DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Isoproterenol hydrochloride. More particularly, the present invention relates to a simple, effective and industrially feasible process for the preparation of Isoproterenol hydrochloride with desired purity.

BACKGROUND OF THE INVENTION
Isoproterenol hydrochloride is chemically known as 3,4-Dihydroxy-a- [(isopropyl amino)methyl]benzyl alcohol hydrochloride and is represented by the following chemical structure of Formula I.

Isoproterenol or Isoprenaline, is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. It is a non-selective ß adrenoreceptor agonist that is the isopropylamine analog of epinephrine (adrenaline).

Isoproterenol and the process for its preparation is first disclosed in U.S 2308232 patent. US ’232 patent discloses the process for the preparation of Isoproterenol sulphate by the reaction of 3,4-dihydroxy-?-chlorine acetophenone with aqueous isopropylamine solution in the presence of ethanol and neutralizing with diluted sulfuric acid followed by re-crystallization from alcohol to give 3,4-dihydroxy-?-isopropylaminoacetophenone sulphate, which upon hydrogenation with palladium(II)chloride, carbon in methanol and water produces Isoproterenol sulfate. The complete process as described in the US ’232 patent is very complex and the use of sulfuric acid is not recommended as it is difficult to handle during large scale manufacturing.

Indian patent application, IN 201621010158 discloses a process for the preparation of Isoproterenol hydrochloride which comprises, hydrogenation of 1-(3,4-dihydroxypheny1)-2 (isopropylamino)ethanone hydrochloride (ketone intermediate) in the presence of sodium borohydride (NaBH4) and further treating with salifying agent like isopropanol HCl to provide crude Isoproterenol hydrochloride. The crude product is purified by using alcohol and anti-solvent to give pure Isoproterenol hydrochloride. The disclosed process uses 4 equivalents of sodium borohydride and this process leads to the formation of significant amount of Impurity-C.

Indian patent application, IN 201721000708 discloses a process for the preparation of Isoproterenol hydrochloride which comprises, hydrogenation of 3',4'-dihydroxy-2- (isopropylamino)acetophenone hydrochloride with palladium catalyst in the presence of ion exchange resin i.e., Amberlyst A-21 resin, to provide Isoproterenol hydrochloride. This process uses expensive ion exchange resin during the hydrogenation, which is not feasible industrially.

An impurity structurally similar to the drug molecule except in the absence of aliphatic hydroxyl group is also formed during the preparation of Isoproterenol hydrochloride. This impurity is known as 1-(3,4-Dihydroxyphenyl)-2- isopropyl aminoethane hydrochloride (or) 4-[2-(propan-2-ylamino) ethyl] benzene-1,2-diol hydrochloride. (Isoproterenol Impurity-C) and is represented as below:

Formation of Impurity C is the major drawback in the above mentioned prior arts. The preparation and purification of Isoproterenol hydrochloride becomes very difficult, as the impurities produced during the ketone-reduction and processes thereof have physico-chemical properties and molecular weight comparable to that of the active substance and hence, removal of such impurities during workup procedures is difficult and requires the use of additional purification techniques like chromatographic purification, ion-exchange purification, repeated crystallization procedures.

In view of the above and to overcome the prior-art problems, the inventors of the present application have developed a simple, cost effective, scalable and commercially viable process for preparing Isoproterenol hydrochloride with desired purity, which is devoid of the drawbacks of prior arts.

OBJECT OF THE INVENTION
The main objective of the present invention is to provide a simple, effective and industrially feasible process for the preparation of Isoproterenol hydrochloride with desired purity.

Yet another objective of the present invention relates to an efficient process for the preparation of highly pure Isoproterenol hydrochloride and its intermediates thereof.

