DESC:FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of pure Labetalol hydrochloride.

BACKGROUND OF THE INVENTION
Labetalol hydrochloride is an alpha1-adrenergic blocker and nonselective, competitive, beta-adrenergic blocker used for the treatment of hypertension. Labetalol hydrochloride was approved by USFDA in 1984 under the brand name of Trandate® with dosage strength of 100 mg, 200 mg and 300 mg for oral administration.
Labetalol hydrochloride, chemically known as 2-hydroxy-5-[1-hydroxy-2-(1-methyl-3-phenyl-propylamino)-ethyl]-benzamide hydrochloride, is represented by a chemical structural formula as shown below:

(I)
The synthesis of Labetalol hydrochloride was first disclosed in US Patent No. 4012444 (referred to as US’444 herein after). The process disclosed in US ‘444 is depicted in scheme-1.

Scheme-1

The process involves the use of expensive catalysts like palladium, platinum for hydrogenation with an overall yield of 12% and is not appropriate for commercial production.
GB 2149399 discloses a process for preparing Labetalol hydrochloride as depicted in Scheme-2.

Scheme-2:
This process does not disclose yield and purity. However this process leads to formation of brominated impurities like 3-Bromo Labetalol impurity as disclosed in Indian Patent application No. 1/MUM/2014.
Scheme 1 and 2 in the prior art require 5-(bromoacetyl)-2-hydroxybenzamide as key intermediate, which is generally prepared by bromination of 5-acetyl-2-hydroxybenzamide as shown in scheme-3.
Scheme-3:

Chinese Patent No. CN 101560170 discloses that bromination reaction of 5-acetyl-2-hydroxybenzamide involves formation of two impurities having chemical structures as given below:

5, 5-Dibromo impurity
3-Bromo impurity
The 5, 5-dibromo impurity is carried forward and further converted into 5,5 - dimer Labetalone impurity and finally 5,5 – dimer Labetalol impurity as represented below in schematically (scheme-4).
Scheme-4:

This dimer impurity is easily washed-off during isolation of final API.

Similarly, the 3-Bromo impurity is carried forward and simultaneously converted into 3-Bromo Labetalone impurity and finally retained as 3-Bromo Labetalol impurity as per scheme-5.
Scheme-5:

It is to be noted that the 3-Bromo Labetalol impurity is difficult to remove by general solvent purifications and multiple re-crystallisations making these schemes commercially non-feasible.
As per ICH guidelines, drug products having maximum daily dose > 1000 mg, the limit of single maximum impurity in final active pharmaceutical ingredient (API) should be < 0.05% and total impurity should be < 0.5%. According to USFDA label and Europe-SmPC, the maximum daily dose of Labetalol hydrochloride is 2400 mg. Therefore, it is necessary to control limit of the single maximum impurity to < 0.05% and the total impurity to < 0.5% in Labetalol hydrochloride.
If the 3-Bromo Labetalone impurity is present in amount > 0.3% in the Labetalone intermediate, it is carried forward and gets converted to 3-Bromo Labetalol impurity in the final API, thereby increasing the number of purification steps to be carried out to obtain Labetalol HCl which is within the ICH guidelines.
As mentioned earlier, it has not been possible to cost effectively remove the 3-Bromo Labetalol impurity from the final API, by minimizing the number of purification steps, thereby making the process commercially unviable.
There is therefore an unmet need to provide a commercially feasible and industrially scalable process for the production of pure Labetalol hydrochloride, substantially free of 3-Bromo Labetalol impurity preferably < 0.05%.

OBJECT OF THE INVENTION
The main object of present invention is to provide an improved process for the preparation of pure Labetalol hydrochloride substantially free of the 3-Bromo Labetalol impurity.
Another object of present invention is to provide an improved, cost effective and industrially scalable process for the preparation of pure Labetalol hydrochloride having 3-Bromo Labetalol impurity < 0.05% measured by HPLC.
Another object of present invention is to provide an improved process for the preparation of Labetalol hydrochloride of at least 99.5 % purity, preferably > 99.8% purity measured by HPLC.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides an improved process for the preparation of pure Labetalol hydrochloride of formula (I) as depicted in scheme – 6.

