DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF VILOXAZINE HYDROCHLORIDE”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA - 500 081

The following specification particularly describes the invention and the manner in which it is to be performed.
AN IMPROVED PROCESS FOR THE PREPARATION OF VILOXAZINE HYDROCHLORIDE

FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of Viloxazine hydrochloride of formula I with high yield and purity.

BACKGROUND OF THE INVENTION:
Viloxazine hydrochloride is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and is chemically known as (±)-2-[(2-ethoxyphenoxy) methyl] morpholine hydrochloride, having the structural formula as represented by formula I:

Formula I
Viloxazine is approved and marketed by Supernus Pharmaceuticals under the trade name QelbreeTM and it is orally administered as capsules containing 100mg, 150mg & 200mg.
Viloxazine and process for its preparation was first disclosed in the US3714161 (the US ‘161 patent) and the process involves the reaction of ethoxyphenol with epichlorohydrin to afford the epoxide intermediate 1-(2-ethoxyphenoxy)-2,3-epoxypropane. This epoxide intermediate is then treated with benzylamine and chloroacetyl chloride, followed by cyclisation with sodium methoxide. The resulting morpholinone is then reduced by lithium aluminum hydride and then by Pd/C-catalyzed hydrogenation to yield Viloxazine free base. The disclosed process is schematically depicted in the following scheme:

The US3712890 (US ‘890 patent) discloses a process for the preparation of Viloxazine hydrochloride. The disclosed process involves the epoxide intermediate, 1,2-epoxy-3-(o-ethoxyphenoxy) propane is reacted with 2-aminoethyl hydrogen sulfate in the presence of sodium hydroxide, ethanol and water to form Viloxazine free base. The product is extracted with diethyl ether from the aqueous solution obtained by evaporating the solvent in the reaction mixture then adding water to the residue. The ethereal extract is dried over magnesium sulphate and evaporated to dryness. The crude product is dissolved in isopropanol, concentrated aqueous HCl, and ethyl acetate followed by filtration to obtain solid compound of Viloxazine hydrochloride. The disclosed process is schematically depicted in the following scheme:

The above reported process for the preparation of Viloxazine suffers low reaction yield and unacceptably large amount of impurities in the resulting product.

The US9403783 (US ‘783 patent) discloses a process for the preparation of Viloxazine, including methods having increased yields and producing decreased amounts of impurities. This patent also describes and characterizes Viloxazine hydrochloride, including novel polymorphs thereof. The disclosed process is schematically depicted in the following scheme:

Still there is a need for an alternate process for the preparation of Viloxazine hydrochloride which is economical, easy to scale up and commercially viable. Thus, main objective of the present invention is to provide an alternate process for the preparation of Viloxazine hydrochloride which avoids the shortcomings of the prior art.

SUMMARY OF THE INVENTION:
The main aspect of the present invention relates to an improved process for the preparation of Viloxazine hydrochloride of formula I with high yield and purity.

In one aspect of the present invention provides an improved process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV;

b) reacting 2-Aminoethanol with sulfuric acid to provide 2-Aminoethylhydrogen sulfate;

c) condensing 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b) to provide Viloxazine;

d) converting Viloxazine into Viloxazine hydrochloride of formula I; and
e) optionally, purifying Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I.

In another aspect of the present invention provides an improved process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III in presence of sodium hydroxide in water at 25°C to 35°C to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV;

b) reacting 2-Aminoethanol with sulfuric acid in presence of tetrabutyl ammonium bromide in toluene and water at 90°C to 110°C;

c) condensing 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b) in presence of potassium hydroxide in water and methanol to provide Viloxazine;

d) converting Viloxazine into Viloxazine hydrochloride of formula I in presence of hydrochloride in methanol, ethanol, isopropanol, water and ethyl acetate or mixture thereof; and
e) optionally, purifying Viloxazine hydrochloride of formula I in methanol, ethanol, isopropanol, water and ethyl acetate or mixture thereof to provide pure Viloxazine hydrochloride of formula I.

