FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"PROCESS FOR PREPARING PROPAFENONE HYDROCHLORIDE AND ITS INTERMEDIATES THEREOF"

We, CADILA HEALTHCARE LIMITED, a company incorporated under the Indian Companies Act, 1956, of, "Zydus Tower", Satellite Cross Roads, Ahmedabad-380 015, Gujarat, India.
The following specification particularly describes the nature of the invention and the manner in which it is performed:


FIELD OF THE INVENTION
The present invention relates to the process for the preparation of Propafenone and its pharmaceutically acceptable salts and intermediates involved thereof. In particular, it relates to process for the preparation of 2-phenylchroman-4-one, a key intermediate and its use in the preparation of Propafenone Hydrochloride. BACKGROUND OF THE INVENTION:
Propafenone chemically known as 2'-(2-hydroxy-3-propylaminopropoxy)-3-phenyl propiophe none) and its pharmaceutically acceptable salt i.e. Propafenone hydrochloride of formula (I)

is successfully used for the therapy of cardiovascular disorders, in particular of cardiac arrhythmias.
In addition to the antiarrhythmic action, propafenone has an additional |3-sympatholytic action.
Propafenone has a center of asymmetry at carbon atom 2 of the aminopropanol side chain and has been used to date only in the form of the racemate. Although the racemate has already been resolved (G. Blaschke and B. Walther, Liebigs Ann. Chem. 1987, 561-563), the pharmacological properties of the enantiomers have not been investigated.
Patent GB 1307455 discloses Propafenone and process for preparing Propafenone comprises reacting the sodium salt of2'-hydroxy-3-phenylpropiophenone withl-chloro-2,3-epaxypropane and reacting the resulting2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone with an alkylamine of the general formulaR-NH2 and optionally converting the resulting base into an acid addition salt thereof. The process for preparing Propafenone as per the patent


Cl(HO)C6H3COCH2CH2Ph with epibromohydrin, then PrNH2 and the reduction with NaBH4.
Patent US 4474986 discloses the process for the preparation of propafenone, wherein2'-hydroxyacetophenone is reacted with epichlorohydrin. The resulting 2-(2',3'-epoxypropoxy)-acetophenone is reacted with propylamine. The resulting 2-(2'-hydroxy-3'-propylaminopropxy)-acetophenone is reacted with bezaldehyde, accompanied by elimination of water and the resulting 2-(2'-hydroxy-3'-propylaminopropxy)-benzalacetophenone is hydrogenated. The process for preparing Propafenone as per patent US '986 is shown in

Patent ES 549139 Al relates to the process for preparing Propafenone via alkylation of PhCH2CH2COC6H40H-2 with epichlorohydrin in aqueous Me2SO containing NaOH gave (epoxypropoxy) propiophenone II. Aminolysis of II by PrNH2 in MeOH at 110°C for 12 h, followed by evaporation, extraction, and acidification gave 78% Propafenone.

Patent CN 85102275 B discloses preparation of Propafenone, in high yield by an economic and simple method. Etherification of o-HOC6H4COCH2CH2Ph with

epichlorohydrin gave glycidyl ether of formula II, which was aminated with PrNH2 and treated with HC1 to give Propafenone Hydrochloride.
Patent US 4945114 relates to the method treatment of arrhythmias in an older patient or a patient suffering from hypotension and cardiac insufficiency, for whom P-blockers are contraindicated, by administering to said patient an effective amount of (R)-propafenone alone.
Patent KR 2009051366 discloses a process for the preparation of a compound A [Rl-R3 = H or alkoxy; R4, R5 = H, alkoxy or halo] characterized by cyclodehydration of a compound B [R1-R5 are same as above]. To a mixture of l-(2'-hydroxyphenyl)-l-oxo-3-phenylpropan-3-ol and PPh3 in CH2C12 was added DEAD (40 wt.% in toluene, 1.5 mL) at 0°C over a period of 3 minutes. The reaction was stirred for 10 min, concentrated in vacuo, chromatographed and recrystallized from hexane to give flavanone of compound A.

