Description:FIELD OF INVENTION:
The present invention relates to a process for the preparation of pure propranolol or its hydrochloride salt (propranolol hydrochloride), wherein the resulting propranolol or propranolol hydrochloride is substantially free of N-nitrosamine impurity (N-Nitroso propranolol).
BACKGROUND OF INVENTION:
Propranolol hydrochloride is a well-known drug, and was first approved in the USA in the year 1967. It is indicated for the treatment of multiple indications such as hypertension, angina pectoris caused due to coronary atherosclerosis, migraine and hypertrophic subaortic stenosis. It is marketed in the USA as INDERAL LA® in extended release dosage form, particularly as capsules for oral administration.
Propranolol contains a secondary amine group in its chemical structure, which is presented herein below as the compound of Formula II, and therefore, it is capable of undergoing nitrosylation to give the corresponding N-nitrosamine derivative termed as N-nitroso propranolol or N-nitroso impurity. In fact, INDERAL LA® product was recalled in Canada, in the year 2022, due to the presence of nitrosamine impurity (N-nitroso propranolol) above the acceptable level (https://recalls-rappels.canada.ca/en/alert-recall/pfizer-recalls-inderal-propranolol-hydrochloride-capsules-due-nitrosamine-impurity). As per ICH harmonized Guideline M7(R1) nitrosamine are classified as Class 1 impurities, “known mutagenic carcinogens” (Ref.: “ICH Harmonised Guideline - Assessment And Control Of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, M7(R1)”; March 31, 2017) and therefore, presence of such impurities in drug substances beyond the permissible levels may increase the risk of cancer if people are exposed to them over longer periods of time.
The chemical name of propranolol hydrochloride is 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol hydrochloride, which is represented by the compound of formula I (the “compound I” ).

I II III
Propranolol, represented above by the compound of formula II (the “compound II)” is described in U.S. Pat. No. 3,337,628. The chemical name of the N-nitrosamine impurity of propranolol hydrochloride is N-(2-hydroxy-3-naphthalen-1-yloxypropyl)-N-propan-2-ylnitrous amide, which is also referred to as N-nitroso propranolol, and it is represented by the compound of formula III (the “compound III”).
Various processes for the preparation of propranolol hydrochloride are reported in the art.
US 3,337,628 (the “US’628 patent”) discloses a process for the preparation of propranolol hydrochloride (the “compound I”), by reacting 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”) with isopropyl amine (the compound V) under reflux conditions to obtain propranolol (the “compound II”), which is further treated with hydrochloric acid in acetone, and crystallized in propanol to obtain propranolol hydrochloride (the compound I). The process disclosed in the US’628 patent is schematically presented below:

IV V II I
GB 2238786B (the “GB’786 patent”) discloses a process for the preparation of propranolol hydrochloride (the “compound I”) by reacting l-naphthol (the “compound VI”) with epichlorohydrin (the “compound VII”) in the presence of triethylamine followed by the treatment with sodium hydroxide and isopropyl amine (the “compound V”) to obtain propranolol (the “compound II”), which is further treated with hydrochloric acid in acetone to obtain propranolol hydrochloride (the “compound I”). The process disclosed in the GB’786 patent is schematically presented below:

VI VII V II I
GB 1079534A (the “GB’534 patent”) discloses a process for the preparation of propranolol (the “compound II”) by heating a reaction mixture containing 1-naphthol (the “compound VI”), epichlorohydrin (the “compound VII”), isopropyl amine (the “compound V”), sodium hydroxide and ethanol at 100°C for 10 hours. The process disclosed in the GB’534 patent is schematically presented below:

VI VII V II
IN 330000B discloses a process for the preparation of propranolol (the “compound II”) by reacting N-benzyl-N-isopropyl-2,3-epoxypropylamine (the “compound VIII”) with 1-naphthol (the “compound VI”) to obtain N-benzyl propranolol (the “compound IX”), which is subjected to debenzylation using hydrogen gas in the presence of Pd/C catalyst to obtain propranolol (the “compound II”). The process disclosed in the IN330000 patent is schematically presented below:

VIII VI IX II
wherein in the compounds of formulae VIII and IX, Ph represents phenyl.
IN 371356 B, discloses a process for the preparation of propranolol (the “compound II”) by heating a mixture of 1-naphthol (the “compound VI”), epichlorohydrin (the “compound VII”) and triethylamine at 60°C for 5 hours followed by treating with isopropyl amine (the “compound V”) to obtain propranolol (the “compound II”).

