Claims:We claim:
1) A process for preparing Isoprenaline hydrochloride comprising;
a) reacting compound of formula I with ethylene glycol in presence of organic solvent to yield compound of formula II

where LG is leaving group,
b) reacting compound of formula II with protecting group in presence of base and organic solvent to yield compound of formula III
where PG is protecting group,
c) converting compound of formula III into compound of formula IV in presence of acid and organic solvent,

d) reacting compound of formula IV with isopropyl amine in an organic solvent to yield compound of formula V or its hydrochloride salt,

e) converting compound of formula V or its hydrochloride salt thereof using reducing agent and in presence of organic solvent to yield Isoprenaline or its hydrochloride salt thereof.

2) The process according to claim 1, organic solvent used in step a) is selected from cyclohexane.

3) The process according to claim 1, the protecting group used in step b) is selected from benzyl group, solvent used is selected from acetone and base used is selected from potassium carbonate.

4) The process according to claim 1, acid used in step c) is selected from hydrochloric acid and organic solvent is selected from acetone.

5) The process according to claim 1, organic solvent used in step d) is selected from ethanol.

6) The process according to claim 1, reducing agent used in step e) is selected from hydrogen gas in presence of palladium on carbon and solvent used is selected from methanol.

7) Compounds of following formula or its pharmaceutically acceptable salts thereof

, ,

,
where LG = Leaving group, PG = Protecting group

8) Crystalline Form ML of Isoprenaline Hydrochloride.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Isoprenaline hydrochloride.

BACK GROUND OF THE INVENTION
Isoprenaline (INN) or isoproterenol (USAN) and its addition salts thereof with pharmaceutically acceptable salts like sulphate and hydrochloride has wide application in the field of medicinal chemistry. More specifically Isoprenaline hydrochloride is used for the treatment of bradycardia (slow heart rate), heart block and asthma and is marketed under brand name ISUPREL. Isoprenaline is a racemic compound and chemically known as 3,4-dihydroxy-a-[(isopropylamino)methyl]benzylalcohol.

Preparation of Isoprenaline was first disclosed in US2308232 involving following reaction.

This process had several drawbacks like low conversion rate, generation of many process impurities and low yield. Further, when inventors tried to reproduce this process by replacing sulphuric acid with hydrochloric acid, the resultant material was dark brown tar like compound.

Further, in Journal of American Chemical Society, 1949, 71, 1045-1048; synthesis of Isoprenaline was attempted using glyoxal intermediates as per the synthetic scheme described below.

Where R= H, Benzyl

Isoprenaline base obtained was further treated with 2N sulphuric acid to yield Isoprenaline sulphate. This procedure also gives low yield and purity.

Apart from that, patent CN107382750A describes a process of preparing Isoprenaline as given below

which is further converted into Isoprenaline sulphate. This procedure also gives low yield and purity.

Thus, due to drawbacks of these prior art processes; there is need for an alternative and improved process for the preparation of highly pure Isoprenaline that would be commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies. Thus inventors of present invention have come up with a novel process; which provides a cost effective and efficient industrial process for the preparation of Isoprenaline in high yield and purity.

OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a simple, efficient and industrially viable novel process for the preparation of Isoprenaline hydrochloride.

SUMMARY OF THE INVENTION
In first aspect of the present invention is to provide industrially feasible, economic and novel process for preparing Isoprenaline hydrochloride.

In second aspect of the present invention is to provide novel intermediates of formula II, formula III, formula IV and formula V or its pharmaceutically acceptable salts; and their process of preparation.

The third aspect of present invention is to provide crystalline Form ML of Isoprenaline hydrochloride and its process of preparation.

BRIEF DESCRIPTION OF FIGURES:

Figure 1 illustrates PXRD pattern of crystalline Form ML of Isoprenaline hydrochloride

Figure 2 illustrates DSC of crystalline Form ML of Isoprenaline hydrochloride

Figure 3 A synthetic scheme of preparing Isoprenaline hydrochloride as per present invention

DETAILED DESCRIPTION
As used herein, the term “Reducing agent” used in current invention refers to reagents that are well known to those skilled in the art. In a particular embodiment refers but not limited to, using hydrogen gas (H2) and catalyst such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C), tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst) and like.

“Acid” used in present invention refers but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids and like.

“Base” used in present invention refers to both organic and inorganic bases.

Organic bases include but not limited to pyridine, DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (N,N-diisopropylethylamine), N-methylpiperidine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo[2.2.2]octane), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N-methylmorpholine and like.

Inorganic bases include but not limited to alkali and alkaline earth metal hydrides like sodium hydride, potassium hydride, lithium hydride etc; alkali and alkaline earth metal carbonates like potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate etc; alkali and alkaline earth metal hydrogen carbonates such as potassium hydrogen carbonate, sodium hydrogen carbonate etc; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide; and alkali and alkaline earth metal hydroxides such as, sodium hydroxide, potassium hydroxide, calcium hydroxide and lithium hydroxide etc; and like.