Scheme-6:

The process of present invention provides Labetalol hydrochloride of formula (I) with substantially pure Labetalol free base < 0.05% 3-Bromo Labetalol impurity by HPLC, thereby making the purification process optional.
In another aspect, the present invention provides an improved, cost effective and industrially scalable process for the preparation of pure Labetalol hydrochloride having 3-Bromo Labetalol impurity < 0.05% measured by HPLC.
In another aspect, the present invention provides an improved process for the preparation of Labetalol hydrochloride of at least 99.5 % purity, preferably > 99.8% purity measured by HPLC.

DETAILED DESCRIPTION OF INVENTION
As used herein, the term “substantially pure Labetalol hydrochloride" refers to Labetalol hydrochloride, of purity > 99.5%, preferably with purity of > 99.9% and substantially free from 3-Bromo Labetalol impurity < 0.05%, measured by HPLC.
The present invention provides an improved process for the preparation of pure Labetalol hydrochloride of formula (I),

comprising the steps of:
(a) reacting 5-bromoacetyl-2-hydroxybenzamide with 4-phenylbutan-2-amine in a solvent to obtain labetalone and further converting to Labetalone hydrochloride;
(b) treating the product of step (a) with aqueous ammonia in a solvent to obtain Labetalone base;
(c) acidifying the product obtained in step (b) to obtain Labetalone hydrochloride;
(d) reducing the product of step (c) with sodium borohydride in a solvent, adjusting the pH to 8.5 - 11 with acetic acid to obtain Labetalol base;
(e) acidifying product of step (d) to Labetalol hydrochloride;
(f) treating Labetalol hydrochloride of step (e) with aqueous ammonia in a solvent to obtain Labetalol base;
(g) acidifying the Labetalol base to Labetalol hydrochloride having purity greater than 99.90 % and having 3-bromo labetalol impurity below 0.05% measured as area percentage by HPLC.
The solvent in step (a) is selected from polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, water or the mixtures thereof; polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile or the mixtures thereof. The preferable solvent is isopropanol.
The reaction step (a) is carried out by reacting 5-bromoacetyl-2-hydroxybenzamide with 4-phenylbutan-2-amine at -15°C to 15°C, preferably between 0°C to 5°C in a suitable solvent, preferably Isopropanol. After completion of the reaction, pH of the reaction mixture is adjusted to < 2 with hydrochloric acid to obtain Labetalone hydrochloride.
The solvent in step (b) is selected from polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, water or the mixtures thereof; polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile or the mixtures thereof. The preferable solvent is methanol.
Aqueous ammonia used in step (b) is 2-9% w/w, preferably 5-7% w/w.
The reaction in step (b) is carried out by reacting the product of step (a) with preferably 5-7% aqueous ammonia at 15 to 45°C, preferably between 25 to 35°C in a suitable solvent, preferably methanol, to obtain Labetalone base.
The solvent in step (c) is selected from ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or the mixtures thereof; esters such as ethyl acetate, methyl acetate, isopropyl acetate or the mixtures thereof; ethers such as tetrahydrofuran, dimethyl ether, diethyl ether, dioxane or the mixtures thereof. The preferable solvent is acetone.
The reaction in step (c) is carried out by reacting the product of step (b) with hydrochloric acid preferably at pH < 2 at 15°C to 45°C, preferably between 25°C to 35°C in a suitable solvent, preferably acetone, to obtain Labetalone hydrochloride.
The solvent in step (d) is selected from solvents comprising polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, water or the mixtures thereof; ketone solvents such as such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof. The preferable solvent is mixture of methanol and water.
In general, step (d) is carried out by first treating the product obtained in step (c) with alkali base in water followed by adding alcoholic solvent and further performing reduction reaction with reducing agent like potassium borohydride, sodium borohydride more preferably sodium borohydride.