VI VII V II
It is desired to provide the drug substance, which is stable, and wherein the amount of nitrosamines impurities does not exceed beyond the FDA acceptable intake limit, particularly for ensuring the safety, efficacy and consistency of the pharmaceutical composition containing the drug substance. Therefore, there remains a need for processes for the synthesis of drug substances that are capable of forming N-nitrosamine impurity so as to reduce or prevent the formation of nitrosamine impurities in simple and cost-effective manner.

SUMMARY OF INVENTION:
In one aspect, the present invention provides an improved process for the preparation of propranolol (the “compound II”) or a hydrochloride salt thereof (interchangeably referred to as propranolol hydrochloride or the “compound I”), wherein the process comprises the steps of;
(a) treating propranolol represented by the compound of formula II (the “compound II”),

II
with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate to obtain pure propranolol (the “compound II”);
(b) optionally treating the pure propranolol (the “compound II”) obtained in the step (a) with hydrochloric acid to obtain its hydrochloride salt represented by the compound of formula I (the “compound I”);

I III
and
(c) isolating propranolol (the “compound II”) from the step (a) or its hydrochloride salt (the “compound I”) from the step (b);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
In another aspect, the present invention provides an improved process for the preparation of pure propranolol (the “compound II”) or its hydrochloride salt (the “compound I”), wherein the process comprises the steps of;
(i) preparing a solution of propranolol represented by the compound of formula II (the “compound II”) in a solvent;

II
(ii) treating the solution of the step (i) with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate;
(iii) heating the reaction mass of the step (ii) at a temperature ranging from about 40°C to about 90°C;
(iv) cooling the reaction mass of the step (iii) to a temperature ranging from about 20°C to about 0°C to obtain propranolol (the “compound II”);
(v) optionally treating the reaction mass of the step (iv) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”);

I III
and
(vi) isolating propranolol (the “compound II”) from the step (iv) or its hydrochloride salt, propranolol hydrochloride (the “compound I”) from the step (v);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
Yet another aspect of the present invention is to provide an improved process for the preparation of pure propranolol (the “compound II”) or its hydrochloride salt (the “compound I”), wherein the process comprises the steps of;
(A) reacting 1- naphthol (the “compound VI”) with epichlorohydrin (the “compound VII”) in the presence of triethylamine to obtain 1-chloro-3-(naphthalene-1-yloxy)propan-2-ol (the “compound X”);

VI VII X
(B) reacting 1-chloro-3-(naphthalene-1-yloxy)propan-2-ol (the “compound X”) obtained in the step (A) without isolating it with sodium hydroxide to obtain 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”);

X IV
(C) reacting 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”) obtained in the step (B) without isolating it with isopropylamine to obtain propranolol (the “compound II”);

(D) preparing a solution of propranolol (the “compound II”) obtained in the step (C) in water or an organic solvent or a mixture thereof; and treating it with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate;
(E) heating the reaction mass of the step (D) at a temperature ranging from about 40°C to about 90°C;
(F) cooling the reaction mass of the step (E) to a temperature ranging from about 20°C to about 0°C to obtain propranolol (the “compound II”);
(G) optionally treating the reaction mass of the step (F) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”); and

(H) isolating propranolol (the “compound II”) as obtained in step (F) or propranolol hydrochloride (the “compound I”) as obtained in step (G);
wherein the resulting propranolol or propranolol hydrochloride salt contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
Yet another aspect of the present invention is to provide propranolol hydrochloride obtained by the processes as described herein, having content of nitrosamine impurity i.e. N-nitroso propranolol about 0.01 ppm to about 0.05 ppm.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides an improved process for the preparation of propranolol (the “compound II”) or a hydrochloride salt thereof (interchangeably referred to as propranolol hydrochloride or the “compound I”), wherein the process comprises the steps of;
(a) treating propranolol represented by the compound of formula II (the “compound II”),

