Process for preparation of isoproterenol hydrochloride

Abstract

The present invention provides a process for preparation of isoproterenol hydrochloride (1a) comprising catalytic hydrogenation of 3,4-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a) in presence of an ion exchange resin, to provide isoproterenol hydrochloride (1a).

Claims

1. A process for the preparation of isoproterenol hydrochloride of formula (1a) comprising reacting catechol (2) with chloroacetyl chloride (3) in presence of aluminium chloride to give 2-chloro-3,4-dihydroxy acetophenone (4), reacting 2-chloro-3,4-dihydroxy acetophenone (4) with isopropyl amine in an organic solvent, treating the reaction product with hydrochloric acid to give 3,4-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a), and hydrogenating 3,4-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a) in the presence of a resin to provide isoproterenol hydrochloride of formula (1a).

2. A process for the preparation of isoproterenol hydrochloride of formula (1a) comprising hydrogenating of 3,4-dihydroxy-2-(isopropylamino)acetophenone hydrochloride (5a) in presence of a resin to provide isoproterenol hydrochloride of formula (1a).

3. The process as claimed in claim 2 wherein the hydrogenation is carried out using 3,4-dihydroxy-2-(isopropylamino)acetophenone (5) to provide isoproterenol (1).

4. The process as claimed in claim 1, wherein the resin is an ion exchange resin.

5. The process as claimed in claim 4, wherein the ion exchange resin is selected from Amberlite IRA-900 CI, Amberlite IRA-904, Amberlyst A-21, Amberlyst A-26 OH, Amberlyst A-27, and Indion 850.

6. The process as claimed in claim 4, wherein the ion exchange resin is a weakly basic resin.

7. The process as claimed in claim 1, wherein the organic solvent is selected from dimethyl formamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethyl acetamide and combinations thereof.

8. The process as claimed in claim 2, wherein the resin is an ion exchange resin.

9. The process as claimed in claim 8, wherein the ion exchange resin is selected from Amberlite IRA-900 CI, Amberlite IRA-904, Amberlyst A-21, Amberlyst A-26 OH, Amberlyst A-27, and Indion 850.

10. The process as claimed in claim 8, wherein the ion exchange resin is a weakly basic resin.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) 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 controlling the formation of impurities.

(2) 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 the final step of reduction of ketone intermediate. Impurity-A, amongst others, was formed to the extent of 1-2% during the course of reaction. 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. The purification technique required was column chromatographic purification followed by repeated crystallizations which then provided isoproterenol with impurity-A barely at the threshold limit of 0.1%. However, they were time-consuming and required large amounts of solvents, or solvent mixtures and hence proved to be uneconomical and thus not suitable for industrial use.

(3) It was surprisingly found by the inventors that during the hydrogenation reaction of the intermediate 3,4-dihydroxy-2-(isopropylamino)-acetophenone use of ion exchange resins significantly restricted the formation of impurity-A. This unexpected observation proved to be advantageous in a number of ways as given below. 1. The resins were commercially available, and hence could be procured easily for industrial scale application. 2. The resins were required in small quantity and could be recycled after solvent washing and activation, making them highly cost-effective additives for each batch run. 3. When the impurity formation itself was controlled, other steps such as chromatographic purification or crystallization were not required. 4. With the use of the said resins, which are preferably weakly basic in nature, impurity-A was brought down well below 0.1%, without any chromatographic purification and which resulted in a clean, robust and economical process for synthesis of isoproterenol hydrochloride. 5. Due to ready availability of the resins and elimination of time-consuming recrystallization steps, the process was easily scaled up for industrial application.

(4) ##STR00003##

(5) In an embodiment, catechol of formula (2) was treated with chloroacetyl chloride (3) in presence of aluminium chloride and solvent dichloromethane in the temperature range of 0-45 C. After completion of the reaction, as monitored by HPLC, the resultant reaction mixture was treated with acid and filtered to give 2-chloro-3,4-dihydroxy acetophenone (4).

(6) Further reaction of compound (4) with isopropyl amine to give 3,4-dihydroxy-2-(isopropylamino)-acetophenone (5) was carried out in presence of an organic solvent in the temperature range of 50-70 C. The organic solvent was selected from aprotic solvents such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide and mixtures thereof.

(7) After completion of the reaction, as monitored by HPLC, the reaction mixture was treated with hydrochloric acid and filtered to provide 3,4-dihydroxy-2-(isopropylamino)acetophenone hydrochloride (5a).

(8) Compound (5a) was subjected to hydrogenation in presence of a palladium catalyst, and a resin in the temperature range of 20-30 C. The reaction was carried out using alcoholic solvent such as methanol, ethanol, isopropanol, optionally mixed with water, under the hydrogen pressure in the range of 2 to 8 Kg/cm.sup.2.

(9) The resin was selected from a group of ion-exchange resins such as Amberlite IRA-900 CI, Amberlite IRA-904, Amberlyst A-21. Amberlyst A-26 OH, Amberlyst A-27, Indion 850 etc. Anion exchange resin such as Amberlyst A-21 having weakly basic properties was preferably used. The amount of resin used during the hydrogenation was in catalytic amounts, ranging from 1-10%, hence, possibility of any side reaction due to the presence of resins was eliminated.

(10) After completion of the reaction, as monitored by HPLC, the reaction mixture was filtered and the filtrate was concentrated after optional treatment with activated carbon to yield a residue, which was treated with alcohol and water to afford isoproterenol hydrochloride (1a).

(11) 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)

(12) Catechol (2, 200 g) was 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 2(10 ml dichloromethane at 0-10 C. The reaction mixture was stirred at 25-35 C. till completion of the reaction as monitored by HPLC. The reaction mass was quenched with aqueous hydrochloric acid followed by filtration to isolate the crude product. Isolation from aqueous acetic acid gave the desired compound, 2-chloro-3,4-dihydroxy acetophenone (4).

(13) Yield: 210 g; (62%).

Example 2: Preparation of 3,4-dihydroxy-2-(isopropylamino)-acetophenone Hydrochloride (5a)

(14) 2-chloro-3,4-dihydroxy acetophenone (4, 200 g) was added to acetonitrile (1400 ml) placed in a round bottom flask. Isopropyl amine solution (221.7 g) was gradually added to the mixture at 20-30 C. The reaction temperature was raised to 55-65 C. and continued till completion of the reaction, as monitored by HPLC.

(15) The reaction mixture was cooled to 20-30 C. and concentrated hydrochloric acid (383 ml) was gradually added to it, till the pH was around 2.0. The reaction mixture was heated to 50-65 C., with stirring, cooled and filtered to give crude 3,4-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (50).

(16) Yield: 120 g; (45%).

Example 3: Preparation of Isoproterenol Hydrochloride (1a)

(17) Methanol (800 ml) was placed in an autoclave and 3,4-dihydroxy-2-(isopropylamino)-acetophenone hydrochloride (5a, 100 g), Pd/C (10%, moisture 50%, 10 g.), were added to it as a slurry in methanol, along with water (60 ml) and Amberlyst A-21 resin (1 g). The reaction was carried out at 20-30 C. in presence of hydrogen gas (3 to 5 Kg/cm.sup.2) which was maintained till completion of the reaction. After reaction completion, as monitored by HPLC, the reaction mixture was filtered and the filtrate was concentrated after optional treatment with activated carbon. The solid thus obtained was treated with ethanol and water followed by filtration to give isoproterenol hydrochloride (1a).

(18) Yield: 66.4 g (65.5%)

(19) Purity: 99.93% (HPLC).