Improved method for preparation of (s)-biloxazine or salt thereof

Abstract

The present invention relates to an improved method for the preparation of optically pure (S)-biloxazine or a salt thereof. The (S)-biloxazine prepared according to the preparation method of the present invention can be selectively administered to prevent or treat attention deficit hyperactivity disorder (ADHD). Accordingly, the dosage of a drug can be reduced by half or more, and side effects can be reduced.

Description

(S)-Improved process for producing a photoinjection agent or a salt thereof The present invention relates to an improved process for preparing optically pure (S)-viloxazine or a salt thereof. Viloxazine HCl is a racemic compound that has been used as an antidepressant in the UK for a long time. It was approved by the FDA in 2021 for the treatment of attention deficit hyperactivity disorder (ADHD) in children and in 2022 for the treatment of adult ADHD, and is sold under the brand name Qelbree as a non-stimulant ADHD treatment. This drug is a 5HT2B receptor antagonist and a 5-HT2C receptor agonist that regulates the activity of serotonin and selectively inhibits norepinephrine reuptake. In addition, viloxazine hydrochloride is evaluated to have a low risk of drug abuse, dependence, and withdrawal symptoms when discontinuing treatment because it has a low effect on dopamine. Viloxazine hydrochloride is available in sustained-release capsule form (100 mg, 200 mg, 400 mg) that can be taken once a day for ADHD patients. It is metabolized by the CYP2D6 enzyme, and most of the metabolites are excreted through urine. In clinical trials, ADHD patients who took viloxazine hydrochloride showed improvement in symptoms compared to patients who took the placebo, and it was confirmed to be effective in alleviating major symptoms of ADHD such as inattention, hyperactivity, and impulsivity. In addition, some patients who received viloxazine hydrochloride experienced increased heart rate and blood pressure. The most common side effects include drowsiness, decreased appetite, fatigue, nausea, and insomnia, and there is a risk of worsening symptoms in patients with bipolar disorder. Suicidal ideation or risk of suicide may increase during initial treatment or dosage adjustment. Meanwhile, viloxazine hydrochloride is known as a drug with a large difference in efficacy between the (R) form and the (S) form. The efficacy of the (S) form is about 5 times higher than that of the (R) form, and the (R) form is known to be ineffective for ADHD when administered for a long period of time. In addition, if the (R) form binds to a non-target receptor non-selectively or follows a different metabolic pathway in the body, side effects may increase. Meanwhile, chiral compounds are generally obtained by synthesizing racemic compounds and then separating each isomer through a chiral resolution process. At this time, the inactive form must be discarded or reprocessed to be converted into an active form, which causes problems in that it requires a lot of manufacturing cost and time. To solve these problems, the inventors of the present invention synthesized a pure (S)-viloxazine free base of the following chemical formula 1 through reaction scheme 1 or 2 using a compound of the following chemical formula 2 as a starting material, and synthesized a novel (S)-viloxazine salt through reaction scheme 3. [Chemical Formula 1] [Chemical formula 2] [Reaction Formula 1] [Reaction Formula 2] [Reaction Formula 3] According to the manufacturing method of the present invention, optically pure (S)-viloxazine or a salt thereof can be manufactured in an improved manner. In addition, the present invention aims to use (S)-viloxazine or a novel salt thereof manufactured according to the present invention for the prevention or treatment of attention deficit hyperactivity disorder (ADHD). [1] In one aspect, the present invention is a method for preparing a compound of the following chemical formula 1 or a salt thereof, comprising the steps of: reacting a compound of the following chemical formula 2 with a compound of the following chemical formula 3 in the presence of a base and a solvent (step A-1); and reacting a compound of the following chemical formula 4 obtained from step A-1 with a compound of the following chemical formula 5 in the presence of a base and a solvent (step A-2). [Chemical Formula 1] [Chemical formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] The present invention relates to a manufacturing method wherein in the chemical formula 3, X is Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl). [2] In another aspect, the present invention provides a method for preparing a compound of the following chemical formula 1 or a salt thereof, comprising the steps of (i) reacting a compound of the following chemical formula 2 with a compound of the following chemical formula 6 in the presence of a solvent (step B-1) or (ii) reacting a compound of the following chemical formula 7 in the presence of a base and a solvent (step B-2); and the step of deprotecting a compound of the following chemical formula 8 obtained from step B-1 or step B-2 (step B-3). [Chemical Formula 1] [Chemical formula 2] [Chemical formula 6] [Chemical formula 7] [Chemical formula 8] In the above chemical formulas 6 to 8, PG is a protecting group, In the above chemical formula 6, Y is OH, The present invention relates to a manufacturing method wherein in the chemical formula 7, Z is Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl). [3] In the above [1], in the step A-1, the compound of chemical formula 3 can be used in an amount of 0.90 to 2.0 equivalents relative to the compound of chemical formula 2. [4] In the above [1], in the step A-1, the base may be at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof. [5] In the above [1], in the step A-1, the base can be used in an amount of 0.9 to 2.0 equivalents relative to the compound of the chemical formula 2. [6] In the above [1], in the step A-1, the solvent may be at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, dimethylformamide, enmethylpyrrolinone, dimethylacetamide, acetonitrile, and diethyl ether. [7] In the above [1], in the step A-1, the solvent can be used in an amount of 6 to 20 times the weight of the compound of the chemical formula 2. [8] In the above [1], in the step A-2, the base may be at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof. [9] In the above [1], in step A-2, the solvent may be at least one selected from the group consisting of purified water, methanol, ethanol, isopropanol, butanol, and hexanol.

[0010] In the above [1], in step A-2, the solvent can be used in an amount of 6 to 20 times the weight of the compound of chemical formula 5.