In another aspect, the Viloxazine hydrochloride of formula I prepared by the present invention having purity greater than 99% and it is substantially free of the impurity compound of formula IX, X and XI:

In another aspect of the present invention provides a process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV with Phthalimide or its salt thereof in presence of a base and a suitable solvent to provide 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V;

b) converting 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V into 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI;

c) reacting 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI with halo acetyl chloride in presence of a base and a suitable solvent to provide 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII;

d) cyclizing 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII with a suitable cyclization reagent in presence of a suitable solvent to provide 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII;

e) reducing 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII with a suitable reducing agent in presence of a suitable solvent to provide Viloxazine;

f) converting Viloxazine into Viloxazine hydrochloride of formula I; and
g) optionally, purifying Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I.

In another aspect of the present invention provides novel compound of formula V, which is useful in the preparation of Viloxazine hydrochloride of formula I.

In another aspect of the present invention provides use of novel compound of formula V for the preparation of Viloxazine hydrochloride of formula I.

DETAILED DESCRIPTION:
Accordingly, the present invention provides an improved process for the preparation of Viloxazine hydrochloride of formula I with high yield and purity.

The term “base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like, ammonia and organic bases such as pyridine, piperidine, triethylamine, 2,6-lutidine, diisopropylamine, diisopropylethyl amine, N-methylmorpholine, dimethyl amino pyridine and the like or mixtures thereof.

The term “solvent/ suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, esters, hydrocarbons and halogenated solvents; wherein “alcohols” is selected from the group consisting of methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; “ethers” is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, cyclopentyl methyl ether and the like; “esters” is selected from the group consisting of ethyl acetate, isopropyl acetate; “hydrocarbons” is selected from the group consisting of heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane and the like; “halogenated solvent” is selected from the group consisting of dichloromethane, chloroform, chlorobenzene, bromobenzene and the like; or mixtures thereof.

The term “substantially free of” used in the present invention is means that less than about 0.2 area-% as measured by HPLC; preferably, less than about 0.15 area-% as measured by HPLC; and more preferably not detectable as measured by HPLC.

In one embodiment, the present invention provides an improved process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV;

b) reacting 2-Aminoethanol with sulfuric acid to provide 2-Aminoethylhydrogen sulfate;

c) condensing 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b) to provide Viloxazine;

d) converting Viloxazine into Viloxazine hydrochloride of formula I; and
e) optionally, purifying Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I.

The starting compound of formula II and formula III can be prepared according to the methods known in the art and it is also commercially available.

The step a) of aforementioned process involves the reaction of 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III, wherein “X” is halogen selected from chlorine, bromine, fluorine and iodine; preferably chlorine; is carried out in presence of a base, with or without the presence of a catalyst and a solvent under appropriate reaction conditions to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV; wherein the base used is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide; and the solvent used is water.

In an embodiment, in the process of step a) the analogous impurity 2-Methoxyphenol in 2-Ethoxyphenol of formula II controlled at below 0.3% level. Accordingly, impurity 2-((2-Methoxyphenoxy) methyl) oxirane also controlled at below 0.3% level in step a) product, 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV.

The step b) of aforementioned process involves the reaction of 2-Aminoethanol with sulfuric acid; is carried out in the presence or absence of a base, catalyst and a solvent under appropriate reaction conditions to provide 2-Aminoethylhydrogen sulfate. Wherein the catalyst used is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl ammonium acetate, tetrabutylammonium hydrogen sulfate, tetrabutyl ammonium hydroxide, preferably tetrabutylammonium bromide; and the solvent used is selected from water and/or hydrocarbons such as heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane and the like; preferably toluene and/or water.

The step c) of aforementioned process involves the condensation of 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b); is carried out in the presence of a base and a solvent under appropriate reaction conditions to provide Viloxazine. Wherein the base used is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably potassium hydroxide; and the solvent used is selected from water and/or alcohols such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; preferably water and/or methanol.