EP04579 relates to the process for preparing flavans or its derivatives thereof.
The processes reported in the art for the preparation of Propafenone Hydrochloride involves lengthy steps and use of solvents for the stages involved. This necessitates an improved process with better yields and purity, decreased effluent load and decreased solvent usage, in comparison with prior art processes. There is a constant need to develop more efficient and economical synthetic routes suitable for industrial scale up. Hence, the inventors of the present invention found the use of flavanone intermediate for the ultimate preparation of Propafenone Hydrochloride OBJECTS OF INVENTION:
It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.

Another important object of the present invention is to provide a process for the preparation of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i)

by using water as the only solvent.
It is also an object of the present invention to provide use of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i), a key intermediate for the preparation of Propafenone Hydrochloride.
It is also an object of the present invention to provide the preparation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)

It is also an object of the present invention to provide use of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) for the preparation of Propafenone Hydrochloride.
It is an object of the present invention to provide an improved process for the preparation of Propafenone Hydrochloride by using flavanone as the key intermediate.
It is an object of the present invention to provide an improved process for the preparation of Propafenone Hydrochloride.
It is an object of the present invention to provide X-ray diffraction pattern (XRPD) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i).
It is an object of the present invention to provide Differential Scanning Calorimetry (DSC) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula
(0-
It is an object of the present invention to provide X-ray diffraction pattern (XRPD) of crystalline form of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)

It is an object of the present invention to provide Differential Scanning Calorimetry (DSC) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (ii).
It is an object of the present invention to provide X-ray diffraction pattern (XRPD) of crystalline form of Propafenone Hydrochloride of formula (I).
It is an object of the present invention to provide Differential Scanning Calorimetry (DSC) of crystalline form of Propafenone Hydrochloride of formula (I). SUMMARY OF THE INVENTION:
According to the first aspect of the present invention, there is provided a process for the preparation of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i),


(0
which comprises of:
(i) reacting o-hydroxy acetophenone and benzaldehyde with suitable base in the presence of
water as the solvent;
(ii) adjusting the pH at less than 1.0 with suitable acid;
(iii) purifying with water as the solvent;
(iv) isolating flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i),
According to second aspect of the present invention, there is provided a process for the purification of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i), which comprises of:
(i) treating flavanone in an organic solvent:
(ii) isolating purified flavanone, wherein the total purity of the purified flavanone is higher than the total purity of the starting flavanone.
According to third aspect of the present invention, there is provided a process for preparation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)

e©
0 ONa

which comprises of:
(i) treating flavanone with suitable base in the presence of organic solvent;
(ii) adding suitable a reducing agent;
(iii) washing and purifying with suitable organic solvent;
(iv) isolating Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)
According to fourth aspect of the present invention, there is provided a process for preparation of Propafenone Hydrochloride of formula (I)

which comprises of:
(i) reacting sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)

withl-chloro-2,3-epaxypropane of the formula (iii);

(iii)
(ii) isolating 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (iv)

(iii) reacting 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (iv) with n-
propylamine for insitu formation of Propafenone free base
(iv) treating Propafenone free base with suitable organic solvent and acid;
(v) isolating Propafenone Hydochloride wherein the total purity of the Propafenone
Hydochloride is higher than the total purity of the starting in situ formed Propafenone free
base.
According to fifth aspect of the present invention, there is provided process for the purification of Propafenone Hydochloride of formula (I),
6