[0011] In the above [2], the protecting group in steps B-1 and B-2 may be tert-butoxycarbonyl (Boc, tert-Butoxycarbonyl), benzylcarbonyl (CBz, Benzyl carbonyl), 9-fluorenylmethoxycarbonyl (Fmoc, 9-Fluorenylmethoxycarbonyl) or benzyl (Bn, Benzyl).

[0012] In the above [2], in the step B-1, the solvent may be at least one selected from the group consisting of tetrahydrofuran, benzene, dichloromethane, toluene, xylene, acetonitrile, and ethyl acetate.

[0013] In the above [2], in the step B-2, the base may be at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof.

[0014] In the above [2], in the step B-2, the solvent may be at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, dimethylformamide, enmethylpyrrolinone, dimethylacetamide, acetonitrile, and diethyl ether.

[0015] In the above [1] or [2], a step of reacting the manufactured compound of chemical formula 1 with an acid in a solvent to form a salt of the compound of chemical formula 1 may be additionally included.

[0016] In the above

[0015] , the solvent may be at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, n-heptane, and diethyl ether.

[0017] In the above

[0015] , the acid may be at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

[0018] In the above

[0015] , the acid may be hydrochloric acid or acetic acid.

[0019] In the above

[0015] , the salt of the compound of chemical formula 1 obtained is (S)-viloxazine hydrochloride, (S)-viloxazine hydrobromide, (S)-viloxazine sulfate, (S)-viloxazine phosphate, (S)-viloxazine nitrate, (S)-viloxazine acetate, (S)-viloxazine glycolate, (S)-viloxazine lactate, (S)-viloxazine pyruvate, (S)-viloxazine malonate, (S)-viloxazine succinate, (S)-viloxazine glutarate, (S)-viloxazine fumarate, (S)-viloxazine malate, (S)-viloxazine mandelate, (S)-viloxazine tartrate, (S)-viloxazine citrate, (S)-viloxazine ascorbate, (S)-viloxazine palmitate, (S)-viloxazine It may be any one selected from the group consisting of (S)-viloxazine maleate, (S)-viloxazine benzoate, (S)-viloxazine hydroxybenzoate, (S)-viloxazine phenylacetate, (S)-viloxazine cinnamate, (S)-viloxazine salicylate, (S)-viloxazine methanesulfonate, (S)-viloxazine ethanesulfonate, (S)-viloxazine benzenesulfonate and (S)-viloxazine toluenesulfonate.

[0020] In the above

[0015] , the salt of the compound of chemical formula 1 obtained may be (S)-viloxazine hydrochloride or (S)-viloxazine acetate.

[0021] In another aspect, the present invention relates to a pharmaceutical composition for treating or preventing attention deficit hyperactivity disorder (ADHD), comprising a compound of formula 1 or a salt thereof prepared according to [1], [2] or

[0015] .

[0022] In the above

[0021] , the pharmaceutical composition can be administered via oral administration, parenteral administration or topical administration routes.

[0023] In another aspect, the present invention relates to a pharmaceutical composition for treating or preventing attention deficit hyperactivity disorder (ADHD) comprising (S)-viloxazine acetate.

[0024] In another aspect, the present invention relates to a method for preventing or treating attention deficit hyperactivity disorder in a subject, comprising administering to the subject a compound of formula 1 or a salt thereof prepared according to [1], [2] or

[0015] .

[0025] In another aspect, the present invention relates to the use of a compound of formula 1 or a salt thereof prepared according to [1], [2] or

[0015] for the preparation of a medicament for preventing or treating attention deficit hyperactivity disorder.

[0026] In another aspect, the present invention relates to the use of a compound of formula 1 or a salt thereof prepared according to [1], [2] or

[0015] for preventing or treating attention deficit hyperactivity disorder.

[0027] In another aspect, the present invention relates to a method for preventing or treating attention deficit hyperactivity disorder in a subject, comprising administering to the subject (S)-viloxazine acetate.

[0028] In another aspect, the present invention relates to the use of (S)-viloxazine acetate for the manufacture of a medicament for preventing or treating attention deficit hyperactivity disorder.

[0029] In another aspect, the present invention relates to the use of (S)-viloxazine acetate for preventing or treating attention deficit hyperactivity disorder. The manufacturing method according to the present invention is economical, and (S)-viloxazine or a salt thereof manufactured according to the manufacturing method of the present invention can be selectively administered to prevent or treat attention deficit hyperactivity disorder (ADHD). Accordingly, the dosage of the drug can be reduced by more than half, and side effects can be reduced. In addition, (S)-viloxazine or a novel salt thereof manufactured according to the manufacturing method of the present invention has excellent norepinephrine reuptake inhibition efficacy and excellent thermal stability. Figure 1 shows the analysis of (R,S)-viloxazine hydrochloride of Comparative Example 1 using chiral HPLC. Figure 2 shows the analysis of (S)-viloxazine hydrochloride of Example 6 by chiral HPLC. Figure 3 shows the analysis of (R)-viloxazine hydrochloride of Comparative Example 2 using chiral HPLC. Figure 4 shows the norepinephrine reuptake inhibition rate (IC) of viloxazine hydrochloride of Example 6 and Comparative Examples 1 and 2. 50 ) was measured. Figure 5 shows the norepinephrine reuptake inhibition rate (IC) of the novel viloxazine salts of Examples 6 to 16. 50 ) was measured. The terminology used in this specification is a term used to appropriately express preferred embodiments of the present invention, and the definitions of these terms should be understood based on the contents throughout this specification. Throughout the specification, when a part is said to "include" a certain component, this does not mean that other components are excluded, but rather that other components can be included, unless specifically stated otherwise. All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as generally understood by a person of ordinary skill in the art in the relevant field of the present invention. In addition, although preferred methods or samples are described in this specification, similar or equivalent ones are also included in the scope of the present invention. The present invention relates, in one aspect, to a method for preparing a compound of formula 1 or a salt thereof from a compound of formula 2, wherein the compound of formula 2 is 2-ethoxyphenol and the compound of formula 1 is (S)-viloxazine free base. [Chemical Formula 1] [Chemical formula 2] Specifically, the present invention is a method for preparing a compound of the following chemical formula 1 or a salt thereof, comprising the step (step A-1) of reacting a compound of the following chemical formula 2 with a compound of the following chemical formula 3 in the presence of a base and a solvent; and A step (step A-2) of reacting the compound of the following chemical formula 4 obtained from the above step A-1 with the compound of the following chemical formula 5 in the presence of a base and a solvent, [Chemical Formula 1] [Chemical formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] The present invention relates to a manufacturing method wherein in the chemical formula 3, X is Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl). In the present invention, steps A-1 and A-2 may be according to the following reaction scheme 1. [Reaction Formula 1] In the present invention, step A-1 is a step of reacting a compound of chemical formula 2 with a compound of chemical formula 3 in the presence of a base and a solvent. The compound of chemical formula 3 is an oxirane derivative of the (R) group, and in chemical formula 3, X can be Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl). The compound of the above chemical formula 3 can be used in an amount of about 0.90 to 2.0 equivalents, about 0.95 to 1.5 equivalents, or about 0.95 to 1.3 equivalents relative to the compound of the chemical formula 2, and preferably about 0.95 to 1.1 equivalents, but is not limited thereto. In the above step A-1, the base may be at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof. The base may be used in an amount of 0.90 to 2.0 equivalents, about 0.95 to 1.5 equivalents, about 0.95 to 1.4 equivalents, or about 0.95 to 1.3 equivalents relative to the compound of chemical formula 2, and preferably about 0.95 to 1.2 equivalents may be used, but is not limited thereto. In the above step A-1, the solvent may be at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, dimethylformamide, enmethylpyrrolinone, dimethylacetamide, acetonitrile, and diethyl ether, and preferably ethyl acetate, methyl-t-butyl ether, or dimethylformamide. The amount of the solvent used is about 6 to 20 times the weight of the compound of chemical formula 2, preferably about 5 to 15 times, and most preferably about 4 to 12 times, but is not limited thereto. The reaction time of the above step A-1 may be about 1 to 24 hours, preferably 3 to 12 hours, and most preferably 4 to 8 hours. The reaction temperature of the above step A-1 is about 25°C to 80°C, preferably about 30 to 70°C, and most preferably about 40 to 60°C. At a temperature of about 80°C or higher, a side reaction of the reaction may occur. In the present invention, step A-2 is a step of reacting the compound of chemical formula 4 obtained from step A-1 with a compound of chemical formula 5 in the presence of a base and a solvent. The compound of chemical formula 5 is ethanolamine-O-sulphate, and (S)-viloxazine free base is synthesized as a result of the reaction in step A-2. In the above step A-2, the base may be at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof, and may be used by appropriately diluting it in purified water. The solvent of the above step A-2 may be at least one selected from the group consisting of purified water, methanol, ethanol, isopropanol, butanol, and hexanol, preferably methanol, ethanol, or isopropanol, and most preferably methanol. The amount of solvent used is 6 to 20 times, preferably 5 to 15 times, and most preferably 4 to 12 times the weight of the compound of chemical formula 5, but is not limited thereto. In addition, for smooth stirring when using the organic solvent, water may be mixed and used at 2 to 15% of the total amount of solvent used. The reaction time of the above step A-2 may be 1 to 12 hours, preferably 2 to 10 hours, and most preferably 3 to 6 hours. The reaction temperature of the above step A-2 is from 40°C or higher to the reflux temperature, and if the temperature is too low, the reaction yield decreases. In another aspect, the present invention is a method for preparing a compound of the following chemical formula 1 or a salt thereof, comprising the steps of (i) reacting a compound of the following chemical formula 2 with a compound of the following chemical formula 6 in the presence of a solvent (step B-1) or (ii) reacting a compound of the following chemical formula 7 in the presence of a base and a solvent (step B-2); and A step (step B-3) of deprotecting the compound of the following chemical formula 8 obtained from the above step B-1 or step B-2, [Chemical Formula 1] [Chemical formula 2] [Chemical formula 6] [Chemical formula 7] [Chemical formula 8] In the above chemical formulas 6 to 8, PG is a protecting group, In the above chemical formula 6, Y is OH, The present invention relates to a manufacturing method wherein in the chemical formula 7, Z is Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl). In the present invention, steps B-1, B-2 and B-3 may be according to the following reaction scheme 2. [Reaction Formula 2] In the present invention, step B-1 is a step of reacting a compound of chemical formula 2 with a compound of chemical formula 6 in the presence of a solvent. The PG (protecting group) of the above chemical formulas 6 to 8 is a protecting group, and may be, for example, tert-butoxycarbonyl (Boc, tert-Butoxycarbonyl), benzylcarbonyl (CBz, Benzyl carbonyl), 9-fluorenylmethoxycarbonyl (Fmoc, 9-Fluorenylmethoxycarbonyl), or benzyl (Bn, Benzyl). Meanwhile, Y of the above chemical formula 6 is OH. In the above step B-1, the solvent may be at least one