FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
PROVISIONAL SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "PROCESS FOR PREPARATION OF ISOPROTERENOL
HYDROCHLORIDE"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act
1957 and having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
The present invention relates to an industrially applicable process for preparation of Isoproterenol hydrochloride (la). The invention specifically relates to the use of an ion exchange resin during hydrogenation reaction of the acetophenone intermediate (5a), which provides significant control on impurities and yields Isoproterenol hydrochloride having desired purity, in good yield.
BACKGROUND OF THE INVENTION
Isoproterenol (1), chemically identified as 3,4-Dihydroxy-a-[(isopropylamino) methyl] benzyl alcohol or l-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol is structurally represented as given below.

Isoproterenol, which is an isopropyl analog of epinephrine, is a beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract etc. It is a non-selective β adrenoreceptor agonist and TAAR1 agonist, which is used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. Isoproterenol hydrochloride is marketed by Hospira Inc. under the trade name Isuprel, which is an injectable with the strength of 0.2mg/ml.
US 2,308,232 discloses a process for the preparation of Isoproterenol comprising reaction of 3,5-dihydroxyphenyl-ω-chloroacetophenone with isopropylamine using ethanol as solvent, followed by palladium catalyzed hydrogenation of the resulting isopropylamino acetophenone derivative to yield the desired product. The disclosed process reveals that in order to achieve the desired purity, repeated crystallizations are required at both the intermediate and final stages. This clearly

indicates formation of impurities in significant proportions, thereby adversely affecting the yield and hence the industrial applicability of the said process. ATI78353 discloses a process for separation of desired enantiomer of Isoproterenol comprising treatment of the racemic mixture with d-tartaric acid and crystallization using methanol as a solvent. US 2,715,141 discloses a similar method for obtaining cnantiopure Isoproterenol wherein a mixture of Isoproterenol and d-tartaric acid is dissolved in water and neutralized with barium hydroxide. Further, precipitate of burium sulfate is filtered, the solution is concentrated, nnd the concentrate is resolved by fractional crystallization using methanol and acetone.
US 5,442,118 discloses a method for preparation of enantiopure isoproterenol comprising use of a borane reducing agent, and a chiral 1,3,2-oxazaborole derivative catalyst. In this method, treatment of corresponding acetophenone with HBr in DMSO, followed by reaction with water provides the arylglyoxal derivative, which after reaction with the appropriate amine gives ketoimine derivative. Reduction of the ketoimine using the organoboranes like Me2S-BH3 in presence of said oxazaborole catalysts provides Isoproterenol.
Thus, it is evident from prior art that conventional synthetic methods reported for Isoproterenol suffer from formation of impurities in significant proportions. In these methods, undesired impurities such as Impurity-A are generated during the penultimate ketone-reduction stage. These impurities, being structurally similar to the final compound Isoproterenol, are difficult to remove during work up procedure and necessitate steps like successive chromatographic purification or repeated crystallization procedure. This causes increase in number of procedural steps, resulting in significant yield loss and ultimately increased project cost. To overcome the problem of impurity formation, some synthetic methods reported in prior art resorted to use of highly specific intermediates like keto-imines, which adds to the synthetic steps and increases the project cost.


Hence, there is a need to have a cost effective, industrially applicable process which avoids use of expensive chiral catalysts, significantly controls the formation of Impurity-A, and provides Isoproterenol having desired purity.
The present inventors have developed a robust and commercially viable synthetic method which avoids the short-comings in the prior art and provides Isoproterenol hydrochloride (1a) conforming to regulatory specifications.
OBJECT OF THE INVENTION
An objective of the present invention is to provide a cost-effective and convenient process for the synthesis of Isoproterenol hydrochloride (la) which does not involve expensive reagents, labile, unstable intermediates and which can easily be scaled up to a commercially viable process.
Another object of the invention is to provide Isoproterenol hydrochloride (la) with good yield and purity wherein the impurity levels conform to the regulatory norms.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Isoproterenol hydrochloride (la) which overcomes limitations in the prior art methods.

