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Process for the preparation of (2-methyl-1-(3-methylbenzyl)-1h-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone

A technology of methylbenzyl and piperidine, which is applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, organic active ingredients, etc., can solve the problems of not being suitable for mass production and low overall yield, and reduce the total quantity , cost reduction effect

Inactive Publication Date: 2017-03-15
LEGOCHEM BIOSCIENCES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the disadvantage of this method is that the process consists of multiple reaction steps, the overall yield is not high and column chromatography is required in each step, making it not suitable for large-scale production

Method used

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  • Process for the preparation of (2-methyl-1-(3-methylbenzyl)-1h-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone
  • Process for the preparation of (2-methyl-1-(3-methylbenzyl)-1h-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone
  • Process for the preparation of (2-methyl-1-(3-methylbenzyl)-1h-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] [Example 1] Preparation of a compound represented by Chemical Formula 2-1

[0057] Preparation of compounds represented by chemical formula 3

[0058] 1,1'-carbonyldiimidazole (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) and stirred for 1 hour. Piperidine (2.7mL, 27.3mmol) was slowly added thereto and stirred at room temperature for 1 hour, then, the resulting mixture was sequentially washed with 6N hydrochloric acid solution (30mL, twice), saturated aqueous sodium bicarbonate (50mL), distilled water (50mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate (20 g) and concentrated under reduced pressure to obtain the compound represented by Chemical Formula 3 (6.39 g, 95%) as a yellow crystalline solid.

[0059] 1 H NMR (600MHz, chloroform-d 1 )δ=7.92(d, J=2.4Hz, 1H), 7.60(d, J=8.4Hz, 1H), 7.56(dd, J 1 =8.1Hz,J 2 =2.1Hz, 1H), 3.71(br, 2H), 3.35(br, 2H), 1....

Embodiment 2

[0065] [Example 2] Preparation of amine compound represented by Chemical Formula 2-2

[0066] Iron (2.85 g, 51.0 mmol) and 1.5 mL of acetic acid were added to a mixed solvent of ethanol and water (5:2, 28 mL) and stirred at 120° C. for 2 hours. After cooling to room temperature, the compound represented by Chemical Formula 2-1 (3.00 g, 8.49 mmol) was added thereto, and a mixed solvent of ethanol and water (5:2, 14 mL) was added thereto again. The reaction mixture was stirred at 110° C. for 1 hour and while it was still hot was filtered using celite under reduced pressure and washed with hot ethanol. The filtrate was concentrated and 2N aqueous sodium hydroxide was added until the pH was 8 or greater. Then, the resulting reaction mixture was extracted with ethyl acetate (50 mL, twice). The organic layer was collected, washed with saturated sodium carbonate solution (20 mL, twice), distilled water (30 mL, twice) and brine (30 mL) and dried over anhydrous sodium sulfate, then c...

Embodiment 3

[0069] [Example 3] Preparation of the compound represented by Chemical Formula 1

[0070]The amine compound represented by Chemical Formula 2-2 (2.74 g, 8.48 mmol) obtained in Example 2 was added to acetic acid (16 mL) and triethyl orthoacetate (4.6 mL, 25.1 mol) and stirred under reflux for 2 hours . The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (50 mL). Then, a saturated sodium carbonate solution was added thereto until the pH was 8 or more, and the organic layer was separated through a separatory funnel. The organic layer was washed with distilled water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to obtain a yellow solid (2.75 g). The solid was recrystallized with 3 mL of ethyl acetate to obtain the compound represented by Chemical Formula 1 (2.23 g, 76%) as a white solid.

[0071] 1 H NMR (600MHz, chloroform-d 1 )δ=7.74(t, J=0.6Hz, 1H), 7.30(dd, J 1...

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Abstract

The present invention relates to the preparation of (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazole-5 having activity as a protease-activated receptor-2 (PAR-2) inhibitor -yl)(piperidin-5-yl)methanone and its intermediates. When using the amine compound according to the present invention as a new intermediate compound to prepare (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl) represented by Chemical Formula 1 (Piperidin-5-yl)methanone, which has activity as a PAR-2 ​​inhibitor and can be used in the treatment and prevention of inflammatory diseases, reduces the overall Reaction steps, cost savings, efficient crystallization and increased overall yield. In addition, regarding the isolation and purification of the compound represented by Chemical Formula 1 as the final product, a crystallization method, an extraction method, etc. suitable for industrial-scale synthesis can be used, and thus will be very economical.

Description

technical field [0001] The present invention relates to a method for preparing (2-methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-5-yl) represented by the following chemical formula 1 Methods for ketones (which are known to have activity as protease activated receptor-2 (PAR-2) inhibitors) and intermediates thereof: [0002] [chemical formula 1] [0003] Background technique [0004] (2-Methyl-1-(3-methylbenzyl)-1H-benzo[d]imidazol-5-yl)(piperidin-5-yl)methanone represented by the following chemical formula 1 can be used as Compositions active as protease-activated receptor-2 (PAR-2) inhibitors and having anti-inflammatory function in inflammatory skin diseases including atopic dermatitis and the like. [0005] [chemical formula 1] [0006] [0007] International Patent Application No. WO12 / 026766 filed by Neopharm Co., Ltd. and the present inventors discloses the efficacy of compounds as PAR-2 ​​inhibitors and methods for their preparation. The prepa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/06A61K31/4439A61P29/00
CPCC07D295/192C07D401/06A61P29/00C07D235/08Y02P20/55A61K31/4439
Inventor 金容柱朴泰教禹成昊李坮衍郑恩美
Owner LEGOCHEM BIOSCIENCES INC