selected from the group consisting of tetrahydrofuran, benzene, dichloromethane, toluene, xylene, acetonitrile, and ethyl acetate. In addition, in step B-1, alcohol (e.g., 2-ethoxyphenol) and triphenylphosphine or tributylphosphine, etc. can be used, and these are combined to form a phosphonium intermediate. The amount used is 0.8 to 2.0 equivalents relative to chemical formula 2, preferably 1.0 to 1.8 equivalents, and most preferably 1.2 to 1.5 equivalents. In addition, DEAD (diethyl azodicarboxylate), DIAD (diisopropyl azodicarboxylate), and DBAD (dibenzyl azodicarboxylate) can be used as oxidizing agents in step B-1 to remove hydrogen from alcohol. The amount used is 0.8 to 2.0 equivalents relative to chemical formula 2, preferably 1.0 to 1.8 equivalents, and most preferably 1.2 to 1.5 equivalents. In the present invention, step B-2 is a step of reacting a compound of chemical formula 2 with a compound of chemical formula 7 in the presence of a base and a solvent. Z in chemical formula 7 may be Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl). In the above step B-2, the base may be at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof, and may be used by appropriately diluting it in purified water. In the above step B-2, the solvent may be at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, dimethylformamide, enmethylpyrrolinone, dimethylacetamide, acetonitrile, and diethyl ether, and preferably ethyl acetate, methyl-t-butyl ether, acetonitrile, or dimethylformamide. The amount of the solvent used is about 6 to 20 times the weight of the compound of chemical formula 2, preferably about 5 to 15 times, and most preferably about 4 to 12 times, but is not limited thereto. The reaction time of steps B-1 and B-2 may be 1 to 12 hours, preferably 2 to 10 hours, and most preferably 3 to 6 hours. In the present invention, step B-3 is a step of deprotecting the compound of chemical formula 8 obtained from steps B-1 and B-2. As a result of the reaction in step B-3, (S)-viloxazine free base is synthesized. In the above B-3 step, deprotection can be appropriately carried out considering the reaction conditions for removing the protecting group and the effect on other functional groups other than the protecting group to be removed. For example, the tert-butoxycarbonyl (Boc, tert-Butoxycarbonyl) protecting group can be removed using a reducing agent such as TFA (Trifluoroacetic Acid), a concentrated acid (e.g., HCl), or lithium aluminum hydride (LAH). The benzylcarbonyl (CBz, Benzyl carbonyl) protecting group can be removed by hydrogenolysis using a catalytic amount of palladium (Pd / C). The 9-fluorenylmethoxycarbonyl (Fmoc, 9-Fluorenylmethoxycarbonyl) protecting group can be removed using a solution of piperidine mixed with DMF. Benzyl (Bn, Benzyl) can be removed by hydrochloric acid or hydrogenation. In the present invention, a step (step C) of reacting the compound of formula 1 manufactured according to the present invention with an acid in a solvent to form a salt of the compound of formula 1 may be additionally included. The above step C may be according to the following reaction scheme 3. [Reaction Formula 3] In the above step C, the solvent may be at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, n-heptane, and diethyl ether, and preferably ethyl acetate and methyl-t-butyl ether. The amount of the solvent used is 6 to 20 times, preferably 5 to 15 times, and most preferably 4 to 12 times the weight of the compound of formula 2, but is not limited thereto. In the above step C, the acid may be a pharmaceutically usable inorganic acid or organic acid. For example, the acid may be at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. In one embodiment, the acid in step C may be hydrochloric acid or acetic acid. The salt of the compound of formula 1 prepared according to the above step C is a novel (S)-viloxazine salt. In the present invention, the salt of the compound of formula 1 obtained is, for example, (S)-viloxazine hydrochloride, (S)-viloxazine hydrobromide, (S)-viloxazine sulfate, (S)-viloxazine phosphate, (S)-viloxazine nitrate, (S)-viloxazine acetate, (S)-viloxazine glycolate, (S)-viloxazine lactate, (S)-viloxazine pyruvate, (S)-viloxazine malonate, (S)-viloxazine succinate, (S)-viloxazine glutarate, (S)-viloxazine fumarate, (S)-viloxazine malate, (S)-viloxazine mandelate, (S)-viloxazine tartrate, (S)-viloxazine citrate, (S)-viloxazine ascorbate, (S)-viloxazine palmitate, (S)-viloxazine maleate, It may be any one selected from the group consisting of (S)-viloxazine benzoate, (S)-viloxazine hydroxybenzoate, (S)-viloxazine phenylacetate, (S)-viloxazine cinnamate, (S)-viloxazine salicylate, (S)-viloxazine methanesulfonate, (S)-viloxazine ethanesulfonate, (S)-viloxazine benzenesulfonate and (S)-viloxazine toluenesulfonate. In one embodiment, the salt of the compound of formula 1 obtained can be (S)-viloxazine hydrochloride or (S)-viloxazine acetate. The reaction time of the above step C can be 1 to 12 hours, preferably 2 to 10 hours, and most preferably 3 to 6 hours. The reaction temperature of the above step C is about -10°C to 60°C, and if the temperature is too high, racemization occurs and the reaction yield decreases. In another aspect, the present invention relates to a pharmaceutical composition for treating or preventing attention deficit hyperactivity disorder (ADHD), comprising a compound of formula 1 or a salt thereof prepared according to the above preparation method. A pharmaceutical composition comprising the compound of the above chemical formula 1 or a salt thereof has an excellent effect of selectively inhibiting norepinephrine reuptake. In the present invention, “treatment” means any act of improving or beneficially changing the symptoms of a disease by administering the composition according to the present invention, “prevention” means any act of suppressing or delaying a disease by administering the composition according to the present invention, and “improvement” means any act of improving the bad state of a disease by administering or ingesting the composition of the present invention to a subject. The disease targeted for “treatment,” “prevention,” or “improvement” of the present invention may be attention deficit hyperactivity disorder (ADHD). For the treatment of the disease or condition described above, the pharmaceutical composition described herein can be administered as follows. Oral administration The compounds of the present invention may be administered orally. Orally is a concept that includes swallowing. By oral administration, the compounds of the present invention may enter the gastrointestinal tract or may be absorbed directly into the bloodstream from the mouth, for example, by buccal or sublingual administration. Compositions suitable for oral administration may be in the form of solids, liquids, gels, or powders, and may have dosage forms such as tablets, lozenges, capsules, granules, or powders. The composition for oral administration may optionally be enteric coated, and may exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern. Liquid formulations may include solutions, syrups and suspensions, and these liquid compositions may be contained in soft or hard capsules. These formulations may include pharmaceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose, or oils. The formulations may also include one or more emulsifying and / or suspending agents. In tablet formulations, the active ingredient drug may be present in an amount of from about 0.05% to about 95% by weight of the total weight of the tablet, more typically from about 2% to about 50% by weight of the formulation. Additionally, the tablet may contain a disintegrant, which comprises from about 0.5% to about 35% by weight, more typically from about 2% to about 25% by weight of the formulation. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof. Suitable lubricants included for manufacturing the tablets may be present in an amount of from about 0.1 wt % to about 5 wt %, and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. Binders for manufacturing tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, and suitable diluents for manufacturing tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, and microcrystalline cellulose. Solubilizing agents that may optionally be included in the tablet may be used in an amount of about 0.1 wt% to about 3 wt% based on the total weight of the tablet, and include, for example, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR. TM (Nikkol), Oleyl Ester, Gelucire TM), caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, solutol HS TM The following may be used in the pharmaceutical composition according to the present invention, but are not limited thereto. Parenteral Administration The compounds of the present invention can be administered directly into the bloodstream, muscle, or viscera. Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like. Suitable devices for parenteral administration include injectors, including needle and needleless syringes, and infusion methods. Compositions for parenteral administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or a sustained release pattern. Most parenteral dosage forms are liquid compositions, which are aqueous solutions containing the active ingredient, salt, buffer, isotonic agent, etc. according to the present invention. Parenteral formulations may also be prepared in a dry form (e.g., lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle, such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions. Topical Administration The compound of the present invention can be administered topically, through the skin or transdermally. Formulations for the topical administration can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for the topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by, but is not limited to, electroporation, iontophoresis, phonophoresis, and the like. Compositions for topical administration may be formulations having an immediate or modified release pattern, wherein the modified release pattern may be a delayed or a sustained release pattern. The pharmaceutical composition of the present invention can be administered in a therapeutically effective amount of the effective ingredient. The therapeutically effective amount refers to a drug dosage that exhibits an effective attention deficit hyperactivity disorder (ADHD) prevention or treatment effect. An appropriate total daily usage amount can be determined by a treating physician within the scope of sound medical judgment. A specific therapeutically effective amount for a specific patient may be applied differently depending on various factors such as the type and degree of the response to be achieved, the type and amount of drugs to be co-administered, the specific composition including whether other agents are used depending on the case, the patient's age, weight, general health condition, sex, and diet, administration time, administration route, treatment period, and similar factors well known in the medical field. In another aspect, the present invention relates to a pharmaceutical composition for treating or preventing attention deficit hyperactivity disorder (ADHD) comprising (S)-viloxazine acetate. In another aspect, the present invention relates to a method for preventing or treating attention deficit hyperactivity disorder (ADHD) in a subject, comprising a step of administering to the subject a compound of formula 1 or a salt thereof prepared according to the above preparation method. In the present invention, the term "subject" is used synonymously with "individual", and the subject may be a mammal, for example, a human, a mouse, a cow, a horse, a pig, a dog, a sheep, a goat or a cat. Any description that overlaps with the pharmaceutical composition of the present invention described above is omitted. In another aspect, the present invention relates to a method for preventing or treating attention deficit hyperactivity disorder in a subject, comprising administering to the subject (S)-viloxazine acetate. In another aspect, the present invention relates to the use of the compound of formula 1 or a salt thereof prepared according to the above preparation method for preparing a medicament for preventing or treating attention deficit hyperactivity disorder (ADHD) in a subject. Any description that overlaps with the pharmaceutical composition of the present invention described above is omitted. In another aspect, the present invention relates to the use of (S)-viloxazine acetate for the manufacture of a medicament for preventing or treating attention deficit hyperactivity disorder. In another aspect, the present invention relates to the use of the compound of formula 1 or a salt thereof prepared according to the above preparation method for preventing or treating attention deficit hyperactivity disorder (ADHD) in a subject. Any description that overlaps with the pharmaceutical composition of the present invention described above is omitted. In another aspect, the present invention relates to the use of (S)-viloxazine acetate for preventing or treating attention deficit hyperactivity disorder. All matters mentioned in the compositions, treatment methods and uses of the present invention apply equally unless they are contradictory to each other. Hereinafter, in order to help understand the present invention, examples and the like will be described in detail. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the field to which the present invention belongs. Example Example 1. Synthesis of (S)-2-((2-ethoxyphenoxy)methyl)oxirane (Step A-1) 2-Ethoxyphenol (13.8 g, purchased from Aldrich) was dissolved in dimethylformamide (120 ml, purchased from Daejung Chemical & Metal), (R)-2-(chloromethyl)oxirane (9.25 g, purchased from Aldrich) and triethylamine (10.1 g) were slowly added, and the mixture was stirred at 30°C for 6 hours. After completion of the reaction, the mixture was purified by silica gel chromatography using a mixed solvent of ethyl acetate:n-hex (4:10) as a developing solvent, and pure (S)-2-((2-ethoxyphenoxy)methyl)oxirane was obtained as a colorless liquid (15.53 g, yield 80%). 1H NMR δ (DMSO-d6) 6.94 (m, 4H), 4.07 (m, 3H), 3.03 (m, 1H), 2.45 (m, 2H), 1.32 (t, 3H). Example 2. Synthesis of (S)-2-((2-ethoxyphenoxy)methyl)oxirane (Step A-1) 2-Ethoxyphenol (13.8 g, purchased from Aldrich) was dissolved in tetrahydrofuran (120 ml, purchased from Daejung Chemical & Metals), (R)-2-(chloromethyl)oxirane (9.25 g, purchased from Aldrich) and triethylamine (10.1 g) were slowly added, and the mixture was stirred at 50°C for 6 hours. After completion of the reaction, the mixture was purified by silica gel chromatography using a mixed solvent of ethyl acetate:n-hex (4:10) as a developing solvent, and pure (S)-2-((2-ethoxyphenoxy)methyl)oxirane was obtained as a colorless liquid (12.23 g, yield 64%). 1H NMR δ (DMSO-d6) 6.94 (m, 4H), 4.07 (m, 3H), 3.03 (m, 1H), 2.45 (m, 2H), 1.32 (t, 3H). Example 3. Synthesis of (S)-Viloxazine Free Base (Step A-2) Ethanolamine-O-sulfate (17.5 g, purchased from EOS) was added to a mixture of (S)-2-((2-ethoxyphenoxy)methyl)oxirane (4 g), 16 M NaOH solution (9.5 g), and methanol (6 ml) of Example 2, and stirred at 40°C for 2 hours. Solid NaOH (7.5 g) and toluene (26 ml) were added to the mixture, and the reaction was performed at 65°C for 7 hours. 