DESC:
FIELD OF THE INVENTION
The present invention relates to a process for preparation of Viloxazine hydrochloride. The present invention also relates to process for preparing intermediates useful in the preparation of viloxazine hydrochloride. In particular, the present invention relates to a solid-state form of intermediate of viloxazine hydrochloride. The present invention also relates to an improved process for preparing viloxazine hydrochloride.

BACKGROUND AND THE PRIOR ART
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Viloxazine hydrochloride is a selective norepinephrine reuptake inhibitor (NRI). Its chemical name is (R,S)-2-(2-Ethoxyphenoxymethyl)morpholine hydrochloride. Viloxazine hydrochloride is having the structure of Formula (I)

U.S. Patent No. 3,714,161 and US 3,712,890 discloses the compound viloxazine and provides its process for preparation.

U.S. Patent No. 9,434,703 B2 relates to impurities of viloxazine hydrochloride.

U.S. Patent No. 10,160,733 B2 relates to polymorph Form-A and Form-B of viloxazine hydrochloride.
Though several processes for the preparation of viloxazine hydrochloride and intermediates thereof have been disclosed, they require many synthetic steps, intermediates are in residue form or oil form and give rise to the desired product in low yield.

It is therefore necessary to develop a new process for obtaining viloxazine hydrochloride as well as key intermediates which overcome all or part of the problems associated with the known processes belonging to the state of the art.

In view of the above art, there is provided an improved process for preparing viloxazine hydrochloride. In particular there is provided a process for preparing intermediates useful in the preparation of viloxazine hydrochloride in solid forms.

SUMMARY OF THE INVENTION
In one general aspect, there is provided a process for the preparation of viloxazine hydrochloride of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);

(b) converting a compound of Formula (E) to a compound of Formula (F) in-situ using chloroacetyl chloride in presence of a base and one or more solvents and further converting compound of Formula (F) in presence of a base and one or more solvents to obtain a compound of formula (G);

(c) converting a compound of Formula (G) to obtain a compound of Formula (H) in-situ using a reducing agent in presence of a base and one or more solvents and further converting compound of Formula (H) using a reducing agent in presence of a base and one or more solvents to obtain a compound of Formula (I)


(d) purifying viloxazine Hydrochloride in one or more solvents.

In another general aspect, there is provided a solid state form of compound of Formula (E)

In another general aspect, there is provided a solid state form of a compound of Formula (E) having purity greater than 99.5% as measured by HPLC.

In another general aspect, there is provided a solid state form of a compound of Formula (E) having water content less than 0.5%.
In another general aspect, there is provided a process for preparation of solid state form of a compound of Formula (E),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);
(b) isolating solid state form of a compound of Formula (E).

In another general aspect, there is provided a solid state form of compound of Formula (G)

In another general aspect, there is provided a solid state form of a compound of Formula (G) having purity greater than 99.5% as measured by HPLC.

In another general aspect, there is provided a solid state form of a compound of Formula (G) having water content less than 0.5%.

In another general aspect, there is provided a process for preparation of solid state form of a compound of Formula (G),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);
(b) converting a compound of Formula (E) to a compound of Formula (F) in-situ using chloroacetyl chloride in presence of a base and one or more solvents and further converting compound of Formula (F) in presence of a base and one or more solvents to obtain a compound of formula (G);
(c) isolating solid state form of a compound of Formula (G).

In another general aspect, there is provided viloxazine hydrochloride having purity greater than 99.9% as measured by HPLC.

In another general aspect, there is provided viloxazine hydrochloride having water content less than 0.5%.

BRIEF DESCRIPTON OF THE ACCOMPANYING DRAWINGS
FIG. 1: X-ray powder diffractogram (XRPD) of compound of Formula (E).
FIG. 2: Differential Scanning Calorimetry (DSC) of compound of Formula (E).
FIG. 3: X-ray powder diffractogram (XRPD) of compound of Formula (G).
FIG. 4: Differential Scanning Calorimetry (DSC) of compound of Formula (G).

DETAILED DESCRIPTION OF THE INVENTION
The aforementioned objectives of the present invention are fulfilled by one or more of the processes described herein.

