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

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

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WO2014104607A1
WO2014104607A1 PCT/KR2013/011221 KR2013011221W WO2014104607A1 WO 2014104607 A1 WO2014104607 A1 WO 2014104607A1 KR 2013011221 W KR2013011221 W KR 2013011221W WO 2014104607 A1 WO2014104607 A1 WO 2014104607A1
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methyl
methylbenzyl
benzo
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김용주
박태교
우성호
이대연
정은미
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주식회사 레고켐 바이오사이언스
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Priority to CN201380068185.3A priority Critical patent/CN104870436B/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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  • 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.
  • 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.
  • PAR-2 prote activated receptor-2
  • 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.
  • a catalyst for example, Raney-nickel, palladium-carbon, palladium oxide, platinum, platinum black, platinum oxide, platinum carbon sulfide, rhodium, ruthenium, alumina, etc.
  • transition metals for example, Raney-nickel, palladium-carbon, palladium oxide, platinum, platinum black, platinum oxide, platinum carbon sulfide, rhodium, ruthenium, alumina, etc.
  • ammonium formate, sodium dihydrogenphosphate, hydrazine may be used as the hydrogen source.
  • the reducing agent may be used in stoichiometric amounts or in excess, and generally in excess.
  • 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.
  • 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.

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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-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온의 제조방법(2-Methyl-1- (3-methylbenzyl) -1H-benzo [d] imidazol-5yl) (piperidin-5-yl) methanone
본 발명은 PAR-2 (protease activated receptor-2) 저해제로 활성이 있는 화합물로 공지된 하기 화학식 1로 표시되는 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하는 방법 및 그 중간체에 관한 것이다.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.
[화학식 1][Formula 1]
Figure PCTKR2013011221-appb-I000001
Figure PCTKR2013011221-appb-I000001
하기 구조의 화학식 1의 2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온은 PAR-2 (protease activated receptor-2) 저해제로 활성이 있으며 아토피 피부염 등을 포함한 염증성 피부질환에 있어 항염 기능을 지닌 조성물로서 사용이 가능하다. 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.
[화학식 1][Formula 1]
Figure PCTKR2013011221-appb-I000002
Figure PCTKR2013011221-appb-I000002
상기 화합물에 대한 PAR-2 저해제로의 효능 및 제조방법은 ㈜네오팜과 본 발명자들에 의해 출원된 국제공개특허 WO12/026766 에 명시되어 있다. 해당 특허에 명시되어 있는 상기 화합물의 제조방법은 하기 반응식 1과 같다. 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.
[반응식 1]Scheme 1
Figure PCTKR2013011221-appb-I000003
Figure PCTKR2013011221-appb-I000003
상기 제조방법은 4-플루오로-니트로벤조산을 출발물질로 하여 보호기의 도입, 친핵성 치환반응을 통한 벤질아민기의 도입, 니트로기의 환원반응, 벤조이미다졸의 고리화 반응, 탈보호기화, 및 탈수 축합반응을 거친다. 그러나 상기 방법은 전체 반응 단계가 길며 전체 수율이 높은 편이 아니며, 대다수의 각 단계별 정제 공정에서 관크로마토그래피를 시행하여야 하므로 대량생산에는 적합하지 않다. 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.
본 발명자들은 전술한 기존의 제조방법의 문제점에 대하여 예의 연구한 결과, 기존의 제조방법과 비교하여, 보호기의 도입 및 탈보호기화 과정을 제거하여 반응 단계를 줄이고, 비용 절감과 효과적인 결정화의 이점이 있는 새로운 중간체들을 발견함으로써 본 발명을 완성하였다.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.
따라서 본 발명의 목적은 전체 반응단계를 줄이며, 전체 수율은 높이며, 분리 및 정제 방법에 있어서도 산업 규모의 합성에 적합한 결정화 방법이나 추출 방법 등을 사용하여 선행 기술과 비교하여 좀 더 단순하고 경제적이며 높은 순도로 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하는 방법을 제공하는 것이다.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.