which comprises of:
(i) treating Propafenone Hydochloride in an organic solvent:
(ii) admixing the solution with finely powdered carbon; and
(iii) filtrating the admixture obtained from step (b),
(iv) treating with suitable organic solvent;
(v) isolating purified Propafenone Hydochloride, wherein the total purity of the purified
Propafenone Hydochloride is higher than the total purity of the starting Propafenone
Hydochloride.
Sixth aspect of the present invention, is to provide X-ray diffraction pattern (XRPD) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i).
Seventh aspect of the present invention is to provide Differential Scanning Calorimetry (DSC) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i).
Eight aspect of the present invention is to provide X-ray diffraction pattern (XRPD) of crystalline form of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)
Ninth aspect of the present invention is to provide Differential Scanning Calorimetry (DSC) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (ii).
Tenth aspect of the present invention is to provide X-ray diffraction pattern (XRPD) of crystalline form of Propafenone Hydrochloride of formula (I).
Eleventh aspect of the present invention is to provide Differential Scanning Calorimetry (DSC) of crystalline form of Propafenone Hydrochloride of formula (I). BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: X-ray powder diffraction pattern of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i).
FIG. 2: Differential Scanning Calorimetry of crystalline form of flavanone i.e. 2-phenyl chro man-4-one intermediate of formula (i).
FIG. 3: X-ray powder diffraction pattern of crystalline form of sodium salt of 2-(3-phenylpro panoyl)phenolate of formula (ii).
FIG. 4: Differential Scanning Calorimetry of crystalline form of sodium salt of 2-(3-phenylpro panoyl)phenolate of formula (ii).
FIG. 5: X-ray powder diffraction pattern of crystalline form of Propafenone Hydrochloride of formula (I).

FIG. 6: Differential Scanning Calorimetry of crystalline form of Propafenone Hydrochloride
of formula (I).
DETAILED DESCRIPTION OF INVENTION:
According to the first embodiment of the present invention, there is provided process for the preparation of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i)

which comprises of:
(i) reacting o-hydroxy acetophenone and benzaldehyde with suitable base in the presence of
water as the solvent;
(ii) adjusting the pH at less than 1.0 with suitable acid;
(iii) crystallizing with water as the solvent;
(iv) isolating flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i),
The suitable base for the condensation reaction of o-hydroxy acetophenone and benzaldehyde is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably sodium hydroxide.
The solvent used for the condensation reaction of o-hydroxy acetophenone and benzaldehyde is water.
The suitable acid for the pH adjustment less than 1.0 is selected from mineral acid, preferably hydrochloric acid. The preferred solvent for the crystallization is water.
According to second embodiment of the present invention there is provided a process for the purification of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i), which comprises of:
(i) treating flavanone in an organic solvent:
(ii) isolating purified flavanone, wherein the total purity of the purified flavanone is higher than the total purity of the starting flavanone.
The organic solvent for the purification of flavanone is selected from the solvents such as n-hexane, cyclohexane, and isopropyl alcohol etc, preferably n-hexane.
The total purity of the purified flavone is atleast 99.99% with respect to the starting flavanone having purity of 95% to 96%.
8

According to third embodiment of the present invention there is provided a process for preparation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)

which comprises of:
(i) treating flavanone with suitable base in the presence of organic solvent;
(ii) adding suitable reducing agent;
(iii) washing and purifying with suitable organic solvent;
(iv) isolating Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)
The suitable base for the formation of Sodium salt of 2-(3-
phenylpropanoyl)phenolate of formula (ii) is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably sodium hydroxide.
The suitable organic solvent for the formation of Sodium salt of 2-(3-phenylpropanoyl) pheno late of formula (ii) is selected from C1-C5 alcohols preferably methanol.
The suitable reducing agent for the formation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) is selected from Pd/C, Raney -Ni etc, preferably Pd/C.
The suitable organic solvent for washing and purification of Sodium salt of 2-(3-phenylpro panoyl) phenolate of formula (ii) is selected from C1-C5 alcohols, C1-C5 ketones, C1-C5 esters etc, preferably acetone.
According to fourth embodiment of the present invention, there is provided a process for preparation of Propafenone Hydrochloride of formula (I)

which comprises of:
(i) reacting sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)
9

and epichlorohydrin of the formula (iii) with base in presence of organic solvent;