While the invention has been described in terms of its specific embodiments, the description, in no way, intends to limit the scope of the present invention to the specifically described embodiments only; equivalents and variants thereof which are apparently obvious to those skilled in the art are also included within the scope of the present invention. The description does not include detailed description of conventional methods used in the field of the invention; such conventional methods are the ones well known to those of ordinary skill in the art either because they are normally practiced routinely by the skilled artisan in the field of the invention and/or are described in detail in various publications – physical as well digital.

The terms ‘reacting’, ‘contacting’ and ‘treating’ are generally interchangeable and are used in their ordinary meaning as they are used in the field of the invention, unless defined specifically otherwise.

The term ‘converting’ means reacting the compound to which it refers to with another compound and/or reagent; and/or subjecting it to condition(s) wherein it transforms to another compound as a result of such treatment.

The terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable and include, but not limited to, decantation, filtration, extraction, evaporation, crystallization, recrystallization and chromatographic operations.

The term ‘substantially’ defines "to a large extent only that is comprised which is specified". The boundaries of the term substantially is therefore to be drawn where the essential characteristics of the specified subject-matter ceased. The scope of the term substantially is therefore interpreted as being identical to that of consisting essentially of.

The expressions that recite a range of values “between” two values include the endpoints. Terms such as “about” and “generally” are to be construed as modifying a term or value to which they are attached such that the term or the value is not absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The product(s) obtained may further be purified to obtain them in purer form.

The product(s) obtained may further be dried additionally to achieve desired level of moisture and/or residual solvents.

The product(s) obtained may further be converted to any other physical forms thereof, which includes but not specifically limited to polymorph(s), salt(s), solvate(s), hydrate(s), co-crystal(s) or solid dispersion(s); and crystalline or amorphous forms thereof.

The product(s) obtained may further be subjected to physical processing which includes, but not limited to, pressing, crushing, triturating, milling or grinding to adjust the particle size of the product(s) to desired levels.

The product(s) obtained may further be combined with pharmaceutically acceptable career to obtain a pharmaceutical composition comprising viloxazine hydrochloride of the invention and pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition may be in the form of solid or liquid dosage forms and may have immediate release or modified release characteristics. The dosage forms include but not limited to tablet, capsule, powder, granules, solution, suspension, emulsion, elixir or cream.

In one general aspect, there is provided a process for the preparation of viloxazine hydrochloride of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);

(b) converting a compound of Formula (E) to a compound of Formula (F) in-situ using chloroacetyl chloride in presence of a base and one or more solvents and further converting compound of Formula (F) in presence of a base and one or more solvents to obtain a compound of formula (G);

(c) converting a compound of Formula (G) to obtain a compound of Formula (H) in-situ using a reducing agent in presence of a base and one or more solvents and further converting compound of Formula (H) using a reducing agent in presence of a base and one or more solvents to obtain viloxazine hydrochloride of compound of Formula (I).

(d) purifying viloxazine Hydrochloride in one or more solvents.

The compound of Formula (A) can be reacted with compound of Formula (B) by using a base in one or more solvents to obtain compound of Formula (C).

In general, the solvent comprises one or more of C1-4 alcohols, C2-6 esters, ketones, aromatic hydrocarbons, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

In general, the C1-4 alcohol is selected from methanol, ethanol, n-propanol, isopropanol, and n-butanol; the C2-6 ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; the ketone is selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; the aromatic hydrocarbon is selected from benzene, toulene and phenol; the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; and the polar aprotic solvent is selected from dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone or mixture thereof.

The base may be selected from an organic or inorganic base. An organic base may be selected from diisopropylethylamine, diisopropylamine, triethylamine, diethylamine, piperidine, morpholine, pyridine, DBU and DABCO. The inorganic base comprises of an alkali and alkaline metal hydroxide and carbonate, in particular the suitable alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide and carbonate comprises of sodium carbonate, potassium carbonate and cesium carbonate.

The compound of Formula (C) may not be isolated and directly reacted with compound of Formula (D) in presence of a base in one or more solvents to obtain compound of Formula (E).

The compound of Formula (E) is reacted with chloroacetyl chloride in presence of a base in one or more solvents to obtain a compound of Formula (F) in-situ. The compound of Formula (F) is treated with a base in one or more solvents to obtain a compound of formula (G);

The compound of Formula (G) is reacted with a reducing agent in one or more solvents to obtain a compound of Formula (H) in-situ. The compound of Formula (H) is treated with a reducing agent in suitable solvent to obtain Viloxazine Base.