또한, 본 발명의 다른 목적은 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하는데 사용되는 제조중간체 및 그의 제조방법을 제공하는 것이다.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.
본 발명은 PAR-2 (protease activated receptor-2) 저해제로 활성이 있으며 아토피 피부염 등을 포함한 염증성 피부질환에 있어 항염 기능을 지닌 조성물로서 사용이 가능한 화학식 1의 화합물인 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하는 방법 및 그 중간체에 관한 것이다. 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.
또한, 하기 화학식 1의 화합물은 다양한 형태의 염을 만들 수도 있으며, 본 발명은 이러한 염의 형태까지도 포함한다. 이 방법은 산업적 규모로 적용될 수 있으며, 특히 본 발명은 신규한 중간체를 이용함으로써 기존의 제조방법에서 반드시 거쳐야 했던 보호기의 도입 및 탈보호기화 과정이 필요 없기 때문에 전체 반응 단계를 줄이고, 비용 절감과 효과적인 결정화의 이점이 있다. 또한, 본 발명은 산업 규모에 적합한 화학적 제조방법을 위해, 비용 절감과 효과적인 결정화의 이점이 있는 중간체로 유용한 신규 아민 화합물 및 그의 부가염 및 이를 제조하는 방법을 포함한다.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.
[화학식 1][Formula 1]
Figure PCTKR2013011221-appb-I000004
Figure PCTKR2013011221-appb-I000004
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 반응식 2에 도시한 바와 같이, As the present invention is shown in Scheme 2,
1) 하기 화학식 4의 4-클로로-3-니트로벤조산과 피페리딘을 탈수 축합반응시켜 시켜 하기 화학식 3의 화합물을 제조하는 단계;1) preparing a compound of formula 3 by dehydrating condensation reaction of 4-chloro-3-nitrobenzoic acid of formula 4 with piperidine;
2) 하기 화학식 3의 화합물과 3-메틸 벤질아민을 반응시켜 하기 화학식 2-1의 화합물을 제조하는 단계;2) preparing a compound of formula 2-1 by reacting a compound of formula 3 with 3-methylbenzylamine;
3) 화학식 2-1의 화합물의 니트로기를 환원시켜 화학식 2-2의 아민 화합물을 제조하는 단계; 및3) reducing the nitro group of the compound of formula 2-1 to prepare an amine compound of formula 2-2; And
4) 하기 화학식 2-2의 아민 화합물을 고리화 반응시켜 화학식 1의 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하는 단계를 포함하는 화학식 1의 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온 또는 이들의 약제학적으로 허용되는 염의 제조방법을 제공한다.(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.
[반응식 2]Scheme 2
Figure PCTKR2013011221-appb-I000005
Figure PCTKR2013011221-appb-I000005
이하, 각 단계에 대해 구체적으로 설명한다.Hereinafter, each step will be described in detail.
[a단계] 화학식 3의 화합물의 제조[a step] Preparation of the compound of Formula 3
화학식 3으로 표시되는 화합물은 출발 물질인 화학식 4의 4-클로로-3-니트로벤조산과 피페리딘을 탈수축합 반응시켜 얻는다. 이러한 탈수축합 반응은 유기합성 분야에 잘 알려져 있으며, 다양한 방법으로 시행될 수 있다. 출발 물질인 4-클로로-3-니트로벤조산은 일반적인 시약 제조업체로부터 구입하거나, 또는 간단한 공지의 방법 (미국 특허 제 4,036,838호)에 따라서 4-클로로벤조산의 니트로화반응을 통하여 쉽게 얻을 수 있다. 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).
상기 반응은 다이클로로메탄을 용매에서 염화 티오닐을 가하여 4-클로로-3-니트로 염화벤조일을 중간체로 얻은 후 피페리딘을 가하여 실온에서 교반하거나, 더욱 바람직하게는 1,1'-카보닐다이이미다졸 (CDI), 또는 1-[3-(다이메틸아미노)프로필]-3-에틸카보다이이마이드 (EDC)와 같은 활성제와 반응시킨 후 피페리딘을 가하여 실온에서 교반하여 얻을 수 있다. 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.
본 발명의 구체적인 예에서, 상기 화합물은 공지의 방법 (미국 특허 제6,313,115 B1)을 따라 화학식 4의 4-클로로-3-니트로벤조산과 1,1'-카보닐다이이미다졸을 에틸 아세테이트 용매에서 반응시킨 후, 피페리딘을 가하여 실온에서 교반시킴으로써 수행되었다. 워크-업에는 증류수를 가하고 유기층을 추출한 뒤 용매를 제거하여 황색 고체를 얻었다. 필요한 경우, 에탄올을 사용하여 재결정법으로 정제하여 목적하는 화학식 3의 화합물을 높은 순도로 얻을 수 있다.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
화학식 2-1의 화합물은 화학식 3으로 표시되는 화합물과 3-메틸 벤질아민을 유기용매에서 환류교반시켜 친핵성치환 반응을 수행하여 얻는다. 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.
이때 사용 가능한 용매로는 아세토나이트릴 등의 나이트릴류; 에탄올, 아이소프로판올 등의 알코올류; 테트라하이드로퓨란, 다이아이소프로필에테르, 다이옥산, 1,2-다이메톡시에탄 등의 에테르류; 벤젠, 톨루엔 등의 방향족 탄화수소류; 다이메틸아세트아마이드, 다이메틸포름아마이드, n-메틸 피로리돈 등의 아마이드류를 예시할 수 있으나, 본 발명은 이들 불활성 용매에 한정되지 않으며, 이들 용매는 단독으로 또는 혼합하여 사용할 수도 있다. 바람직하게는 다이메틸아세트아마이드 또는 n-메틸 피로리돈 등이 적당하며, 더욱 바람직하게는 n-메틸 피로리돈이 좋다. 반응 온도는 60 내지 130℃의 온도 범위에서 수행할 수 있으나, 바람직하게는, 100 내지 120℃의 온도에서 수행될 수 있다. 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.
이 반응은 3-메틸 벤질아민의 사용량에 따라 염기 존재 또는 부재하에서도 할 수 있는데 화학식 3으로 표시되는 화합물 대비 3-메틸 벤질아민을 2.5 당량 이상의 과량으로 사용하는 경우에는 염기를 사용하지 않을 수도 있으나, 바람직하게는 1.2 당량의 3-메틸 벤질아민을 사용하고 0.6 내지 1.2 당량의 염기를 사용하는 것이 좋다. 적절한 염기에는 예를 들어 탄산나트륨, 탄산칼륨 또는 탄산칼슘과 같은 알칼리금속 및 알칼리토금속 탄산염; 수산화나트륨, 수산화칼륨, 수산화칼슘과 같은 알칼리금속 및 알칼리토금속 수산화염; 초산나트륨, 초산칼륨, 초산암모늄과 같은 아세트산염; 트리에틸아민, 다이에틸아이소프로필아민, 피콜린 또는 피리딘과 같은 유기염기; 및 인산칼륨과 같은 인산염이 포함된다. 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.
재결정화에 사용되는 용매는 메탄올, 에탄올, n-프로판올, 아이소프로판올, n-부탄올, 아이소부탄올과 같은 C1-C4 알콜; 에틸 아세테이트와 같은 C4-C8 에스테르; t-부틸 메틸 에테르, 아이소프로필 에테르와 같은 C4-C8 에테르; 또는 상술한 용매 혼합물 또는 상술한 용매와 물의 혼합물을 포함한다. 화학식 2-1의 화합물의 추가의 정제를 위한 재결정화의 가장 적절한 예는 에탄올로부터의 재결정화이다.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.
본 발명의 구체 예에서, 상기 반응은 n-메틸 피로리돈을 용매로 사용하고 화학식 3의 화합물과 1.2 당량의 3-메틸 벤질아민, 1.2 당량의 탄산수소나트륨을 사용하여 120℃에서 2시간동안 환류 교반함으로써 수행하였다. 워크-업에는 반응물을 실온으로 냉각한 후 에틸 아세테이트로 묽히고 수산화나트륨 수용액 및 증류수로 세척한 후 유기용매를 제거하여 얻은 고체 잔류물을 에탄올에서 재결정을 통해 얻는 방법을 사용한다.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
화학식 2-2로 표시되는 아민 화합물은, 상기 반응에서 얻어진 화학식 2-1의 화합물을 불활성 용매 중에서 니트로 기를 환원시켜 얻는다. 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.
상기 본 반응에서 사용할 수 있는 불활성 용매로는 본 반응의 진행을 현저히 저해하지 않는 것이면 사용가능하며, 예를 들면 메탄올, 에탄올, 프로판올 등의 알코올; 테트라히드로퓨란, 다이아이소프로필에테르, 다이옥산, 1,2-다이메톡시에탄 등의 에테르류; 아세트산 등의 유기산; 염산 등의 무기산, 물 등을 들 수 있다. 상기 니트로기의 환원은 환원제를 이용하거나 접촉수소첨가법으로 수행할 수 있다. 본 반응에서 사용할 수 있는 환원제로는, 보란 복합체, 다이보란, 소듐 보로하이드리드, 리튬 보로하이드리드, 소듐 보로하이드리드-염화리튬, 알루미늄 리튬 하이드리드, 또는 다이아이소부틸알루미늄 하이드리드와 같은 금속성 환원시약; 산성조건하에서는 예를 들면 아연, 철, 주석 및 염화주석 등과 같은 금속을 들 수 있고, 아연만은 중성 또는 염기성 조건하에서도 사용할 수 있다. 또, 접촉수소첨가법에서는 상압 또는 기압하에서 반응할 수 있으며, 촉매로, 예를 들면 라니-니켈, 팔라듐-탄소, 산화팔라듐, 백금, 백금흑, 플래티늄 옥사이드, 황화 백금탄소, 로듐, 루테늄, 알루미나 등 전이 금속을 사용한다. 촉매 환원이 적용되는 경우, 암모늄 포메이트, 소듐 다이하이드로젠포스페이트, 하이드라진이 수소 원으로 사용될 수도 있다. 환원제 사용량은 산성조건하에서 반응을 행할 경우, 환원제는 화학양론적 양 내지 과량으로 사용할 수 있고, 일반적으로는 과량 사용한다. 접촉환원법에서는 라니-니켈 등을 사용하는 경우는 화학식 2-1의 화합물의 중량에 대해 5 내지 30중량%, 백금, 팔라듐 등의 귀금속 촉매를 사용하는 경우는 동일하게 0.02 내지 30중량%의 비율로 사용할 수 있다. 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.
반응온도는 0 내지 150℃ 범위 중에서 선택하여 사용할 수 있고, 바람직하게는 10 내지 110℃ 범위에서 수행할 수 있다. 반응시간은 반응량, 반응온도 등에 따라 일정하지 않으나, 수분 내지 48시간의 범위 중에서 선택할 수 있다. 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
화학식 1의 화합물은 화학식 2-2의 아민 화합물을 오소아세테이트(orthoacetate)와 함께 아세트산에서 반응시켜 벤조이미다졸 고리를 만들어 얻어진다. 이 때, 벤조이미다졸 고리화 반응은 아세트산을 용매로 하여 과량의 트리메틸오소포메이트(trimethylorthoformate)와 환류 교반시키는 것이 바람직하다.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.
결정화에 사용되는 용매는 톨루엔, 자일렌과 같은 탄화수소; 에틸 아세테이트와 같은 C4-C8 에스테르; t-부틸 메틸 에테르, 아이소프로필 에테르와 같은 C4-C8 에테르; 또는 상술한 용매 혼합물을 포함한다. 화학식 1의 화합물의 추가의 정제를 위한 재결정화의 가장 적절한 예는 에틸 아세테이트로부터의 재결정화이다.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.
화학식 1의 화합물은 다양한 형태의 염으로 만들 수도 있으며 이때 가능한 염으로는 약제로 사용할 수 있는 가능한 모든 염을 포함한다. 약제학적으로 허용가능한 염은 약제학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염을 포함한다. 상기 유리산으로는 무기산과 유기산을 모두 사용할 수 있으며, 사용되는 무기산은 염산, 브롬산, 황산 및 인산 등이 있으며, 사용되는 유기산은 구연산, 초산, 젖산, 말레인산, 우마린산, 글루콘산, 메탄술폰산, 글리콘산, 숙신산, 4-톨루엔술폰산, 트리플루오로아세트산, 갈룩투론산, 엠본산, 글루탐산 및 아스파르트산 등이 있다. 또한 본 발명은 상기한 화학식 1의 화합물의 염의 수화물을 포함하며, 특히 상기한 염이 흡습성을 갖는 경우 결정성을 갖는 수화물 형태의 사용하는 경우 유용하다.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.
본 발명에서 사용되는 용매 및 시약은 당업계에게 알려진 그의 기능적 대체물 또는 유도체로 대체될 수 있으며, 반응 시간 및 온도 등의 반응 조건은 반응을 최적화하기 위해 조정될 수 있다. 본 발명과 유사하게, 반응으로부터 생성물은 분리될 수 있고, 경우에 따라, 추출, 결정화, 및 트리투레이션(trituration)과 같은 당업계에 일반적인 방법에 따라 추가로 정제될 수 있다. 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.
또한, 본 발명은 화학식 1의 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하기 위한 중간체로 하기 화학식 2로 표시되는 신규한 아민 화합물을 제공한다.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).
[화학식 2][Formula 2]
Figure PCTKR2013011221-appb-I000006
Figure PCTKR2013011221-appb-I000006
식 중, R은 니트로기(NO2) 또는 아미노기(NH2)를 나타낸다.In the formula, R represents a nitro group (NO 2 ) or an amino group (NH 2 ).
이상에서 살펴본 바와 같이 본 발명에 따라, 새로운 중간체 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, 분리 및 정제 방법에 있어서도 산업 규모의 합성에 적합한 결정화 방법이나 추출 방법 등을 사용하여 선행 기술과 비교하여 경제적이며 높은 순도로 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 산업적 규모로 합성할 수 있다.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.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 및 실험예를 제시한다. 그러나 하기의 실시예 및 실험예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.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
화학식 3의 화합물의 제조Preparation of Compound of Formula 3
1,1'-카보닐다이이미다졸 (4.22 g, 26.04 mmol)을 에틸 아세테이트 50 mL에 녹인 후 실온에서 천천히 4-클로로-3-니트로벤조산 (화학식 4, 5.00 g, 24.80 mmol)을 가한 후 1시간동안 교반시켰다. 피페리딘 (2.7 mL, 27.3 mmol)을 천천히 가한 후 상온에서 1시간동안 교반시킨 후 6 N 염산 수용액 (30 mL, 2회), 탄산수소나트륨 포화수용액 (50 mL), 증류수 (50 mL), 염수 (50 mL)로 차례로 세척하였다. 유기층을 무수 황산나트륨 (20 g)으로 건조 시킨 후 감압 농축하여 노란색 결정성 고체로 화학식 3의 화합물(6.39 g, 95%)을 얻었다.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.
1H NMR (600 MHz, chloroform-d1) 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). 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: C12H13ClN2O3 에 대하여 269 (M+H+)LCMS: 269 (M + H + ) for C 12 H 13 ClN 2 O 3
화학식 2-1의 화합물의 제조Preparation of Compound of Formula 2-1
화합물 3의 화합물 (5.00 g, 18.61 mmol)을 n-메틸 피로리돈 (15 mL)에 녹인 후 탄산수소나트륨 (1.88 g, 22.38 mmol)을 넣고 3-메틸 벤질아민 (2.8 mL, 22.3 mmol)을 실온에서 천천히 넣어주었다. 반응 혼합물을 120℃에서 2시간동안 환류교반시킨 뒤 에틸 아세테이트 60 mL로 묽히고 증류수 (50 mL)로 세척한 후, 유기층을 2 N 수산화나트륨 수용액 (40 mL, 2회), 증류수 (40 mL, 2회), 염수 (40 mL)로 차례로 세척한다. 유기층을 무수 황산나트륨 (20 g)으로 건조시킨 후 감압 여과하여 주황색 고체를 얻어, 이를 무수 에탄올에서 재결정을 하여 주황색의 결정성 고체로 화학식 2-1의 화합물을 (6.13 g, 93%)을 얻었다. 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%).
1H NMR (600 MHz, chloroform-d1) 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) 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: C20H23N3O3 에 대하여 354 (M+H+)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
에탄올과 물의 혼합 용매 (5 : 2, 28 mL)에 철 2.85 g (51.0 mmol)과 아세트산 1.5 mL를 넣고 120℃에서 2시간 동안 환류교반시킨 후 실온으로 식혀 화학식 2-1의 화합물 (3.00 g, 8.49 mmol)을 가해주고, 에탄올과 물의 혼합용매 (5 : 2, 14 mL)를 더 가한다. 상기 반응물을 110℃에서 1시간 동안 환류교반시킨 후 뜨거운 상태로 celite를 이용하여 감압 여과하고 뜨거운 에탄올로 씻어준다. 여액을 농축하여 pH 8 이상이 될 때까지 2 N 수산화나트륨 수용액을 가하고 에틸 아세테이트 (50 mL, 2회)로 추출한다. 유기층을 모아서 이를 다시 탄산나트륨 포화용액 (20 mL, 2회), 증류수 (30 mL, 2회), 및 염수 30 mL로 세척한 뒤, 무수 황산나트륨으로 건조하고 감압 농축하여 베이지색 고체로 화학식 2-2의 화합물 (2.74 g, 99%)을 얻었다. 화학식 2-2의 아민 화합물은 더 이상의 정제과정 없이 곧바로 다음 합성에 이용할 수 있다.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.
1H NMR (600 MHz, chloroform-d1) 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) 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: C20H25N3O 에 대하여 324 (M+H+)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
상기 반응에서 얻은 화학식 2-2의 아민 화합물 (2.74 g, 8.48 mmol)을 아세트산 (16 mL) 와 트리에틸오소아세테이트 (4.6 mL, 25.1 mol)에 넣고 2시간 동안 환류교반 시켰다. 용매를 감압 농축시키고 에틸 아세테이트 (50 mL)로 묽힌 뒤 pH 8 이상이 될 때까지 탄산나트륨 포화용액을 가하고, 분액깔대기로 유기층을 분리하였다. 유기층을 증류수 (40 mL)와 염수 (40 mL)로 세척한 후 무수 황산나트륨으로 건조한 후 여과하고, 감압 농축하여 황색 고체를 2.75 g 얻었다. 이를 3 mL의 에틸 아세테이트로 재결정하여 백색의 고체로서 화학식 1의 화합물 (2.23 g, 76%)을 얻었다.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.
1H NMR (600 MHz, chloroform-d1) 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) 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: C22H25N3O 에 대하여 347 (M+H+)LCMS: 347 (M + H + ) for C 22 H 25 N 3 O
이상에서 살펴본 바와 같이 본 발명에 따라, 새로운 중간체 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, 분리 및 정제 방법에 있어서도 산업 규모의 합성에 적합한 결정화 방법이나 추출 방법 등을 사용하여 선행 기술과 비교하여 경제적이며 높은 순도로 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 산업적 규모로 합성할 수 있다.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.

Claims (4)

  1. 하기 화학식 2-2의 아민 화합물을 고리화 반응시켜 화학식 1의 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온을 제조하는 단계를 포함하는 하기 화학식 1의 (2-메틸-1-(3-메틸벤질)-1H-벤조[d]이미다졸-5일)(피페리딘-5-일)메탄온 또는 이들의 약제학적으로 허용되는 염을 제조하는 방법.(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.
    [화학식 1][Formula 1]
    Figure PCTKR2013011221-appb-I000007
    Figure PCTKR2013011221-appb-I000007
    [화학식 2-2][Formula 2-2]
    Figure PCTKR2013011221-appb-I000008
    Figure PCTKR2013011221-appb-I000008
  2. 제 1항에 있어서, The method of claim 1,
    하기 화학식 2-2의 아민 화합물은,The amine compound of formula 2-2 is
    화학식 2-1의 화합물의 니트로기를 환원시켜 화학식 2-2의 아민 화합물을 제조하는 단계로 제조되는 것을 특징으로 하는 제조방법.Reducing the nitro group of the compound of formula 2-1 to produce an amine compound of formula 2-2.
    [화학식 2-2][Formula 2-2]
    Figure PCTKR2013011221-appb-I000009
    Figure PCTKR2013011221-appb-I000009
    [화학식 2-1][Formula 2-1]
    Figure PCTKR2013011221-appb-I000010
    Figure PCTKR2013011221-appb-I000010
  3. 제 1항에 있어서, The method of claim 1,
    하기 화학식 2-1의 화합물은, To the compound of formula 2-1,
    1) 하기 화학식 4의 4-클로로-3-니트로벤조산과 피페리딘을 탈수 축합반응시켜 하기 화학식 3의 화합물을 제조하는 단계; 및1) preparing a compound of formula 3 by dehydrating condensation reaction of 4-chloro-3-nitrobenzoic acid of formula 4 with piperidine; And
    2) 하기 화학식 3의 화합물과 3-메틸 벤질아민을 반응시켜 하기 화학식 2-1의 화합물을 제조하는 단계;2) preparing a compound of formula 2-1 by reacting a compound of formula 3 with 3-methylbenzylamine;
    로 제조되는 것을 특징으로 하는 제조방법.Manufacturing method characterized in that it is manufactured as.
    [화학식 2-1][Formula 2-1]
    Figure PCTKR2013011221-appb-I000011
    Figure PCTKR2013011221-appb-I000011
    [화학식 3][Formula 3]
    Figure PCTKR2013011221-appb-I000012
    Figure PCTKR2013011221-appb-I000012
    [화학식 4][Formula 4]
    Figure PCTKR2013011221-appb-I000013
    Figure PCTKR2013011221-appb-I000013
  4. 하기 화학식 2로 표시되는 아민 화합물.An amine compound represented by the following formula (2).
    [화학식 2][Formula 2]
    Figure PCTKR2013011221-appb-I000014
    Figure PCTKR2013011221-appb-I000014
    식 중, R은 니트로기(NO2) 또는 아미노기(NH2)를 나타낸다.In the formula, R represents a nitro group (NO 2 ) or an amino group (NH 2 ).
PCT/KR2013/011221 2012-12-28 2013-12-05 Method for preparing (2-methyl-1-(3-methylbenzyl)-1h-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone WO2014104607A1 (en)

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US6110935A (en) * 1997-02-13 2000-08-29 The Regents Of The University Of California Benzofurazan compounds for enhancing glutamatergic synaptic responses
CN1229351C (en) * 1998-05-22 2005-11-30 西奥斯股份有限公司 Heterocyclic compounds and methods to treat cardiac failure and other disorders
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US4036838A (en) * 1974-01-09 1977-07-19 Bayer Aktiengesellschaft Process for the production of nitro derivatives of aromatic compounds
WO2012026766A2 (en) * 2010-08-25 2012-03-01 (주)네오팜 Novel heterocyclic compound, and composition for treating inflammatory diseases using same

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