In step (d) the product of step (c) is treated with sodium hydroxide in water, followed by reacting with sodium borohydride at 5-30°C, preferably between 15-20°C in a suitable solvent, preferably methanol. After completion of the reaction, the reaction mass is treated with acetic acid to attain pH of 8.5-11 pH, preferably to 9-10.5 at 15-45°C, preferably between 25-35°C to obtain Labetalol base.
The solvent in step (e) is carried out by reacting the product of step (d) with hydrochloric acid at pH < 2 at 15°C to 45°C, preferably between 25°C to 35°C in a suitable solvent, preferably acetone, to obtain Labetalol hydrochloride. is selected from ketone solvents such as such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or the mixtures thereof; esters such as ethyl acetate, methyl acetate, isopropyl acetate or the mixtures thereof; ethers such as tetrahydrofuran, dimethyl ether, diethyl ether, dioxane or the mixtures there. The preferable solvent is acetone.
The reaction in step (e) is carried out by reacting the product of step (b) with hydrochloric acid at pH < 2 at 15°C to 45°C, preferably between 25- 35°C in a suitable solvent, preferably acetone, to obtain Labetalone hydrochloride.
The solvent in step (f) is selected from solvents comprising polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, water or the mixtures thereof; polar aprotic solvents like dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile or the mixtures thereof. The preferable solvent is methanol.
Aqueous ammonia used in step (f) is 2-9% w/w, preferably 5-7% w/w.
The reaction in step (f) is carried out by reacting the product of step (a) with preferably 5-7% aqueous ammonia at 15-45°C, preferably between 25°C to 35°C in a suitable solvent, preferably methanol, to obtain Labetalol base.
The solvent in step (g) is selected from ketone solvents such as such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or the mixtures thereof; esters such as ethyl acetate, methyl acetate, isopropyl acetate or the mixtures thereof; ethers such as tetrahydrofuran, dimethyl ether, diethyl ether, dioxane or the mixtures there. The preferable solvent is acetone.
The reaction in step (g) is carried out by reacting the product of step (f) with hydrochloric acid at pH < 2 at 15°C to 45°C, preferably between 25°C to 35°C in a suitable solvent, preferably acetone, to obtain Labetalol hydrochloride.
It has been observed that if 3-Bromo Labetalone impurity is not controlled < 0.3 % at intermediate stage, then it gets converted to 3-Bromo Labetalol impurity during subsequent steps and is carried forward to final API > 0.05%, thereby requiring multiple purification step to reduce impurity level.
Further, it has also been observed that it is difficult to remove 3-Bromo Labetalone impurity to less than 0.3% from Labetalone hydrochloride by conventional solvent purifications. The results for different solvent purifications of Labetalone HCl performed to remove 3-Bromo Labetalone impurity are given in table-1.
Table-1
No. Solvent Content of
3-Bromo Labetalone impurity %
Labetalone hydrochloride Pure Labetalone hydrochloride
1 Acetone 0.34 0.33
2 n-Butanol 0.37 0.33
3 Water + SDS 0.37 0.33
4 Methanol 0.37 0.33
5 DMF 0.37 0.27
6 THF 0.37 0.36
7 1,4 Dioxane 0.37 0.34
8 MIBK 0.37 0.37
9 MDC 0.37 0.37
10 Ethyl Acetate 0.37 0.34
11 MEK 0.37 0.37
12 IPA 0.37 0.41

It has surprisingly been found that pure Labetalol hydrochloride of formula (I) having purity > 99.5% and of 3-Bromo impurity < 0.05% is prepared in steps of:
• treating Labetalone hydrochloride with aqueous ammonia and further treating the obtained Labetalone base with hydrochloric acid;
• reducing Labetalone hydrochloride with a borohydride, adjusting the pH of reaction mixture after reduction reaction with acetic acid to obtain Labetalol base, and converting it to hydrochloride salt with hydrochloric acid;
• treating the Labetalol hydrochloride with aqueous ammonia, and further treating the obtained Labetalol base with hydrochloric acid.