An aspect of the present invention relates to an improved and cost-effective process for the preparation of Isoproterenol hydrochloride (la), comprising treatment of 2-. chloro-3',4'-dihydroxy acetophenone (4) with isopropyl amine and hydrochloric acid to provide 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a), followed by hydrogenation in presence of palladium catalyst and weakly basic resin such as Amberlyst A?.1 to afford Isoproterenol hydrochloride (1a) having desired purity.
The following detailed description will make the objectives of the present invention Hilly apparent.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors, while working on development of a convenient, cost effective, industrially applicable process for synthesis of Isoproterenol, carried out extensive experimentation which primarily focused on control on formation of impurities. Accordingly, various synthetic routes, with different hydroxyl protecting groups as well as varied reaction parameters were studied for synthesis of Isoproterenol. It was observed that undesired side products, associated impurities were inevitably formed during reduction. Impurity-A, amongst others, was predominantly formed during the course of reactions, to the extent of 1-2 %. The inventors also observed that removal of impurity -A, which was formed at the final stage was particularly difficult due to its structural similarity with Isoproterenol. During the experimentation, surprisingly it was found that impurity-A was significantly controlled with the use of ion exchange resins, especially anion exchange resins during the hydrogenation reaction of the acetophenone derivative (5 a). Further, the polymeric resin was commercially available, was required in small quantity and could be recycled after solvent washing and activation. With the use of said resin, formation of the impurity-A was brought down to less than 0.1% which resulted in substantial increase in the yield and

provided a clean, robust and economical process for synthesis of Isoproterenol hydrochloride which could easily be scaled up to industrial scales.

In an embodiment, catechol of formula (2) is treated with chloroacetyl chloride (3) in presence of aluminium chloride, solvent dichloromethane in the temperature range of 25-45°C. After completion of the reaction, as monitored by HPLC, the resultant 2-chloro-3',4'- dihydroxy acetophenone (4) is treated with isopropyl amine in presence of solvent acetonitrile followed by treatment with hydrochloric acid to provide 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a). Hydrogenation of (5a) in presence of palladium catalyst and a resin in the temperature range of 20-30°C provides, after completion of the reaction, the hydrochloride salt of corresponding alcohol Isoproterenol (la). The resin is selected from a group of ion-exchange resins, such as amberlite resins like IRA-900, IRA-904, amberlyst resins A-21, A-26, A-27 etc., preferably anion exchange resin such as Amberlyst A-21 having weakly basic properties.

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 2-chloro-3',4'- dihydroxy acetophenone (4)
Catechol (2, 200 g) is added lot wise to the mixture of Aluminium chloride (606 g) and dichloromethane (1800 ml) at 0-10°C followed by gradual addition of chloroacetyl chloride (3, 217.3 g) in 200 ml dichloromethane at 0-10°C. After complete addition, the reaction mixture is stirred at 25-35°C till completion of the reaction as monitored by IIPLC. After completion, the reaction mass is quenched with ice-cold aq. HC1 followed by filtration to isolate crude product which is further purified by crystallization from aqueous acetic acid to give the desired compound, 2-chloro-3',4'- dihydroxy acetophenone (4) Yield: 210 g (62%).
Example 2: Preparation of 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a)
2-chloro-3',4'- dihydroxy acetophenone (4, 200 g) is added to acetonitrile (1200 ml) placed in a round bottom flask. Solution of isopropyl amine (221.7 g in 200 ml acetonitrile) is gradually added to the mixture at 20-30°C. The reaction temperature is raised to 55-65°C and the reaction is continued at the same temperature. After completion of the reaction, the mass is cooled to 20-30°C and concentrated hydrochloric acid (383 ml) is gradually added to it, till the pH of around 2 is attained. The reaction mixture is heated to 50-65°C, followed by stirring at the same temperature, cooled and filtered to give crude 3',4'-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a) which is optionally further purified by crystallization form water to give the desired product (5a).

Yield: 120 g, (45%).
Example 3: Preparation of Isoproterenol hydrochloride (la)
Methanol (800 ml) is placed in an autoclave and 3',4'-dihydroxy-2-(isopropylamino)-acctophcnone hydrochloride (5a, 100 g), Fd/C (10%, moisture 50%, 10 g.), are added to it as slurry in methanol, along with water (60 ml) and the resin, Amberlyst A-21 (1g), The flow of hydrogen gas is started, the pressure is adjusted to 3 to 5 Kg/cm2 and maintained till completion of the reaction at 20-30°C. After reaction completion, as monitored by HPLC, the reaction mixture is filtered and filtrate is concentrated after optional treatment with activated carbon. The solid thus obtained is treated with the mixture of ethanol and water in the temperature range of 50-80 C followed by cooling and filtration to give Isoproterenol hydrochloride (1a). Yield: 66 g (65%)