II
with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate to obtain pure propranolol (the “compound II”);
(b) optionally treating the pure propranolol (the “compound II”) obtained in the step (a) with hydrochloric acid to obtain its hydrochloride salt represented by the compound of formula I (the “compound I”);

I III
and
(c) isolating propranolol (the “compound II”) from the step (a) or its hydrochloride salt (the “compound I”) from the step (b);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
The hydrochloride salt of propranolol represented herein by a compound of formula I is interchangeably referred to as propranolol hydrochloride or the compound I.
In the context of the present invention, the term “substantially free” means that propranolol (the compound II) or propranolol hydrochloride (the compound I) obtained by the process of the present invention contains the N-nitrosamine impurity (N-nitroso propranolol) in a range from about 0.01 ppm to about 0.05 ppm as measured by LC-HRMS (liquid chromatography-High resolution mass spectrometry).
In the context of the present invention, the term “pure” used in reference to propranolol or its hydrochloride salt means that propranolol (the compound II) or propranolol hydrochloride (the compound I) obtained by the process of the present invention is substantially free of the N-nitrosamine impurity (N-nitroso propranolol or the compound III).
As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
In the context of the present invention, the term “optionally” used in one or more aspects of the present invention means that the process step involving addition of hydrochloric acid to obtain propranolol hydrochloride (the compound I) is not mandatory to perform the invention as disclosed herein. It will be apparent to a person skilled in the art that the step involving addition of hydrochloric acid is optional, and that it does not deviate from the scope of the present invention.
In an embodiment of the present invention, in the step (a) of the process, propranolol (the compound II) is treated with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate in a solvent.
In an embodiment of the present invention, in the step (a) of the process a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate is used in molar equivalent of about 0.1 to about 5.0 with respect to propranolol.
In an embodiment of the present invention, the reagent used in the step (a) of the process is dimethylamino hydrochloride.
In an embodiment of the present invention, the reagent used in the step (a) of the process is ascorbic acid or sodium ascorbate.
In an embodiment of the present invention, the solvent used in the step (a) is selected from water, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol, toluene, xylene, benzene, chlorobenzene, cyclohexane or a mixture thereof.
In another embodiment of the present invention, the step (a) is carried out at a temperature ranging from about 40°C to about 90 °C.
In a further embodiment of the present invention, in the step (b) of the process, pure propranolol (the compound II) obtained in the step (a) is optionally treated with hydrochloric acid at a temperature ranging from about 50°C to about 80°C to obtain its hydrochloride salt (the compound I) i.e. propranolol hydrochloride in pure form.
In another further embodiment of the present invention, in the step (c) of the process, pure propranolol (the compound II) obtained in the step (a) or pure propranolol hydrochloride (the compound I) obtained in the step (b) is isolated by any method known in the art. The method may involve any of techniques known in the art, including filtration by gravity or by suction, centrifugation, drying and the like.
In another aspect, the present invention provides an improved process for the preparation of pure propranolol (the “compound II”) or its hydrochloride salt (the “compound I”), wherein the process comprises the steps of;
(i) preparing a solution of propranolol represented by the compound of formula II (the “compound II”) in a solvent;

II
(ii) treating the solution of the step (i) with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate;
(iii) heating the reaction mass of the step (ii) at a temperature ranging from about 40°C to about 90°C;
(iv) cooling the reaction mass of the step (iii) to a temperature ranging from about 20°C to about 0°C to obtain propranolol (the “compound II”);
(v) optionally treating the reaction mass of the step (iv) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”);