45 ml of water and 15 ml of toluene were added to the cooled mixture, and the organic layer was separated, toluene was extracted with 2 N HCl, and the acidic extract was alkalized to pH 11 with 4 M NaOH and extracted again with toluene. The toluene layer was washed with an aqueous sodium chloride (NaCl) solution, dried, and purified by silica gel chromatography using a mixed solvent of ethyl acetate:ethanol (4:0.1) as a developing solvent, to obtain pure (S)-viloxazine (3.5 g, 19.8 mmol, 66% yield). [α]D 20 -1.47 (c=1, MeOH), 1H NMR δ (DMSO-d6) 6.94 (m, 4H), 3.97 (m, 7H), 3.13 (m, 4H), 1.32 (t, 3H). Example 4. Synthesis of (S)-Biloxazine Free Base (Step A-2) Ethanolamine-O-sulfate (17.5 g) was added to a mixture of (S)-2-((2-ethoxyphenoxy)methyl)oxirane (4 g, 29.9 mmol), 8 M NaOH solution (19 g), and methanol (6 ml) of Example 2, and stirred at 40°C for 2 hours. Solid NaOH (7.5 g) and toluene (26 ml) were added to the mixture, and the reaction was performed at 65°C for 7 hours. To the cooled mixture, 45 ml of water and 15 ml of toluene were added, and the organic layer was separated, toluene was extracted with 2 N HCl, and the acidic extract was alkalized to pH 11 with 4 M NaOH and extracted again with toluene. The toluene layer was washed with an aqueous sodium chloride (NaCl) solution, dried, and purified by silica gel chromatography using a mixed solvent of ethyl acetate:ethanol (4:0.1) as a developing solvent, to obtain pure (S)-viloxazine free base (3.4 g, 60% yield). [α]D 20 -1.47 (c=1, MeOH), 1H NMR δ (DMSO-d6) 6.94 (m, 4H), 3.97 (m, 7H), 3.13 (m, 4H), 1.32 (t, 3H). Example 5-1. Synthesis of (S)-Biloxazine Free Base (Step B-1 and Step B-3) 10.0 g (46.03 mmol) of tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate, 11.45 g (82.85 mmol) of 2-ethoxyphenol, 18.11 g (69.04 mmol) of triphenylphosphine (purchased from Daejung Chemicals), and 100 ml (10V) of ethyl acetate were placed in a reactor and cooled to 0°C. Next, 12.10 g (59.83 mmol) of diisopropyl azodicarboxylate (purchased from Aldrich) was slowly added dropwise. The reaction was carried out by raising the temperature from 25°C to 70°C. After completion of the reaction, 100 ml (10V) of water was added, the water layer was removed, and 20 g of MgSO₄ was added to the organic layer and filtered. To the filtered solution, HCl dissolved in isopropyl alcohol (IPA) was added and reacted at room temperature for 24 hours. After completion of the reaction, the solution was neutralized with ammonia water, and the resulting solid was filtered, washed with isopropyl alcohol (IPA), concentrated under reduced pressure in a vacuo, and then purified by silica gel chromatography using a mixed solvent of ethyl acetate:ethanol (4:0.1) as a developing solvent, to obtain pure (S)-viloxazine free base (7.64 g, yield 70%). [α]D 20 -1.47 (c=1, MeOH), 1H NMR δ (DMSO-d6) 6.94 (m, 4H), 3.97 (m, 7H), 3.13 (m, 4H), 1.32 (t, 3H). Example 5-2. Synthesis of (S)-Biloxazine Free Base (Step B-2 and Step B-3) 28.0 g (100 mmol) of tert-butyl (R)-2-(bromomethyl)morpholine-4-carboxylate, 13.81 g (100 mmol) of 2-ethoxyphenol, 13.12 g (100 mmol) of potassium carbonate (purchased from Daejung Chemicals) and 280 ml (10V) of acetonitrile were placed in a reactor, heated to 60°C and stirred for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, 280 ml (10V) of water and 280 ml (10V) of ethyl acetate were added, the water layer was removed, 30 g of MgSO₄ was added to the organic layer and filtered. HCl dissolved in isopropyl alcohol (IPA) was added to the filtered solution and the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the mixture was neutralized with ammonia water, filtered, washed with isopropyl alcohol (IPA), concentrated under reduced pressure in a vacuum, and purified by silica gel chromatography using a mixed solvent of ethyl acetate:ethanol (4:0.1) as a developing solvent, to obtain pure (S)-viloxazine free base (18.6 g, yield 80%). [α]D 20 -1.47 (c=1, MeOH), 1H NMR δ (DMSO-d6) 6.94 (m, 4H), 3.97 (m, 7H), 3.13 (m, 4H), 1.32 (t, 3H). Example 6. Synthesis of (S)-Viloxazine hydrochloride (Step C) In Example 5-2, 5 g of (S)-viloxazine free base obtained was added to 50 ml of ethyl acetate, and then 7 g (1 equivalent) of 3 M HCl in IPA was slowly added dropwise. After stirring at room temperature for 1 to 2 hours, the mixture was filtered under reduced pressure and washed with 10 ml of ethyl acetate. After drying in vacuum at 50°C, (S)-viloxazine hydrochloride was obtained as a white solid (yield 83%). Below, using the same method, viloxazine salts were obtained by changing the type of acid (Examples 7 to 16 in Table 1). Comparative Example 1. Synthesis of (R,S)-Viloxazine hydrochloride In Example 1, (R,S)-viloxazine hydrochloride was synthesized in the same manner using (R,S)-2-(chloromethyl)oxirane instead of (R)-2-(chloromethyl)oxirane. Comparative Example 2. Synthesis of (R)-Viloxazine hydrochloride In Example 1, (R)-viloxazine hydrochloride was synthesized in the same manner using (S)-2-(chloromethyl)oxirane instead of (R)-2-(chloromethyl)oxirane. The synthesized compounds are shown in Table 1. [Table 1] Experimental Example 1. High-Performance Liquid Chromatography (HPLC) Analysis The viloxazine hydrochloride of Example 6 and Comparative Examples 1 and 2 was subjected to HPLC analysis under the following conditions. As a result, it was confirmed that the (S)-viloxazine hydrochloride of Example 6 was obtained with high purity. 1) Preparation of test solution Weigh accurately 50 mg of the sample, place it in a 50 mL volumetric flask, add ethanol to the indicated volume, dissolve it using ultrasonication for 10 minutes, and use this as the test solution. 2) HPLC conditions - Column: CHIRALPAK OD-H column (4.6 mm ⅹ 250 mm, 5 μm) - Mobile phase: 2-propanol, heptane, diethylamine, and trifluoroacetic acid mixture (150:850:1.5:2.0, v / v) - Flow rate: 1.0 mL / min - Detector: UV spectrophotometer (230 nm) - Column temperature: 30℃ - Injection volume: 10 μL - Diluent: Ethanol - Analysis time: 35 minutes 3) Calculation Experimental Example 2: Norepinephrine reuptake inhibition rate (IC 50 ) measurement Norepinephrine reuptake ability in cell lines expressing norepinephrine receptors was determined using a kit (Neurotransmitter Transporter Uptake Assay Kit, Molecular Devices) consisting of a fluorescent substance mimicking an amine neurotransmitter and a masking dye. First, HEK-293T cells stably expressing norepinephrine receptors were seeded at 6 x 10 in 100 μl of cell culture medium per well in a 96-well Black / Clear Bottom Plate. 4 The cells were seeded so that they contained the target cells. After culturing for 20 hours in a 37°C, 5% CO2 incubator to ensure proper attachment and stabilization on the plate, the cell culture medium was removed, and 100 μl of HBSS+0.1% BSA with 20 mM HEPES aqueous solution containing the drug at the desired concentration was dispensed into each well. For the control group, 100 μl of drug-free buffer solution (HBSS+0.1% BSA with 20 mM HEPES aqueous solution) was dispensed into each well. Incubation was performed for 30 minutes in a 37°C, 5% CO2 incubator to allow the drug to sufficiently react to the receptor. Afterwards, fluorescence plate reader (SpectraMax ® ) was used to measure fluorescence for a total of 30 minutes in Kinetic reading mode at Ex / Em=440 nm / 520 nm. The measured fluorescence intensity values ​​were converted to the value of "absorption inhibition rate (%)" using the following formula, and then a dose-response curve was drawn using 4-parameter (Log) logistic regression to obtain the IC of each drug. 50 The values ​​were calculated and compared (Figures 4 and 5). It was confirmed that the novel (S)-viloxazine salts of Examples 6 to 16 exhibited superior inhibitory efficacy compared to (R,S)-viloxazine hydrochloride of Comparative Example 1 or (R)-viloxazine hydrochloride of Comparative Example 2. Experimental Example 3: Thermal Stability Test Each of 8 mg of the viloxazine hydrochloride of Comparative Examples 1 and 2 and the new (S)-viloxazine salts of Examples 6 to 16 was placed in an opaque glass vial and stored at 40±2℃, 75±5% RH. After 8 weeks, each sample was taken out, the content was analyzed by high-performance liquid chromatography (HPLC), and the discoloration was checked with the naked eye (Table 2). [Table 2] While the (R,S)-viloxazine hydrochloride of Comparative Example 1 and the (R)-viloxazine hydrochloride of Comparative Example 2 turned beige, the new (S)-viloxazine salts of Examples 6 to 16 maintained their colors. In addition, the change in the content of the new (S)-viloxazine salts of Examples 6 to 16 was minimal. Therefore, it was confirmed that the new (S)-viloxazine salts of Examples 6 to 16 had superior stability compared to the (R,S)-viloxazine hydrochloride of Comparative Example 1 and the (R)-viloxazine hydrochloride of Comparative Example 2.