(ii) crystallizing with organic solvent to isolate 2'-(2,3 -epoxypropoxy)-3 -phenyl
propiophenone of formula (iv) /\/°
(iii) reacting 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (iv) with n-propyl
amine in neat reaction condition (without solvent) for insitu formation of Propafenone free
base
(iv) treating insitu formed Propafenone free base with suitable organic solvent and acid;
(v) isolating Propafenone acid addition salt thereof.
The suitable base for the formation of the condensation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) with Epichlorohydrin of the formula (iii) is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably potassium carbonate.
The suitable organic solvent for the condensation of Sodium salt of 2-(3-phenylpropanoyl) phenolate of formula (ii) with Epichlorohydrin of the formula (iii) is selected from C1-C5 alcohols preferably isopropyl alcohol.
The suitable organic solvent for crystallization of 2'-(2,3-epoxypropoxy)-3-phenylpropio phenone of formula (iv) is selected from C1-C5 alcohols, water or a mixture thereof preferably mixture of isopropyl alcohol and water.
The suitable organic solvent for the conversion of insitu formed Propafenone free base into Propafenone acid addition salt is selected from C1-C5 alcohols, C1-C5 ketones etc preferably acetone.
The preferred acid for the conversion of insitu formed Propafenone free base into Propafenone acid addition salt is hydrochloric acid.
10

According to fifth embodiment of the present invention, there is provided a process for the purification of Propafenone Hydochloride of formula (I), which comprises of:
(i) treating Propafenone Hydochloride in an organic solvent: (ii) admixing the solution with finely powdered carbon; and (iii) filtrating the admixture obtained from step (ii), (iv) treating with suitable organic solvent;
(v) isolating purified Propafenone Hydochloride, wherein the total purity of the purified Propafenone Hydochloride is higher than the total purity of the starting Propafenone Hydochloride.
The suitable organic solvent for step (i) and (ii) is selected from C1-C5 alcohols, water or a mixture thereof preferably methanol.
The suitable organic solvent for the purification of Propafenone Hydrochloride as in step (iv) is selected from the C1-C5alcohols, C1-C5 ketones or a mixture thereof preferably mixture of methanol and acetone.
The total purity of the purified Propafenone Hydochloride is greater than 99.99% with respect to the starting Propafenone Hydochloride having purity of 99.6%.
According to sixth embodiment of the present invention, there is provided X-ray diffraction pattern (XRPD) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i) as depicted in Fig. 1.
XRPD of crystalline form of flavanone i.e. 2-phenyl chroman-4-one of formula (i) shows characteristic peaks at 9.20, 15.74, 16.32, 17.92, 18.22, 19.98, 20.84, 22.36, 24.04, 24.61, 25.36, 26.54, 27.66, 28.95, 29.31, 31.95, 33.15 and 35.99 +/- 0.26.
The seventh embodiment of the present invention is to provide Differential Scanning Calorimetry (DSC) of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i) as depicted in Fig. 2.
The DSC thermogram of crystalline form of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i) shows one characteristic endothermic peak between about 78°C to 80°C.
The eight embodiment of the present invention is to provide X-ray diffraction pattern (XRPD) of crystalline form of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) as depicted in Fig. 3.
XRPD of crystalline form of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) shows characteristic peaks at 3.48, 6.07, 7.03, 9.32, 10.58, 12.73, 14.14, 15.43,
11

