KR102080239B1 - Novel method of preparing Epinastine - Google Patents

Abstract

The present invention relates to a novel manufacturing method for synthesizing an anti-histamine pharmaceutical medicine, epinastine. The novel manufacturing method for synthesizing epinastine according to the present invention has fewer synthesizing steps than a conventional epinastine manufacturing method, and is a safe synthesis method, thereby being expected to be used for inexpensively synthesizing the anti-histamine pharmaceutical medicine, epinastine by the manufacturing method, and supplying the same to the market.

Description

Novel method of preparing Epinastine

The present invention relates to a novel process for synthesizing epinastine, an antihistamine drug.

As an antihistamine drug, a treatment for patients with allergic diseases, which are increasing every year as a result of environmental pollution, epinastine, the second-generation antihistamine drug, has a much improved effect on the central nervous system than the first-generation antihistamine drug, resulting in drastic drowsiness. It is an improved medicine. Domestic sales are increasing every year and export demand is very high. Known synthesis method has a long synthesis step, there is a disadvantage of using a high explosive and highly toxic reagent, it is a method of synthesizing epinastine hydrochloride through a short synthesis step using a low toxicity reagent to improve this.

For a known method for synthesizing epinastine hydrochloride, US Patent (Patent Document 0001), Palladium / Carbon (Pd / C) reagent, and hydrazine, which use phosgene and lithium aluminum hydride (LiAlH ₄ ) as the core reactions. There is a European patent (Patent Document 0002) which makes the use of a (hydrazine) reagent as a core reaction, and recently introduced an amine group into cyclopropylamine and imine group using sodium borohydride (NaBH ₄ ) reagent. Korean patent (patent document 0003) which introduces the manufacturing method to reduce the amount of the like. In addition, Korean Patent (Patent Document 0004) describes a method for preparing 2-benzyl aniline, which is a synthetic starting material commonly used in known synthesis methods.

In the case of (Patent Document 0001), a very toxic substance such as phosgene is used as in [Scheme 1], and a very explosive substance such as lithium aluminum hydride (LiAlH ₄ ) is used. Very disadvantageous.

Scheme 1

In the case of (Patent Document 0002), a hydrogen reaction and a toxic hydrazine reagent are used at 50 atmospheres and 140 ° C. using a palladium / carbon (Pd / C) reagent as in [Scheme 2].

Scheme 2

In the case of (Patent Document 0003), a very inexpensive and nontoxic cyclopropylamine is used as in Scheme 3, and a sodium borohydride (NaBH ₄ ) reagent, which is an inexpensive reducing agent, is used. The reagent has the advantage of not using, but compared with the present technology, the synthesis step is long, and has the disadvantage of passing through the bromate, which requires special equipment as an intermediate.

Scheme 3

United States Patent No. 4,313,931 European Patent No. 0496306A1 Republic of Korea Patent No. 10-1576620 Republic of Korea Patent No. 10-1859516

The present invention has been made to solve the above problems, the present inventors have studied to find a synthetic method for supplying synthesized inexpensive synthesis of epinastine, a second-generation antihistamine medicine for coping with allergy patients, epina A new method for synthesizing stine hydrochloride was invented and the present invention was completed.

Accordingly, an object of the present invention is to provide a novel synthesis method of efinastin.

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

In order to achieve the above object,

The present invention is a first step of obtaining a compound of formula 2 by reacting a compound of formula 1 with cyanamide; And a second step of reducing the compound of Formula 2 to obtain a compound of Formula 3 below.

[Formula 1]

[Formula 2]

[Formula 3]

In Formula 3, A means an acid addition salt which is not present or is pharmaceutically acceptable.

In one embodiment of the invention, the first step of reacting the compound of formula 1 of the present invention with cyanamide to obtain the compound of formula 2 may be carried out on a solvent to which a base is added.

Here, "base" refers to a property of a substance that gives off hydroxide ions or absorbs hydrogen ions in aqueous solution. Commonly referred to as alkali, it is a substance corresponding to acid and neutralizes each other to make salt and water. The strong bases include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH) ₂ ), and the weak bases include ammonia water (NH ₄ OH) and magnesium hydroxide (Mg (OH) ₂ ). There is this.

In the present invention, the solvent in the one-step reaction is not limited thereto, but is a polar aprotic solvent, more specifically dimethylformamide, tetrahydrofuran, acetonitrile, dichloroethane, dimethyl sulfur monoxide, dichloromethane, ethyl acetate , Acetone, dimethylacetamide and N-methylpyrrolidone.