The step d) of aforementioned process involves the conversion of Viloxazine into Viloxazine hydrochloride of formula I, which can be carried out by reacting Viloxazine with hydrochloric acid in a suitable solvent under appropriate reaction conditions to provide Viloxazine hydrochloride of formula I; wherein the suitable solvent is selected from water, alcohols and esters such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol, ethyl acetate, isopropyl acetate and the like; preferably water, methanol, ethanol, isopropanol and ethyl acetate or mixtures thereof.

In an embodiment, the analogous impurity 2-[(2-methoxyphenoxy) methyl] morpholine hydrochloride in Viloxazine hydrochloride of formula I prepared by the present invention is controlled at below 0.3% level.

The step e) of aforementioned process involves the purification of Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I; wherein the suitable solvent used is selected from water, alcohols or esters such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol or ethyl acetate, isopropyl acetate and the like; preferably water, methanol, ethanol, isopropanol and ethyl acetate or mixtures thereof.

In another embodiment, the present invention provides an improved process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III in presence of sodium hydroxide in water at 25°C to 35°C to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV;

b) reacting 2-Aminoethanol with sulfuric acid in presence of tetrabutyl ammonium bromide in toluene and water at 90°C to 110°C;

c) condensing 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b) in presence of potassium hydroxide in water and methanol to provide Viloxazine;

d) converting Viloxazine into Viloxazine hydrochloride of formula I in presence of hydrochloride in methanol, ethanol, isopropanol, water and ethyl acetate or mixture thereof; and
e) optionally, purifying Viloxazine hydrochloride of formula I in methanol, ethanol, isopropanol, water and ethyl acetate or mixture thereof to provide pure Viloxazine hydrochloride of formula I.

In another embodiment, the Viloxazine hydrochloride of formula I prepared by the present invention having purity greater than 99% and it is substantially free of 1-(2-ethoxyphenoxy)-3-(oxiran-2-ylmethoxy) propan-2-ol [compound of formula IX], 1-(2-ethoxyphenoxy)-3-((2-(2-((2-ethoxyphenoxy) methyl) morpholino) ethyl) amino) propan-2-ol [compound of formula X] and 1-(2-ethoxyphenoxy)-3-(2-((2-ethoxyphenoxy) methyl) morpholino) propan-2-ol [compound of formula XI].

In an embodiment, the Viloxazine hydrochloride of formula I prepared by the present invention is efficient to control all possible N-nitroso impurities of Viloxazine at regulatory acceptable level of intake.

In another embodiment, the present invention provides a process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV with Phthalimide or its salt thereof in presence of a base and a suitable solvent to provide 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V;

b) converting 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V into 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI;

c) reacting 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI with halo acetyl chloride in presence of a base and a suitable solvent to provide 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII;

d) cyclizing 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII with suitable cyclization agent in presence of a suitable solvent to provide 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII;

e) reducing 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII with a suitable reducing agent in presence of a suitable solvent to provide Viloxazine;

f) converting Viloxazine into Viloxazine hydrochloride of formula I; and
g) optionally, purifying Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I.

The step a) of aforementioned process involves the reaction of 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV with phthalimide or its salt thereof in presence of a base and a suitable solvent under appropriate reaction conditions to provide 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V; wherein the base used is selected from organic base such as pyridine, piperidine, triethylamine, 2,6-lutidine, diisopropylamine, diisopropylethyl amine, N-methylmorpholine, dimethyl amino pyridine and the like; preferably pyridine; and the suitable solvent used is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol, iso-butanol and the like; preferably isopropanol.

The step b) of aforementioned process involves the conversion of 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V into 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI, which can be carried out by reacting the compound of formula V with hydrazine or a suitable amine in a suitable solvent under appropriate reaction conditions to provide the compound of formula VI; wherein the suitable amine is monomethylamine, ethanolamine and the like; preferably monomethylamine; and the suitable solvent used is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol, iso-butanol and the like; preferably ethanol.

