DESC:Field of the Invention:
The present application relates to an improved process for the preparation of Viloxazine Hydrochloride and its intermediate’s thereof, represented by the following structural formula-I

Formula-I

Background of the Invention:
Viloxazine, having the chemical name as 2-[(2-Ethoxy phenoxy) methyl]morpholine approved as hydrochloride is USA on 2021 for the treatment Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age with the brand name of QELBREE™ as extended-release capsules: 100 mg, 150 mg and 200 mg .
Viloxazine was marketed for more than two decades as an antidepressant in Europe before being repurposed as a treatment for ADHD.
The US patent number US3714161A first reported viloxazine as product, and process for preparation thereof and isolated as viloxazine acetate salt.
The US3712890A disclosed various processes for the preparation viloxazine hydrochloride and other pharmaceutical acceptable salts.
The GB1427097 and US7659394B1 are reported various processes for chiral isomers of viloxazine hydrochloride.
There are various processes are reported for viloxazine salts and intermediate’s thereof by using different starting materials, reagents and solvents.
Based on the prior art process drawbacks, there is a need for providing an improved process for the preparation of viloxazine hydrochloride, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords highly pure viloxazine hydrochloride..
The present invention provides an improved process for preparation of viloxazine hydrochloride and intermediates thereof and free from other impurities or isomers. The present invention involves by using cheap and easily available key starting material, reagents and solvents, which are efficient, industrially viable and cost effective.

Brief Description:
The first aspect of the present invention is to provide a process for the preparation of Viloxazine hydrochloride.
The second aspect of the present invention is to provide a purification process for Viloxazine hydrochloride.

Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form of 2-[(2-Ethoxy phenoxy) methyl] morpholine hydrochloride compound of formula-I obtained as per example-5.
Figure 2: Illustrates the PXRD pattern of crystalline Form of 2-[(2-Ethoxy phenoxy) methyl] morpholine hydrochloride compound of formula-I obtained as per example-7.
Figure 3: Illustrates the PXRD pattern of amorphous solid dispersion of Viloxazine hydrochloride with Hydroxypropyl methylcellulose.
Figure 4: Illustrates the PXRD pattern of amorphous solid dispersion of Viloxazine hydrochloride with Eudragit.

Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxy ethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The first aspect of the present invention provides an improved process for the preparation of Viloxazine hydrochloride compound of formula-I

Comprising of:
a) Reacting compound of formula-1

[1]

with epichlorohydrine in presence of suitable reagent, solvents to provide compound of formula-2,

b) reacting the compound of formula-2 with compound of formula-3 in presence of suitable solvent and reagents to provide compound of formula-4,

c) optionally purifying the compound obtained in step-c) with suitable solvent to provide pure compound of formula-I.
Wherein in step-a), b), c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, toluene, acetone, polar aportic solvents, polor protic solvents, alcohol solvents, water or any mixture thereof; suitable temperature: 10-100°C;
Wherein in step-a) is suitable bases such as inorganic base, organic base, and suitable reagent terabutyl ammonium bromide;
Wherein in step-b) the suitable base such as inorganic base, organic base. Suitable acids methnolic HCl , ethanolic HCl, isopropanol HCl, ether HCl, ethyl acetate HCl, aq. HCl,
Preferred embodiment of the present invention provides a process for the preparation of the compound of formula-I,

Comprising of:
a) Reacting compound of formula-1

[1]

with epichlorohydrine in presence of potassium carbonate, tetrabutyl ammoniumbromide in toluene to produce compound of formula-2,

b) reacting the compound of formula-2 with compound of formula-3 in presence of sodium hydroxide in a mixture of water, methanol to provide compound of formula-4,


c) purifying the compound obtained in step-b) in a mixture of methanol, water to provide the compound of formula-I.
The second aspect of the present invention provides a purification process for Viloxazine hydrochloride compound of formula-I