In one embodiment of the invention,

The second step of preparing the compound of formula 2 to the compound of formula 3 may be carried out in a solvent in the presence of an acid and / or a catalyst under hydrogen gas.

Here, "acid" refers to a substance which ionizes when dissolved in water to give hydrogen ions. Substances corresponding to bases neutralize each other to form salts and water. In addition, hydrogen gas is generated by reaction with a metal having a higher ionization tendency than hydrogen. Representative acids include hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ) and the like, 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 small amounts can affect the reaction rate, and in general, with the catalyst, the reaction proceeds faster because it requires less activation energy in the presence of the catalyst. 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 ), solids Acid catalysts (zeolites, heteropolyacids), 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 in a state supported on carbon.

Although not limited thereto, the cyanamide in the first step may include 2 to 5 equivalents, such as 2 to 3 equivalents, 2 to 4 equivalents, 2 to 5 equivalents, 3 to 5 equivalents, to 1 equivalent of the compound of Formula 1, Or any interval within this range, or 2, 3, 4, 5 equivalents.

In one embodiment of the present invention, the reaction temperature of the first stage is not limited thereto, but is from 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 ℃, 50 ℃ to 90 ℃, 50 ℃ to 120 ℃, 50 ℃ to 160 ℃, 50 ℃ to 200 ℃, 90 ℃ to 120 ℃, 90 ℃ to 160 ℃, 90 ℃ to 200 ℃, 120 ℃ to 160 ℃, Any interval within this 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 may be any one of heating and microwave, although not limited thereto.

In one embodiment of the present invention, the reaction time of one step 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 minutes. 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 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 stage reaction is selected from the group consisting of diisopropylethylamine, potassium carbonate, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydroxide, sodium iodide It may be abnormal.

In one embodiment of the present invention, the equivalent of the base in the first stage reaction is not limited to 1 to 3, such as 1 to 1.5, 1 to 2, 2 to 3, It can be any interval within this range, such as 1.5 to 2, 1.5 to 3, 2 to 3, or the like, or 1, 1.5, 2, 3.

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 any one of hydrochloride, bromate, nitrate, acetate and sulfate. It is preferably hydrochloride, but is not limited thereto.

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

In the present invention, the final target material is preferably hydrochloride, but in Formula 3, A may be absent or may be hydrochloride, bromate, nitrate, acetate, and sulfate. In the case of bromate, nitrate, acetate and sulfate, the neutralization reaction can be used to convert to efinastin freebase and back to efinastin hydrochloride.

"Reduction" is a chemical reaction in which the number of oxidation of atoms 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 of the second step may be selected from the group consisting of alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dichloromethane, cyclohexane, chloroform and diethyl ether. Preferably it may be methanol, but is not limited thereto.

The present invention provides 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), which is 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 reducing the compound of formula (2) to obtain a compound of formula (3), and detailed conditions are as described above.

[Formula 2]

[Formula 3]

In Formula 3, A means an acid addition salt which is not present or is pharmaceutically acceptable.

The new manufacturing method for synthesizing efinastin according to the present invention has fewer synthetic steps than the conventional efinastin preparation method, and is a safe synthetic method: efina, a second generation antihistamine medicine for coping with allergy patients with the preparation method. It can be used to synthesize synthesized inexpensively and supply it to the market.

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

Hereinafter, preferred preparation examples are provided to aid the understanding of the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following preparation examples.

<Manufacture example 1> N Preparation of-(2-benzylphenyl) -2-chloroacetamide (1)

Under 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 the reaction was terminated by addition of water (5 mL). The resulting mixture was stirred for 20 minutes, diluted with ethyl acetate (200 mL), washed with 1 N hydrochloric acid 3 * 30 mL) and saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated under reduced pressure to give 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.