The step c) of aforementioned process involves the reaction of 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI with halo acetyl chloride such as chloroacetyl chloride, bromo acetyl chloride and the like; preferably chloroacetyl chloride; in presence of a base and a suitable solvent under appropriate reaction conditions to provide 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII; wherein the base used is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; preferably sodium carbonate; and the suitable solvent used is selected from hydrocarbons such as heptane, hexane, cyclohexane, toluene, xylene and the like; preferably toluene.

The step d) of aforementioned process involves the cyclisation of 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII with a suitable cyclization agent in presence of a suitable solvent under appropriate reaction conditions to provide 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII. The suitable cyclization agent used is selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, tosyl chloride, brosyl chloride, nosyl chloride and mesyl chloride, DMSO, alumina and the like; preferably sodium methoxide; and the suitable solvent selected from alcohols such as methanol, ethanol, isopropanol, n-butanol, iso-butanol and the like; preferably methanol.

The step e) of aforementioned process involves the reduction of 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII with a with a suitable reducing agent in presence of a suitable solvent under appropriate reaction conditions to provide Viloxazine. The suitable reducing agent used is selected from vitride, lithium aluminium hydride, diisobutylaluminium hydride and the like; preferably vitride; and the suitable solvent used is selected from hydrocarbons such as heptane, hexane, cyclohexane, cycloheptane, toluene, xylene and the like; preferably toluene.

The step f) and step g) of the aforementioned process can be carried out as described for step d) and step e) of first embodiment of the invention

In another embodiment, the present invention provides novel compound of formula V, which is useful in the preparation of Viloxazine hydrochloride of formula I.

In another embodiment, the present invention provides use of novel compound of formula V for the preparation of Viloxazine hydrochloride of formula I.

EXAMPLES
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example-1: Preparation of 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione (Formula V):
To a clean and dry RBF, 2-((2-ethoxyphenoxy) methyl) oxirane (40 g), isopropanol (200 ml), phthalimide (33.3 g) and pyridine (2 ml) were added at 25 to 35°C, temperature rises to 80 to 90°C and stirred for 4 to 5 hours at same temperature. After completion of reaction, distilled out the isopropanol completely under vacuum at below 50oC. Water (160 ml) and ethyl acetate (160 ml) was added to the reaction mass at 25 to 35°C and stirred for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with ethyl acetate and dried to get the titled compound.
Yield: 47 g

Example-2: Preparation of 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol (Formula VI):
To a clean and dry RBF, 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione (45 g), ethanol (135 g) and 40% monomethylamine (90 ml) were added at 25 to 35°C, temperature rises to 75 to 85°C and stirred for 2 to 3 hours at same temperature. After completion of reaction, distilled out the ethanol completely under vacuum at below 50oC. Water (450 ml) and methylene chloride (450 ml) were added into the above reaction mass at 25 to 35°C and stirred for 10 to 15 mins at same temperature. The aqueous and MDC layers were separated, the aqueous layer was extracted with methylene chloride, combine both the MDC layers and distilled out completely. To the above reaction mass, methanol (135 ml) was added at 25 to 35°C, temperature rises to 35-45°C and stirred for 10 to 15 mins at same temperature, then slowly add methyl tert butyl ether (450 ml) at 35-45°C, cooled to 0-5oC and stirred for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with methyl tert butyl ether and dried to get the titled compound. Yield: 20 g

Example-3: Preparation of 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide (Formula VII):
To a clean and dry RBF, 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol (18 g), toluene (90 ml) and sodium carbonate solution (18 g of sodium carbonate in 36 ml of water) were added at 25 to 35°C, cool to 0 to 5°C, then slowly add chloroacetyl chloride solution (16.45g of chloroacetyl chloride in 54 ml of toluene) and maintained for 1 to 2 hours at same temperature. After completion of reaction, water (180 ml) and methylene chloride (180 ml) were added to the reaction mass at 25 to 35°C and stirred for 15 mins at same temperature. The aqueous and MDC layers were separated, the aqueous layer was extracted with methylene chloride, combine both the MDC layers and distilled out completely under vacuum at below 50oC. To the above reaction mass, methyl tert butyl ether (180 ml) was added at 25 to 35°C, temperature rises to 35 to 45°C and stirred for 5 to 10 mins at same temperature, then slowly add n-hexane (180 ml) at 35 to 45°C, cool to 25 to 35°C and stirred for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with methyl tert butyl ether and dried to get the titled compound. Yield: 15 g

