Claims:1. A for the of Esmolol of formula-1 or its , comprising:
a) reacting 1-chloro-3-(isopropylamino) propan-2-ol of formula-2 or its
with methyl 3-(4-hydroxyphenyl) acrylate of formula-3 to provide methyl 3-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl) acrylate of formula-4 or its

b) converting formula-4 or its to Esmolol of formula-1 or its

Formula-1.
2. The as claimed in claim 1, wherein step-a) is carried out in-presence of an inorganic base selected from metal carbonates or metal bicarbonates.
3. The as claimed in claim 1, wherein step-a) is carried out in a solvent selected from ester solvents or ketone solvents or hydrocarbon solvents or ether solvents.
4. A for the of Esmolol hydrochloride of formula-1a, comprising:
a) reacting 1-chloro-3-(isopropylamino) propan-2-ol hydrochloride of formula-2a with methyl 3-(4-hydroxyphenyl) acrylate of formula-3 in-presence of potassium carbonate in ethyl to provide methyl 3-(4-(2-hydroxy-3-(isopropylamino)propoxy) phenyl) acrylate hydrochloride of formula-4a

b) converting formula-4a to Esmolol hydrochloride of formula-1a

Formula-1a.
, Description:Field of the invention:
The present invention relates to an improved for the of Esmolol of formula-1 or its .

Formula-1
Background of the invention:
Esmolol is a beta adrenergic receptor blocker chemically known as (±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate.
Esmolol approved as its hydrochloride indicated for the short-term treatment of control of ventricular rate in supra-ventricular tachycardia and control of heart rate in non-compensatory sinus tachycardia. And also indicated for to control perioperative tachycardia and hypertension.

US4593119A patent discloses the for the of Esmolol hydrochloride by esterification of 3-(4-hydroxyphenyl)propionic acid with methanol and concentrated sulfuric acid followed by condensation reaction with epichlorohydrin in-presence of potassium carbonate in acetone, further reaction with isopropylamine in methanol to give Esmolol which is then converted to its hydrochloride by reacting with ethereal hydrochloric acid.
described in US’119 patent is shown in the following scheme

The above said has some disadvantages i.e. in the above said , in all the stages, intermediates are in the of oils (liquid in nature). Isolation and purification of oils is very difficult, this will impact the final product quality. Moreover, stage 1 reaction is longer hour reaction (72 hours) and yields of stage 2 and stage 3 reactions are very low i.e., 45% and 47% respectively. By considering the above demerits, this is not suitable in commercial scale.
IN178535 patent discloses the for the of Esmolol hydrochloride by reacting methyl 3-(4-hydroxyphenyl) propanoate with 1,3-dichloropropan-2-ol in-presence of potassium carbonate in acetone, followed by reaction with isopropylamine in methanol to give Esmolol which is then converted to its hydrochloride by reacting with ethereal hydrochloric acid in isopropanol.
described in the above is shown in the following scheme

The above said has some disadvantages i.e. formation of dimer impurities with 1,3-dichloropropan-2-ol. This will impact the final product quality. Moreover, stage 1 reaction is longer hour reaction (24 hours).
Chinese Journal of Pharmaceuticals, 1995, 26 (5), 194-196 discloses the for the of Esmolol by reacting 4-hydroxybenzaldehyde with malonic acid, pyridine and aniline in toluene to produce 3-(4-hydroxy-phenyl)-acrylic acid. This compound undergoes reduction by using 10% Pd/C followed by esterification with methanol in-presence of concentrated sulfuric acid to give methyl 3-(4-hydroxyphenyl) propionate which is further reacted epichlorohydrine in-presence of sodium hydroxide followed by reaction with isopropylamine in methanol to give Esmolol which is then converted to its hydrochloride by reacting with ethereal hydrochloric acid in methanol.
described in the above is shown in the following scheme.

The above said has some disadvantages i.e. in the above said , stage 4 and stage 5 intermediates are in the of oils (liquid in nature). Isolation and purification of oils is very difficult and it will impact the final product quality.
Thus, there remains a need to develop an improved for the of Esmolol or its , which is simple, economic and industrially viable with excellent yields and good quality.
The present inventors have developed an improved industrially viable which does not involve the usage of any costly reagents critical workup procedures. Accordingly, the present invention provides an improved for the of Esmolol hydrochloride which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.
Summary of the invention
The first embodiment of the present invention provides a for the of Esmolol of formula-1 or its .

Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like "hydrocarbon solvent" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl , ethyl , isopropyl , n-butyl , isobutyl or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; "nitrile solvents" selected from acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term “pharmaceutically acceptable ” or ”” described in hereinbefore are obtained by reacting organic compound with acid selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof.
The term " inorganic base " used in the present invention selected from but not limited to "metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate or carbonate mixtures and the like; "metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate or mixtures and the like;
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
"Substantially pure" as used in the present invention herein refers to the compound of formula-1a is substantially free from the impurities and having purity ranges from about 99.0% to 99.99% as measured by a liquid chromatography .

The first embodiment of the present invention provides a for the of Esmolol of formula-1 or its , comprising:
a) reacting 1-chloro-3-(isopropylamino) propan-2-ol of formula-2 or its
with methyl 3-(4-hydroxyphenyl) acrylate of formula-3 to provide methyl 3-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl) acrylate of formula-4 or its

b) converting formula-4 or its to Esmolol of formula-1 or its

Formula-1.
and optionally purifying the compound to provide substantially pure compound of Esmolol of formula-1 or its .
In first aspect of first embodiment, methyl 3-(4-hydroxyphenyl) acrylate of formula-3 used in step-a) is a key intermediate for the of Esmolol of formula-1.
In second aspect of first embodiment of present invention, methyl 3-(4-hydroxyphenyl) acrylate of formula-3 and 1-chloro-3-(isopropylamino) propan-2-ol of formula-2 or its used in step-a) are commercially available in the market (or) it can be prepared according to the any of the known in the prior art.
In third aspect of first embodiment, wherein step-a) is carried out in-presence of an inorganic base selected from metal carbonates or metal bicarbonates; preferably potassium carbonate.
In fourth aspect of first embodiment, wherein step-a) is carried out in a solvent selected from ester solvents or ketone solvents or hydrocarbon solvents or ether solvents; preferably ethyl .
In fifth aspect of first embodiment, formula-4 or its can be converted to Esmolol of formula-1 or its by according to the present invention or by other similar known in the prior art.
In sixth aspect of first embodiment of the present invention provides a for the of Esmolol hydrochloride of formula-1a, comprising:
a) reacting 1-chloro-3-(isopropylamino) propan-2-ol hydrochloride of formula-2a
with methyl 3-(4-hydroxyphenyl) acrylate of formula-3 in-presence of potassium carbonate in ethyl to provide methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride of formula-4a

b) converting formula-4a to Esmolol hydrochloride of formula-1a.

Formula-1a
Wherein formula-4a can be converted to Esmolol hydrochloride of formula-1a by according to the present invention or by other similar known in the prior art.

Advantages of the present invention:
• The described in the present invention is simple, safe, economic, eco-friendly and suitable for the of Esmolol hydrochloride of formula-1a on commercial scale with a high reproducibility.
• Starting materials and intermediate used in the present invention are solids. By this, the present invention avoids the critical workup and additional purifications.
• Usage of commercially available reagents and solvent provides cost-effective .
• Solvent(s) used in the present invention are recycled and reused in the .
• Usage of low cost reactants provides cost-effective .

The other embodiment of the present invention provides a of to control of ventricular rate in supra-ventricular tachycardia and control of heart rate in non-compensatory sinus tachycardia in patients comprising administering to the patients with a therapeutically effective amount of Esmolol hydrochloride obtained by the of the present invention.
Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the known in the prior art.
High Performance Liquid Chromatography (HPLC) analysis :
Esmolol of formula-1 or its and its related substances of present invention were analysed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is equipped with variable wavelength UV detector; Column: octadecylsilyl silica; 10 μm (or) equivalent; Wavelength: 222 nm; Flow rate: 2 mL/min; Injection volume: 20 μL; Elution: Gradient; Diluent: methanol and water (80:20 V/V); Buffer: 3.0 g/ 650 mL of potassium dihydrogen phosphate. Mobile phase: mixture of acetonitrile, methanol, and buffer (150:200:650).
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.
Examples:
Example-1: of Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride
1-chloro-3-(isopropylamino) propan-2-ol hydrochloride (95.2 g, 0.9 mole equivalent) was added to the mixture of methyl 3-(4-hydroxyphenyl) acrylate (100 g, 1 mole equivalent), potassium carbonate (117 g, 1.5 mole equivalent) and ethyl (500 ml) at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 60-65°C and stirred for 8 hours at same temperature. Water was added to the reaction mixture at room temperature and stirred for 10 minutes at same temperature. Organic layer was acidified with isopropanol- hydrochloride and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 159.86 (86.36%).
Example-2: of Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride
1-chloro-3-(isopropylamino) propan-2-ol hydrochloride (95.2 g, 0.9 mole equivalent) was added to the mixture of methyl 3-(4-hydroxyphenyl) acrylate (100 g, 1 mole equivalent), potassium carbonate (117 g, 1.5 mole equivalent) and acetone (500 ml) at room temperature and stirred for 10 minutes at same temperature. Reaction mixture was refluxed for 12 hours. Distilled off the solvent completely from the reaction mixture. Water and ethyl were added to the above obtained residue at room temperature and stirred for 10 minutes at same temperature. Organic layer was acidified with isopropanol- hydrochloride and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 149.7 (80.87%).
Example-3: of Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride
1-chloro-3-(isopropylamino) propan-2-ol hydrochloride (95.2 g, 0.9 mole equivalent) was added to the mixture of methyl 3-(4-hydroxyphenyl) acrylate (100 g, 1 mole equivalent), potassium carbonate (117 g, 1.5 mole equivalent) and methyl isobutyl ketone (500 ml) at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 80-90°C and stirred for 6 hours at same temperature. Water was added to the reaction mixture at room temperature and stirred for 10 minutes at same temperature. Organic layer was acidified with isopropanol- hydrochloride and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 144.93 (78.29%).
Example-4: of Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride
1-chloro-3-(isopropylamino) propan-2-ol hydrochloride (95.2 g, 0.9 mole equivalent) was added to the mixture of methyl 3-(4-hydroxyphenyl) acrylate (100 g, 1 mole equivalent), potassium bicarbonate (142 g, 2.5 mole equivalent) and ethyl (500 ml) at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 60-65°C and stirred for 12 hours at same temperature. Water was added to the reaction mixture at room temperature and stirred for 10 minutes at same temperature. Organic layer was acidified with isopropanol- hydrochloride and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 152.83 (82.56%).
Example-5: of Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride
1-chloro-3-(isopropylamino) propan-2-ol hydrochloride (95.2 g, 0.9 mole equivalent) was added to the mixture of methyl 3-(4-hydroxyphenyl) acrylate (100 g, 1 mole equivalent), potassium carbonate (117 g, 1.5 mole equivalent) and toluene (500 ml) at room temperature and stirred for 10 minutes at same temperature. Reaction mixture was refluxed for 18 hours. Water was added to the reaction mixture at room temperature and stirred for 10 minutes. Organic layer was acidified with isopropanol- hydrochloride and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 142.90 (77.20%).
Example-6: of Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride
1-chloro-3-(isopropylamino) propan-2-ol hydrochloride (95.2 g, 0.9 mole equivalent) was added to the mixture of methyl 3-(4-hydroxyphenyl) acrylate (100 g, 1 mole equivalent), potassium carbonate (117 g, 1.5 mole equivalent) and tetrahydrofuran (500 ml) at room temperature and stirred for 10 minutes at same temperature. Reaction mixture was refluxed for 8 hours. Distilled off the solvent completely from the reaction mixture. Water and ethyl were added to the above obtained residue at room temperature and stirred for 10 minutes at same temperature. Organic layer was acidified with isopropanol- hydrochloride and stirred for 1 hour. Filtered the solid and dried to get the title compound.
Yield: 129.05 (69.71%).
Example-7: of Esmolol hydrochloride of formula-1a
Methyl 3-(4-(2-hydroxy-3-(isopropylamino) propoxy) phenyl) acrylate hydrochloride (100 g) was added to the mixture of methanol and 10% palladium on carbon at room temperature and stirred for 10 minutes at same temperature. Hydrogen gas is passed through the reaction until absorption stops. Filtered reaction mixture through high-flow bed and washed with methanol. Distilled off the solvent completely from the filtrate. Ethyl was added to the above obtained residue at 0-5°C and stirred for 10 minutes at same temperature. Filtered the solid and dried to get the title compound.
Yield: 95.17 (94.59%); Purity: 99.98% (by HPLC);
Esmolol acid impurity: 0.02% (by HPLC).