WO2021025442A1 - Novel method for producing epinastine - Google Patents

Abstract

The present invention pertains to a novel production method for synthesizing epinastine, which is an antihistamine medicine. The novel production method for synthesizing epinastine according to the present invention is a safe synthesis method having fewer synthesis steps compared to conventional methods for producing epinastine. Thus, it is expected that the production method can be used to inexpensively synthesize, and bring to market, epinastine, which is an antihistamine medicine.

Description

New manufacturing method of epinastine

The present invention relates to a novel method for synthesizing epinastine, an anti-histamine drug.

The present invention was made by the project number 201800000000361 under the support of Ansan City, Korea, and the research management institution for the project is "Korea Institute of Industrial Technology", the name of the research project is "Ansan City Small Small Enterprise Support Promotion Project", and the name of the research project is "Hydrochloric Acid Epina Development of a new synthesis method and mass production of Steen", the research period is "2016.10.01.-2018.12.31".

The present invention was made by the project number 201700000002998 under the support of the Ministry of Education of the Republic of Korea, and the research management institution of the project is "Korea Research Foundation", the name of the research project is "Personal Basic Research (Ministry of Education)", and the name of the research project is "Vosomal Stress Regulator Research", the study period is "2017.11.01.-2018.10.31".

This patent application claims priority to Korean Patent Application No. 10-2019-0095561 filed with the Korean Intellectual Property Office on August 06, 2019, and the disclosures of the patent application are incorporated herein by reference.

As a result of environmental pollution, it is a type of antihistamine drug that is a treatment for patients with allergic diseases, which is increasing every year. It is an improved medicine. In Korea, sales are increasing every year and export demand is also very high. Known synthesis methods have a disadvantage in that the synthesis step is long and the use of explosive and highly toxic reagents is a method of improving this and synthesizing epinastine hydrochloride through a short synthesis step using a reagent with low toxicity.

For the known synthesis method of epinastine hydrochloride, the U.S. patent (U.S. Patent No. 4,313,931), palladium/carbon (Pd/C), which uses Phosgene and lithium aluminum hydride (LiAlH ₄ ) as a key reaction There is a European patent (European Patent No. 0496306A1) that uses a reagent and a hydrazine reagent as a key reaction, and recently, an amine group is introduced with cyclopropylamine and sodium borohydride (NaBH ₄ ). There are Korean patents (Korean Patent Registration No. 10-1576620) that introduce a method to reduce immigration groups using reagents. In addition, the Korean patent (Korean Patent No. 10-1859516) describes a method for preparing 2-benzylaniline, a synthetic starting material commonly used in known synthesis methods.

In the case of (US Patent No. 4,313,931), a very toxic material such as Phosgene is used as shown in [Reaction Formula 1], and a very explosive material such as lithium aluminum hydride (LiAlH ₄ ) is used. , The process is very disadvantageous.

[Scheme 1]

In the case of (European Patent Registration No. 0496306A1), a hydrogen reaction and a toxic hydrazine reagent at 140°C and 50 atm using a palladium/carbon (Pd/C) reagent are used as in [Reaction Scheme 2].

[Scheme 2]

In the case of (Korea Patent Registration No. 10-1576620), as shown in [Reaction Scheme 3], cyclopropylamine, which is very inexpensive and non-toxic, is used, and sodium borohydride (NaBH ₄ ), an inexpensive reducing agent, is used. It has the advantage of not using highly toxic reagents, but it has a disadvantage that the synthesis step is longer than that of the present technology, and bromate, which requires special equipment, is passed as an intermediate.

[Scheme 3]

The present invention was conceived to solve the above problems, and the present inventors studied to find a synthesis method for inexpensively synthesizing and supplying epinastine, a second-generation antihistamine drug for dealing with allergic patients, Epina A new method for synthesizing Stine hydrochloride was invented, and the present invention was completed based on this.

Accordingly, an object of the present invention is to provide a novel method for synthesizing epinastine.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

To achieve the above purpose,

The present invention provides a first step of reacting a compound of formula 1 with cyanamide to obtain a compound of formula 2; And it provides a method for producing epinastine comprising a second step of reducing the compound of formula (2) to obtain a compound of formula (3).

[Formula 1]

[Formula 2]

[Formula 3]

In Formula 3, A is absent or refers to a pharmaceutically acceptable acid addition salt.

In one embodiment of the present invention, the first step of obtaining the compound of Formula 2 by reacting the compound of Formula 1 of the present invention with cyanamide may be performed in a solvent to which a base is added.

Here, "base" refers to the property of a substance that emits hydroxide ions or absorbs hydrogen ions in an aqueous solution. Commonly referred to as alkali, as substances corresponding to acids, they neutralize each other to form salt and water. Although not limited thereto, strong bases include sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca(OH) ₂ ), and weak bases such as aqueous ammonia (NH ₄ OH), magnesium hydroxide (Mg(OH) ₂ ) There is this.

In the present invention, the solvent in the first step reaction is not limited thereto, but a polar aprotic solvent, more specifically, dimethylformamide, tetrahydrofuran, acetonitrile, dichloroethane, dimethyl sulfur monoxide, dichloro It may be any one of methane, ethyl acetate, acetone, dimethylacetamide and N-methylpyrrolidone.

In one embodiment of the present invention,

The second step of preparing the compound of Formula 2 to the compound of Formula 3 of the present invention may be carried out in a solvent phase in the presence of a hydrogen gas, an acid and/or a catalyst.

Here, "acid" refers to a substance that ionizes and releases hydrogen ions when dissolved in water. Substances that correspond to bases cause a neutralization reaction to form salt and water. In addition, hydrogen gas is generated by reacting with metals having a higher ionization tendency than hydrogen. Typical acids include hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ) as strong acids, and acetic acid (CH ₃ COOH) and carbonic acid (H ₂ CO ₃ ) as weak acids.

Here, "catalyst" refers to a substance that changes the reaction rate without being consumed in the reaction process. Even a small amount can affect the reaction rate, and in general, the reaction proceeds faster if there is a catalyst because, in the presence of the catalyst, less activation energy is required. Catalysts include noble metal catalysts (Pt, Pb, Ir, Rh, etc.), metal catalysts (Fe, Ni, Co), metal oxide catalysts (MgO, TiO _2, etc.), complex oxide catalysts (Fe ₂ O ₃ -MoO ₃ ), solid Acid catalysts (zeolite, heteropolyacid), inorganic acid catalysts (HF, H ₂ SO ₄ , H ₃ PO _4, etc.), ion exchange resin catalysts, and the like. In addition, the catalyst may be supported on carbon.

Although not limited thereto, cyanamide in the first step is 2 to 5 equivalents, such as 2 to 3 equivalents, 2 to 4 equivalents, 2 to 5 equivalents, 3 to 5 equivalents, based on 1 equivalent of the compound of Formula 1, Or any interval within the above range, or 2, 3, 4, 5 equivalents may be used.

In one embodiment of the present invention, the reaction temperature in step 1 is not limited thereto, but is room temperature to 200°C, such as room temperature to 50°C, room temperature to 90°C, room temperature to 120°C, room temperature to 160°C, room temperature to 200°C. ℃, 50 ℃ to 90 ℃, 50 ℃ to 120 ℃, 50 ℃ to 160 ℃, 50 ℃ to 200 ℃, 90 ℃ to 120 ℃, 90 ℃ to 160 ℃, 90 ℃ to 200 ℃, 120 ℃ to 160 ℃, It may be an arbitrary section within the above range, such as 120°C to 200°C, 160°C to 200°C, or any temperature, such as 90°C, 120°C, 160°C, 200°C.

In the present invention, the temperature control method is not limited thereto, but any one of heating and microwave may be used.

In one embodiment of the present invention, the reaction time of step 1 is not limited thereto, but 20 minutes to 24 hours, such as 20 minutes to 50 minutes, 20 minutes to 8 hours, 20 minutes to 12 hours, 20 minutes to 18 hours. Time, 20 minutes to 24 hours, 30 minutes to 50 minutes, 30 minutes to 8 hours, 30 minutes to 12 hours, 30 minutes to 18 hours, 30 minutes to 24 hours, 50 minutes to 8 hours, 50 minutes to 8 hours, 50 minutes to 12 hours, 50 minutes to 18 hours, 50 minutes to 24 hours, 8 hours to 12 hours, 8 hours to 18 hours, 8 hours to 24 hours, 12 hours to 18 hours, 12 hours to 24 hours, 18 hours To 24 hours, or any interval within the above range, or any time, such as 20 minutes, 30 minutes, 50 minutes, 8 hours, 12 hours, 18 hours, 24 hours.

In the present invention, the base in the first step reaction is one selected from the group consisting of diisopropylethylamine, potassium carbonate, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydroxide, and sodium iodide. It can be more than that.

In one embodiment of the present invention, the equivalent of the base in the first step reaction is not limited thereto, but 1 to 3, such as 1 to 1.5, 1 to 2, 2 to 3, based on 1 equivalent of the compound of Formula 1 Any section within the above range, such as 1.5 to 2, 1.5 to 3, 2 to 3, etc., or 1, 1.5, 2, 3 may be.

In the present invention, the acid in the second step reaction may be any one selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid and sulfuric acid.

In one embodiment of the present invention, A in Formula 3 may be absent or may be any one of hydrochloride, bromate, nitrate, acetate and sulfate. It is preferably a hydrochloride salt, but is not limited thereto.

"Acid addition salt" is formed with a pharmaceutically acceptable free acid, and inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl -Obtained from non-toxic organic acids such as substituted alkanoates, hydroxy alkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids. Acid addition salts can be prepared by a conventional method, for example, by dissolving a compound in an excess acid aqueous solution, and precipitating this salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. have. In addition, the mixture may be prepared by evaporating a solvent or an excess of acid and then drying it or by suction filtration of the precipitated salt.

In the present invention, the final target material is preferably a hydrochloride salt, but A may not exist in Chemical Formula 3 or may be hydrochloride, bromate, nitrate, acetate, and sulfate. In the case of bromate, nitrate, acetate, and sulfate, it can be converted to epinastine free base by neutralization and then converted to epinastine hydrochloride.

"Reduction" is a chemical reaction in which the number of oxidation of an atom varies. Reduction in the present invention refers to obtaining hydrogen.

In the present invention, the catalyst of the second step may be any one of palladium, platinum, nickel, and rhodium. Preferably, it may be palladium, and the metal catalyst may be supported on carbon, but is not limited thereto.

In the present invention, the solvent in the second step may be selected from the group consisting of alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dichloromethane, cyclohexane, chloroform, and diethyl ether. It may be preferably methanol, but is not limited thereto.

The present invention provides a method for preparing a compound of Formula 2 including the step of reacting a compound of Formula 1 with cyanamide to obtain a compound of Formula 2 as an intermediate, and detailed conditions are as described above.

[Formula 1]

[Formula 2]

The present invention provides a method for preparing a compound of Formula 3 comprising the step of obtaining a compound of Formula 3 by reducing the compound of Formula 2 below, and detailed conditions are the same as described above.

[Formula 2]

[Formula 3]

In Formula 3, A is absent or refers to a pharmaceutically acceptable acid addition salt.

The new manufacturing method for synthesizing epinastine according to the present invention has fewer synthesis steps than the conventional epinastine manufacturing method, and is a safe synthesis method. The second generation antihistamine drug Epina for coping with allergic patients with the above manufacturing method It can be used inexpensively synthesized and supplied to the market.

1 is a method for synthesizing epinastine hydrochloride of the present invention.

Hereinafter, a preferred manufacturing example is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following preparation examples.

<Production Example 1> N Preparation of -(2-benzylphenyl)-2-chloroacetamide (1)

In an argon atmosphere, commercially available 2-benzylaniline (1841 mg, 10.05 mmol) in toluene (10 mL) was treated with chloroacetyl chloride (0.82 mL, 10.25 mmol) and pyridine (0.98 mL, 12.11 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour, and water (5 mL) was added to the reaction to terminate the reaction. The resulting mixture was stirred for 20 minutes, diluted with ethyl acetate (200 mL), washed with 1 N hydrochloric acid 3*30 mL) and a saturated aqueous sodium chloride solution, dried (MgSO ₄ ), and concentrated under reduced pressure to form a gray solid N -(2-Benzylphenyl)-2-chloroacetamide was obtained (2205 mg, 85%):

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.99 (br s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.34-7.11 (m, 8H), 4.06 (s, 2H), 4.00 (s , 2H); CAS Registry: 21535-43-3.

<Production Example 2> 6-(chloromethyl)-11 H -Dibenzo[ b,e ] Preparation of azepine (2)

A flask containing polyphosphoric acid (4.0 g, 46.9 mmol) was treated with 1 (610 mg, 2.3 mmol) and phosphoryl chloride (1.0 mL). The reaction mixture was equipped with a reflux condenser and heated at 120° C. for 2 hours without stirring. The reaction mixture was poured into ice water (200 mL), and the flask was washed with diethyl ether (200 mL). The combined aqueous phase and organic wash were stirred for 1 hour and the phases were separated. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous sodium chloride solution, dried (MgSO ₄ ), and concentrated under reduced pressure to obtain compound 2 (509 mg, 90%):

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.44 (d, J = 8.0 Hz, 1H), 7.31 (td, J = 7.2, 1.2 Hz, 1H), 7.22-7.02 (m, 6H), 4.69 (br s , 2H), 3.53 (s, 2H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 164.8, 144.5, 143.6, 132.9, 131.8, 130.6, 127.4, 127.3, 127.2, 127.1, 126.69, 126.68, 125.5, 49.0, 39.0; CAS Registry: 21535-44-4.

<Example 1> Preparation of Epinastine Hydrochloride

Step 1: Synthesis of dihydroepinastine (3)

A solution of compound 2 (479mg, 1.98mmol) in acetonitrile (MeCN, 20mL) was treated with commercially available cyanamide (250mg, 5.94mmol) and sodium tert-butoxide (285mg, 2.97mmol). The reaction mixture was exposed to microwave reaction conditions (120° C., 30 minutes, normal absorption). The reaction mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium chloride solution, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was separated by flash chromatography (SiO ₂ , gradient, 0-3% MeOH-CH ₂ Cl ₂ ) to obtain dihydroepinastine (323 mg. 66%): mp 181-184 ^o C;

¹ H NMR (DMSO-d6, 400 MHz) δ 7.60 (dd, J = 8.0, 1.2 Hz, 1H), 7.48 (dd, J = 7.2, 1.6 Hz, 1H), 7.38 (dd, J = 7.4, 1.4 Hz , 1H), 7.35-7.13 (m, 5H), 6.87 (s, 1H), 5.72 (s, 2H), 3.80 (dd, J = 8.0, 1.2 Hz, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 149.0, 138.1, 136.8, 134.4, 129.3, 129.1, 128.8, 127.6, 127.54 (2C), 127.47, 127.29, 127.27, 123.5, 122.5, 39.1; MS (ESI+) m/z 248 [M+H]+

Step 2: Synthesis of Epinastine Hydrochloride (4)

A solution of compound 3 (100 mg, 0.40 mmol) in an aqueous solution of ethanol (20 mL) and 6N hydrochloric acid (4 mL) was treated with 10 wt% palladium/activated carbon (100 mg). The reaction mixture was stirred under hydrogen gas for 24 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give epinastine hydrochloride as a white solid (98 mg, 87%):

¹ H NMR (DMSO- d6 , 400 MHz) δ 8.51 (s, 1H), 8.23 (br s, 2H), 7.53-7.31 (m, 5H), 7.28-7.13 (m, 3H), 5.36 (t, J = 9.8 Hz, 1H), 4.50 (d, J = 14.4 Hz, 1H), 4.30 (t, J = 9.6 Hz, 1H), 3.71 (d, J = 14.4 Hz, 1H), 3.53 (t, J = 9.8 Hz, 1H); ¹³ C NMR (DMSO- d6 , 100 MHz) δ 157.8, 139.9, 135.1, 134.8, 133.3, 130.0, 128.9, 128.5, 128.2, 128.0, 127.5, 127.1, 126.6, 62.5, 49.7, 36.9; CAS Registry: 108929-04-0.

Experimental Example 1. Optimization study of dihydroepinastine synthesis

Synthetic route of epinastine hydrochloride using dihydroepinastine (3) has not been reported, but the olefinic double bond on the imidazole ring of dihydroepinastine (3) is selective to provide the desired epinastine. Since it can be reduced to, it was decided to use 3 as a precursor of epinastine in the present invention, and an optimization study for 3 was performed, and the conditions and results are as follows (Table 1).

Item	Reaction conditions					result
	5 (eq.)	Base (eq.)	Solvent a	Temperature. b	time
One	2.0	-	DMF	130 o C	18 h	decomp. c
2	2.0	K 2 CO 3 (1.5)	DMF	90 o C	8 h	decomp. d
3	2.0	DIPEA (1.5)	DMF	90 o C	8 h	10%
4	2.0	NaO t Bu (1.5)	DMF	90 o C	18 h	17%
5	2.0	NaO t Bu (1.5)	THF	reflux	18 h	15%
6	2.0	NaO t Bu (1.5)	MeCN	reflux	18 h	32%
7	3.0	NaO t Bu (1.5)	MeCN	reflux	12 h	85%
8	2.0	NaO t Bu (1.5)	DMF	MW, 120 o C	30 min	20%
9	2.0	NaO t Bu (1.5)	DMF	MW, 160 o C	30 min	29%
10	2.0	NaO t Bu (1.5)	DCE	MW, 120 o C	50 min	a very small amount
11	2.0	NaO t Bu (1.5)	THF	MW, 120 o C	50 min	a very small amount
12	2.0	NaO t Bu (1.5)	DMSO	MW, 200 o C	30 min	38%
13	2.0	NaO t Bu (1.5)	DMSO	MW, 120 o C	30 min	55%
14	2.0	NaO t Bu (1.5)	MeCN	MW, 120 o C	30 min	63%
15	2.0	NaO t Bu (2.0)	MeCN	MW, 120 o C	30 min	56%
16	3.0	NaO t Bu (1.5)	MeCN	MW, 120 o C	30 min	66%
17	2.0	KO t Bu (2.0)	MeCN	MW, 120 o C	30 min	38%
18	2.0	Na 2 CO 3 ,(2.0)	MeCN	MW, 120 o C	50 min	5%
19	2.0	K 2 CO 3 ,(2.0)	MeCN	MW, 120 o C	50 min	51%
20	2.0	Cs 2 CO 3 ,(2.0)	MeCN	MW, 120 o C	50 min	13%
21	2.0	KHCO 3 (2.0)	MeCN	MW, 120 o C	50 min	NR e
22	2.0	NaOH (2.0)	MeCN	MW, 120 o C	50 min	29%
23	2.0	DIPEA (3.0)	MeCN	MW, 120 o C	50 min	10%
24	2.0	NaI (1.0)	MeCN	MW, 120 o C	50 min	decomp. d
25	3.0	NaI (1.0)/NaOtBu (1.5)	MeCN	reflux	18 h	28%
26	5.0	NaI (3.0)/NaOtBu (1.5)	MeCN	reflux	18 h	28%
a) The reaction concentration is 0.1 M b) MW = microwave reaction c) decomposition of 2. d) Dechlorinated compound 2 was observed. e) NR = no reaction

Experimental Example 2. Preparation of Epinastine Hydrochloride

The selective reduction procedure for the CC double bond of the 3 compounds prepared under the above conditions was investigated. Metal hydrides such as sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ), diisobutyl aluminum hydride (DiBAl-H) and lithium aluminum hydride (LiAlH ₄ ) do not undergo reduction. And most of the starting material 2 was recovered.

Next, compound 3 was exposed to hydrogenation conditions in various solvents, but when methanol, ethanol, ethyl acetate, dimethylformamide, and tetrahydrofuran were used as solvents, the hydrogenation of 3 proceeded in a low yield and was not successful. When hydrogenated in a mixture of methanol and 6N hydrochloric acid aqueous solution as a co-solvent, the final compound, epinastine hydrochloride (3) was obtained. Not only does this method have a high yield of up to 87%, it is also quite simple to synthesize.

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting.

Claims (18)

1. A first step of reacting a compound of formula 1 with cyanamide to obtain a compound of formula 2; And

   A method for producing epinastine comprising a second step of reducing the compound of Formula 2 to obtain a compound of Formula 3.

   [Formula 1]

   

   [Formula 2]

   

   [Formula 3]

   

   In Formula 3, A is absent or refers to a pharmaceutically acceptable acid addition salt.
2. The method of claim 1,

   The first step of reacting the compound of Formula 1 with cyanamide to obtain the compound of Formula 2 is performed in a solvent to which a base is added.
3. The method of claim 1,

   The second step of reducing the compound of Formula 2 to obtain the compound of Formula 3 is carried out in a solvent in the presence of a hydrogen gas, an acid and/or a catalyst.
4. The method of claim 1,

   The cyanamide of the first step is a method for producing epinastine that is used in an amount of 2 to 5 equivalents based on 1 equivalent of the compound of Formula 1.
5. The method of claim 4,

   The cyanamide of the first step is a method for producing epinastine that is used in an amount of 2 to 3 equivalents based on 1 equivalent of the compound of Formula 1.
6. The method of claim 1,

   The reaction temperature of the first step is a method for producing epinastine that is room temperature to 200 ℃.
7. The method of claim 6,

   The reaction temperature in the first step is a method of producing epinastine that is applied using any one of heating and microwave.
8. The method of claim 1,

   The reaction time of the first step is a method for producing epinastine that is 20 minutes to 24 hours.
9. The method of claim 1,

   The solvent in the first step is a method for producing epinastine, which is a polar aprotic solvent.
10. The method of claim 9,

    The polar aprotic solvent is any of dimethylformamide, tetrahydrofuran, acetonitrile, dichloroethane, dimethyl sulfur monoxide, dichloromethane, ethyl acetate, acetone, dimethylacetamide and N-methylpyrrolidone A method for producing one of the epinastines.
11. The method of claim 2,

    The base of the first step is epinastine, which is one or more components selected from the group consisting of diisopropylethylamine, potassium carbonate, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydroxide, and sodium iodide. Method of manufacturing.
12. The method of claim 2

    The method for producing epinastine in the first step is used in an amount of 1 to 3 equivalents based on 1 equivalent of the compound of Formula 1.
13. The method of claim 3,

    The acid in the second step is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid and sulfuric acid.
14. The method of claim 1,

    The compound of Formula 3 is an epinastine free salt without A, or A is a method for producing an epinastine salt in which any one of hydrochloride, bromate, nitrate, acetate, and sulfate.
15. The method of claim 3,

    The catalyst in the second step is any one of palladium, platinum, nickel, and rhodium.
16. The method of claim 1,

    The second step of the solvent is alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dichloromethane, cyclohexane, chloroform, and the method for producing epinastine is selected from the group consisting of diethyl ether.
17. The method of claim 16,

    The alcohol is methanol, the method of producing epinastine.
18. A method for preparing a compound of Formula 2 comprising the step of reacting a compound of Formula 1 with cyanamide to obtain a compound of Formula 2 below.

    [Formula 1]

    

    [Formula 2]

    

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