Example-4: Preparation of 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one (Formula VIII):
To a clean and dry RBF, 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide (14 g), methanol (280 ml) and 30% sodium methoxide in methanol (70 ml) were added at 25 to 35°C, temperature rises to 55 to 65°C and maintained for 2 to 3 hours at same temperature. After completion of reaction, distilled out methanol completely under vacuum at below 55oC. Water (70 ml) and methylene chloride (140 ml) were added to the reaction mass at 25 to 35°C and stirred for 10 to 15 mins at same temperature. The aqueous and MDC layers were separated, the aqueous layer was extracted with methylene chloride, combine both the MDC layers and distilled out completely under vacuum at below 50oC. To the above reaction mass, methylene chloride (42 ml) was added at 25 to 35°C, temperature rises to 35 to 45°C and stirred for 10 to 15 mins at same temperature, then slowly add n-hexane (140 ml) at 35 to 45°C, cool to 0 to 5°C and stirred for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with n-hexane and dried to get the titled compound.
Yield: 10 g

Example-5: Preparation of Viloxazine:
To a clean and dry RBF, vitride solution (36 ml of vitride in 45 ml of toluene) was added to 25 to 35°C, heated to 80 to 90°C, then 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one (9 g) was added and maintained for 2 to 3 hours at same temperature. After completion of reaction, the temperature of the reaction mass cooled to 25 to 35°C, add water (45 ml) and 50% sodium hydroxide (90 ml), further toluene (45 ml) was added at 25 to 35°C and stirred for 10 to 15 mins at same temperature. The aqueous and toluene layers were separated, the aqueous layer was extracted with toluene, combine both the toluene layers and distilled out completely under vacuum at below 50oC to get the titled compound. Yield: 7 g

Example-6: Preparation of Viloxazine hydrochloride (Formula I):
To a clean and dry RBF, crude Viloxazine (6 g), methanol (8.4 ml) was added at 25 to 35°C, stirred for 10 to 15 mins at same temperature, then add concentrated hydrochloric acid (4.2 ml) and ethyl acetate (36 ml) to the reaction mass at 25 to 35°C, cool to 0-5oC and maintained for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with ethyl acetate and dried to get the titled compound.
Yield: 4.5 g; Purity by HPLC: >99%

Example-7: Preparation of 2-((2-Ethoxyphenoxy) methyl) oxirane (Formula IV):
To a clean and dry RBF, sodium hydroxide solution (167.4 g sodium hydroxide in 500 ml of water), 2-ethoxyphenol (100 g) and 2-(chloromethyl) oxirane (133.9 g) were added at 25 to 35oC and stirred for 10 to 12 hours at same temperature, again add sodium hydroxide solution (28.94 g sodium hydroxide in 300 ml of water) and stirred for 10 to 12 hours at 25 to 35oC. After completion of reaction, add toluene (500 ml) was added to the reaction mass at 25 to 35oC. The aqueous and toluene layers were separated, the aqueous layer was extracted with toluene, then combine both the toluene layers and distilled out the solvent completely under vacuum at below 55oC to get the titled compound. Yield: 320 g