Reducing agent may be selected from sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), and diisobutyl aluminum hydride (DIBAH), metal catalyst consisting of palladium, platinum, and nickel.

The compound of Formula (H) is treated with sodium borohydride (NaBH4) in one or more solvents to obtain a compound of Formula (H) in-situ.

The compound of Formula (H) obtained in-situ is treated with metal catalyst such as 10%Pd/C in suitable solvent to obtain Viloxazine Base which directly treated with conc. hydrochloric acid in one or more solvents to obtain viloxazine hydrochloride of Formula (I).

The solvents may be selected from one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyl tetrahydro furan, dioxane, water or mixtures thereof.

Further crude Viloxazine hydrochloride may be purified in IPA-Water/Ethyl acetate solvent.

In another general aspect, there is provided a solid state form of compound of Formula (E)

In another general aspect, solid state form of compound of Formula (E) may be characterized by X-ray powder diffractogram (XPRD).

In another general aspect, solid state form of compound of Formula (E) may be characterized by X-ray powder diffractogram (XPRD) as depicted in FIG. 1

In another general aspect, solid state form of compound of Formula (E) is characterized by XRPD pattern having characteristic peaks at about 6.7, 8.3, 13.4, 16.6, 19.7, 21.4, 22.1, 24.9, 26.4, and 27.1 ±0.2 degrees 2-theta.

In another general aspect, solid state form of compound of Formula (E) may be characterized by Differential scanning calorimetry (DSC) having single endotherm at about 80.2 0C.

In another general aspect, solid state form of compound of Formula (E) may be characterized DSC as depicted in FIG. 2

In another general aspect, there is provided a compound of Formula (E) is having purity greater than 99.5% as measured by HPLC.

In another general aspect, there is provided a compound of Formula (E) is substantially free from impurities designated as impurity (1) and impurity (2)

Impurity (1)- Dimer Impurity Impurity (2)- Bis impurity
In another general aspect, there is provided a compound of Formula (E) having water content less than 0.5%.

In another general aspect, there is provided a process for preparation of solid state form of a compound of Formula (E),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);

(b) isolating solid state form of a compound of Formula (E).

The base may be selected from an organic or inorganic base.

In general, the solvent comprises one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

In another general aspect, there is provided a solid state form of compound of Formula (G)

In another general aspect, solid state form of compound of Formula (G) may be characterized by X-ray powder diffractogram (XPRD).

In another general aspect, solid state form of compound of Formula (G) may be characterized by X-ray powder diffractogram (XPRD) as depicted in FIG. 3.

In another general aspect, solid state form of compound of Formula (G) is characterized by XRPD pattern having characteristic peaks at about 9.1, 11.5, 14.0, 16.5, 18.8, 20.1, 20.9, 21.9, 23.1, 24.0, 25.2, 26.7, 27.8 and 28.6 ±0.2 degrees 2-theta.

In another general aspect, solid state form of compound of Formula (G) may be characterized by Differential scanning calorimetry (DSC) having single endotherm at about 81.3 0C.

In another general aspect, solid state form of compound of Formula (G) may be characterized DSC as depicted in FIG. 4

In another general aspect, there is provided a compound of Formula (G) is having purity greater than 99.5% as measured by HPLC.

In another general aspect, there is provided a compound of Formula (G) is substantially free from impurities designated as Impurity (3), Impurity (4) and Impurity (5).

Impurity (3) Dichloro Impurity Impurity (4)

Impurity (5)- O-Alkylating Impurity
In another general aspect, there is provided a compound of Formula (G) having water content less than 0.5%.

In another general aspect, there is provided a process for preparation of solid state form of a compound of Formula (G),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);

(b) converting a compound of Formula (E) to a compound of Formula (F) in-situ using chloroacetyl chloride in presence of a base and one or more solvents and further converting compound of Formula (F) in presence of a base and one or more solvents to obtain a compound of formula (G);

(c) isolating solid state form of a compound of Formula (G).

The solvent may be selected from one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydro- furan, dioxane, or mixtures thereof.
The base may be selected from an organic or inorganic base.