I III
and
(vi) isolating propranolol (the “compound II”) from the step (iv) or its hydrochloride salt, propranolol hydrochloride (the “compound I”) from the step (v);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
In an embodiment of the present invention, the solvent used in step (i) is selected from the same solvents as described herein above in respect of the step (a) of the process of the first aspect of the invention.
In an embodiment of the present invention, in the step (ii) of the process a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate is used in molar equivalent of about 0.1 to about 5.0 with respect to propranolol.
In an embodiment of the present invention, the reagent used in the step (ii) of the process is dimethylamino hydrochloride.
In an embodiment of the present invention, the reagent used in the step (ii) of the process is ascorbic acid or sodium ascorbate.
In another embodiment of the present invention, the reaction in step (v) is carried out at a temperature ranging from about 50 °C to about 80 °C.
In a further embodiment of the present invention, in the step (vi) of the process, propranolol (the compound II) or propranolol hydrochloride (the compound I) is isolated by any method known in the art. The method may involve any of techniques known in the art, including filtration by gravity or by suction, centrifugation, drying and the like.
Yet another aspect of the present invention is to provide an improved process for the preparation of pure propranolol (the “compound II”) or its hydrochloride salt (the “compound I”), wherein the process comprises the steps of;
(A) reacting 1-naphthol (the “compound VI”) with epichlorohydrin (the “compound VII”) in the presence of triethylamine to obtain 1-chloro-3-(naphthalene-1-yloxy)propan-2-ol (the “compound X”);

VI VII X
(B) reacting 1-chloro-3-(naphthalene-1-yloxy)propan-2-ol (the “compound X”) obtained in the step (A) without isolating it with sodium hydroxide to obtain 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”);

X IV
(C) reacting 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”) obtained in the step (B) without isolating it with isopropylamine to obtain propranolol (the “compound II”);

(D) preparing a solution of propranolol (the “compound II”) obtained in the step (C) in water or an organic solvent or a mixture thereof; and treating it with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate;
(E) heating the reaction mass of the step (D) at a temperature ranging from about 40°C to about 90°C;
(F) cooling the reaction mass of the step (E) to a temperature ranging from about 20°C to about 0°C to obtain propranolol (the “compound II”);
(G) optionally treating the reaction mass of the step (F) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”); and

(H) isolating propranolol (the “compound II”) as obtained in step (F) or propranolol hydrochloride (the “compound I”) as obtained in step (G);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
In an embodiment of the present invention, the reaction in the step (A) is carried out at a temperature ranging from about 50 °C to about 80 °C.
In another embodiment of the present invention, the reaction of the step (B) is carried out at a temperature ranging from about 40°C to about 60°C.
In a further embodiment of the present invention, the reaction of the step (C) is carried out at a temperature ranging from about 20°C to about 40°C.
In an embodiment of the present invention, in the step (D) of the process, a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate is used in molar equivalent of about 0.1 to about 5.0 with respect to propranolol.
In an embodiment of the present invention, the reagent used in the step (D) of the process is dimethylamino hydrochloride.
In an embodiment of the present invention, the reagent used in the step (D) of the process is ascorbic acid or sodium ascorbate.
In further embodiment of the present invention, the reaction in the step (G) is carried out at a temperature ranging from about 50°C to about 80°C.
In a further embodiment of the present invention, in the step (H) of the process, propranolol (the “compound II”) or propranolol hydrochloride (the “compound I”) is isolated by any method known in the art. The method may involve any of techniques known in the art, including filtration by gravity or by suction, centrifugation, drying and the like.
In the process of the present invention as described in the preceding paragraphs, the step of treating propranolol with the reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate, and wherein the reagent is used in molar equivalent of about 0.1 to about 5.0 with respect to propranolol.
In an embodiment of the present invention, the pure propranolol (the “compound II”) or the pure propranolol hydrochloride (the “compound I”) obtained by the process of the present invention is substantially free of the N-nitrosamine impurity, N-nitroso propranolol (the “compound III”) wherein the content of the N-nitroso propranolol (the “compound III”) ranges from about 0.01 ppm to about 0.05 ppm.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples:
General Methods:
1. HPLC method: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software or equivalent.
Column: Inertsil ODS 3V, 150 X 4.6mm, 5µ
Make: GL Science
Part no: (Part No:5020-01801)
Welch Ghostbuster Column: 50x4.6mm (Part No. 06100-31000) to be attached between solvent mixing chamber and sample injector.
Column temperature: 30°C
Sample Cooler temperature: 10°C
Buffer: 1.0 ml Perchloric acid in 1000 ml water
Mobile phase: A = Buffer:Acetonitrile(90:10 v/v)
Mobile Phase: B = Buffer:Acetonitrile(10:90 v/v)
Gradient program:
Time (Min) % Mobile Phase A %Mobile Phase B
0.01 90 10
30 10 90
47 10 90
48 90 10
58 90 10 90 90 10 10 90 10