Example-9: Preparation of Viloxazine:
To a clean and dry RBF, potassium hydroxide solution (80.86 g of potassium hydroxide in 120 ml of water), 2-aminoethylhydrogen sulfate (159.8 g), 2-((2-ethoxyphenoxy) methyl) oxirane solution (40 g of 2-((2-ethoxyphenoxy) methyl) oxirane in 400 ml of methanol) were added at 25 to 35°C, temperature rises to 50 to 65°C and stirred for 3 to 4 hours at same temperature. Potassium hydroxide solution (161.3 g of potassium hydroxide in 55 ml of water) was added to the reaction mass and stirred for 15 to 16 hours at 50 to 65°C. After completion of reaction, distilled out methanol completely under vacuum at below 50oC. To the above reaction mass, water (12 L) and methyl tert butyl ether (400 ml) were added at 25 to 35°C and stirred for 10 to 15 mins at same temperature. The reaction mass was filtered through hyflow bed, aqueous and MTBE layers were separated and the aqueous layer was extracted with methyl tert butyl ether. Combine both the MTBE layers and washed with sodium chloride solution, separate MTBE layer and distilled out completely under vacuum at below 55oC to get the titled compound. Yield: 43 g

Example-10: Preparation of Viloxazine hydrochloride (Formula I):
To a clean and dry RBF, crude Viloxazine (40 g), methanol (56 ml) was added at 25 to 35°C, stirred for 10 to 15 mins at same temperature, then add concentrated hydrochloric acid (28 ml) and ethyl acetate (224 ml) to the reaction mass at 25 to 35°C, cool to 0-5oC and maintained for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with ethyl acetate and dried. To the above wet material, add isopropanol (96 ml) and water (48 ml) at 25 to 35°C, heated to 75 to 85°C and maintained for 10 to 15 mins at same temperature. Then the reaction mass cooled to 45 to 55oC and maintained for 10 to 15 mins, then add ethyl acetate (240 ml), further cooled to 0 to 5oC and maintained for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with ethyl acetate and dried to get the titled compound.
Yield: 16 g; Purity by HPLC: >99%
Compound of formula X: <0.1% and Compound of formula XI: Not detected

Example-11: Preparation of 2-((2-Ethoxyphenoxy) methyl) oxirane (Formula IV):
To a clean and dry RBF, sodium hydroxide solution (52.11 g sodium hydroxide in 1500 ml of water), 2-ethoxyphenol (300 g) and 2-(chloromethyl) oxirane (441.94 g) were added at 25 to 35oC and stirred for 10 to 12 hours at same temperature, again add sodium hydroxide solution (86.85 g sodium hydroxide in 300 ml of water) and maintained for 8 to 10 hours at 25 to 35oC. After completion of reaction, add toluene (600 ml) was added to the reaction mass at 25 to 35oC and stirred for 10-15 mins at same temperature. The aqueous and toluene layers were separated, the aqueous layer was extracted with toluene, then combine both the toluene layers and distilled out the solvent completely under vacuum and degas the reaction mass for 8 to 10 hours at below 60oC, then cool the obtained reside to 25 to 35oC to get the titled compound.
Yield: 421.71g; Compound of formula IX: <0.2%

Example-12: Preparation of 2-Aminoethylhydrogen sulfate:
To a clean and dry RBF, toluene (400 ml), ethanolamine (100 g), water (50 ml) and tetra butyl ammonium bromide (1 g) were added at RT. Then the reaction mass cooled to below 10oC, slowly add sulfuric acid (168.6 g) at below 60oC, temperature rises to reflux and maintained for azeotropic collection of water complies. Cool the reaction mass temperature to below 75 oC, distilled out the solvent, then slowly add water (100 ml) and stirred for 2 to 3 hours at 70 to 75 oC. Cool the reaction mass temperature to below 50 to 55 oC, then slowly add methanol (400 ml), again cooled to 25 to 35 oC and stirred for 1 to 2 hours at same temperature. The solid obtained was filtered, washed with methanol, suck dry and dried at 60 to 80oC for 4 to 6 hours under vacuum to get the titled compound. Yield: 22.4 g

Example-13: Preparation of Viloxazine hydrochloride (Formula I):
To a clean and dry RBF, potassium hydroxide solution (230.65 g of potassium hydroxide in 200 ml of water), 2-aminoethylhydrogen sulfate (545 g) were added at 25 to 35°C, stirred for 10 to 15 min and raise the temperature to 40 to 45°C. Add 2-((2-ethoxyphenoxy) methyl) oxirane solution (100 g of 2-((2-ethoxyphenoxy) methyl) oxirane in 800 ml of methanol) to the reaction mass at 40 to 45°C and maintained for 2 to 3 hours at same temperature. Potassium hydroxide solution (576.63 g of potassium hydroxide in 400 ml of water) was added to the reaction mass, temperature raises to 60 to 65°C, maintained for 24 to 26 hours and cooled to below 40°C. After completion of reaction, water (1500 ml) and dichloromethane (500 ml) was added to the reaction mass at 25 to 30°C, stirred for 10 to 15 mins at same temperature. The reaction mass filtered through hyflow bed, washed with dichloromethane and add dichloromethane (300 ml), stirred for 10 to 15 mins at 25 to 30°C and maintained for 10 to 20 mins. Aqueous layer and organic layers separated, the aqueous layer charged with dichloromethane (500 ml), stirred for 10 to 15 mins and maintained for 10 to 20 mins. Potassium hydroxide solution (144.15 g of potassium hydroxide in 300 ml of water) added to the reaction mass at 25 to 30°C, temperature raises to 35 to 40°C and maintained for 3 to 4 hours, then cool to 25 to 30°C, stirred for 10 to 15 mins and maintained for 10 to 20 mins. Aqueous layer and organic layers separated, the aqueous layer charged with dichloromethane (500 ml), stirred for 10 to 15 mins and maintained for 10 to 20 mins. Combine both dichloromethane layers, add water (200 ml) to the reaction mass at 25 to 30°C, stirred for 10 to 15 mins and settled for 10 to 20 mins. Aqueous layer and dichloromethane layers separated, distill off the solvent from the dichloromethane layer completely under vacuum and degas the reaction mass for 2 to 3 hours at below 45°C.Methanol (90 ml) and water (10 ml) was added to the reaction mass at 25 to 35°C, stirred for 10 to 15 mins, then add hydrochloric acid (37 ml) and ethyl acetate (400 ml), heated to 50 to 55°C and maintained for an hour. Cool the reaction mass to 25 to 35°C, further cool to 0 to 10°C and maintained for 1 to 2 hours at same temperature. The reaction mass was filtered and washed with ethyl acetate, suck dry the compound under vacuum until no mLs was observed. Isopropyl alcohol (120 ml) and water (60 ml) were added to the above wet material at 25 to 35°C, heated to 70 to 80°C to get the clear solution and maintained for 10 to 15 mins at same temperature. Cool the reaction mass to 50 to 55°C, ethyl acetate (450 ml) was added, gradually cool to 20 to 25°C and maintained for 1 to 2 hours at same temperature. Filtered the reaction mass, washed with ethyl acetate and dried at 70 to 90°C under vacuum for 6 to 8 hours to get the titled compound. Yield: 53g

Example-14: Purification of Viloxazine hydrochloride (Formula I):
To a clean and dry RBF, methanol (270 ml) and water (130 ml) were added to Viloxazine hydrochloride (100 g), heated to 60 to 65°C until clear solution observed and maintained for 10 to 15 mins at same temperature. Ethyl acetate (650 ml) was added to the reaction mass at 50 to 55°C, maintained for an hour, cool to 10 to 15°C and maintained for 1 to 2 hours at same temperature. The reaction mass filtered, washed with ethyl acetate and dried to get wet material. Ethyl acetate (400 ml) was added to the above reaction mass, heated to 50 to 55°C, maintained for 4 to 6 hours, cool to 25 to 35°C and maintained for 1 to 2 hours at same temperature. The reaction mass filtered, washed with ethyl acetate and dried at 60 to 80°C under vacuum for 6 to 8 hours to get the titled compound. Yield: 90g; Purity by HPLC: >99%
Compound of formula X: <0.1% and Compound of formula XI: Not detected

Dated this: 28th day of March, 2024.

