FIELD OF THE INVENTION
Present invention relates to a process for the preparation of propranolol hydrochloride of Formula I,

BACKGROUND OF THE INVENTION
Propranolol hydrochloride is a sold under the trade name Inderal. Propranolol hydrochloride chemically known as l-(l-naphthoxy)-3-isopropylamino-2-propanol hydrochloride, represented by Formula I, is used in the prevention and treatment of arrhythmia, angina pectoris, hypertension, myocardial infarction, coronary heart disease, hyperthyroidism etc.

US 3,337,628 describes a process for the preparation of propranolol hydrochloride by reacting 2-epoxy-3-naphthoxypropane and isopropyl amine under reflux condition. Propranolol free base is converted into its hydrochloride salt in acetone and ION HC1 followed by the crystallisation in propanol.
GB 2238786 B, describes a process for the preparation of propranolol hydrochloride by reaction between 1-naphthol and epichlorohydrin in the presence of triethylamine as catalyst, wherein a major side product of the reaction is l-(l-naphthoxy)-3-chloropropan-2-ol. This side product, however, can be substantially converted to the desired intermediate of the reaction, i.e. l-(l-naphthoxy)-2,3-epoxypropane, by treatment of the product mixture with sodium hydroxide. Process as disclosed in

GB'786 results in the formation of many impurities which affects the overall yield. Also, said process involves the use of magnesium trisilicate along with hyflow supercell in toluene as a solvent, which makes the process cumbersome and expensive.
GB 1079534 A, describes a process for the preparation of propranolol hydrochloride by heating the reaction mixture containing 1-naphthol, epichlorohydrin, isopropyl amine, sodium hydroxide and ethanol at 100°C for 10 hours.
IN 2071/DEL/2012, describes a process for the preparation of propranolol by reacting benzylated isopropylamine with epichlorohydrin followed by reaction with (2-[(l-naphthyloxy)methyl]oxirane). The process involves several protecting and de-protecting steps making the said process highly expensive to be followed at large scale production.
Journal of the Serbian Chemical Society 2006 Volume 71, Issue 8-9: 867-877, describes a process of propranolol by reacting 1-naphthol with epichlorohydrin in the presence of PTC (tetrabutylammonium bromide) which is an expensive reagent.
IN 2643/DEL/2015, describes a process for the preparation of propranolol by heating a mixture of 1-naphthol, epichlorohydrin and triethylamine at 60°C for 5 hours followed by adding cone. HC1 and further reacted for 3 hours that results in the formation of undesired products along with the desired propranolol.
The processes as described in prior published references, result with a product having many impurities, which impacts the overall yield. Also, the work up processes as disclosed in the prior references are more cumbersome, tedious and time consuming. To avoid the above stated drawbacks, present invention provides a simple and cost effective process for preparation of propranolol hydrochloride wherein, the workup and isolation of product is simple as compared to the processes disclosed in prior published references.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved, cost effective and environment friendly process for the preparation of propranolol hydrochloride of Formula I.

Formula I
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of propranolol hydrochloride of Formula I,

wherein said process comprising the steps of:
a) treating the propranolol free base of Formula VI with suitable solvent and cone.
hydrochloric acid,

Formula VI Formula I
b) isolating the propranolol hydrochloride of Formula I.
The other aspect of the present invention is to provide an improved process for the preparation of propranolol hydrochloride of Formula I,

or ^Y N^

OH H ^ .HCI

Formula I
wherein said process comprising the steps of:
a)treating the propranolol free base of Formula VI with methyl ethyl ketone and cone, hydrochloric acid,



AH H ^

Formula VI

Formula I

and

b) isolating the propranolol hydrochloride of Formula I.
The other aspect of the present invention is to provide an improved process for the preparation of propranolol hydrochloride of Formula I,


OH H ^ .HCI

Formula I
wherein said process comprising the steps of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of
Formula III in presence of a base to obtain a reaction mixture comprising the
compounds of Formula IV and V,

-o

OH
" "CI OH

O

Formula IV Formula V Formula IV.
f
c) treating the compound of Formula IV with isopropyl amine to obtain propranolol
free base of Formula VI, -o

o

Formula IV

NH,

O'

Formula VI

OH

d) treating the propranolol free base of Formula VI with methyl ethyl ketone and cone, hydrochloric acid,



OH

OH

N H
.HCI

Formula VI

Formula I

and

e) isolating the propranolol hydrochloride of Formula I.
In one another aspect, the present invention provides substantially pure propranolol hydrochloride of Formula I, wherein said pure propranolol hydrochloride is substantially free from impurities with each impurity is less than about 0.3% w/w.