Flow rate: 1.0 mL/minute
Detection wavelength: UV 292 nm
Injection volume: 10 mL
Diluent-: Buffer:Acetonitrile (45:55 v/v)
Run time: 58 minutes
Needle wash: water: Acetonitrile (10:90, v/v)
Seal Wash: Water: Acetonitrile (80:20, v/v)
2. LC-HRMS. (Liquid chromatography-High resolution mass spectrometry).
Chromatographic Conditions:
Apparatus: A Liquid Chromatography and Mass spectrometry equipped with quarternary gradient pumps, variable wavelength UV and Mass detector attached with data recorder and integrator software
Column: Avantor ACE 3, C18, PFP 150 x 4.6mm x 3µm
Make: Avantor ACE
Part No.: A220544799
Column temperature: 50°C
Sample cooler temperature: 10°C
Mobile Phase:
Mobile Phase A = Buffer (100%)
Buffer: 0.63gm Ammonium formate and 1.0 ml Formic acid into 1000 ml of water.
Mobile Phase B = Acetonitrile
Time (min.) % Mobile Phase A % Mobile Phase B
00.00 45 55
15.00 45 55
Diluent: Acetonitrile: Water (90:10)
Flow Rate: 0.6 mL/minute
Injection Volume: 5 µL
Run Time: 15 minutes
Mass spectroscopy condition:
Source: ESI or equivalent (MRM mode +ve)
Source temperature: 150ºC
Desolvation temperature: 650ºC
Capillary Voltage (kV):0.7
Disolvation Gas Flow (L/Hr.):1000
Example 1: Preparation of pure propranolol hydrochloride (the “compound I”)
In a clean and dry flask, a solution of propranolol base (50 gm) in isopropyl alcohol (150 ml) was added with dimethylamino hydrochloride (1.57 gm). The reaction mass was heated to a temperature ranging from 60°C to 70°C to obtain a clear solution, which was stirred for 30 minutes. The reaction mass was cooled to a temperature ranging from 15°C to 20°C, and aqueous hydrochloric acid (22.14 gm) was added to the reaction mass. The reaction mass was heated to a temperature ranging from 60°C to 70°C, and was stirred for 30 minutes. The reaction mass was cooled to a temperature ranging from 5°C to 10°C, and stirred at the same temperature of 5°C to 10? for 1 hour. The reaction mass was filtered, and the wet cake was washed with isopropyl alcohol (25 ml). The wet cake was unloaded and dried in vacuum tray drier at a temperature ranging from 70°C to 75?
Yield: 51.41 gm
Purity: 99.98%
N-Nitroso-propranolol (N-Nitrosamine Impurity): 0.009 ppm
N-Nitrosodimethylamine: Below Detection Limit.
Example 2: Preparation of pure propranolol hydrochloride (the compound I)
In a clean and dry flask, a solution of propranolol base (10 gm) in toluene (50 ml) was added with ascorbic acid (8.5 gm) and water (55 ml). The reaction mass was heated to a temperature ranging from 50°C to 55? and was stirred for 30 minutes. The stirring was stopped and layers were separated. Toluene layer was distilled and degassed. Isopropyl alcohol (40 ml) was added to the degassed mass. The reaction mass was heated to a temperature ranging from 60°C to 70°C to obtain a clear solution. Isopropanol hydrochloride (IPA.HCl) (6.20 ml) was added to the reaction mass. The reaction mass was stirred at a temperature ranging from 60°C to 70? for 30 minutes. The reaction mass was cooled to a temperature ranging from 5°C to 10°C and was stirred at the same temperature ranging from 5°C to 10? for 1 hour. The reaction mass was filtered, and the wet cake was washed with isopropyl alcohol (5 ml). Wet cake was unloaded and dried in vacuum tray drier at a temperature ranging from 70°C to 75°C.
Yield: 7 gm
Purity: 99.50%
N-Nitroso-propranolol (N-Nitrosamine Impurity): 0.014 ppm
N-Nitrosodimethylamine: Below Detection Limit.
Example 3: Preparation of pure propranolol (the compound II)
In a clean and dry flask, a solution of 1-naphthol (50 gm), epichlorohydrin (160 gm) and triethylamine (1.12 gm) was heated to a temperature ranging from 70°C to 75? and was stirred for 3 to 4 hours. The reaction mass was cooled to a temperature ranging from 50°C to 55?. A solution of sodium hydroxide (21 gm) in water (35 ml) was added to the reaction mass. Reaction mass was stirred at a temperature ranging from 50°C to 55? for 2 to 3 hours. The reaction mass was distilled under vacuum to remove epichlorohydrin. The reaction mass was cooled to a temperature ranging from 20°C to 30? and aqueous isopropyl amine (82 ml) was added to the reaction mass. The reaction mass was warmed to a temperature ranging from 30°C to 35? and maintained at the same temperature of 30°C to 35? for 6 to 7 hours. The reaction mass was distilled to remove excess isopropyl amine. The reaction mass was added with toluene (57 ml), water (100 ml) & sodium ascorbate (2 gm). The reaction mass was heated to a temperature ranging from 60°C to 70?and was stirred for 30 minutes. Stirring was stopped and layers were separated. Toluene layer was added with water and sodium ascorbate (2 gm). The reaction mass was heated to a temperature ranging from 60? to 70°C and stirred for 30 minutes. Stirring was stopped and layers were separated. Toluene layer was added with water and sodium ascorbate (2 gm). Reaction mass was heated to a temperature ranging from 60°C to 70? and was stirred for 30 minutes. The stirring was stopped and layers were separated. The reaction mass was cooled to a temperature ranging from 0°C to 5? and was stirred for 1 hour. The reaction mass was filtered & wet cake was washed with toluene (50 ml). Wet cake was unloaded and dried in vacuum tray drier at a temperature ranging from 55? to 60°C.
Yield: 66.5 gm
Purity: 99.52%
N-Nitroso-propranolol (N-Nitrosamine Impurity): 0.01 ppm
N-Nitrosodimethylamine: Below Detection Limit.