SUMMARY OF THE INVENTION
The present invention relates to the process for the preparation of Isoproterenol hydrochloride of Formula (I).

comprising the steps of:
i) reacting 2-chloro-3',4'-dihydroxy acetophenone of Formula II

with isopropylamine in an organic solvent and further treating with hydrochloric acid to give 3',4'-dihydroxy-2-(isopropyl amino)acetophenone hydrochloride of Formula III;

Formula III
ii) dissolving the 3',4'-dihydroxy-2-(isopropylamino)acetophenone hydrochloride of Formula III in a solvent to give reaction mixture;
iii) adjusting the pH of the reaction mixture from step ii) with organic amine;
iv) hydrogenating the reaction mixture obtained from step iii) in a solvent to give crude Isoproterenol hydrochloride;
v) purifying the crude Isoproterenol hydrochloride from alcohol and water to give pure Isoproterenol hydrochloride of Formula I.
The following detailed description will make the objectives of the present invention fully apparent.

DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention provides a simple, effective and industrially feasible process for the preparation of Isoproterenol hydrochloride with desired purity.

Scheme 1 illustrates the process for preparation of Isoproterenol hydrochloride according to the present invention:

Step i) reacting 2-chloro-3',4'-dihydroxy acetophenone of Formula II with isopropylamine in an organic solvent and further treating with hydrochloric acid to give 3',4'-dihydroxy-2-(isopropylamino)acetophenone hydrochloride of Formula III. The temperature during this step ranges from 20-65°C for a suitable period of time. The organic solvent used in the reaction is an aprotic solvent and is selected from acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide and combinations thereof;

Step ii) dissolving the 3',4'-dihydroxy-2-(isopropylamino)acetophenone hydrochloride of Formula III in a solvent to give a reaction mixture. The solvent used in the reaction is an alcoholic solvent and is selected from methanol, ethanol, isopropanol, optionally mixed with water and combinations thereof;

Step iii) adjusting the pH of the reaction mixture from stage ii) to about 4 to about 6 by using an organic amine. The organic amine used for the pH adjustment can be a primary (1°) amine, secondary (2°) amine or tertiary (3°) amine. Primary amine is selected from methyl amine, ethyl amine, n-propyl amine, n-butyl amine, isopropyl amine and the like. Secondary amine is selected from dimethylamine, diethylamine, dibutylamine, diisopropylamine, diphenylamine, dibenzylamine and the like. Tertiary amine is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine and the like;

The pH of the reaction plays a crucial role and should be maintained between about 4 to about 6 by using an organic amine. If pH is less than 4 or is more than 6, it would result in the formation of impurities, such as impurity C;

Step iv) hydrogenating the reaction mixture obtained from step iii) in a solvent to give crude Isoproterenol hydrochloride;

The hydrogenation step is carried out using a suitable hydrogenating agent. An example of a suitable hydrogenating agent is hydrogen, preferably in the presence of a metal catalyst such as nickel or palladium. Most preferably 10% palladium on carbon is used. The reaction may be carried out in a suitable solvent, which is selected from an alcoholic solvent, an ester solvent or an acid solvent and combinations thereof. The alcoholic solvent is selected from methanol, ethanol, isopropanol, optionally mixed with water and combinations thereof; ester solvent is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and combinations thereof; acid solvent is selected from acetic acid, formic acid, propionic acid, butyric acid, valeric acid and combinations thereof. The reaction can be carried out at normal pressure or preferably at elevated pressure, e.g. from 3 to 5 Kg/cm2. The reaction temperature is less than 45? for a suitable period of time;

Step v) purifying the crude Isoproterenol hydrochloride from alcoholic solvent and water to give pure Isoproterenol hydrochloride of Formula I;

The alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, butanol and combinations thereof. The temperature in this reaction ranges from 50-60? for a suitable period of time.