Claims

1. A method for producing a compound of the following chemical formula 1 or a salt thereof, A step (step A-1) of reacting a compound of the following chemical formula 2 with a compound of the following chemical formula 3 in the presence of a base and a solvent; and A step (step A-2) of reacting the compound of the following chemical formula 4 obtained from the above step A-1 with the compound of the following chemical formula 5 in the presence of a base and a solvent, [Chemical Formula 1] [Chemical formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] A manufacturing method wherein in the chemical formula 3 above, X is Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl).

2. A method for producing a compound of the following chemical formula 1 or a salt thereof, A step (i) of reacting a compound of the following chemical formula 2 with a compound of the following chemical formula 6 in the presence of a solvent (step B-1) or (ii) of reacting a compound of the following chemical formula 7 in the presence of a base and a solvent (step B-2); and A step (step B-3) of deprotecting the compound of the following chemical formula 8 obtained from the above step B-1 or step B-2, [Chemical Formula 1] [Chemical formula 2] [Chemical formula 6] [Chemical formula 7] [Chemical formula 8] In the above chemical formulas 6 to 8, PG is a protecting group, In the above chemical formula 6, Y is OH, A manufacturing method wherein in the chemical formula 7 above, Z is Cl, Br, I, OMs(O-methane sulfonyl) or OTs(O-Tosyl).