Example-4: Preparation of pure propranolol hydrochloride (the compound I)
In a clean and dry flask solution of 1-naphthol (50 gm), epichlorohydrin (160 gm) and triethylamine (1.12 gm) was heated to a temperature ranging from 70°C to 75? and was stirred for 3 to 4 hours. The reaction mass was cooled to a temperature ranging from 50°C to 55?. A solution of sodium hydroxide (21 gm) in water (35 ml) was added to the reaction mass. Reaction mass was stirred at a temperature ranging from 50°C to 55? for 2 to 3 hours. The reaction mass was distilled under vacuum to remove epichlorohydrin. The reaction mass was cooled to a temperature ranging from 5°C to 15? and aqueous isopropyl amine (82 ml) was added to the reaction mass. The reaction mass was warmed to a temperature ranging from 30°C to 35? and maintained at the same temperature of 30°C to 35? for 6 to 7 hours. The reaction mass was distilled to remove excess isopropyl amine. The reaction mass was added with water (150 ml) and toluene (150 ml). The reaction mass was heated at a temperature ranging from 60°C to 70? and was stirred for 30 minutes. The reaction mass was cooled to a temperature ranging from 0°C to 10? and was stirred for 1 hour. The reaction mass was filtered & wet cake was washed with water (75 ml) and chilled toluene (50 ml). Wet cake was added with isopropyl alcohol (197 ml) and dimethylamino hydrochloride (2.06 gm). The reaction mass was heated to a temperature ranging from 60°C to 70°C to obtain a clear solution and was stirred for 30 minutes. The reaction mass was cooled to a temperature ranging from 15°C to 20°C, and aqueous hydrochloric acid (29 gm) was added to the reaction mass. The reaction mass was heated to a temperature ranging from 60°C to 70°C and was stirred for 30 minutes. The reaction mass was cooled to a temperature ranging from 5°C to 10°C, and stirred at the same temperature of 5°C to 10? for 1 hour. The reaction mass was filtered and the wet cake was washed with isopropyl alcohol (30 ml). The wet cake was unloaded and dried in vacuum tray drier at a temperature ranging from 70°C to 75?
Yield: 66 gm
Purity: 99.98%
N-Nitroso-propranolol (N-Nitrosamine Impurity): 0.02 ppm
N-Nitrosodimethylamine: Below Detection Limit.
, Claims:We Claim:
1. A process for the preparation of propranolol (the “compound II”) or a hydrochloride salt thereof (propranolol hydrochloride or the “compound I”), wherein the process comprises the steps of;
(a) treating propranolol represented by the compound of formula II (the “compound II”),