Yet an another embodiment of the present invention, relates to a process for the preparation of Isoproterenol hydrochloride of Formula I

comprising the steps of:
i) dissolving the 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride of Formula III

in a solvent to give reaction mixture;
ii) adjusting pH of the reaction mixture of step i) to about 4 to 6 with organic amine;
iii) hydrogenating the reaction mixture obtained from step ii) in presence of Pd/C and solvent to give crude Isoproterenol hydrochloride;
wherein the solvent used in step i) is selected from methanol, ethanol, isopropanol, optionally mixed with water and combinations thereof; wherein the organic amine used in the step ii) is selected from methyl amine, ethyl amine, n-propyl amine, n-butyl amine, isopropyl amine, dimethylamine, diethylamine, dibutylamine, butylisopropylamine, diphenylamine, dibenzylamine, triethylamine, trimethyl amine, tributylamine, diisopropylethylamine; wherein the solvent used in step iii) is selected from methanol, ethanol, isopropanol, optionally mixed with water; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate; acetic acid, formic acid, propionic acid, butyric acid, valeric acid and combinations thereof;
iv) purifying the crude Isoproterenol hydrochloride from alcoholic solvent and water to give pure Isoproterenol hydrochloride of Formula I;

wherein the alcoholic solvent used in the step iv) is selected from methanol, ethanol, isopropanol and combinations thereof.

The process of the present invention consistently gives better quality of Isoproterenol Hydrochloride as per ICH (International Conference on Harmonization) guidelines.

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride of Formula (III)
2-chloro-3',4'-dihydroxy acetophenone of formula (II) (100g) was added to acetonitrile (850 mL) and isopropyl amine solution (110 g) at 20-25? and the reaction mass was stirred for 1 hour at 55-65?. After completion of the reaction, it is cooled to 20-25?. The reaction mass was quenched with concentrated hydrochloric acid (190 mL) and the pH was maintained at about 2. The reaction mixture was heated to 55-65ºC and maintained for 30 minutes. The precipitated solid was isolated by filtration and washed with acetonitrile. Wet solid was recrystallized in water (400 mL) and solid was filtered, dried under vacuum 55-60ºC to get 3',4'-dihydroxy-2-(isopropylamino)acetophenone hydrochloride of Formula (III).
Yield: 65.5 g.

Example 2: Preparation of Isoproterenol hydrochloride of Formula (I)
To the stirred solution of methanol (1400 mL) and 3',4'-Dihydroxy-2-(isopropylamino) acetophenone hydrochloride of formula (III) (100g), isopropyl amine (0.3 mL) was added and the pH was adjusted between about 4 to about 6. Then, 10% Pd/C (10g) was added and the reaction mass was stirred under hydrogen pressure of 3 to 5 Kg/cm2 for about 6 to 9 hours at 25-35 ºC. After completion of the reaction, the reaction mass was filtered and palladium was removed. The reaction mass was then treated with activated carbon for 1 hour. The reaction mass was filtered through hyflo bed and then the filtrate and washing were combined. The combined layer was distilled out under vacuum to get crude Isoproterenol hydrochloride, which was further purified using ethanol (2000 mL) and water (30 mL) to give Isoproterenol Hydrochloride.
Yield: 68 g.

Example 3: Preparation of 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride of Formula (III)
2-Chloro-3',4'-dihydroxy acetophenone of formula (II) (200g) was added to acetonitrile (1200 mL), and isopropyl amine (221 g) at 20-25? and the reaction mass was stirred for 1 hour at 55-65?. After completion of the reaction, the reaction mass was cooled to 20-30?. The reaction mass was quenched with concentrated hydrochloric acid (383 mL) and the pH was maintained at about 2. The reaction mixture was heated to 50-65?, under stirring, cooled and filtered to give 3',4'-dihydroxy- 2-(isopropylamino)-acetophenone hydrochloride of Formula (III).
Yield: 132 g.

Example 4: Preparation of Isoproterenol hydrochloride of Formula (I)
3',4'-Dihydroxy-2-(isopropylamino)acetophenone hydrochloride of formula (III) (100 g) was added to methanol (558 mL) and water (42 mL) at 25-35?. The reaction mixture was stirred for 15 to 30 minutes followed by the addition of isopropyl amine in methanol (0.3 mL), and the pH was maintained between about 4 to about 6. Further, 10% Pd/C (10g) was added, and the reaction mass was stirred under hydrogen pressure of 3 to 5 Kg/cm2 for about 6 to 9 hours at 25-35?. After completion of the reaction, the reaction mass was filtered and palladium was removed. The reaction mass was then treated with activated carbon for 1 hour. The solvent was distilled out completely and was co-distilled with ethanol under vacuum to get crude Isoproterenol hydrochloride, which was further purified using ethanol (975 mL) and water (67.5 mL) to give Isoproterenol hydrochloride.
Yield: 65 g.