DETAILED DESCRIPTION
Brief Description of the accompanying drawing
Fig. 1 represents the X-ray (powder) diffraction (XRPD) pattern of the crystalline
form of Propranolol hydrochloride of Formula I.
Fig. 2 represents the Differential Scanning Calorimetry (DSC) pattern of the
crystalline form of propranolol hydrochloride of Formula I.
The term "suitable solvent" as used in the context of the present invention refers to solvents selected from the group comprising of, but not limited to, esters, alcohols, halogenated solvent, nitriles, ketones, hydrocarbons, ethers, sulfoxides, amides, carbonates, water and mixture thereof. Specifically, the suitable solvent is selected from, but not limited to, the group comprising of ethyl acetate, isopropyl acetate, butyl acetate, t-butyl acetate, propyl acetate, propylene acetate, acetonitrile, acetone, methyl tert-butyl ketone, methyl ethyl ketone, tetrahydrofuran, 1,4-dioxane, dichloromethane, methanol, ethanol, t-butanol, isopropyl alcohol, dimethyl formamide, dimethyl sulfoxide, toluene, cyclohexane, n-heptane, chloroform, carbon tetrachloride, and mixture thereof.
The preparation of propranolol hydrochloride of Formula I may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
In one embodiment, the present invention provides an improved process for the preparation of propranolol hydrochloride of Formula I,


wherein said process comprising the steps of:
a) treating the propranolol free base of Formula VI with suitable solvent and cone, hydrochloric acid,

Formula VI Formula I
b) isolating the propranolol hydrochloride of Formula I.
In another embodiment, the present invention provides an improved process for the preparation of propranolol hydrochloride of Formula I,

wherein said process comprising the steps of:
a) treating the propranolol free base of Formula VI with methyl ethyl ketone and cone, hydrochloric acid,

Formula VI Formula I
b) isolating the propranolol hydrochloride of Formula I.
In another embodiment, the present invention provides an improved process for the preparation of propranolol hydrochloride of Formula I,


Formula I
wherein said process comprising of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of
Formula III in the presence of a base to obtain a reaction mixture comprising the
compounds of Formula IV and V,




4. °\. xcl

Formula II
Formula III Formula IV Formula V
t
b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the of Formula IV,
-P ^o


Formula IV

Formula V

Formula IV .

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol
free base of Formula VI, -o
°rc^<
Formula VI
Formula IV
NH?
d) treating the propranolol free base of Formula VI with suitable solvent and cone, hydrochloric acid to obtain propranolol hydrochloride of Formula I,



AH H .HCI

Formula VT

Formula I

and

e) isolating the propranolol hydrochloride of Formula I.
In another embodiment, the present invention provides an improved process for the preparation of propranolol hydrochloride of Formula I,

Formula I
wherein said process comprising of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of
Formula III in the presence of a base to obtain a reaction mixture comprising the
compounds of Formula IV and V,

Formula II Formula III

Formula IV Formula V

b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the of Formula IV,
Formula IV Formula V
Formula IV .

-o

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol
free base of Formula VI, -o
^^Cw<
Formula IV
NH,


d) treating the propranolol free base of Formula VI with methyl ethyl ketone and cone, hydrochloric acid to obtain propranolol hydrochloride of Formula I,
Formula VI Formula I . an(j
e) isolating the propranolol hydrochloride of Formula I.
In other embodiment, the base used in step a) is selected from diisopropylethyl amine (DIPEA), DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), triethylamine, dicyclohexyl amine. The preferred bases are DIPEA and DBU and the most preferred base used in step a) is DIPEA.
In one another embodiment, the present invention provides a stable and substantially pure propranolol hydrochloride of Formula I, wherein said crystalline form is substantially free from amorphous form.
In one another embodiment, the present invention provides a stable and substantially pure propranolol hydrochloride of Formula I, wherein said amorphous form is substantially free from crystalline form.
In another embodiment, the present invention provides a process for the preparation of an amorphous form of propranolol hydrochloride salt, comprising the steps of:
a) providing a solution of propranolol hydrochloride salt in a suitable solvent (s);
b) removing the solvent from the solution obtained in step a) through lyophilization; and
c) isolating the amorphous form of propranolol hydrochloride salt.
In one another embodiment, the present invention provides substantially pure propranolol hydrochloride of Formula I wherein said propranolol hydrochloride is substantially free from impurities with each impurity is less than about 0.3% w/w.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of propranolol or its hydrochloride salt, comprising the steps of:
a) providing a solution of propranolol or its hydrochloride salt in a suitable solvent(s);
b) adding suitable pharmaceutically acceptable excipient in a suitable solvent;
c) combining solution of step a) and b); and
d) isolating solid dispersion of propranolol or its hydrochloride salt.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In one another embodiment propranolol hydrochloride of Formula I is characterized by its XRPD having peaks at diffraction angles 2-theta of 8.30, 9.69, 12.41, 12.77, 13.53, 14.42, 16.66, 17.15, 18.54, 19.42, 19.83, 21.16, 22.00, 22.19, 22.98, 23.53, 24.00, 24.99, 25.32, 25.73, 26.30, 26.98, 27.36, 27.75, 28.91, 29.83, 29.55, 30.50, 31.29, 31.96, 32.41, 32.91, 33.54, 33.82, 34.91, 35.64, 36.59, 36.87, 37.96 and 38.98 ±0.2° 20.
In yet another embodiment propranolol hydrochloride of Formula I is characterized by its XRPD as depicted in Fig-1.

In one another embodiment propranolol hydrochloride of Formula I is characterized by its DSC curve having endothermic peak at 164.98°C as depicted in Fig-2.
In another embodiment, the present invention provides a substantially pure amorphous form of propranolol hydrochloride of Formula I, wherein said amorphous form is substantially free of any crystalline form.
In a preferred embodiment, the present invention provides a substantially pure crystalline form of propranolol hydrochloride of Formula I.
In other embodiment, the present invention provides propranolol hydrochloride of Formula I, wherein propranolol hydrochloride of Formula I is the mixture of amorphous and crystalline form.
In a preferred embodiment, the propranolol hydrochloride of Formula I may be isolated from the reaction mixture by purification, centrifugation, crystallization, filtration, extraction or evaporation.
In a preferred embodiment, the present invention provides a solid dispersion of propranolol and its hydrochloride salt suitable for powder handling and downstream processes. A solid dispersion of propranolol and its hydrochloride salt of the present application was surprisingly found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In another preferred embodiment, the propranolol hydrochloride of Formula I is characterized by the particle size distribution wherein, d9o is between 0.1 um to 200um. More preferably, the propranolol hydrochloride salt of Formula I is characterized by particle size distribution wherein, d9o is between 2.0 um to 150um.

In still another embodiment, the present invention provides a pharmaceutical composition comprising propranolol hydrochloride of Formula I prepared as per the process of the present invention along with atleast one pharmaceutical acceptable excipients/ carrier.
In one another embodiment, the present invention provides substantially pure propranolol hydrochloride of Formula I wherein said propranolol hydrochloride is substantially free from impurities with each impurity is less than about 0.3% w/w.
In preferred embodiment, the present invention provides substantially pure propranolol hydrochloride of Formula I wherein said propranolol hydrochloride is substantially free from impurities of Formula A, B, C and D, with each impurity is less than about 0.3% w/w,

Formula A

Formula B

Formula C

CI

In a preferred embodiment, the present invention provides a substantially pure crystalline form of propranolol hydrochloride of Formula I, wherein said crystalline form is substantially free of amorphous form.
In one another embodiment, the present invention further provides a composition comprising propranolol hydrochloride of Formula I prepared by the process of present invention along with one or more pharmaceutical acceptable excipients.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference of the following examples, which are provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.
EXAMPLES
Example-1: Synthesis of (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV
To a 1.0 L, three-necked round bottom flask fitted with condenser and temperature probe on a mechanical stirrer was charged epichlorohydrin (70.65g, 0.763 moles, 2.2 eq), 1-naphthol (50.Og, 0.347 moles, 1.0 eq.) and catalytic amount of N,N-diisopropylethylamine (8.97 g, 0.069 moles, 0.2 eq.). The resultant mixture was heated to 110-115°C and was allowed to stir at same temperature for 2-3 hours. After completion of the reaction, as monitored by HPLC, the mixture was distilled at 90°C under vacuum to recover epichlorohydrin and then cooled to 25-30°C. 50% aq. NaOH solution (13.88g, 0.347 moles, 1.0 eq.) was added to the above oily material and stirred the mass for 5-6 hours at 20-25°C for complete conversion of l-chloro-3-(l-naphthoxy)-2-propanol of Formula V to (2-[(l-naphthyloxy) methyl] oxirane) of Formula IV. After complete conversion, toluene (500 ml) and DM water (500 ml) was charged to the above suspension and stirred for 15 min for layer separation. Water layer was extracted with 500 ml toluene. Toluene layer was washed with 500 ml DM water followed by 500 ml brine solution. The resultant toluene layer was treated with 5% activated carbon followed by distillation and degassing to get compound of Formula IV as reddish-brown oily material (55.3 g, 79.6% yield, -92% on HPLC).
Example-2: Synthesis of (2-[(l-naphthyloxy)methyl]oxirane) of Formula IV
Charged epichlorhydrin (70.62g, 0.763 moles, 2.2 eq) and DBU (1,8-Diazabicyclo[5.4.0] undec-7-ene) (10.5g, 0.069 moles, 0.2 eq) at room temperature and stirred the reaction mass. 1-naphthol was added in single lot and heated to 70°C. The reaction was allowed to run at 70°C for 4-6 hours. After the completion of

reaction, mixture was distilled and degassed. To the reaction, charged 50% solution of sodium hydroxide (13.88g, 0.347 moles, 1.0 eq) at room temperature and stirred for 1 hour. After the completion of reaction, charged dichloromethane (500 ml) and DM water (500ml) and stirred. The organic layers was separated and water layer is extracted with dichloromethane (100ml). Organic layer was again washed with DM water (100 ml) followed by brine solution (100ml). Organic layer was distilled and degased to get the compound of Formula IV as oily mass.
Example-3: Synthesis of propranolol free base of Formula VI
To a three neck round bottom flask was added compound of Formula IV (65.3 g, 0.326 moles, 1.0 eq.) and cooled to 15°C, followed by addition of isopropyl amine 82.6g (70% aq. solution). The reaction was stirred at 55-60°C for 12-15 hours and monitored by UPLC. After completion of reaction, excess isopropylamine was recovered at 80°C under vacuum at 400-500 mbar. The crude mass thus obtained was dissolved in 260 ml of toluene. DM water (260 ml) was charged to the above clear solution and stirred for 15 min to separate layer. Water layer extracted with 50 ml toluene. Total toluene layer was washed with DM water (195 ml><2 times). Toluene layer was chilled to 5-10°C and stirred for 1.0 hr at 5-10 °C. The crude was filtered and washed with 65 ml of chilled toluene to get propranolol free base of Formula VI as off white solid material (61g, 72.2% yield, -98 % purity on HPLC).
Example-4: Synthesis of Propranolol hydrochloride of Formula I
To a stirred solution of propranolol free base of Formula VI (35.5g, 0.12 moles) in acetone (285 ml, 8V) was charged 1.775g (5%) activated carbon (pH= 5-7) and stirred for about 0.5 hours at 20-25°C. The resultant mixture was filtered through hyflo bed and washed with 70 ml acetone. The filtrate was charged in another three neck round bottom flask and pH was adjusted to 2.0 with cone. HC1 solution at 20-25°C. The reaction mass was stirred for 10-12 hours, at 20-25°C for complete salt formation. The solid was filtered and washed with 70 ml acetone. Dried in hot air oven at 45-50°C for 5-6 hours to get propranolol hydrochloride of Formula I (28.5g, 70.4% yield, and 99.5% purity).

Example-6: Synthesis of propranolol hydrochloride of Formula I
To a stirred solution of propranolol free base of Formula VI (35.5g, 0.12 moles) in methyl ethyl acetone (285 ml, 8V) was charged 1.775g (5%) activated carbon (pH= 5-7) and stirred for about 0.5 hours. The resultant mixture was filtered through hyflo bed. To this filtrate charged cone. HCl. The reaction mass was stirred for 2-3 hours at 20-25°C for complete salt formation. The solid was filtered and washed with 70 ml methyl ethyl ketone, dried in hot air oven at 45-50°C for 5-6 hours to get propranolol hydrochloride of Formula I (27.3g, 67.4% yield, with 99% purity).

Claim

WE CLAIM

1. A process for the preparation of propranolol hydrochloride of Formula I,

wherein said process comprising the steps of:
a) treating the propranolol free base of Formula VI with suitable solvent and cone, hydrochloric acid,

Formula VI Formula I an(j
b) isolating the propranolol hydrochloride of Formula I.
2. A process for the preparation of propranolol hydrochloride of Formula I,

wherein said process comprising the steps of:
a) treating the propranolol free base of Formula VI with cone, hydrochloric acid in
methyl ethyl ketone,

Formula VI Formula I
b) isolating the propranolol hydrochloride of Formula I.

3. An improved process for the preparation of propranolol hydrochloride of Formula I,


OH
.HCI Formula I
wherein said process comprising the steps of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound
of Formula III in the presence of base to obtain a reaction mixture comprising the
compounds of Formula IV and Formula V,


-o

Formula II Formula III

Formula IV Formula V

b) treating the reaction mixture of step a) with aq. sodium hydroxide to get the compound of Formula IV,

-o ^o


Formula IV Formula V

Formula IV .

c) treating the compound of Formula IV with isopropyl amine to obtain propranolol
free base of Formula VI, -o
?^cT»^
Formula VI
Formula IV
NH?
d) treating the propranolol free base of Formula VI with aq. hydrochloric acid in suitable solvent,



OH

OH

.HCI

Formula VI

Formula I

and

e) isolating the propranolol hydrochloride of Formula I.
4. An improved process for the preparation of propranolol hydrochloride of Formula I,

Formula I
wherein said process comprising the steps of:
a) refluxing 1-naphthol compound of Formula II with epichlorohydrin compound of Formula III in the presence of N,N-diisopropylethylamine (DIPEA) to obtain a reaction mixture comprising the compounds of Formula IV and Formula V,


-O