butyrate avoids unwanted purification at final stages, thereby reducing the solvent usage and yield loss.

Further it was found that the compound of formula-5 can be further purified by converting into its amine salts by treating with a suitable amine salts selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, isobutyl amine, sec-butyl amine, tertiarybutyl amine, dimethyl amine, diethyl amine, di(n- propyl)amine, di(isopropyl)amine, di(n-butyl)amine, di(isobutyl)amine, di(sec- butyl)amine, di(tertiarybutyl)amine, trimethyl amine, triethyl amine, tri(n-propyl)amine, tri(isopropyl)amine, tri(n-butyl)amine, tri(isobutyl)amine, tri(sec-butyl)amine and tri(tertiarybutyl)amine in a suitable solvents to provide the corresponding amine salt compound of formula-5. The same amine salt has converted back into highly pure ccmpound of formula-5 by treating with a suitable acid by the conventional methods. The formation of amine salt of 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl- l,4-dihydropyridine-3-carboxylic acid and its usage in the preparation of formula-1 further enhances the purity of clevidipine butyrate.

The fourth aspect of the present invention provides a novel crystalline form of clevidipine butyrate, here in designated as crystalline form-M. Further, the crystalline form-M of clevidipine butyrate in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 7.5, 8.5, 10.1, 10.8, 14.3, 15.0, 16.2, 18.7, 19.5, 21.3, 24.8 and 25.8 ± 0.2 degrees two-theta and substantially as shown in figure-1; its IR spectrum having peaks at about 3332.75,1731.43, 1458.41, 2932.66 and 2806.15 cm"' and substantially as shown in figure-2; by its DSC thermogram showing endotherm at about 139.28°C as shown in figure-3.

Further, the present invention also provides process for the preparation of crystalline form-M of clevidipine butyrate, which comprises of following steps:

a) Suspending clevidipine butyrate compound of formula-1 in 2-propanol or n-propanol,
b) heating the contents of reaction mixture,
c) filtering the reaction mixture,
d) cooling the obtained filtrate,
e) filtering the precipitated solid and washing with 2-propanol or n-propanol,
f) drying the solid to get crystalline form-M of clevidipine butyrate compound of formula-1.

The fifth aspect of the present invention provides a novel crystalline form of 3,5- dimethyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxyate compound of fonnula-4, here in designated as crystalline form-S. The novel crystalline form-S of compound of formula-4 of the present invention is characterized by its powder XRD pattern having peaks at about 7.9,11.2,11.5,11.9,13.2, 15.9,16.4,23.1,23.8,26.2, 26.6, 27.0 and 27.3±0.2 degrees two-theta and substantially as shown in figure-4; by its IR spectrum having peaks at 3334.68, 3103.56, 2948.35, 2837.73, 1703.79 and 1502.51 cm-1 and substantially as shown in figure-5.

Further, the present invention also provides a process for the preparation of crystalline form-S of compound of formula-4, which comprises of following steps:

a) Suspending 2,3-dichlorbenzaldehyde compound of formula-2 in a suitable alcoholic solvent,

b) adding an ammonia source such as ammonium acetate, followed by methylacetoacetate to the reaction mixture,

c) heating the reaction mixture to 80-85°C,

d) cooling the reaction mixture,

e) filtering the obtained solid, washing with an alcoholic solvent and then dried to get crystalline from-S of compound of formula-4.

The sixth aspect of the present invention provides a novel crystalline form of 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- corboxylicacid compound of formula-5, here in designated as crystalline form-N. Further, the novel crystalline form-N of compound of formula-5 of the present invention is characterized by its powder XRD pattern having peaks at about 11.1, 13.2, 16.4, 16.6, 21.8, 22.6, 23.0, 26.1 and 29.9±0.2 degrees two-theta and substantially as shown in figure-6; by its IR spectrum having peaks at about 3340.14, 1682.33, 1668.56, 3070.48, 2949.94,2840.79 and 1487.52 cm"' and substantially as shown in figure-7.

Further, the present invention also provides a process for the preparation of crystalline form-N of compound of formula-5, which comprises of following steps:

a) Suspending the 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4- dihydropyridine-3-carboxylicacid in a suitable ketone solvent,

b) heating the reaction mixture to 80-85°C,

c) cooling the reaction mixture,

d) filtering the obtained solid and washing with a ketone solvent,

e) drying the solid to get crystalline form-N of compound of formula-5.

The present invention schematically represented as follows:
Clevidipine butyrate of the present invention can be further micronized or milled to get the desire particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.

Related substances of the clevidipine butyrate and its intermediate were analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Inertsil ODS-4 250 x 4.6nim, 5^m or Equivalent; Flow rate: 1.0 ml/min; Wavelength: 238 nm; Temperature: 55°C; Injection volume: 10 L; Run time: 58 min; Diluent: Acetonitrile: water (75:25 v/v); Elution: Gradient; Mobile phase-A: Buffer (100%) v/v; Mobile phase-B: Acetonitrile: water (90:10) v/v; Buffer: 1.36 grams of potassium dihydrogen phosphate in 1000 ml of water, adjust pH to 3.0 with diluted orthophosphoric acid. Filtered this solution through 0.45Mm Nylon membrane filter paper and sonicate to degas it.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:

Examples:

Example 1: Preparation of crystalline form-S of 3,5-dimethyl 4-(2'3'- dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate (Formula-4)

Ammonium acetate (88 g) followed by methyl acetoacetate (265.1 g) was added to a solution of 2,3-dichlorobenzaldehyde (200 g) in isopropanol (1450 ml) at 25-35°C. The reaction mass was heated to 80-85°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 25-35°C, further to 0-5°C and stirred for 60 minutes at 0-5°C. Filtered the obtained solid, washed with isopropanol and dried to get the title compound,

yield: 217 grams
MP: 180-184°C.

Example 2: Preparation of 4-(2'3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6- dimethyl-l,4-dihydropyridine-3-carboxylic acid (Formula-5)

A solution of potassium hydroxide (48.4 g) in water (160 ml) was added to a mixture of 3,5-dimethyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4-dihydro pyridine-3,5- dicarboxylate compound of formula-4 (160 g) in isopropanol (960 ml) and water (800 ml). The reaction mixture was heated to 80-85°C and stirred for 18 hours. Distilled off the solvent completely and cooled to 25-35°C. Water was added to the reaction mixture and stirred for 30 minutes at 25-35°C. Filtered the reaction mixture and washed with water. Toluene was added to the filtrate and both the layers were separated. P" of the aquoeus layer was adjusted to 4.3 using acetic acid and stirred for 30 minutes at 25-35°C. Filtered the obtained solid, washed with water and dried to get the solid. Cyclohexane (160 ml) was added to the solid, heated to reflux temperature and stirred for 30 minutes at reflux temperature. The obtained solid was filtered, washed with water and dried to get the title compound.

Purity by HPLC: 96%

Example 3: Purification of 4-(2'3'-dichlorophenyl)-5-(methoxycarbonyI)-2,6- dimethyI-l,4-dihydropyridine-3-carboxyIic acid (Formula-5)

Acetone (140 ml) was added to compound of formula-5 obtained in example-2, heated to reflux temperature and stirred for 30 minutes at reflux temperature. The reaction mixture was cooled to 25-35°C, further to 15-20°C and stirred for 30 minutes at 15-20°C. Filtered the precipitated solid, washed with acetone and dried to get the highly pure title compound.

Purity by HPLC: 99.15%.
MP: 180-187°C.

Example 4: Preparation of Clevidipine butyrate (Formula-1)

Chloromethyl butyrate compound of formula-6 (28.8 g) was added to a mixture of 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylic acid compound of formula-5 (50 g), dimethylformamide (2438 ml) and sodiumbicarbonate (23.6 g) at 25-35°C under nitrogen condition. The reaction mixture was heated to 80-85°C and stirred for 18 hours. After the reaction was completed, the reaction mass was cooled to 25-35°C and filtered. Water was added to the filtrate and the reaction mixture was extracted with ethyl acetate. Ethylacetate layer was washed with water followed by brine solution and distilled off the solvent to get the title compound. Methanol (250 ml) was added to the obtained residue and heated to 40-45°C. Carbon was added to the reaction mixture at 40-45°C and stirred for 30 minutes at 40-45°C. The reaction mixture was filtered and washed with methanol. Water (50 ml) was added to the filtrate slowly at 25-35°C and stirred the reaction mixture for 2 hours at 25-35°C. Filtered the precipitated solid, washed and then dried to get title compound.

Purity by HPLC: 98.7%

Example 5: Process for the preparation of Clevidipine butyrate form-M (Formula-1)

Isopropanol (90 ml) was added to the compound obtained in example 4 (15 g) and the reaction mixture was heated to reflux temperature. Filtered the reaction mixture, the filtrate was cooled to 25-35°C and stirred for 2 hours at 25-35°C. Filtered the precipitated solid, washed with isopropanol and then dried to get the crystalline form-M of clevidipine butyrate. Purity by HPLC: 99.7%;

Example 6: Process for the preparation of crystalline form-N of 4-(2',3'- dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylic acid (Formula-5).
A solution of potassium hydroxide (48.4 g) in water (160 ml) was added to a mixture of 3,5-dimethyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5- dicarboxylate (160 g) in a mixture of isopropanol (960 ml) and water (800 ml). The reaction mixture was heated to 80-85°C and stirred for 18 hours. Distilled off the solvent completely and the reaction mixture was cooled to 25-35°C. Water was added to the reaction mixture and stirred for 30 minutes at 25-35°C. Filtered the reaction mixture and washed with water. Toluene was added to the reaction mixture and both the layers were separated. P" of the aqueous layer was adjusted to 4.3 using acetic acid and stirred for 30 minutes at 25-35°C. Filtered the obtained solid, washed with water and then dried. Cyclohexane (160 ml) was added to the obtained solid and then heated to reflux temperature and stirred for 30 minutes at reflux temperature. Filtered the reaction mixture, washed with cyclohexane and dried. Acetone (140 ml) was added to the solid, heated to reflux temperature and stirred for 30 minutes at reflux temperature. The reaction mass was cooled to 25-35°C, further to 15-20°C and stirred for 30 minutes at 15-20°C. Filtered the obtained solid, washed with acetone and dried to get the pure title compound.

Purity by HPLC: 99.15%. MP: 180-187°C.

Example 7: Purification of clevidipine butyrate compound of formula-1.

n-propanol (4.5 ml) was added to clevidipine butyrate obtained in example-4 (0.75 g) and the reaction mixture was heated to reflux temperature for about 15-20 minutes. Filtered the reaction mixture and the filtrate was cooled to room temperature and stirred until the solid precipitated out. Filtered the precipitated solid, washed with n-propanol and then dried to get pure clevidipine butyrate.

Yield: 0.17 grams
MP: 131.6-134.5°C;
Purity by HPLC: 99.8%

We Claim:

1. An improved process for the preparation of clevidipine butyrate compound of
formula-1, which comprises of following steps;

a) Condensing the 2,3-dichIorobenzaldehyde compound of formula-2 with methylacetoacetate compound of formula-3 in the presence of an ammonia source in a suitable solvent to provide 3,5-dimethyl-4-(2',3'-dichlorophenyl)-2,6- dimethyl-l,4-dihydropyridine-3,5-dicarboxyate compound of formula-4,

b) hydrolyzing the compound of formula-4 in the presence of a suitable base in a suitable solvent to provide 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6- dimethyl-l,4-dihydropyridine-3-carboxylic acid compound of formula-5, where in the suitable base used in the mole ratio less than 2.0 molar equivalents w.r.to the compound of formula-4,

c) purifying the compound of formula-5 with a ketone solvent provides highly pure 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine- 3-carboxylicacid, compound of formula-5,

d) reacting the compound of formula-5 with chloromethyl butyrate compound of formula-6 in the presence of a suitable base in a suitable solvent to get clevidipine butyrate,

e) recrystallizing the clevidipine butyrate from a suitable solvent provides highly pure clevidipine butyrate compound of formula-1.

2. A process according to claim 1, wherein

In step a) the ammonia source selected from ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, ammonium sulphate and ammonium nitrate; the suitable solvent selected from alcoholic solvents such as isopropanol, methanol and ethanol;

In step b) the suitable base selected from hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; the suitable solvent selected from polar solvents such as methanol, ethanol, isopropanol and water or mixture thereof;

In step c) the suitable solvent selected from ketone solvents such as acetone, methyl
ethyl ketone, methyl isobutyl ketone;

In step d) the suitable base is selected from hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassiumbicarbonate; the suitable solvent is selected from polar aprotic solvents such as dimethylacetamide, dimethylformamide; chloro solvents such as dichloromethane, chloroform and ether solvents such as methyltertiarybutyl ether, diethylether, dioxane, tetrahydrofuran;

In step e) the suitable solvent is selected from alcoholic solvents such as isopropanol, n-propanol.