Preparation Example 2 6- (chloromethyl) -11 H -Dibenzo [ b, e ] Preparation of Azepine (2)

The 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 warmed 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 washes are stirred for 1 hour and the phases are separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and concentrated under reduced pressure to give 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 Epineast Hydrochloride

Step 1: Synthesis of Dihydroepineastin (3)

A solution of compound 2 (479 mg, 1.98 mmol) in acetonitrile (MeCN, 20 mL) was treated with commercially available cyanamide (250 mg, 5.94 mmol) and sodium tert-butoxide (285 mg, 2.97 mmol). 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 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 give dihydroepineast (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); 13 C NMR (DMSO-d 6, 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] &lt; + &gt;

Step 2: Synthesis of Epineast Hydrochloride (4)

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

No synthetic route to efinastin hydrochloride using dihydroepineaste (3) has been reported, but olefinic double bonds on the imidazole ring of dihydroepineastine (3) are selective to provide the desired efinastin. Since it can be reduced to the present invention, it was decided to use 3 as a precursor of efinastin in the present invention was carried out optimization studies for 3 and the conditions and results are as follows (Table 1).

Item Reaction conditions result 5 (eq.) Base (eq.) menstruum ^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 Trace 11 2.0 NaO ^t Bu (1.5) THF MW , 120 ^o C 50 min Trace 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 Epineast Hydrochloride

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

Next, although compound 3 was exposed to hydrogenation conditions in various solvents, the hydrogenation of 3 proceeded in low yields when using methanol, ethanol, ethyl acetate, dimethylformamide and tetrahydrofuran as solvents and was not successful. When the mixture was hydrogenated in a mixture of methanol and 6N hydrochloric acid aqueous solution as a cosolvent, the final compound, epinastine hydrochloride (3) was obtained. In addition to high yields of up to 87%, this method is quite simple.

The above description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in 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 exemplary in all respects and not restrictive.

Claims (19)

A first step of reacting a compound of Formula 1 with cyanamide to obtain a compound of Formula 2; And
A method for preparing efinastin comprising the second step of reducing the compound of Formula 2 to obtain a compound of Formula 3.
[Formula 1]

[Formula 2]

[Formula 3]

In Chemical Formula 3, A means an acid addition salt which is not present or is pharmaceutically acceptable.
The method of claim 1,
The first step of reacting a compound of Formula 1 with cyanamide to obtain a compound of Formula 2 is performed on a solvent to which a base is added.
The method of claim 1,
The second step of reducing the compound of formula 2 to obtain a compound of formula 3 is carried out in a solvent in the presence of an acid and / or a catalyst under hydrogen gas.
The method of claim 1,
The cyanamide of the first step, using 2 to 5 equivalents to 1 equivalent of the compound of formula (1).
The method of claim 4, wherein
The cyanamide of the first step is used in the amount of 2 to 3 equivalents to 1 equivalent of the compound of formula (1).
The method of claim 1,
The reaction temperature of the first step is room temperature to 200 ℃ manufacturing method of efinastin.
The method of claim 6,
The reaction temperature of the first step is a method for producing efinastin that is applied using any one of heating, microwave.
The method of claim 1,
The reaction time of the first step is 20 minutes to 24 hours manufacturing method of efinastin.
The method of claim 1,
The first step of the solvent is a polar aprotic solvent manufacturing method of efinastin.
The method of claim 9,
The polar aprotic solvent is epinastine, which is any one of dimethylformamide, tetrahydrofuran, acetonitrile, dichloroethane, dimethyl sulfur monoxide, dichloromethane, ethyl acetate, acetone, dimethylacetamide and N-methylpyrrolidone. Manufacturing method.
The method of claim 2,
The base of the first step is epinastine which is at least one component selected from the group consisting of diisopropylethylamine, potassium carbonate, sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydroxide and sodium iodide Manufacturing method.
The method of claim 2
The base of the first step, 1 to 3 equivalents to 1 equivalent of the compound of the formula (1) is used in the preparation of efinastin.
The method of claim 3, wherein
The acid of the second step is a method for producing the epinastine salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, acetic acid and sulfuric acid.
The method of claim 1,
The compound of Formula 3 is an efinastin free salt without A, A is a method for preparing an efinastin salt of any one of hydrochloride, bromate, nitrate, acetate and sulfate.
The method of claim 3, wherein
The second step of the catalyst is palladium, platinum, nickel and rhodium any one of the manufacturing method of efinastin.
The method of claim 1,
The solvent of the second step is a process for producing efinastin is selected from the group consisting of alcohol, ethyl acetate, acetic acid, tetrahydrofuran, dichloromethane, cyclohexane, chloroform and diethyl ether.
The method of claim 16,
Wherein said alcohol is methanol.
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
[Formula 1]

[Formula 2]

delete

Images