KR101421032B1 - Method for preparing (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone - Google Patents

Abstract

본 발명에 따른 신규 중간체 화합물로 아민 화합물을 이용하여 PAR-2 (protease activated receptor-2) 저해제로 활성이 있으며 염증성 질환의 치료 및 예방에 사용될 수 있는 화학식 1의 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온를 제조하는 경우, 보호기의 도입 및 탈보호기 반응이 필요없기 때문에 전체 반응 단계를 줄이고, 비용 절감과 효과적인 결정화의 이점이 있을 뿐 아니라, 전체 수율을 높이며, 최종 목적물인 화학식 1의 화합물의 분리 및 정제 방법에 있어서도 산업 규모의 합성에 적합한 결정화 방법이나 추출 방법 등을 사용할 수 있어 매우 경제적이다.(2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) benzoic acid derivative represented by the following Formula 1, which is active as a protease activated receptor- (Piperidin-5-yl) methanone, and intermediates thereof.
[Chemical Formula 1]

(2-methyl-1- (3 (3-methyl-1- (3-methoxyphenyl) -1,3- (Piperidin-5-yl) methanone, the overall reaction step can be reduced and the cost of the process can be reduced, Not only has the advantages of reduction in yield and effective crystallization but also increases the overall yield and is also economical since it is possible to use a crystallization method or an extraction method suitable for industrial scale synthesis in the method of separation and purification of the compound of formula 1 as the final object.

Description

(2-methyl-1 (3-methylbenzyl) -lH- benzo [d] imidazol-5-yl) (piperidin- - (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin-1-yl) methanone}

The present invention relates to the use of (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazole -5-yl) (piperidin-5-yl) methanone, and intermediates thereof.

[Chemical Formula 1]

2-Methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin- -2) inhibitor and can be used as a composition having anti-inflammatory function in inflammatory skin diseases including atopic dermatitis and the like.

[Chemical Formula 1]

The efficacy of the compound as a PAR-2 inhibitor and the preparation method thereof are disclosed in Neopham Co., Ltd. and International Patent Publication WO12 / 026766 filed by the present inventors. The method for preparing the compound described in the patent is shown in the following Reaction Scheme 1.

[Reaction Scheme 1]

The preparation method uses 4-fluoro-nitrobenzoic acid as a starting material, introducing a protecting group, introducing a benzylamine group through a nucleophilic substitution reaction, reducing the nitro group, cyclizing the benzoimidazole, Dehydration condensation reaction is carried out. However, this method is not suitable for mass production because the whole reaction step is long and the overall yield is not high and most of the purification steps of each stage require tube chromatography.

WO 12/026766 (Mar. 1, 2012)

As a result of intensive studies on the problems of the above-mentioned conventional production methods, the inventors of the present invention found that the introduction of a protecting group and elimination of a deprotection vaporization process are reduced to reduce the reaction step and the advantages of cost reduction and effective crystallization ≪ / RTI &

Accordingly, it is an object of the present invention to reduce the total reaction step, increase the overall yield, and make it possible to obtain a simpler, more economical and higher purity than the prior art by using a crystallization method or an extraction method suitable for industrial- (3-methylbenzyl) -lH-benzo [d] imidazol-5-yl) (piperidin-5-yl) methanone.

Another object of the present invention is to provide a process for the preparation of (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin- To provide a production intermediate and a method for producing the same.

The present invention relates to the use of a compound of formula (1), which is active as a protease activated receptor-2 (PAR-2) inhibitor and has antiinflammatory activity in inflammatory skin diseases including atopic dermatitis, (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin-5-yl) methanone.

The compounds of formula (I) may also form salts of various forms, and the present invention includes such salts. This method can be applied on an industrial scale. In particular, the present invention uses a novel intermediate to eliminate the introduction and de-protection of the protective group, There is an advantage of crystallization. In addition, the present invention includes novel amine compounds and their addition salts useful as intermediates with the advantage of cost-effective crystallization, and methods for making them, for chemical manufacturing processes suitable for industrial scale.

[Chemical Formula 1]

Hereinafter, the present invention will be described in more detail.

As shown in the following Reaction Scheme 2,

1) dehydrating and condensing 4-chloro-3-nitrobenzoic acid of the following formula (4) with piperidine to prepare a compound of formula (3);

2) reacting a compound of formula (3) with 3-methylbenzylamine to prepare a compound of formula (2-1);

3) reducing the nitro group of the compound of Formula 2-1 to produce an amine compound of Formula 2-2; And

4) cyclizing the amine compound of the following formula (2-2) to obtain (2-methyl-1- (3-methylbenzyl) -1H- benzo [d] imidazol- (3-methylbenzyl) -lH-benzo [d] imidazol-5-yl) (piperidin-5-yl) -methanone, Methanone or a pharmaceutically acceptable salt thereof.

[Reaction Scheme 2]

Hereinafter, each step will be described in detail.

[Step a] Preparation of the compound of formula (3)

The compound represented by the formula (3) is obtained by dehydration condensation reaction of 4-chloro-3-nitrobenzoic acid of the formula (4) as a starting material with piperidine. This dehydration condensation reaction is well known in the field of organic synthesis and can be carried out in various ways. The starting material, 4-chloro-3-nitrobenzoic acid, can be readily obtained from the generic reagent manufacturer or via the nitration of 4-chlorobenzoic acid according to simple known methods (US Pat. No. 4,036,838).

The reaction is carried out by adding dichloromethane to a solution of thionyl chloride in a solvent to obtain 4-chloro-3-nitrobenzoyl chloride as an intermediate, adding piperidine and stirring at room temperature, more preferably 1,1'-carbonyldiimide (CDI), or 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC), followed by stirring at room temperature with addition of piperidine.

In a specific example of the present invention, the compound is prepared by reacting 4-chloro-3-nitrobenzoic acid of Formula 4 with 1,1'-carbonyldiimidazole in an ethyl acetate solvent according to a known method (U.S. Patent No. 6,313,115 B1) Followed by addition of piperidine and stirring at room temperature. Distilled water was added to the work-up, the organic layer was extracted, and the solvent was removed to obtain a yellow solid. If necessary, the desired compound of formula (3) can be obtained in high purity by purification by recrystallization using ethanol.

[Step b] Preparation of the compound of formula (2-1)

The compound of the formula (2-1) is obtained by carrying out a nucleophilic substitution reaction by stirring the compound represented by the formula (3) and 3-methylbenzylamine in an organic solvent under reflux.

Examples of the solvent include nitrites such as acetonitrile; Alcohols such as ethanol and isopropanol; Ethers such as tetrahydrofuran, diisopropyl ether, dioxane and 1,2-dimethoxyethane; Aromatic hydrocarbons such as benzene and toluene; Amides such as dimethylacetamide, dimethylformamide and n-methylpyrrolidone can be mentioned, but the present invention is not limited to these inert solvents, and these solvents may be used alone or in combination. Preferably dimethylacetamide or n-methylpyrrolidone, and more preferably n-methylpyrrolidone. The reaction temperature can be carried out at a temperature range of 60 to 130 캜, but preferably at a temperature of 100 to 120 캜.

The reaction may be carried out in the presence or absence of a base, depending on the amount of 3-methylbenzylamine used. In the case where 3-methylbenzylamine is used in excess of 2.5 equivalents to the compound represented by the formula (3), a base may not be used , Preferably 1.2 equivalents of 3-methylbenzylamine and 0.6 to 1.2 equivalents of base are preferably used. Suitable bases include, for example, alkali metal and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate or calcium carbonate; Alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; Acetic acid salts such as sodium acetate, potassium acetate and ammonium acetate; Organic bases such as triethylamine, diethylisopropylamine, pyridine, picoline or pyridine; And phosphates such as potassium phosphate.

The solvent used for the recrystallization is C1-C4 alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; C4-C8 esters such as ethyl acetate; C4-C8 ethers such as t-butyl methyl ether, isopropyl ether; Or a mixture of the above-mentioned solvent mixture or water and the above-mentioned solvent. 2-1 The most suitable example of recrystallization for further purification of the compound is recrystallization from ethanol.

In an embodiment of the present invention, the reaction is carried out by refluxing stirring at 120 DEG C for 2 hours using n-methylpyrrolidone as a solvent, 1.2 equivalents of 3-methylbenzylamine and 1.2 equivalents of sodium hydrogencarbonate, . In the work-up, the reaction product is cooled to room temperature, diluted with ethyl acetate, washed with an aqueous solution of sodium hydroxide and distilled water, and then the organic solvent is removed to obtain a solid residue, which is recrystallized in ethanol.

[Step c] Preparation of compound of formula (2-2)

The amine compound represented by the formula (2-2) is obtained by reducing the nitro group in an inert solvent with the compound of the formula (2-1) obtained in the above reaction.

The inert solvent which can be used in the present reaction is not particularly limited as long as it does not significantly inhibit the progress of the reaction. Examples thereof include alcohols such as methanol, ethanol and propanol; Ethers such as tetrahydrofuran, diisopropyl ether, dioxane, and 1,2-dimethoxyethane; Organic acids such as acetic acid; Inorganic acids in hydrochloric acid, and water. The reduction of the nitro group can be carried out by using a reducing agent or by catalytic hydrogenation. Reducing agents that can be used in the present reaction include metal reducing agents such as borane complex, diborane, sodium borohydride, lithium borohydride, sodium borohydride-lithium chloride, aluminum lithium hydride, or diisobutyl aluminum hydride reagent; Under acidic conditions, for example, metals such as zinc, iron, tin and tin chloride can be mentioned, and only zinc can be used under neutral or basic conditions. In the catalytic hydrogenation, the reaction can be carried out at atmospheric pressure or atmospheric pressure. Examples of the catalyst include Raney nickel, palladium-carbon, palladium oxide, platinum, platinum black, platinum oxide, platinum sulfide carbon, rhodium, ruthenium, alumina Transition metals are used. When catalytic reduction is applied, ammonium formate, sodium dihydrogen phosphate, hydrazine may also be used as the hydrogen source. When the reaction is carried out under an acidic condition, the reducing agent may be used in a stoichiometric amount or an excessive amount, and an excessive amount is generally used. In the catalytic reduction method, when Raney nickel or the like is used, it is used in an amount of 5 to 30% by weight based on the weight of the compound of the formula (2-1), and 0.02 to 30% by weight when the noble metal catalyst such as platinum or palladium is used .

The reaction temperature may be selected from the range of 0 to 150 ° C, preferably 10 to 110 ° C. The reaction time is not constant depending on the reaction amount, the reaction temperature, etc., but can be selected from the range of several minutes to 48 hours.

[Step d] Preparation of compound of formula (1)

The compound of formula (1) is obtained by reacting the amine compound of formula (2-2) with orthoacetate in acetic acid to form a benzimidazole ring. At this time, it is preferable that the benzimidazole ring-forming reaction is carried out with an excess amount of trimethylorthoformate using acetic acid as a solvent.

The solvent used for crystallization may include hydrocarbons such as toluene and xylene; C4-C8 esters such as ethyl acetate; C4-C8 ethers such as t-butyl methyl ether, isopropyl ether; Or a solvent mixture as described above. (1) The most suitable example of recrystallization for further purification of the compound is recrystallization from ethyl acetate.

The compounds of formula (I) may be made into various forms of salts, where possible salts include all possible salts that can be used as pharmaceuticals. Pharmaceutically acceptable salts include acid addition salts formed by pharmaceutically acceptable free acids. Examples of the free acid include inorganic acids and organic acids. Examples of the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. The organic acids used are citric acid, acetic acid, lactic acid, maleic acid, Sulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid. The present invention also relates to a hydrate of a salt of the compound of formula (1), particularly when the salt is hygroscopic and is in the form of a hydrate having crystallinity.

The solvents and reagents used in the present invention may be replaced with functional substitutes or derivatives thereof known to those skilled in the art and reaction conditions such as reaction time and temperature may be adjusted to optimize the reaction. Similar to the present invention, the product from the reaction can be separated and, if desired, further purified according to methods generally known in the art such as extraction, crystallization, and trituration.

The present invention also provides an intermediate for the preparation of (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin- To provide a novel amine compound represented by the following formula (2).

(2)

In the formulas, R represents a nitro group (NO ₂ ) or an amino group (NH ₂ ).

As described above, according to the present invention, a novel intermediate compound, which is active as a protease activated receptor-2 (PAR-2) inhibitor and can be used for the treatment and prevention of inflammatory diseases, In the preparation of 1- (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin-5-yl) methanone, Not only has advantages of cost reduction and effective crystallization but also enhances the overall yield and is also economical and high purity compared with the prior art by using crystallization method or extraction method suitable for industrial scale synthesis in the separation and purification method (3-methylbenzyl) -lH-benzo [d] imidazol-5-yl) (piperidin-5-yl) methanone can be synthesized on an industrial scale.

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[ Example  1] Preparation of the compound of formula (2-1)

Preparation of the compound of formula (3)

(4.22 g, 26.04 mmol) was dissolved in 50 mL of ethyl acetate, and 4-chloro-3-nitrobenzoic acid (Formula 4, 5.00 g, 24.80 mmol) was slowly added at room temperature and stirred for 1 hour. (50 mL) and distilled water (50 mL) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. , Brine (50 mL). The organic layer was dried over anhydrous sodium sulfate (20 g) and then concentrated under reduced pressure to obtain the compound of Formula 3 (6.39 g, 95%) as a yellow crystalline solid.

^{1 H NMR (600 MHz, chloroform} -d 1) δ = 7.92 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.4 Hz), 7.56 (dd, 1H _{J 1 = 8.1 Hz, J 2} = 2.1 Hz, 1H), 3.71 (br, 2H), 3.35 (br, 2H), 1.71-1.54 (br, 6H).

LCMS: C ₁₂ H ₁₃ 269 with respect to the _{-ClN 2 O 3 (M + H} +)

Preparation of compound of formula (2-1)

The compound 3 (5.00 g, 18.61 mmol) was dissolved in n-methylpyrrolidone (15 mL), sodium bicarbonate (1.88 g, 22.38 mmol) was added thereto and 3-methylbenzylamine (2.8 mL, 22.3 mmol) I put it slowly. The organic layer was washed with 2 N aqueous sodium hydroxide solution (40 mL, twice), distilled water (40 mL, 2 times), and the organic layer was washed with distilled water (50 mL) 2 times) and brine (40 mL). The organic layer was dried over anhydrous sodium sulfate (20 g) and filtered under reduced pressure to obtain an orange solid which was recrystallized from anhydrous ethanol to obtain the compound of Formula (2-1) (6.13 g, 93%) as an orange crystalline solid.

^{1 H NMR (600 MHz, chloroform} -d 1) δ = 8.55 (t, J = 5.4 Hz, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.51 (dd, J 1 = 8.7 Hz, J 2 = 2.1 Hz, 1H), 7.14 (m, 3H), 6.85 (d, J = 9.0 Hz, 1H), 4.54 (d, J = 5.4 Hz, 2H), 3.55 (br, 4H), 2.36 (s, 3H ), 1.67-1.61 (br m, 6H)

_{LCMS: C 20 H 23 N 3} O 3 354 with respect to the (M + H ⁺⁾

[ Example  2] Preparation of amine compound of formula (2-2)

2.85 g (51.0 mmol) of iron and 1.5 mL of acetic acid were added to a mixed solvent of ethanol and water (5: 2, 28 mL), and the mixture was refluxed at 120 ° C for 2 hours. After cooling to room temperature, 8.49 mmol), and a mixed solvent of ethanol and water (5: 2, 14 mL) is further added. The reaction mixture is refluxed and stirred at 110 ° C for 1 hour, filtered under reduced pressure using celite in a hot state, and washed with hot ethanol. The filtrate is concentrated, the aqueous 2 N sodium hydroxide solution is added until the pH is 8 or higher, and the mixture is extracted with ethyl acetate (50 mL, twice). The organic layer was collected and washed again with a saturated sodium bicarbonate solution (20 mL, twice), distilled water (30 mL, twice) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give To obtain the compound (2.74 g, 99%). The amine compound of formula (2-2) can be used immediately for further synthesis without further purification.

^{1 H NMR (600 MHz, chloroform} -d 1) δ = 7.24 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 7.2 Hz, 1H), 2H), 6.59 (d, J = 7.8 Hz, 1H), 4.29 (s, 2H), 3.54 (br s, 1.57 (br, 4H)

LCMS: 324 with respect to _{C 20 H 25 N 3 O (} M + H +)

[ Example  3] Preparation of the compound of formula (1)

The amine compound (2.74 g, 8.48 mmol) of the formula 2-2 obtained in the above reaction was placed in acetic acid (16 mL) and triethyl orthoacetate (4.6 mL, 25.1 mol) and refluxed for 2 hours. The solvent was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), saturated sodium carbonate solution was added until the pH was 8 or higher, and the organic layer was separated with a separatory funnel. The organic layer was washed with distilled water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.75 g of a yellow solid. This was recrystallized with 3 mL of ethyl acetate to obtain the compound of Formula 1 (2.23 g, 76%) as a white solid.

^{1 H NMR (600 MHz, chloroform} -d 1) δ = 7.74 (t, J = 0.6 Hz, 1H), 7.30 (dd, J 1 = 8.1 Hz, J 2 = 0.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.84-6.83 (m, 2H), 5.29 (s, 2H), 3.72 (br 2H), 1.57 (br, 2H), 3.42 (br s, 2H), 3.54 (br s, 7H), 2.58 (s, 3H)

LCMS: C ₂₂ H ₂₅ -N 347 with respect to the O ₃ (M + H ⁺⁾

Claims (4)

(2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5-yl) (piperidin- (3-methylbenzyl) -lH-benzo [d] imidazol-5-yl) (piperidin-5-yl) methane ≪ / RTI > or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

[Formula 2-2]

The method according to claim 1,
The amine compound of the following formula (2-2)
And reducing the nitro group of the compound of formula (2-1) to produce an amine compound of formula (2-2).
[Formula 2-2]

[Formula 2-1]

3. The method of claim 2,
The compound of the formula (2-1)
1) dehydrating and condensing 4-chloro-3-nitrobenzoic acid of the following formula (4) with piperidine to prepare a compound of formula (3); And
2) reacting a compound of formula (3) with 3-methylbenzylamine to prepare a compound of formula (2-1);
. ≪ / RTI >
[Formula 2-1]

(3)

[Chemical Formula 4]

An amine compound represented by the following formula (2).
(2)

In the formulas, R represents a nitro group (NO ₂ ) or an amino group (NH ₂ ).