3. In paragraph 1, A manufacturing method wherein in the above step A-1, the compound of formula 3 is used in an amount of 0.90 to 2.0 equivalents relative to the compound of formula 2.

4. In paragraph 1, A manufacturing method wherein in the above step A-1, the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof.

5. In paragraph 1, A manufacturing method wherein in the above step A-1, the base is used in an amount of 0.9 to 2.0 equivalents relative to the compound of the above chemical formula 2.

6. In paragraph 1, A manufacturing method wherein in the above step A-1, the solvent is at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, dimethylformamide, enmethylpyrrolinone, dimethylacetamide, acetonitrile, and diethyl ether.

7. In paragraph 1, A manufacturing method wherein in the above step A-1, the solvent is used in an amount of 6 to 20 times the weight of the compound of the above chemical formula 2.

8. In paragraph 1, A manufacturing method wherein in the above step A-2, the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof.

9. In paragraph 1, A manufacturing method in which in the above step A-2, the solvent is at least one selected from the group consisting of purified water, methanol, ethanol, isopropanol, butanol, and hexanol.

10. In paragraph 1, A manufacturing method wherein in the above step A-2, the solvent is used in an amount of 6 to 20 times the weight of the compound of the above chemical formula 5.

11. In paragraph 2, A manufacturing method wherein the protecting group in the above steps B-1 and B-2 is tert-butoxycarbonyl (Boc, tert-Butoxycarbonyl), benzylcarbonyl (CBz, Benzyl carbonyl), 9-fluorenylmethoxycarbonyl (Fmoc, 9-Fluorenylmethoxycarbonyl) or benzyl (Bn, Benzyl).

12. In paragraph 2, A manufacturing method wherein in the above step B-1, the solvent is at least one selected from the group consisting of tetrahydrofuran, benzene, dichloromethane, toluene, xylene, acetonitrile, and ethyl acetate.

13. In paragraph 2, A manufacturing method wherein in the above step B-2, the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, diethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium acetate, potassium acetate, and mixtures thereof.

14. In paragraph 2, A manufacturing method wherein in the above step B-2, the solvent is at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, dimethylformamide, enmethylpyrrolinone, dimethylacetamide, acetonitrile, and diethyl ether.

15. In paragraph 1 or 2, A manufacturing method further comprising a step of reacting the manufactured compound of chemical formula 1 with an acid in a solvent to form a salt of the compound of chemical formula 1.

16. In paragraph 15, A manufacturing method wherein the solvent is at least one selected from the group consisting of ethyl acetate, dichloromethane, toluene, methyl-t-butyl ether, acetone, tetrahydrofuran, n-heptane, and diethyl ether.

17. In paragraph 15, A manufacturing method wherein the acid is at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

18. In paragraph 15, A manufacturing method wherein the above acid is hydrochloric acid or acetic acid.

19. In Article 15, The salt of the compound of formula 1 obtained is (S)-viloxazine hydrochloride, (S)-viloxazine hydrobromide, (S)-viloxazine sulfate, (S)-viloxazine phosphate, (S)-viloxazine nitrate, (S)-viloxazine acetate, (S)-viloxazine glycolate, (S)-viloxazine lactate, (S)-viloxazine pyruvate, (S)-viloxazine malonate, (S)-viloxazine succinate, (S)-viloxazine glutarate, (S)-viloxazine fumarate, (S)-viloxazine malate, (S)-viloxazine mandelate, (S)-viloxazine tartrate, (S)-viloxazine citrate, (S)-viloxazine ascorbate, (S)-viloxazine palmitate, (S)-viloxazine maleate, (S)-viloxazine A method for producing any one selected from the group consisting of (S)-viloxazine benzoate, (S)-viloxazine hydroxybenzoate, (S)-viloxazine phenylacetate, (S)-viloxazine cinnamate, (S)-viloxazine salicylate, (S)-viloxazine methanesulfonate, (S)-viloxazine ethanesulfonate, (S)-viloxazine benzenesulfonate and (S)-viloxazine toluenesulfonate.

20. In paragraph 15, A method for producing a salt of the compound of formula 1 obtained is (S)-viloxazine hydrochloride or (S)-viloxazine acetate.

21. A pharmaceutical composition for treating or preventing attention deficit hyperactivity disorder (ADHD), comprising a compound of formula 1 or a salt thereof prepared according to claim 1, claim 2 or claim 15.

22. In paragraph 21, The above pharmaceutical composition is a pharmaceutical composition to be administered by oral administration, parenteral administration or topical administration route. 23.(S)-A pharmaceutical composition for treating or preventing attention deficit hyperactivity disorder (ADHD) comprising viloxazine acetate.

24. A method for preventing or treating attention deficit hyperactivity disorder in a subject, comprising administering to the subject a compound of formula 1 or a salt thereof prepared according to claim 1, claim 2 or claim 15.

25. Use of a compound of formula 1 or a salt thereof prepared according to claim 1, 2 or 15 for preparing a medicament for preventing or treating attention deficit hyperactivity disorder.

26. Use of a compound of formula 1 or a salt thereof prepared according to claim 1, 2 or 15 for preventing or treating attention deficit hyperactivity disorder. 27.(S)-A method for preventing or treating attention deficit hyperactivity disorder in a subject, comprising administering to the subject viloxazine acetate.

28. Use of (S)-viloxazine acetate for the manufacture of a medicament for preventing or treating attention deficit hyperactivity disorder.

29. Use of (S)-viloxazine acetate for preventing or treating attention deficit hyperactivity disorder.

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