II
with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate to obtain pure propranolol (the “compound II”);
(b) optionally, treating the pure propranolol (the “compound II”) obtained in the step (a) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”);

I III
and
(c) isolating propranolol (the “compound II”) from the step (a) or its hydrochloride salt, (propranolol hydrochloride or the “compound I”) from the step (b);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
2. A process for the preparation of pure propranolol (the “compound II”) or its hydrochloride salt (propranolol hydrochloride or the “compound I”), wherein the process comprises the steps of;
(i) preparing a solution of propranolol represented by the compound of formula II (the “compound II”) in a solvent;

II
(ii) treating the solution of the step (i) with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate;
(iii) heating the reaction mass of the step (ii) at a temperature ranging from about 40°C to about 90°C;
(iv) cooling the reaction mass of the step (iii) to a temperature ranging from about 20°C to about 0°C to obtain propranolol (the “compound II”);
(v) optionally treating the reaction mass of the step (iv) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”);

I III
and
(vi) isolating propranolol (the “compound II”) from the step (iv) or its hydrochloride salt, propranolol hydrochloride (the “compound I”) from the step (v);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
3. The process according to claim 2, wherein the solvent used in the step (i) is selected from water, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol, toluene, xylene, benzene, chlorobenzene, cyclohexane or a mixture thereof.
4. The process according to claim 2, wherein the reaction in the step (v) is carried out at a temperature ranging from about 50°C to about 80°C.
5. A process for the preparation of pure propranolol (the “compound II”) or its hydrochloride salt (the “compound I”) wherein the process comprises the steps of;
(A) reacting 1-naphthol (the “compound VI”) with epichlorohydrin (the “compound VII”) in the presence of triethylamine to obtain 1-chloro-3-(naphthalene-1-yloxy)propan-2-ol (the “compound X”);

VI VII X
(B) reacting 1-chloro-3-(naphthalene-1-yloxy)propan-2-ol (the “compound X”) obtained in the step (A) without isolating it with sodium hydroxide to obtain 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”);

X IV
(C) reacting 2-((naphthalene-1-yloxy)methyl)oxirane (the “compound IV”) obtained in the step (B) without isolating it with isopropylamine to obtain propranolol (the “compound II”);

(D) preparing a solution of propranolol (the “compound II”) obtained in the step (C) in water or an organic solvent or a mixture thereof; and treating it with a reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate;
(E) heating the reaction mass of the step (D) at a temperature ranging from about 40°C to about 90°C;
(F) cooling the reaction mass of the step (E) to a temperature ranging from about 20°C to about 0°C to obtain propranolol (the “compound II”);
(G) optionally treating the reaction mass of the step (F) with hydrochloric acid to obtain its hydrochloride salt, propranolol hydrochloride represented by the compound of formula I (the “compound I”); and

(H) isolating propranolol (the “compound II”) as obtained in step (F) or propranolol hydrochloride (the “compound I”) as obtained in step (G);
wherein the resulting propranolol or propranolol hydrochloride contains about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”).
6. The process according to claim 5, wherein the reaction of step (D) is carried out in an organic solvent selected from methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol, toluene, xylene, benzene, chlorobenzene, cyclohexane or a mixture thereof.
7. The process according to claim 5, wherein the reaction in step (G) is carried out at a temperature ranging from about 50°C to about 80°C.
8. The process according to any one of the claims 1, 2 and 5, wherein in the step of treating propranolol with the reagent selected from the group consisting of dimethylamino hydrochloride, ascorbic acid and sodium ascorbate, and wherein the reagent is used in molar equivalent of about 0.1 to about 5.0 with respect to propranolol.
9. Propranolol (the “compound II”) having about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”) prepared by the process according to any one of the claims 1, 2 and 5.
10. Propranolol hydrochloride (the “compound I”) having about 0.01 ppm to about 0.05 ppm of N-nitrosamine impurity (the “compound III”) prepared by the process according to any one of the claims 1, 2 and 5.