3. An improved process for the preparation of clevidipine butyrate compound of formula-1, comprises of following steps;

a) Condensing the 2,3-dichlorobenzaldehyde compound of formula-2 with methylacetoacetate compound of formula-3 in the presence of ammonium acetate in isopropanol to provide 3,5-dimethyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4- dihydropyridine-3,5-dicarboxyate compound of formula-4,

b) hydrolyzing the compound of formula-4 in the presence of aqueous potassium hydroxide in aquoeus isoproanol provides 4-(2',3'-dichlorophenyl)-5- (methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylicacid compound of formula-5, where in potassium hydroxide used in the mole ratio less than 2.0 molar equivalents w.r.to the compound of formula-4,

c) purifying the compound of formula-5 with acetone provides highly pure 4-(2',3'- dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydro pyridine-3- carboxylicacid compound of formula-5,

d) reacting the 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4- dihydropyridine-3-carboxylic acid compound of formula-5 with chloromethyl butyrate compound of formula-6 in the presence of sodium bicarbonate in dimethyl formamide to get clevidipine butyrate compound of formula-1,

e) recrystallizing the clevidipine butyrate from isopropanol provides pure clevidipine butyrate, compound of formula-1.

4. A process for purification of clevidipine butyrate compound of formula-1, which comprises of following steps;

a) Suspending the clevidipine butyrate compound of formula-1 in 2-propanol or n- propanol,

b) heating the contents of reaction mixture,

c) filtering the reaction mixture,

d) cooling the obtained filtrate,

e) filtering the precipitated solid and washing with 2-propanol or n-propanol, Q drying the solid to get highly pure compound of formula-1.

5. An improved process for the preparation of 3,5-dimethyl-4-(2',3'-dichlorophenyl)-2,6- dimethyl-l,4-dihydropyridine-3,5-dicarboxyate compound of formula-4, which comprises of condensing 2,3-dichlorobenzaldehyde compound of formula-2 with methylacetoacetate compound of formula-3 in the presence of an ammonia source in a suitable solvent, characterized in that the suitable ammonia source is selected from ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, ammonium sulphate and ammonium nitrate.

6. Crystalline form-M of clevidipine butyrate compound of formula-1 characterized by

a) its powder X-ray diffractogram having peaks at about 7.5, 8.5, 10.1, 10,8, 14.3, 15.0,16.2,18.7, 19.5, 21.3,24.8 and 25.8 ± 0.2 degrees two-theta as illustrated in figure-1,

b) its Infrared spectrum having peaks at about 3332.75, 1731.43, 1458.41, 2932.66 and 2806.15 cm"as illustrated in figure-2,

c) its DSC thermogram showing endotherm at 139.28°C as illustrated in figure-3.

7. A process for preparation of crystalline form-M of clevidipine butyrate compound of formula-1 of claim-6 comprises of following steps;

a) Suspending clevidipine butyrate in 2-propanol or n-propanol,

b) heating the contents of reaction mixture,

c) filtering the reaction mixture,

d) cooling the obtained filtrate,

e) filtering the precipitated solid and washing with 2-propanol or n-propanol.

f) drying the solid to get the crystalline form-M of clevidipine butyrate.

8. Crystalline form-S of 3,5-dimethyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-l,4- dihydropyridine-3,5-dicarboxylate compound of formula-4 characterized by

a) its powder X-ray diffractogram having peaks at about 7.9, 11.2, 11.5, 11.9, 13.2, 15.9, 16.4, 23.1, 23.8, 26.2, 26.6, 27.0 and 27.3±0.2 degrees two-theta as illustrated in figure-4;

b) its Infrared spectrum having peaks at about 3334.68, 3103.56, 2948.35, 2837.73, 1703.79 and 1502.51 cm"' as illustrated in figure-5.

9. Crystalline form-N of 4-(2',3'-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl- l,4-dihydropyridine-3-carboxylic acid compound of formula-5 characterized by

a) its powder X-ray dififractogram having peaks at about 11.1, 13.2,16.4, 16.6, 21.8, 22.6,22.9,26.1, and 29.9 ±0.2 degrees two-theta as illustrated in figure-6;

b) its Infrared spectral peaks at about 3340.14, 1682.33, 1668.56, 3070.48, 2949.94, 2840.79 and 1487.52 cm"' as illustrated in figure-7.

10. A purification process for the preparation of highly pure 4-(2',3'-dichlorophenyl)-5- (methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylic acid compound of formula-5, which comprises of following steps;

a) Suspending the compound of formula-5 in a suitable ketone solvent,

b) heating the reaction mixture,

c) cooling the reaction mixture,

d) filtering the compound from the reaction mixture and washing with ketone solvent,

e) drying the solid to get highly pure compound of formula-5.