16.24, 17.72, 18.44, 19.00, 21.50, 23.50, 24.68, 25.90, 26.39, 28.36, 30.05, 31.44, 34.34, 37.80 and 38.32 +/- 0.28.
The ninth embodiment of the present invention is to provide Differential Scanning Calorimetry (DSC) of crystalline form of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) as depicted in Fig. 4.
The DSC thermogram of crystalline form of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) shows one characteristic endothermic peak between about 147°C to 150°C.
The tenth embodiment of the present invention is to provide X-ray diffraction pattern (XRPD) of crystalline form of Propafenone Hydrochloride of formula (I) as depicted in Fig. 5.
XRPD of crystalline form of Propafenone Hydrochloride of formula (I) shows characteristic peaks at 4.58, 5.40, 7.62, 12.16, 13.67, 15.36, 16.36, 16.71, 19.69, 2.72, 21.86, 22.78, 23.41, 25.22, 25.96, 27.06, 27.55, 28.22, 29.66, 31.77, 33.14, 34.39, 35.46, 37.23, and 39.34 +/- 0.26.
The eleventh embodiment of the present invention is to provide Differential Scanning Calorimetry (DSC) of crystalline form of Propafenone Hydrochloride of formula (I) as depicted Fig. 6.
The DSC thermogram of crystalline form of Propafenone Hydrochloride of formula (I) shows one characteristic endothermic peak between about 174°C to 177°C.
According to the present invention, the process for the preparation of Propafenone Hydrochloride of formula (I) can be illustrated by below mentioned Scheme-3, which should not be considered as limiting the scope of the invention.


Me . HCI

Examples
While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present invention, therefore, includes variations form the particular examples embodiments described herein, as will be applicant to one of skill in the art.
Working Example 1 Preparation of flavanone i.e. 2-phenyI chroman-4-one of formula (i)

Sodium hydroxide (198.40 g of sodium hydroxide and 200.0 ml of water) solution is prepared along with the solution of a mixture of o-hydroxyacetophenone (100.0 g, 0.73 mole) and benzaldehyde (94.31 g, 0.88 mole). To the prepared solution of sodium hydroxide mixture of o-hydroxyacetophenone and benzaldehyde solution is added into within 2.0 hours at 20°C to 25°C. The reaction mass is stirred for 7.0 to 10.0 hours at 25°C to 35°C. The reaction mass is filtered and washed with water (300.0 ml). Charge the reaction mass into another round bottom flask and add water (2000.0 ml) 25°C to 35°C. The reaction mass is stirred for 15 minute at 25°C to 35°C.
Reaction mass is heated at 50°C to 55°C and pH is adjusted less than 1.0 by cone. HC1 (150ml) and reaction mass is stirred for 30 minute at 50°C to 55°C. Recheck pH of reaction mass should be less than 1.0, if not, then adjust pH less than 1.0 by cone. HC1. The reaction mass is cooled to 25°C to 35°C and stirred for 2.0 hours at 25°C to 35°C. The reaction mass is filtered and washed with water (300.0 ml). The product is dried at 50°C to 55°C for 18.0 to 22.0 hours to afford the title compound as flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i). Further, the product is purified by using n-Hexane (400.0 ml).
(Yield : 90.90 to 96.96%). Working Example 2 Preparation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)
Charge methanol (1000.0 ml) and sodium hydroxide (32.32 g, 0.80 mole) and stir the reaction mass for 30 minute to get clear solution at 30°C to 45°C. The reaction mass is cooled to 25°C to 30°C. Charge flavanone i.e. 2-phenyl chroman-4-one (100.0 g, 0.44 mole) at 25°C to 30°C. the reaction mass is stirred to get clear solution. Charge Pd/C (10.0 g) and hydrogen gas purging at 25°C to 30°C. The reaction mass is stirred for 2-4 hours. The reaction mass is filtered through hyflow bed and washed with methanol (100.0 ml). Methanol is distilled out completely under vacuum at 30°C to 40°C. Stripping by acetone (2x 150.0 ml) is done under vacuum at 30°C to 40°C. After stripping charge acetone (500.0 ml) in reaction mass and reflux for 60 minutes under stirring at 65°C to 70°C. the reaction mass is cooled to 10°C to 15°C and stirred for 2 hours. The reaction mass is filtered and washed with chilled acetone (100.0 ml) to afford the title compound as Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) which is dried for 20-24 hours at 65°C to 70°C. (Yield: 77.27%) Working Example 3 Preparation of 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (iv)
14