Signature:
Name: Mr. Srinivasa Reddy Madduri
Patent Agent Reg. No.: IN/PA-1268
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd
Block, Madhapur, Hyderabad,
Telangana, INDIA-500 081
,CLAIMS:We claim:
1. An improved process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV;

b) reacting 2-Aminoethanol with sulfuric acid to provide 2-Aminoethylhydrogen sulfate;

c) condensing 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b) to provide Viloxazine;

d) converting Viloxazine into Viloxazine hydrochloride of formula I; and
e) optionally, purifying Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I.

2. The process as claimed in claim 1, wherein in step a) the reaction is carried out in presence of a base, with or without the presence of a catalyst and a solvent; in step b) the reaction is carried out in the presence or absence of a base, catalyst and a solvent; and in step c) the condensation is carried out in the presence of a base and a solvent.

3. An improved process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
f) reacting 2-Ethoxyphenol of formula II with 2-(Halomethyl) oxirane of formula III in presence of sodium hydroxide in water at 25°C to 35°C to provide 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV;

a) reacting 2-Aminoethanol with sulfuric acid in presence of tetrabutyl ammonium bromide in toluene and water at 90°C to 110°C, followed by methanol purification to provide 2-Aminoethylhydrogen sulfate;

b) condensing 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV of step a) with 2-Aminoethylhydrogen sulfate of step b) in presence of potassium hydroxide in water and methanol to provide Viloxazine;

c) converting Viloxazine into Viloxazine hydrochloride of formula I in presence of hydrochloride in in methanol, ethanol, isopropanol, water and ethyl acetate or mixture thereof; and
d) optionally, purifying Viloxazine hydrochloride of formula I in methanol, ethanol, isopropanol, water and ethyl acetate or mixture thereof to provide pure Viloxazine hydrochloride of formula I.

4. The process as claimed in claim 1 and 3, wherein the Viloxazine hydrochloride of formula I obtained is having purity greater than 99% and it is substantially free of the compound of formula IX, formula X and formula XI.

5. A process for the preparation of Viloxazine hydrochloride of formula I, which comprises:
a) reacting 2-((2-Ethoxyphenoxy) methyl) oxirane of formula IV with Phthalimide or its salt thereof in presence of a base and a suitable solvent to provide 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V;

b) converting 2-(3-(2-Ethoxyphenoxy)-2-hydroxypropyl) isoindoline-1,3-dione of formula V into 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI;

c) reacting 1-Amino-3-(2-ethoxyphenoxy) propan-2-ol of formula VI with halo acetyl chloride in presence of a base and a suitable solvent to provide 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII;

d) cyclizing 2-Chloro-N-(3-(2-ethoxyphenoxy)-2-hydroxypropyl) acetamide of formula VII with a suitable cyclization reagent in presence of a suitable solvent to provide 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII;

e) reducing 6-((2-Ethoxyphenoxy) methyl) morpholin-3-one of formula VIII with a suitable reducing agent in presence of a suitable solvent to provide Viloxazine;

f) converting Viloxazine into Viloxazine hydrochloride of formula I; and
g) optionally, purifying Viloxazine hydrochloride of formula I in a suitable solvent to provide pure Viloxazine hydrochloride of formula I.

6. The process as claimed in claim 5, wherein in step b) the conversion of formula V into formula VI, can be carried out by reacting the compound of formula V with hydrazine or a suitable amine selected from monomethylamine and ethanolamine.

7. The process as claimed in claim 5, wherein in step d) the cyclization agent is selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, tosyl chloride, brosyl chloride, nosyl chloride and mesyl chloride, DMSO and alumina.

8. The process as claimed in claim 5, wherein in step e) the reducing agent is selected from vitride, lithium aluminium hydride and diisobutylaluminium hydride.

9. A compound of formula V.

10. Impurity compounds of formula IX, formula X and formula XI.

Dated this: 28th day of March, 2024.

Signature:
Name: Mr. Srinivasa Reddy Madduri
Patent Agent Reg. No.: IN/PA- 1268
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd
Block, Madhapur, Hyderabad,
Telangana, INDIA-500 081