Comprising of:
a) Stirring compound of formula-I in suitable solvent, suitable temperature,
b) isolating the compound of formula-I to get the pure compound.
Wherein in step-a) and b) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, toluene, acetone, polar aportic solvents, polor protic solvents, alcohol solvents, water or any mixture thereof; suitable temperature: 10-100°C,
The preferred embodiment of the present invention provides a purification process for Viloxazine hydrochloride compound of formula-I
Comprising of:
a) Stirring compound of formula-I in a mixture of methanol and water at 60-70°C,
b) isolating the compound of formula-I to get the pure compound.
The process for the preparation of Viloxazine Hydrochloride developed by the present inventors produces highly pure product with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
Viloxazine Hydrochloride and its polymorphs produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of Viloxazine Hydrochloride was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
The process of the present invention can be represented schematically as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of the compound of formula-2.
A round bottom flask was charged with compound of formula-1 (100 g), epichlorohydrin (167.4 g), potassium carbonate (200 g), tetrabutylammonium bromide (11.6 g) and toluene (500 mL) were stirred for 8 hr at 60-70°C. Cooled the reaction mixture to 25-35°C, charged with water (700 ml) and separated the both layers. The toluene layer was washed with water, and dried over sodium sulphate and evaporated to get the title compound.
Yield: 140 g.
Example-2: Preparation of the compound of formula-2.
A round bottom flask was charged with compound of formula-1 (50 g), epichlorohydrin (85 g), potassium carbonate (100 g), and toluene (250 mL) were stirred for 10 hr at 55-60°C. Cooled the reaction mixture to 25-35°C, charged with water (400 ml) and separated the both layers. The toluene layer was washed with water, and dried over sodium sulphate and evaporated to get the title compound.
Yield: 70.5 g.
Example-3: Preparation of the compound of formula-2.
A round bottom flask was charged with compound of formula-1 (10 g), epichlorohydrin (13.4 g), potassium carbonate (20 g), tetrabutylammonium bromide (1.2 g) and toluene (50 mL) were stirred for 8 hr at 55-60°C. Cooled the reaction mixture to 25-35°C, charged with water (700 ml) and separated the both layers. The toluene layer was washed with water, and dried over sodium sulphate and evaporated to get the title compound.
Yield: 140 g.
Example-4: Preparation of the compound of formula-4.
A round bottom flask was charged with compound of formula-3 (305.2 g), aq. sodium hydroxide solution (572 g) and water (280 mL) stirred for 15 min. A solution of compound-2 (140 g) in methanol (560 mL) was added to reaction mixture and heated to 60-70°C stirred for 16 hr. Cooled the reaction mixture and distilled off the methanol and charged with water, toluene and stirred for 1 hr. The both layer were separated, the organic layer was extracted with toluene. The combined organic layer was washed with water, dried and evaporated to get the compound as residue. The compound was charged with methanolic HCl and heated to 45-55°C, and stirred for 1 hr. Cooled the reaction mixture to 0-10°C, the precipitated solid was filtered and washed with methanol. The wet compound was stirred in a mixture of methanol and water and filtered the obtained solid and washed with methanol dried to get the title compound.
Yield: 78 g
Example-5: Preparation of the compound of formula-I.
A round bottom flask was charged with compound of formula-4 (80 g), methanol (240 mL) and water (60 mL) and heated to 60-70°C and stirred to 30 min. Cooled the reaction mixture and filtered the precipitated solid and washed with methanol. The compound was dried to get the title compound. The PXRD of the compound obtained is depicted in figure -1.
Yield: 54 g, DSC: 189°C.
Purity by HPLC >99.9 %
Example-6: Preparation of the 2-aminoethyl hydrogen sulfate
A round bottom flask was charged with ethanolamine (0.750 kg), toluene (3 L) and tetra butylammonium bromide (0.198 kg) stirred to 30 min. Cooled the reaction mixture to 0-10°, charged sulphuric acid (1.324 kg) and heated to 110-115°C and collected water through azeotropic distillation setup. Cooled the reaction mixture to 25-35°C, and filtered the precipitated solid and washed with toluene. The wet compound was stirred in methanol, filtered the solid compound and dried to get the title compound.
Yield: 1.65 kg.
Example-7: Preparation of the compound of formula-4.
A round bottom flask was charged with compound of formula-3 (70.5 g), aq. sodium hydroxide solution (40 g) and water (200 mL) stirred for 15 min. A solution of compound of formula-2 (19.4 g) in methanol (400 mL) was added slowly to reaction mixture and heated to 60-70°C stirred for 16 hr. Cooled the reaction mixture and distilled off the methanol and charged with water (200) and methyl tertiary butyl ether (150 mL) and stirred for 1 hr. The both layer were separated, the organic layer was extracted with MTBE (2x150 mL). The combined organic layer was washed with water, dried and evaporated to get the residue compound. The residue compound was charged with isopropanol (20 mL), con.HCl (10.5 mL) and ethyl acetate (75 mL) stirred for 2hr at 25-35°C. The precipitated solid was filtered and dried to get the title compound. The PXRD of the compound obtained is depicted in figure-2 ; DSC: 188°C.
Yield: 6.05 g
Example-8: Preparation of the compound of formula-I.
A round bottom flask was charged with compound of formula-4 (10 g), isopropylalcohol (30 mL) and water (10 mL) and heated to 60-70°C and stirred to 1 hr. Cooled the reaction mixture and filtered the precipitated solid and washed with isopropanol. The compound was dried to get the title compound. The PXRD of the compound obtained is similar to figure -1.
Yield: 6.5 g.
Purity by HPLC >99.9 %
Example-9: Preparation of amorphous solid dispersion of Viloxazine hydrochloride with Hydroxypropyl methylcellulose.
A round bottom flask was charged with compound of formula-4 (1.0 g), methanol ( 25 mL) and a solution of Hydroxypropyl methylcellulose (2 g) in methanol, dichloromethane (1:1; 30 mL) and stirred for 2 hr at 25-35°C. The reaction mixture was distilled off completely and dried to get the title compound.
The PXRD of the compound obtained is depicted in figure-3
Yield: 2.8 g
Example-10: Preparation of amorphous solid dispersion of Viloxazine hydrochloride with Eudragit
A round bottom flask was charged with compound of formula-4 (10 g), methanol (300 mL) and stirred at 60°C for 10 min. A solution of eudragit (20 g) in methanol (300 mL) was charged to the reaction mixture stirred for 1 hr. The reaction mixture was distilled off completely and dried to get the title compound.
The PXRD of the compound obtained is depicted in figure-4
Yield: 28.5 g
Example-11: Preparation of amorphous solid dispersion of Viloxazine hydrochloride with PVP-K30.
A round bottom flask was charged with compound of formula-4 (1 g), methanol (25 mL) and Polyvinylpyrrolidone (PVPK-30) (2 g in water) stirred for 10 min. The reaction mixture was distilled off completely and dried to get the title compound.
Yield: 2.75 g
Example-12: Preparation of amorphous solid dispersion of Viloxazine hydrochloride with Hydroxypropyl cellulose – HPC.
A round bottom flask was charged with compound of formula-4 (2 g), methanol (50 mL), Hydroxypropyl cellulose – HPC (3.5 g) and dichloromethane (50 mL) stirred for 10 min. Filtered the isolated solid and dried to get the title compound.
Yield: 5.2 g
Example-13: Preparation of the 2-aminoethyl hydrogen sulfate
A round bottom flask was charged with ethanolamine (0.750 kg), toluene (3 L) and stirred for 30 min. Cooled the reaction mixture to 0-10°, charged sulphuric acid (1.324 kg) slowly and heated to 110-115°C and stirred for 16 hr to collected water through azeotropic distillation setup. Cooled the reaction mixture to 25-35°C, and filtered the precipitated solid and washed with toluene. The wet compound was stirred in methanol, filtered the obtained solid compound and dried to get the title compound.
Yield: 1.7 kg.
Example-14: Preparation of the compound of formula-4
A Round bottomed flask is charged with acetone (200 mL), water (40 mL), 2-(chloromethyl) oxirane (669.6 g), potassium carbonate (800.2 g) and compound-1 (400 g) at 25-35°C and stirred for 30 min. The reaction mass was heated to 50-60°C and maintained the reaction at same temperature for 6 hr. The reaction mixture was distilled off, charged with water (2 L), toluene (2 L) and stirred the reaction for 20 min and separated the two layers. The organic layer was charged with water (1.2 L) and stirred for 20 min and separated the two layers. The organic layer was distilled out completely and stirred in methanol to get the residue compound. A clean RBF was charged with water (1.12 L), sodium hydroxide (231.6 g) and 2-aminoethyl hydrogen sulfate (1225.96 g) stirred the reaction mass for 15 min at 25-35°C. To the reaction mixture the above obtained residue compound was charged and heated to 60-70°C and maintained for 3 hr. The reaction mixture gradually cooled to 40-50°C and charged with a solution of sodium hydroxide, and further heated the reaction mass to 60-70°C and maintained for 16 hr at same temperature. The reaction mixture was distilled off, further the reaction mass was charged with water, toluene and stirred for 30 min at 25-35°C. The both layers were separated, the aqueous layer was charged with toluene, stirred the reaction mass for 30 min at 25-35°C and separated the two layers. The combined organic layer was distilled off completely, cooled the residue to 25-35°C and charged methanol hydrochloride slowly at 25-35°C and stirred for 1 hr at 45-55°C. Cooled the reaction mass to 0-10°C and stirred for 60 min, filtered the resulting solid and washed with methanol, dried to get the title compound.
Yield: 275 g.

,CLAIMS:We claim
1. An improved process for the preparation of Viloxazine hydrochloride compound of formula-I

Comprising of:
a) Reacting compound of formula-1

[1]

with epichlorohydrine in presence of suitable reagent, solvents to provide compound of formula-2,

b) reacting the compound of formula-2 with compound of formula-3 in presence of suitable solvent and reagents to provide compound of formula-4,

c) optionally purifying the compound obtained in step-c) with suitable solvent to provide pure compound of formula-I.
2. A process for preparation of compound of formula-I as claimed in claim 1 wherein in step-a), b), c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, toluene, acetone, polar aportic solvents, polor protic solvents, alcohol solvents, water or any mixture thereof; suitable temperature: 10-100°C;
Wherein in step-a) is suitable bases such inorganic base, organic base, and suitable reagent terabutyl ammonium bromide;
Wherein in step-b) the suitable base such as inorganic base, organic base. Suitable acids are methnolic HCl , ethanolic HCl, isopropanol HCl, ether HCl, ethyl acetate HCl, aq. HCl,
3. An improved process for the preparation of Viloxazine hydrochloride compound of formula-I

Comprising of:
a) Reacting compound of formula-1

[1]

with epichlorohydrine in presence of potassium carbonate, tetrabutyl ammoniumbromide in toluene to produce compound of formula-2,

b) reacting the compound of formula-2 with compound of formula-3 in presence of sodium hydroxide in a mixture of water, methanol to provide compound of formula-4,


c) purifying the compound obtained in step-b) in a mixture of methanol, water to provide the compound of formula-I.
4. A purification process for Viloxazine hydrochloride compound of formula-I

Comprising of:
a) Stirring compound of formula-I in suitable solvent, suitable temperature,
b) isolating the compound of formula-I to get the pure compound.
5. A purification process for viloxazine hydrochloride as claimed in claim 4 wherein in step-a) and b) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, toluene, acetone, polar aportic solvents, polor protic solvents, alcohol solvents, water or any mixture thereof; suitable temperature: 10-100°C,

6. A purification process for viloxazine hydrochloride compound of formula-I
Comprising of:
a) Stirring compound of formula-I in a mixture of methanol and water at 60-70°C,
b) isolating the compound of formula-I to get the pure compound.
7. Viloxazine hydrochloride compound of formula-I obtained according to any of preceding claims having purity > 95%, preferably > 99% by HPLC.

Dated this day 15-Apr-2023.