Charge Sodium salt of 2-(3-phenylpropanoyl)phenolate (100 g, 0.40) and slowly add epichlorohydrine (700.0 ml) under stirring at 25°C to 35°C. Stir the reaction mass for 15 minutes. Charge potassium carbonate (111.28 g) and 1PA (200.0 ml) at 25°C to 35°C and heat the reaction mass to reflux temperature at 85°C -90°C. Stir the reaction mass for 3-4 hour at 85°C -90°C. After completion of the reaction cool the reaction mass to 25°C to 35°C. Charge charcoal (3.0 g) stir for 30 min. Filter through hyflow bed and bed wash with IPA (100.0 ml). Distill out totally (IPA + Epichlorohydrine) under vacuum at 60°C to 65°C. Degas the residue for 2.0 hours at 80°C to 85°C. Further, cool the residue to 50°C to 55°C. Charge IPA (100.0 ml) in residue at 50°C to 55°C. Charge water (1000.0 ml) in another round bottom flask at 25°C to 35°C. Slowly add above (residue + IPA) in water (1000.0 ml) under stirring at 25°C to 35°C. Stir the reaction for 4.0 hours. The product is filtered and washed with water (400.0 ml) to afford the title compound as
2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (iv) which is dried at 35°C to 40°C for 20.0-24.0 hours. (% Yield = 80.70%) Working Example 4 Preparation of Propafenone Hydrochloride of formula (I)
Charge 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone (100 g) and n-propylamine (700.0 ml) at 25°C to 35°C. Heat to get temperature at 50°C to 55°C. Reflux up to 8-10 hours at 50°C to 55°C. After completion of the reaction distill out n-propylamine atmospherically at 60°C to 65°C. Strip out by acetone (2 x 50.0 ml) at 60°C to 65°C and degas for 30 minute. Cool the reaction mass to 25°C to 35°C. Charge acetone (500.0 ml) into reaction mass at 25°C to 35°C and add cone. HC1 (64.65 g). Heat the reaction mass to get reflux temperature at 60°C to 65°C. Reflux reaction mass for 1.0 hour at 60°C to 65°C. Cool the reaction mass to 25°C to 35°C. The reaction mass is filtered and washed with acetone (2 x 100.0 ml) to afford the title compound as Propafenone Hydrochloride crude which is dried for 12.0 hours at 50°C to 55°C. (Yield: 86.46%) Working Example 5 Purification of Propafenone Hydrochloride of formula (I)
Charge Propafenone Hydrochloride crude (100.0 g) and methanol (550.0 ml) at 25°C to 35°C and heat to get temperature at 65°C to 70°C. Stir the reaction mass at reflux temperature to get clear solution. Charge charcoal (5.0 g) at 65°C to 70°C. Reflux for 30 minutes. Filter through hyflow bed and bed wash with methanol (2 x 50.0 ml) at 65°C to

70°C. Distil out methanol completely under vacuum at 60°C to 65°C. Charge methanol (100.0 ml) and acetone (400.0 ml) and reflux forl.O hour at 60°C to 65°C. Cool the reaction mass to 25°C to 35°C and stir the reaction mass for 2.0 hours. Cool the reaction mass to 0°C to 5°C. The reaction mass is filtered and washed with mixture of chilled acetone + methanol (80.0 ml + 20.0 ml) to afford the title compound as Propafenone Hydrochloride which is dried for 8.0 hours at 50°C to 55°C. (Yield: 90.0%) Advantage of the present invention:
1. The present invention provides a process for the preparation of flavanone i.e. 2-phenyl chroman-4-one of formula (i) by using water as the solvent.
2. The present invention provides an improved process for the ultimate preparation of Propafenone Hydrochloride via utilizing flavanone of formula (i) and sodium salts of 2-(3-phenylpropanoyl)phenolate of formula (ii).
3. The present invention provides purification process preparing Propafenone Hydrochloride having purity greater than 99.99%.
4. The present invention provides XRPD and DSC of crystalline form of flavanone i.e. 2-phenyl chroman-4-one of formula (i)
5. The present invention provides XRPD and DSC of crystalline form of sodium salts of 2-(3-phenylpropanoyl) phenolate of formula (ii).
6. The present invention provides XRPD and DSC of crystalline form of Propafenone Hydrochloride of formula (I).
7. The present invention is economically viable, eco-friendly and easily scalable for large scale productions with better yields and purity, decreased effluent load and decreased solvent usage.

We claim:
1. A process for the preparation of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i)

which comprises of:
(i) reacting o-hydroxy acetophenone and benzaldehyde with suitable base in the presence of
water as the solvent;
(ii) adjusting the pH at less than 1.0 with suitable acid;
(iii) crystallizing with water as the solvent;
(iv) isolating flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i),
2. The process as claimed in claim l(i), wherein base is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably sodium hydroxide.
3. The process as claimed in claim l(ii), wherein is acid is selected from mineral acid, preferably hydrochloric acid.
4. A process for the purification of flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i), which comprises of:
(i) treating flavanone in an organic solvent:
(ii) isolating purified flavanone, wherein the total purity of the purified flavanone is higher
than the total purity of the starting flavanone.
5. The process as claimed in claim 4(i), wherein organic solvent for the purification of flavanone is selected from the solvents such as n-hexane, cyclohexane, and isopropyl alcohol etc, preferably n-hexane.
6. The process as claimed in claim 4(ii), wherein purified flavanone is atleast 99.99% with respect to the starting flavanone having purity of 95% to 96%.
7. A process for preparation of Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)


which comprises of:
(i) treating flavanone with suitable base in the presence of organic solvent;
(ii) adding suitable reducing agent;
(iii) washing and purifying with suitable organic solvent;
(iv) isolating Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)
8. The process as claimed in claim 7(i), wherein base is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably sodium hydroxide.
9. The process as claimed in claim 7(i), wherein suitable organic solvent is selected from Cr C5 alcohols preferably methanol.

10. The process as claimed in claim 7(H), wherein reducing agent is selected from Pd/C, Raney -Ni etc, preferably Pd/C.
11. The process as claimed in claim 7(iii), wherein suitable organic solvent is selected from C1-C5 alcohols, C1-C5 ketones, C1-C5 esters etc, preferably acetone.
12. An improved process for the preparation of Propafenone Hydrochloride of formula (I)

which comprises of:
(i) reacting o-hydroxy acetophenone and benzaldehyde with suitable base in the presence of
water as the solvent;
(ii) adjusting the pH at less than 1.0 with suitable acid;
(iii) crystallizing with water as the solvent;
(iv) isolating flavanone i.e. 2-phenyl chroman-4-one intermediate of formula (i),
(v) treating flavanone with suitable base in the presence of organic solvent;
(vi) adding suitable reducing agent;
(vii) washing and purifying with suitable organic solvent;
(viii) isolating Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii).
(ix) reacting sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii)

and epichlorohydrin of the formula (iii) with base in presence of organic solvent;

(x) crystallizing with organic solvent to isolate 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (iv)
(xi) reacting 2'-(2,3 -epoxypropoxy)-3 -phenyl propiophenone of formula (IV) with n-propyl
amine in neat reaction condition (without solvent) for insitu formation of Propafenone free
base
(xii) treating insitu formed Propafenone free base with suitable organic solvent and acid;
(xiii) isolating Propafenone acid addition salt thereof.
13. The process as claimed in claim 12(i), wherein base is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably sodium hydroxide.
14. The process as claimed in claim 12(H), wherein is acid is selected from mineral acid, preferably hydrochloric acid.
15. The process as claimed in claim 12(v), wherein base is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably sodium hydroxide.
16. The process as claimed in claim 12(v), wherein suitable organic solvent is selected from C1-C5 alcohols preferably methanol.
17. The process as claimed in claim 12(vi), wherein reducing agent is selected from Pd/C, Raney -Ni etc, preferably Pd/C.
18. The process as claimed in claim 12(vii), wherein suitable organic solvent is selected from C1-C5 alcohols, C1-C5 ketones, C1-C5 esters etc, preferably acetone.
19. The process as claimed in claim 12(ix), wherein base is selected from alkali and alkaline metal hydroxide and carbonates such as sodium hydroxide, potassium hydroxide, lithium
19

hydroxide, sodium carbonate, potassium carbonate, lithium carbonate etc, preferably potassium carbonate.
20. The process as claimed in claim 12(ix), wherein organic solvent is selected from C1-C5 alcohols preferably isopropyl alcohol.
21. The process as claimed in claim 12(x), wherein organic solvent is selected from C1-C5 alcohols, water or a mixture thereof preferably mixture of isopropyl alcohol and water.
22. The process as claimed in claim 12(xii), wherein organic solvent is selected from C1-C5 alcohols, C1-C5 ketones etc preferably acetone.
23. The process as claimed in claim 12(xii), wherein preferred acid is hydrochloric acid.
24. Crystalline flavanone i.e. 2-phenyl chroman-4-one of formula (i) being characterized by XRPD as depicted in Fig. 1 having characteristic peaks at 9.20, 15.74, 16.32, 17.92, 18.22, 19.98, 20.84, 22.36, 24.04, 24.61, 25.36, 26.54, 27.66, 28.95, 29.31, 31.95, 33.15 and 35.99 +/- 0.29.
25 Crystalline flavanone i.e. 2-phenyl chroman-4-one of formula (i) being characterized by DSC as depicted in Fig. 2 having one characteristic endothermic peak between about between about 78°C to 80°C.
26. Crystalline Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) being characterized by XRPD as depicted in Fig. 3 having characteristic peaks at 3.48, 6.07, 7.03, 9.32, 10.58, 12.73, 14.14, 15.43, 16.24, 17.72, 18.44, 19.00, 21.50, 23.50, 24.68, 25.90, 26.39, 28.36, 30.05, 31.44, 34.34, 37.80 and 38.32 +/- 0.29.
27. Crystalline Sodium salt of 2-(3-phenylpropanoyl)phenolate of formula (ii) being characterized by DSC as depicted in Fig. 4 having one characteristic endothermic peak between about between about 147°C to 150°C.

28. Crystalline Propafenone Hydrochloride of formula (I) being characterized by XRPD as depicted in Fig. 5 having characteristic peaks at 4.58, 5.40, 7.62, 12.16, 13.67, 15.36, 16.36, 16.71, 19.69, 2.72, 21.86, 22.78, 23.41, 25.22, 25.96, 27.06, 27.55, 28.22, 29.66, 31.77, 33.14, 34.39, 35.46, 37.23, and 39.34 +/- 0.29.
29. Crystalline Propafenone Hydrochloride of formula (I) being characterized by DSC as depicted in Fig. 6 having one characteristic endothermic peak between about between aboutl74°Cto 177°C.
30. A process for the purification of Propafenone Hydochloride of formula (I),

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which comprises of:
(i) treating Propafenone Hydochloride in an organic solvent:
(ii) admixing the solution with finely powdered carbon; and
(iii) filtrating the admixture obtained from step (ii),
(iv) treating with suitable organic solvent;
(v) isolating purified Propafenone Hydochloride, wherein the total purity of the purified
Propafenone Hydochloride is higher than the total purity of the starting Propafenone
Hydochloride.
31. The process as claimed in claim 30(i), wherein organic solvent for step (i) and (ii) is selected from C1-C5 alcohols, water or a mixture thereof preferably methanol.
32. The process as claimed in claim 30(iv), wherein organic solvent is selected from the C1-C5 alcohols, C1-C5 ketones or a mixture thereof preferably mixture of methanol and acetone.
33. The process as claimed in claim 30(v), wherein the total purity of the purified
Propafenone Hydochloride is greater than 99.99% with respect to the starting Propafenone
Hydochloride having purity of 99.6%.
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34. Propafenone Hydochloride of formula (I) substantially as herein described with reference
to any of the embodiments of the invention illustrated in the accompanying drawings and/or
examples.