In another general aspect, there is provided viloxazine hydrochloride substantially free from impurities designated as Impurity (1), Impurity (2), Impurity (3), Impurity (4) and Impurity (5).

In another general aspect, there is provided viloxazine hydrochloride having impurities designated as Impurity (1), Impurity (2), Impurity (3), Impurity (4) and Impurity (5) less than 0.5%.

In another general aspect, there is provided a process for the preparation of viloxazine hydrochloride as depicted in Scheme-1.

The present invention is further illustrated by the following examples which are provided merely to exemplify the invention and do not limit the scope of it.
EXAMPLES:
Example-1: Preparation of compound of Formula (E)

(2-Ethoxy phenol) compound of Formula (A) (100 g), epichlorohydrin compound of Formula (B) (115 g), sodium hydroxide (14 g) and water (350 ml) were added to a 2000 ml RBF at 25 to 35 °C and stirred for 60 minutes. The reaction mass was cooled to 10 to 15 °C and stirred for about 600 minutes. The reaction mass was heated to 25 to 30 °C. The layers were separated. The lower layer was treated with water (350 ml) and sodium hydroxide (25 g) solution and stirred for 5 hours at 25 to 30 °C. The layers were separated and lower layer was treated with toluene (200 ml) and water (200 ml) and stirred for 30 minutes. After layer separation, the toluene layer was distilled out under vacuum at 60 0C. The residue was treated with benzyl amine (550 g) at 25 to 35 °C and heated to 50 to 60 0C. The reaction mass was stirred for 3 hours. The reaction mass heated to 100 to 105 0C and benzyl amine was distilled out under vacuum below 1100C. The reaction mass was cooled to 65 to 75 0C and ethyl acetate (350 mL) and stirred for 30 minutes. The reaction mass was cooled to 25 to 35 °C followed by addition of diisopropyl ether (540 ml) and stirred for 30 minutes. The reaction mass was cooled to 0 to 5 °C and stirred for 30 minutes. The reaction mass was filtered to obtain solid compound of Formula (E).
Yield (75%)

Example-2: Preparation of compound of Formula (G)

Compound of Formula (E) (100 g), dichloromethane (500 ml) and triethyl amine (36 g) were added to a 1000 ml RBF at 25 to 35 °C. Chloroacetyl chloride solution was added and reaction mass was heated to 35 to 45 °C. The reaction mass was stirred for 1 hour. The reaction mass was cooled to 25 to 35 °C followed by addition of water (200 ml) and stirred for 30 minutes. The layers were separated. The organic layer was treated with methanol (100 ml) was added and cooled to 0 to 5 °C followed by addition of sodium hydroxide (16 g). Methanol (25 ml) was added at 0 to 20 °C. The reaction mass was heated to 34 to 44 °C. The reaction mass was cooled to 25 to 35 °C and added of dil. HCl (200 ml). Stirred for 30 minutes and layers were separated. Further MDC layer was washed with water (150 ml). Finally, MDC was distilled out and IPA (400 ml) was added. The reaction mass was heated to 80 to 90 °C. The reaction mass was cooled to 20 to 30 °C and stirred for 30 minutes. The reaction mass was cooled to 5 to -5 °C and stirred for 60 minutes. The reaction mass was filtered and washed with IPA (2 x 25 ml) to obtain solid compound of Formula (G).
Yield (93%)
Example-3: Preparation of viloxazine hydrochloride crude
Compound of Formula (G) (100 g) and THF (450 ml) were added to a 1000 ml RBF at 25 to 35 °C. The reaction mass was cooled to 10 to 20°C followed by addition of sodium borohydride (35 g). Further THF (25 ml) was added and stirred for 20 minutes. Followed by addition boron trifluoride etherate (340 ml). The reaction mass was heated to 25 to 35 °C and stirred for 60 minutes. The reaction mass was cooled to 10 to 20 °C followed by addition of water & sodium hydroxide solution. The reaction mass was heated slowly to 50 to 60 °C and stir for 1 hour at same temperature. After cooling ethyl acetate was added and mass was stirred for 30 minutes and layer was separated. Further ethyl acetate layer was distilled out to get residue. Obtained residue was treated with methanol (800 ml) and stirred for 30 minutes in an autoclave at 25 to 35 °C. Palladium/carbon (5 g) was added and flushed with nitrogen. The reaction mass was heated to 54 to 64°C with hydrogen pressure of 2 to 3 kg was and stirred for 5 hours. After that mass was cool to 25 to 35 °C and catalyst was filtered off and from obtained organic layer methanol was distilled out to get residue. To this residue IPA (100 ml) & ethyl acetate was added and mass was stirred at 25 to 35 °C. Cone. HCl (30 g) was added and stirred for 3 hours. The reaction mass was filtered and washed with IPA (50 ml) and ethyl acetate (50 ml) to obtain viloxazine hydrochloride. Yield (90%).
Example-4: Preparation of viloxazine hydrochloride Pure
Viloxazine hydrochloride crude (100 g), IPA (450 ml) and water (125 ml) were added to a 2000 ml RBF at 25 to 35 °C. Reaction mass was heated to 80 to 90 °C and stirred for 15 minutes on same temperature to get clear solution. After that the reaction mass was filtered and washed with IPA. Followed by filtration reaction mass was cooled to 25 to 35 °C and ethyl acetate (700 ml) was added and mass was stirred for 2 hours at same temperature. Finally, product was isolated by filtration and drying.
Yield (90%).