Tables-2 and 3 present the results obtained according to present invention.
Table-2:
Content of 3-Bromo impurity in Labetalone hydrochloride
on treatment with 5-7% w/w aqueous ammonia / hydrochloric acid
Before treatment After treatment Bromo Impurity reduction %
0.50% 0.26% 48 %

Table-3
Content of 3-Bromo impurity in Labetalol hydrochloride
on treatment with 5-7% w/w Aqueous ammonia / Hydrochloric acid
Before treatment After treatment Bromo Impurity reduction %
0.07% 0.03% 57.14 %

It has surprisingly that been found that acid-base treatment of Labetalone when carried out with aqueous ammonia 2-9% w/w produces the desired results. Similarly acid-base treatment carried out using other bases does not produce the desired results. The results of comparative experiments are given in table-4.

Table-4
Content of 3-Bromo impurity in Labetalone
on treatment with various bases
Base Before treatment % After treatment %
5-7% Aq. Ammonia 0.34 0.15
TEA 0.44 0.37
NaOH 0.44 0.37
K2CO3 0.44 0.36

The results of comparative experiments in table-4 demonstrate the superiority of the present invention.
The invention is illustrated with non-limiting examples.
Example-1: Preparation of 5-Bromoacetyl salicylamide.
Ethyl acetate (400 ml), 5-acetyl salicylamide (100 gm) and Isopropanol (120 ml) were mixed under stirring at 25°C to 30°C and the reaction mixture was heated to 38°C to 43°C. Bromine was gradually added to the reaction mixture and maintained for 2 hours and the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was filtered. The wet cake was washed with ethyl acetate, followed by water. The product was washed with aqueous sodium bisulphite solution and dried at 55-60°C to obtain 112 gm 5-Bromoacetyl salicylamide. Yield: 77.80%; Purity: 96.06%.
Example-2: Preparation of Labetalone hydrochloride
Isopropanol (600 ml), 3-aminophenyl butane (289 gm) and 5-bromoacetyl salicylamide (100 gm) were mixed under stirring at 0-5°C for 3 hours. Reaction was monitored by HPLC. After completion of the reaction, 1:1 mixture of HCl and DM water (320 ml) was added to adjust the pH below 2.0, stirred at 25°C to 30°C for 15-17 hours and filtered. The wet cake was washed with Isopropanol (200 ml) and dried at 55-60°C to obtain 100 gm Labetalone hydrochloride. Yield: 71.19 %; Purity: 96.06%, 3-Bromo Labetalone: 0.50%.
Example-3: Preparation of Labetalone free base
Labetalone Hydrochloride (100 gm) in methanol (200 ml) and 6% aqueous ammonia (100 ml) were mixed under stirring at 25°C to 30°C for 2 hours, filtered, washed with Acetone (100 ml) and suck dried at 25-30°C to obtain wet cake of Labetalone free base.
Example-4: Preparation of Labetalone Hydrochloride
Concentrated Hydrochloric acid (35 ml) was added to a stirred solution of Labetalone free base from example-3 in acetone (400 ml) at 25°C to 30°C. The reaction mixture was stirred for 2 hours, filtered, washed with Acetone (200 ml) and dried at 55°C to 60°C to obtain Labetalone Hydrochloride. Purity: 99.62%, 3-Bromo Labetalone: 0.26%.
Example-5: Preparation of Labetalol free base
Aqueous NaOH solution (27.28 gm NaOH in 200ml DM water) was added under stirring to a solution of Labetalone Hydrochloride (100 gm) in water (300 ml) at 10-15°C. Methanol (100 ml) and sodium borohydride (10.41 gm) were added to the reaction mixture and maintained at 25°C to 35°C for 10-12 hours. After completion of the reaction, pH was adjusted to 9-10.5 using dilute acetic acid at 25°C to 35°C. The reaction mixture was stirred for 2-3 hours and filtered. The wet cake was washed with acetone (200 ml) and dried at 25°C to 30°C to obtain Labetalol free base.
Example-6: Preparation of Labetalol Hydrochloride
Concentrated hydrochloric acid was added to a stirred solution of Labetalol free base from example-5 in acetone (500 ml) at 10°C to 15°C. The reaction mixture was stirred for 2 hours, filtered, washed with Acetone (200 ml) and dried at 55°C to 60°C to obtain Labetalone Hydrochloride (Content of 3-Bromo Labetalone: 0.07%).
Example-7: Preparation of Labetalol free base
Labetalol Hydrochloride from example-6 in methanol (200 ml) and aqueous ammonia (100 ml) in various conc. as given in table-5 were mixed under stirring at 25°C to 30°C for 2 hours, filtered, washed with Acetone (200 ml) and suck dried at 25°C to 30°C to obtain wet cake of labetalol free base. The results of comparative experiments are given in table-5.
Content of 3-Bromo impurity in Labetalol on treatment with various conc. of aq. Ammonia
Example Aq. ammonia Conc. Condition Before treatment % After treatment %
7a 4% 20-30 ? 0.37% 0.18%
7b 5% 20-30 ? 0.23% 0.092%
7c 6% 20-30 ? 0.23% 0.062%
7d 7% 20-30 ? 0.23% 0.052%
Table-5

Example-8: Preparation of pure Labetalol hydrochloride
Concentrated hydrochloric acid (35 ml) was added to a stirred solution of Labetalol free base (100 gm) from example-7 in acetone (500 ml) at 10°C to 15°C. The reaction mixture was stirred for 2 hours, filtered, washed with acetone (200 ml) and dried at 70°C to 75°C to obtain pure Labetalol Hydrochloride. Yield: 88.32%; Purity: 99.96 %, 3-Bromo Labetalol: 0.03%. ,CLAIMS:1) An improved process for the preparation of substantially pure labetalol hydrochloride of formula (I),

comprising the steps of:
(a) reacting 5-bromoacetyl-2-hydroxybenzamide with 4-phenylbutan-2-amine in a solvent to obtain labetalone and further converting to Labetalone hydrochloride;
(b) treating the product of step (a) with aqueous ammonia in a solvent to obtain Labetalone base;
(c) acidifying the product obtained in step (b) to obtain Labetalone hydrochloride;
(d) reducing the product of step (c) with sodium borohydride in a solvent, adjusting the pH to 8.5 - 11 with acetic acid to obtain Labetalol base;
(e) acidifying product of step (d) to Labetalol hydrochloride;
(f) treating Labetalol hydrochloride of step (e) with aqueous ammonia in a solvent to obtain Labetalol base;
(g) acidifying the Labetalol base to Labetalol hydrochloride having purity greater than 99.90 % and having 3-bromo labetalol impurity below 0.05% measured as area percentage by HPLC;
(h) optionally, further purifying labetalol hydrochloride.

2) The process as claimed in claim 1, wherein the aqueous ammonia used in step (b) and step (f) is 2-9% w/w, preferably 5-7% w/w.

3) The process as claimed in claims 1, wherein the solvent used in step (a), step (b) and step (f) is selected from polar protic solvents like methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, water or the mixtures thereof; polar aprotic solvents like dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile or the mixtures thereof.

4) The process as claimed in claims 1, wherein the solvent used in step (c), step (e) and step (g) is selected from ketone solvents like acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or the mixtures thereof; esters like ethylacetate, methylacetate, isopropylacetate or the mixtures thereof; ethers like tetrahydrofuran, dimethyl ether, diethyl ether, dioxane or the mixtures thereof.

5) The process as claimed in claims 1, wherein the solvent used in step (d) is selected from polar protic solvents like methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, water or the mixtures thereof; ketone solvents such as such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof.

6) The process as claimed in claim 1, wherein the reaction step (a) is performed at -15°C to 15°C, preferably between 0°C to 5°C.

7) The process as claimed in claim 1, wherein the reaction step (b) to (g) is performed at 15 °C to 45°C, preferably between 25 °C to 35°C.