“Organic solvent” used in present invention refers but not limited to "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "amide solvents" such as N,N-dimethylacetamide, N,N-dimethylformamide (DMF) and like; "sulfoxide solvents" such as dimethylsulfoxide (DMSO) and the like; “pyrrolidone solvents” such as N-methylpyrrolidone (NMP) and the like; "halogenated solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, anisole and the like; water or their mixtures.

“Leaving group” (LG) used in present invention refers to any group that is eliminated from the main moiety during the reaction. Examples of leaving groups include, but are not limited to halogens such as Cl, Br, I and like; sulfonic acid derivatives i.e. mesylate, tosylate and like.

“Protecting groups” (PG) used in present invention is hydroxy protecting groups such as silyl groups and aryl alkyl group. In some such embodiments, such groups are t-butyldimethylsilyl group (TBDMS), trimethylsilyl group (TMS), triethylsilyl group (TES), Triisopropylsilyl group (TIPS), t-butyldiphenylsilyl group (TBDPS), benzyl group and like.

“Antioxidants” used in the reaction is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, ascorbyl palmitate, lecithin, norhydroguaiaretic acid, propyl gallate, ?-tocopherol, sodium bisulfate, cysteine, sodium metabisulfite, thioglycerol, thioglycolic acid, thiomersal, DIPEA (N,N-diisopropylethylamine) and like.

“Pharmaceutically acceptable salts” refers to salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, salicylic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acids and like.

The first embodiment of present invention provides a process for preparing Isoprenaline hydrochloride; comprising
a) reacting compound of formula I with ethylene glycol in presence of organic solvent to yield compound of formula II

where LG is leaving group
b) reacting compound of formula II with protecting group in presence of base and organic solvent to yield compound of formula III

where PG is protecting group

c) converting compound of formula III into compound of formula IV in presence of acid and organic solvent

d) reacting compound of formula IV with isopropyl amine in an organic solvent to yield compound of formula V or its hydrochloride salt

e) converting compound of formula V or its hydrochloride salt thereof using reducing agent and in presence of organic solvent to yield Isoprenaline or its hydrochloride salt thereof.

In an embodiment, LG used in step a) is selected from halogens, preferably chlorine.

In an embodiment, organic solvent used in step a) is selected from esters, amides, sulfoxides, halogenated solvents, ketones, nitriles, alcohols, hydrocarbons, ethers, water or their mixtures; preferably hydrocarbons, more preferably cyclohexane.

In an embodiment, the protecting group used in step b) is selected from aryloxyalkyl group, preferably benzyl group.

In an embodiment, the organic solvent used in step b) is selected from esters, amides, sulfoxides, halogenated solvents, ketones, nitriles, alcohols, hydrocarbons, ethers, water or their mixtures; preferably ketones and more preferably acetone.

In an embodiment, the base used in step b) is selected from inorganic base, preferably alkali and alkaline earth metal carbonates and more preferably potassium carbonate.

In an embodiment, acid used in step c) is selected from hydrochloric acid.

In an embodiment, organic solvent used in step c) is selected from esters, amides, sulfoxides, halogenated solvents, ketones, nitriles, alcohols, hydrocarbons, ethers, water or their mixtures; preferably ketones and more preferably acetone.

In an embodiment, the organic solvent used in step d) is selected from esters, amides, sulfoxides, halogenated solvents, ketones, nitriles, alcohols, hydrocarbons, ethers, water or their mixtures; preferably alcohols and more preferably ethanol.

In an embodiment, reducing agent used in step e) is selected from hydrogen gas (H2) and catalyst palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C) or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst); preferably hydrogen gas (H2) and catalyst palladium on carbon (Pd/C).

In an embodiment, the organic solvent used in step e) is selected from esters, amides, sulfoxides, halogenated solvents, ketones, nitriles, alcohols, hydrocarbons, ethers, water or their mixtures; preferably alcohols and more preferably methanol.

In an embodiment, the intermediates obtained in any stages are optionally taken to the next stage without isolation.

The second embodiment of the present invention provides novel intermediates of formula II, formula III, formula IV and formula V or its pharmaceutically acceptable salts and their process of preparation.

where LG = Leaving group, PG = Protecting group

The third embodiment of present invention provides a storage stable crystalline Form ML of Isoprenaline hydrochloride and its process of preparation.

In particular, Form ML of Isoprenaline hydrochloride does not show any change in the XRD pattern after storage for six months in accelerated stability conditions (40°C and 75% relative humidity).

In an embodiment, Form ML of Isoprenaline hydrochloride is prepared from organic solvent, preferably alcohols, more preferably ethanol; optionally in presence of antioxidant, preferably butylated hydroxytoluene.