,CLAIMS:We Claim:

1. A process for the preparation of viloxazine hydrochloride of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) in presence of a base and one or more solvents to obtain a compound of Formula (C) in-situ and further reacting compound of Formula (C) with benzyl amine of Formula (D) in presence of a base and one or more solvents to obtain a compound of Formula (E);

(b) converting a compound of Formula (E) to a compound of Formula (F) in-situ using chloroacetyl chloride in presence of a base and one or more solvents and further converting compound of Formula (F) in presence of a base and one or more solvents to obtain a compound of formula (G);

(c) converting a compound of Formula (G) to obtain a compound of Formula (H) in-situ using a reducing agent in presence of a base and one or more solvents and further converting compound of Formula (H) using a reducing agent in presence of a base and one or more solvents to obtain viloxazine hydrochloride of compound of Formula (I).

(d) purifying viloxazine Hydrochloride in one or more solvents.
2. The process as claimed in claim 1, wherein the solvent may be selected from one or more of C1-4 alcohols, C2-6 esters, ketones, aromatic hydrocarbons, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

3. The process as claimed in claim 1, wherein the base may be selected from an organic or inorganic base.

4. The process as claimed in claim 3, wherein the organic base may be selected from diisopropylethylamine, diisopropylamine, triethylamine, diethylamine, piperidine, morpholine, pyridine, DBU, and DABCO.

5. The process as claimed in claim 3, wherein inorganic base may be selected from an alkali and alkaline metal hydroxides and carbonates, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

6. The process as claimed in claim 1, wherein reducing agent may be selected from sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), and diisobutyl aluminum hydride (DIBAH), metal catalyst consisting of palladium, platinum, and nickel.

7. The process as claimed in claim 1, wherein solid state form of compound of Formula (E) is characterized by XRPD pattern having characteristic peaks at about 6.7, 8.3, 13.4, 16.6, 19.7, 21.4, 22.1, 24.9, 26.4, and 27.1 ±0.2 degrees 2-theta as depicted in FIG. 1

8. The process as claimed in claim 1, wherein solid state form of compound of Formula (E) is substantially free from impurities designated as impurity (1) and impurity (2)

Impurity (1)- Dimer Impurity Impurity (2)- Bis impurity

9. The process as claimed in claim 1, wherein solid state form of compound of Formula (G) is characterized by XRPD pattern having characteristic peaks at about 9.1, 11.5, 14.0, 16.5, 18.8, 20.1, 20.9, 21.9, 23.1, 24.0, 25.2, 26.7, 27.8 and 28.6 ±0.2 degrees 2-theta as depicted in FIG. 3.

10. The process as claimed in claim 1, wherein solid state form of compound of Formula (G) is substantially free from impurities designated as Impurity (3), Impurity (4) and Impurity (5).

Impurity (3) Dichloro Impurity Impurity (4)

Impurity (5)- O-Alkylating Impurity.

Dated this 11th day of October 2022.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS