WO2014104607A1

WO2014104607A1 - Method for preparing (2-methyl-1-(3-methylbenzyl)-1h-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone

Info

Publication number: WO2014104607A1
Application number: PCT/KR2013/011221
Authority: WO
Inventors: 김용주; 박태교; 우성호; 이대연; 정은미
Original assignee: 주식회사 레고켐 바이오사이언스
Priority date: 2012-12-28
Filing date: 2013-12-05
Publication date: 2014-07-03
Also published as: KR20140085965A; CN104870436A; CN104870436B; KR101421032B1

Abstract

The present invention relates to a method for preparing (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-1-yl)(piperidin-5-yl)methanone having an activity as a protease activated receptor-2 (PAR-2) inhibitor, and an intermediate thereof. When (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-1-yl)(piperidin-5-yl)methanone represented by chemical formula 1, which has an activity as a PAR-2 inhibitor and can be used for treating and preventing inflammatory diseases, is prepared using an amine compound as a novel intermediate compound according to the present invention, the reaction steps are reduced as a whole, costs are saved, crystallization is effective and the total yield is increased since the introduction of a protecting group and the reaction of a deprotecting group are unnecessary. In addition, with respect to separation and purification of the compound represented by chemical formula 1, which is a final product, a crystallization method, an extraction method and the like suitable for industrial-sized synthesis can be used, thereby being very economical.

Description

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

The present invention relates to (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazole represented by the following Chemical Formula 1, which is known as a compound that is active as a PAR-2 (protease activated receptor-2) inhibitor. -5 days) (piperidin-5-yl) methanone and intermediates thereof.

[Formula 1]

2-Methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone of formula (I) having the structure PAR-2 (protease activated receptor) -2) It is active as an inhibitor and can be used as a composition with anti-inflammatory function in inflammatory skin diseases including atopic dermatitis.

[Formula 1]

Efficacy and preparation of PAR-2 inhibitors for the above compounds are specified in Neofam, Inc. and in International Publication No. WO12 / 026766 filed by the present inventors. The method for preparing the compound described in the patent is shown in Scheme 1 below.

Scheme 1

The preparation method is the introduction of a protecting group, 4-fluoro-nitrobenzoic acid as a starting material, the introduction of benzylamine groups through nucleophilic substitution reaction, reduction of nitro group, cyclization reaction of benzoimidazole, deprotection, And dehydration condensation reaction. However, the method is not suitable for mass production because the overall reaction step is long and the overall yield is not high, and the majority of each step purification process is performed by tube chromatography.

The present inventors have diligently studied the problems of the conventional manufacturing method described above, and compared with the conventional manufacturing method, the introduction of a protecting group and eliminating the deprotection process to reduce the reaction step, the cost reduction and effective crystallization advantages The present invention has been completed by finding new intermediates.

Therefore, the object of the present invention is to reduce the overall reaction step, increase the overall yield, and in the separation and purification method, using a crystallization method or extraction method suitable for industrial scale synthesis, more simple, economical and high It is to provide a process for preparing (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone with purity.

Another object of the present invention is also to prepare (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone It is to provide an intermediate and a method for producing the same.

The present invention is a compound of formula (1), which is active as a PAR-2 (protease activated receptor-2) inhibitor and can be used as a composition having anti-inflammatory function in inflammatory skin diseases including atopic dermatitis. 3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone and intermediates thereof.

In addition, the compound of formula 1 may also make salts of various forms, the present invention includes even the form of such salts. This method can be applied on an industrial scale. In particular, the present invention uses a novel intermediate, which eliminates the introduction and deprotection process of the protecting group, which must pass through the existing manufacturing method, thereby reducing the overall reaction step, reducing the cost, and effectively There is an advantage of crystallization. The present invention also encompasses novel amine compounds and their addition salts which are useful as intermediates with the advantages of cost savings and effective crystallization, for chemical production methods suitable for industrial scale and methods for preparing them.

[Formula 1]

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

As the present invention is shown in Scheme 2,

1) preparing a compound of formula 3 by dehydrating condensation reaction of 4-chloro-3-nitrobenzoic acid of formula 4 with piperidine;

2) preparing a compound of formula 2-1 by reacting a compound of formula 3 with 3-methylbenzylamine;

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

(4) (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidine-5) (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) of formula 1 comprising the step of preparing -yl) methanone Provided is a method of preparing methanone or a pharmaceutically acceptable salt thereof.

Scheme 2

Hereinafter, each step will be described in detail.

[a단계] 화학식 3의 화합물의 제조[a step] 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 and piperidine of the formula (4) as the starting material. Such dehydration reactions are well known in the field of organic synthesis and can be carried out in a variety of ways. The starting material 4-chloro-3-nitrobenzoic acid can be easily obtained from a general reagent manufacturer or through the nitration of 4-chlorobenzoic acid according to a simple known method (US Pat. No. 4,036,838).

The reaction is obtained by adding thionyl chloride in a solvent to dichloromethane to obtain 4-chloro-3-nitro benzoyl chloride as an intermediate, followed by piperidine and stirring at room temperature, or more preferably 1,1'-carbonyldiiimi It can be obtained by reacting with an active agent such as dozol (CDI) or 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDC) and then adding piperidine to stir at room temperature.

In a specific embodiment of the present invention, the compound is reacted with 4-chloro-3-nitrobenzoic acid of formula 4 and 1,1'-carbonyldiimidazole in an ethyl acetate solvent according to a known method (US Pat. No. 6,313,115 B1). Thereafter, piperidine was added to carry out 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 desired, the desired compound of formula 3 can be obtained by high purity by recrystallization using ethanol.

[b단계] 화학식 2-1의 화합물의 제조[b] Preparation of Compound of Chemical Formula 2-1

The compound of Chemical Formula 2-1 is obtained by carrying out a nucleophilic substitution reaction by refluxing the compound represented by Chemical Formula 3 and 3-methyl benzylamine in an organic solvent.

At this time, as a solvent which can be used, Nitriles, 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, n-methyl pyrrolidone and the like can be exemplified, 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-methyl pyrrolidone is suitable, and more preferably n-methyl pyrrolidone is preferable. The reaction temperature may be performed in a temperature range of 60 to 130 ° C., but preferably, at a temperature of 100 to 120 ° C.

The reaction may be performed in the presence or absence of a base, depending on the amount of 3-methyl benzylamine used. When the amount of 3-methyl benzylamine is used in excess of 2.5 equivalents to the compound represented by Formula 3, the base may not be used. Preferably, 1.2 equivalents of 3-methyl benzylamine and 0.6 to 1.2 equivalents of base are used. Suitable bases include, for example, alkali 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; Acetates such as sodium acetate, potassium acetate, ammonium acetate; Organic bases such as triethylamine, diethylisopropylamine, picoline or pyridine; And phosphates such as potassium phosphate.

Solvents used for recrystallization include C1-C4 alcohols 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 the solvent mixture described above or a mixture of the solvent and water described above. Of Formula 2-1 The most suitable example of recrystallization for further purification of the compound is recrystallization from ethanol.

In an embodiment of the invention, the reaction is refluxed at 120 ° C. for 2 hours using n-methyl pyrrolidone as a solvent and using the compound of formula 3, 1.2 equivalents of 3-methyl benzylamine, 1.2 equivalents of sodium hydrogencarbonate It was carried out by stirring. The work-up uses a method of cooling the reaction to room temperature, diluting with ethyl acetate, washing with aqueous sodium hydroxide solution and distilled water, and then removing the organic solvent to recrystallize from ethanol.

[c단계] 화학식 2-2의 화합물의 제조[c step] Preparation of a compound of Formula 2-2

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

The inert solvent that can be used in the present reaction can be used as long as it does not significantly inhibit the progress of the present reaction, and 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, such as hydrochloric acid, water, etc. are mentioned. Reduction of the nitro group may be performed using a reducing agent or by catalytic hydrogenation. Reducing agents that can be used in this reaction include metallic reducing agents such as borane complexes, diboranes, sodium borohydride, lithium borohydride, sodium borohydride-lithium chloride, aluminum lithium hydride, or diisobutylaluminum hydride. reagent; Under acidic conditions, for example, metals such as zinc, iron, tin, tin chloride and the like can be cited, and only zinc can be used even under neutral or basic conditions. In the catalytic hydrogenation method, the reaction can be carried out at atmospheric pressure or atmospheric pressure, and as a catalyst, for example, Raney-nickel, palladium-carbon, palladium oxide, platinum, platinum black, platinum oxide, platinum carbon sulfide, rhodium, ruthenium, alumina, etc. Use transition metals. Where catalytic reduction is applied, ammonium formate, sodium dihydrogenphosphate, hydrazine may be used as the hydrogen source. When the amount of reducing agent used is reacted under acidic conditions, the reducing agent may be used in stoichiometric amounts or in excess, and generally in excess. In the catalytic reduction method, Raney-Nickel or the like is used in an amount of 5 to 30% by weight relative to the weight of the compound of Formula 2-1, and when using a noble metal catalyst such as platinum or palladium, 0.02 to 30% by weight. Can be used.

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

[d단계] 화학식 1의 화합물의 제조[d step] 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, the benzimidazole cyclization reaction is preferably stirred under reflux with an excess of trimethylorthoformate using acetic acid as a solvent.

Solvents used for crystallization 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 the solvent mixture described above. The most suitable example of recrystallization for further purification of the compound of formula 1 is recrystallization from ethyl acetate.

The compound of formula 1 may be made of various forms of salts, and possible salts include all possible salts that can be used as medicaments. Pharmaceutically acceptable salts include acid addition salts formed by pharmaceutically acceptable free acid. The inorganic acid and organic acid may be used as the free acid, and the inorganic acid used may include hydrochloric acid, bromic acid, sulfuric acid, and phosphoric acid, and the organic acid used may be citric acid, acetic acid, lactic acid, maleic acid, umarin acid, gluconic acid, and methane. Sulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galluxuronic acid, embonic acid, glutamic acid and aspartic acid. The present invention also encompasses hydrates of the salts of the compounds of formula 1 described above, particularly useful when used in the form of hydrates having crystallinity when the salts are hygroscopic.

Solvents and reagents used in the present invention may be replaced with functional substitutes or derivatives thereof known 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 can be separated from the reaction and optionally further purified according to methods common in the art, such as extraction, crystallization, and trituration.

In addition, the present invention provides an intermediate for preparing (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone of Formula 1 It provides a novel amine compound represented by the following formula (2).

[Formula 2]

In the formula, 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 is used 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-5yl) (piperidin-5-yl) methanone, the entire reaction step is not necessary since the introduction of a protecting group and the deprotecting group reaction are not necessary. Cost reduction and effective crystallization, as well as higher overall yields, separation and purification methods are more economical and higher purity compared to the prior art using crystallization or extraction methods suitable for industrial scale synthesis. (2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone can be synthesized on an industrial scale.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following examples and experimental examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

[실시예 1] 화학식 2-1의 화합물의 제조Example 1 Preparation of a Compound of Formula 2-1

Preparation of Compound of Formula 3

Dissolve 1,1'-carbonyldiimidazole (4.22 g, 26.04 mmol) in 50 mL of ethyl acetate, and slowly add 4-chloro-3-nitrobenzoic acid (Formula 4, 5.00 g, 24.80 mmol) at room temperature for 1 hour. Was stirred. Piperidine (2.7 mL, 27.3 mmol) was added slowly and stirred at room temperature for 1 hour, followed by 6 N aqueous hydrochloric acid solution (30 mL, 2 times), saturated aqueous sodium hydrogen carbonate solution (50 mL), distilled water (50 mL), Washed sequentially with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate (20 g) and concentrated under reduced pressure to obtain a 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, 1H), 7.56 (dd, 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: 269 (M + H ⁺ ) for C ₁₂ H ₁₃ ClN ₂ O ₃

Preparation of Compound of Formula 2-1

Compound 3 (5.00 g, 18.61 mmol) was dissolved in n-methyl pyrrolidone (15 mL), followed by sodium hydrogen carbonate (1.88 g, 22.38 mmol), and 3-methyl benzylamine (2.8 mL, 22.3 mmol) was added to room temperature. I put it in slowly. The reaction mixture was refluxed at 120 ° C. for 2 hours, diluted with 60 mL of ethyl acetate and washed with distilled water (50 mL), and then the organic layer was washed with 2 N aqueous sodium hydroxide solution (40 mL, twice), distilled water (40 mL, Twice), followed by brine (40 mL). The organic layer was dried over anhydrous sodium sulfate (20 g) and filtered under reduced pressure to give an orange solid, which was recrystallized from anhydrous ethanol to give the compound of formula 2-1 as an orange crystalline solid (6.13 g, 93%).

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: 354 (M + H ⁺ ) for C ₂₀ H ₂₃ N ₃ O ₃

[실시예 2] 화학식 2-2의 아민 화합물의 제조Example 2 Preparation of an 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 stirred under reflux at 120 ° C. for 2 hours, and then cooled to room temperature to give a compound of Formula 2-1 (3.00 g, 8.49 mmol) and then a mixed solvent of ethanol and water (5: 2, 14 mL) are further added. The reaction was stirred under reflux at 110 ° C. for 1 hour, filtered under reduced pressure using celite in a hot state, and washed with hot ethanol. Concentrate the filtrate and add 2 N aqueous sodium hydroxide solution until pH is above 8 and extract with ethyl acetate (50 mL, twice). The organic layer was collected and washed again with saturated sodium carbonate solution (20 mL, twice), distilled water (30 mL, twice), and brine 30 mL, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a beige solid (2-2). Compound (2.74 g, 99%) was obtained. The amine compound of Formula 2-2 can be used immediately for the next 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), 6.87-6.84 (m, 2H), 6.59 (d, J = 7.8 Hz, 1H), 4.29 (s, 2H), 3.54 (br s, 7H), 2.35 (s, 3H), 1.65 (m, 2H), 1.57 (br, 4H)

LCMS: 324 (M + H ⁺ ) for C ₂₀ H ₂₅ N ₃ O

[실시예 3] 화학식 1의 화합물의 제조Example 3 Preparation of Compound of Formula 1

The amine compound of the formula 2-2 (2.74 g, 8.48 mmol) obtained in the reaction was added to acetic acid (16 mL) and triethylosoacetate (4.6 mL, 25.1 mol) and stirred under reflux 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 give 2.75 g of a yellow solid. It was recrystallized with 3 mL of ethyl acetate to give 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 s, 2H), 3.54 (br s, 7H), 3.42 (br s, 2H), 2.58 (s, 3H), 2.29 (s, 3H), 1.67 (m, 2H), 1.57 (br, 4H)

LCMS: 347 (M + H ⁺ ) for C ₂₂ H ₂₅ N ₃ O

Claims

(2-methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) (2-Methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methane of formula 1 comprising the step of preparing methanone: On or a pharmaceutically acceptable salt thereof.

[Formula 1]

[Formula 2-2]
The method of claim 1,

The amine compound of formula 2-2 is

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]
The method of claim 1,

To the compound of formula 2-1,

1) preparing a compound of formula 3 by dehydrating condensation reaction of 4-chloro-3-nitrobenzoic acid of formula 4 with piperidine; And

2) preparing a compound of formula 2-1 by reacting a compound of formula 3 with 3-methylbenzylamine;

Manufacturing method characterized in that it is manufactured as.

[Formula 2-1]

[Formula 3]

[Formula 4]
An amine compound represented by the following formula (2).

[Formula 2]

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