Advantages of the invention:
1) The organic amine used is commercially available, easy to handle, and is relatively inexpensive.
2) Impurity formation is controlled, ultimately improving the yield.
3) Avoided repeated purification steps.
4) Present invention is industrially applicable, reliable and is a robust process. ,CLAIMS:We Claim:
1. A process for preparing Isoproterenol hydrochloride of Formula (I),

comprising:
i) reacting 2-chloro-3',4'-dihydroxy acetophenone of Formula II

with isopropylamine in an organic solvent and treating with hydrochloric acid to give 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride of Formula III;

ii) dissolving the 3',4'-dihydroxy-2-(isopropylamino)acetophenone hydrochloride of Formula III in a solvent to give reaction mixture;
iii) adjusting the pH of the reaction mixture from step ii) with organic amine;
iv) hydrogenating the reaction mixture obtained from step iii) in a solvent to give crude Isoproterenol hydrochloride;
v) purifying the crude Isoproterenol hydrochloride from alcoholic solvent and water to obtain pure Isoproterenol hydrochloride of Formula (I).
2. The process as claimed in claim 1, wherein the organic solvent used in step i) is selected from acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide and combinations thereof.
3. The process as claimed in claim 1, wherein the solvent used in step ii) is an alcoholic solvent selected from methanol, ethanol, isopropanol, optionally mixed with water and combinations thereof;
4. The process as claimed in claim 1, wherein the organic amine used in step iii) is a primary (1°) amine, a secondary (2°) amine or a tertiary (3°) amine and is selected from methyl amine, ethyl amine, n-propyl amine, n-butyl amine, isopropyl amine, dimethylamine, diethylamine, dibutylamine, butylisopropylamine, diphenylamine, dibenzylamine, triethylamine, trimethyl amine, tributylamine and diisopropylethylamine.
5. The process as claimed in claim 1, wherein the pH of the reaction is between about 4 to about 6.
6. The process as claimed in claim 1, wherein the hydrogenation is carried in the presence of palladium on carbon.
7. The process as claimed in claim 1, wherein the solvent used in step iv) is an alcoholic solvent, an ester solvent or an acid solvent; wherein alcoholic solvent is selected from methanol, ethanol, isopropanol, optionally mixed with water and combinations thereof; ester solvent is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and combinations thereof; and acid solvent is selected from acetic acid, formic acid, propionic acid, butyric acid, valeric acid and combinations thereof.
8. The process as claimed in claim 1, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol and combinations thereof.
9. A process for preparing Isoproterenol hydrochloride of Formula I

comprising:
i) dissolving the 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride of Formula III

in a solvent to give reaction mixture;
ii) adjusting pH of reaction mixture from step i) to about 4 to 6 with organic amine;
iii) hydrogenating the reaction mixture obtained from step iii) in presence of Pd/C and solvent to give crude Isoproterenol hydrochloride;
iv) purifying the crude Isoproterenol hydrochloride from alcoholic solvent and water to give pure Isoproterenol hydrochloride of Formula I.
10. The process as claimed in claim 9, wherein the solvent used in step i) is selected from methanol, ethanol, isopropanol, optionally mixed with water and combinations thereof; where in the organic amine used in step ii) is selected from methyl amine, ethyl amine, n-propyl amine, n-butyl amine, isopropyl amine, dimethylamine, diethylamine, dibutylamine, butylisopropylamine, diphenylamine, dibenzylamine, triethylamine, trimethyl amine, tributylamine and diisopropylethylamine; wherein the solvent used in step iii) is selected from methanol, ethanol, isopropanol, optionally mixed with water; methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate; acetic acid, formic acid, propionic acid, butyric acid, valeric acid and combinations thereof; wherein the alcoholic solvent used in the step iv) is selected from methanol, ethanol, isopropanol and combinations thereof.