The techniques used for the characterization of polymorph are PXRD and DSC whose instrument parameters are given below for reference.
PXRD
X-ray powder diffraction (XRPD) was performed on X-Ray powder diffractometer: PanAlytical X'pert Pro powder diffractometer, CuKa radiation, ? = 1.5405980 A. X’Celerator detector active length (2 theta) = 3.3473mm, laboratory temperature 22-25 °C. Zero background sample-holders. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a microscopic glass slide.

DSC
DSC measurements were performed on Differential Scanning Calorimeter DSC1 (Mettler Toledo). Aluminum crucibles 40 µl with lid were used for sample preparation. The lid was not perforated before analysis. Typical weight of sample was 1-4 mg. Program: temperature range 50°C - 250°C, 10°C/min under flow of nitrogen 80 ml/min. Onset temperature is determined as a crossing of tangents constructed on the baseline and at start of the event peak.

Certain specific aspects and embodiments of this invention are described in further detail by the examples given below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES
Preparation of 2-chloro-1-(3,4-dihydroxyphenyl)ethanone (Formula I, LG = Cl)
In a round bottomed flask, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (75 mL), aluminium chloride (24 g) and chloroacetyl chloride (7 mL) was taken. Catechol (10 g) was added drop wise at 0 to -5 °C and stirred. The reaction was quenched with water and Conc. Hydrochloric acid was added (24 mL). The product obtained was filtered, washed with water and dried to yield title compound.

Preparation of 4-[2-(chloromethyl)-1,3-dioxolan-2-yl]benzene-1,2-diol (Formula II, LG = Cl)
Ethylene glycol (15 mL) and cyclohexane (50 mL) was taken in round bottomed flask fitted with Dean-Stark apparatus. 2-Chloro-1-(3,4-dihydroxyphenyl)ethanone was added and the reaction mass was refluxed at 80 0C. After 12 hours, reaction mixture was quenched with isopropyl alcohol (10 mL). The product obtained was filtered, washed with cyclohexane (7 mL) and dried to yield title compound.

Preparation of 2-(3,4-bis(benzyloxy)phenyl)-2-(chloromethyl)-1,3-dioxolane (Formula III; LG = Cl, PG = CH2C6H5)
4-[2-(Chloromethyl)-1,3-dioxolan-2-yl]benzene-1,2-diol prepared in previous step and potassium carbonate (12 g) were taken in acetone (70 mL). Benzyl bromide (12 mL) was added to the reaction mixture and contents were heated at 60 °C. After 12 h, reaction mass was filtered. Filtrate was distilled and resulting contents were diluted with water. Obtained solid mass was filtered and purified using cyclohexane (80 mL). The resultant wet cake was used in next step without any further purification.

Preparation of 1-(3,4-bis(benzyloxy)phenyl)-2-chloroethanone (Formula IV; LG = Cl, PG = CH2C6H5)
2-(3,4-Bis(benzyloxy)phenyl)-2-(chloromethyl)-1,3-dioxolane obtained in previous step was taken in acetone (90 mL), Conc. Hydrochloric acid (5 mL) was added and heated for 4 h. Distilled excess of acetone and quenched resultant mass with water (50 mL). Solid obtained was filtered, washed with water (20 mL) and dried to yield title compound.

Preparation of 1-(3,4-bis(benzyloxy)phenyl)-2-(isopropylamino)ethanone Hydrochloride (Formula V; PG = CH2C6H5)
Ethanol (160 mL), isopropyl amine (8 mL) and product obtained in previous step i.e. 1-(3,4-bis(benzyloxy)phenyl)-2-chloroethanone was taken in a round bottomed flask and contents were refluxed for 2 h at 80 °C. Now, hydrochloric acid solution was added (8 mL of Conc. HCl in 50 mL water) to the reaction mass. Excess of ethanol was distilled, quenched the reaction mass with water (160 mL). The resultant mass was filtered, dried and purified using acetone (50 mL) followed by methanol (35 mL) to yield title compound.

Preparation of Isoprenaline Hydrochloride
Methanol (80 mL), butylated hydroxytoluene (1 % w/w) and product obtained in previous step i.e. 1-(3,4-bis(benzyloxy)phenyl)-2-(isopropylamino)ethanone hydrochloride was taken in autoclave. Palladium on carbon (5 % w/w) in methanol (20 mL) was charged and contents were reduced under H2 in inert atmosphere. After 2h contents were cooled and filtered. Filtrate was subjected to charcoal treatment and distilled excess methanol. The resultant mass was purified using ethanol (20 mL) and dried to yield title compound.

Preparation of crystalline Form ML of Isoprenaline Hydrochloride
A portion of Isoprenaline Hydrochloride (5 g) obtained in previous step was dissolved in ethanol (100 mL), butylated hydroxytoluene (0.1 % w/w) was added and contents were heated to 80 °C. Filtered the reaction mass through micron filter and obtained filtrate was distilled out. The resultant solid was filtered, washed with cold ethanol and dried to yield crystalline form ML of Isoprenaline Hydrochloride.