Preparation method of bilastine intermediate

Abstract

The invention discloses a preparation method of a bilastine intermediate, and particularly relates to a preparation method of 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazole-2-yl)-1-methyl-ethyl]phenyl}-ethyl)-piperidine-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole. The preparation method has the advantages of short steps, simple post-treatment and low cost, and is suitable for industrial production.

Description

technical field

[0001] The invention relates to a preparation method of a novel bilastine intermediate. Background technique

[0002] Bilastine, a second-generation histamine H1 receptor antagonist developed by FAES in Spain, was approved in the European Union in 2010. Bilastine is mainly used for the treatment of allergic rhinitis, urticaria and chronic asthma. The Chinese chemical name of bilastine is: 2-[4-(2-(4-(1-(2-ethoxyethyl)-benzimidazol-2-yl)piperidin-1-yl)ethyl Base) phenyl] -2-methyl propionic acid, its structural formula is as follows:

[0003]

[0004] The original research patent uses p-toluenesulfonyl chloride in the process of preparing the intermediate. Although the reaction conditions are mild in this step, the operation is cumbersome. Contents of the invention

[0005] The invention provides a bilastine intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1 -Methyl-ethyl] phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole ...

Examples

Embodiment 1

[0021] Embodiment 1: the synthesis of compound 2

[0022] 5.00 g (19.1 mmoL) of 4-[1-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1-methylethyl]phenethyl alcohol (compound 1) and di Add 50 mL of methyl chloride into a 250 mL single-necked bottle, start stirring, add 2.50 g (21.0 mmoL) of thionyl chloride dropwise, and stir for 45 minutes. Add 50 ml of water to wash, separate the layers, and concentrate the organic phase. Compound 2 was obtained, 4.02 g, yield 75.2%.

Embodiment 2

[0023] Embodiment 2: the synthesis of compound 2

[0024] 4-[1-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1-methylethyl]phenethyl alcohol (compound 1) 10.00 g (38.2mmoL) and chloroform Add 100mL into a 250mL single-necked bottle, start stirring, add 5.00 g (42.0mmoL) of thionyl chloride dropwise, and stir for 60 minutes. Add 100 ml of water to wash, separate the layers, and concentrate the organic phase. Compound 2 was obtained, 8.57g, yield 80.1%.

Embodiment 3

[0025] Embodiment 3: the synthesis of compound 3

[0026] Weigh 5.00g (17.9mmoL) of 2-{2-[4-(2-chloroethyl)phenyl]propyl}-4,5-dihydro-4,4-dimethyloxazole (compound 2) , 1-(2-ethoxy-ethyl)-2-piperidin-4-yl-1H-benzimidazole 5.37g (19.6mmoL), K 2 CO 3 Add 3.7 g and 50 mL of DMF into a 250 ml three-necked flask, heat to 90°C, and stir for 3 h. Cool down to room temperature, add 80 mL of water, filter with suction, collect the filter cake and put it in a blast oven for drying to obtain 7.70 g of the target compound 3 with a yield of 83.4%.

technical field

[0001] The invention relates to a preparation method of a novel bilastine intermediate. Background technique

[0002] Bilastine, a second-generation histamine H1 receptor antagonist developed by FAES in Spain, was approved in the European Union in 2010. Bilastine is mainly used for the treatment of allergic rhinitis, urticaria and chronic asthma. The Chinese chemical name of bilastine is: 2-[4-(2-(4-(1-(2-ethoxyethyl)-benzimidazol-2-yl)piperidin-1-yl)ethyl Base) phenyl] -2-methyl propionic acid, its structural formula is as follows:

[0003]

[0004] The original research patent uses p-toluenesulfonyl chloride in the process of preparing the intermediate. Although the reaction conditions are mild in this step, the operation is cumbersome. Contents of the invention

[0005] The invention provides a bilastine intermediate 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-2H-oxazol-2-yl)-1 -Methyl-ethyl] phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzimidazole ...

Examples

Embodiment 1

[0021] Embodiment 1: the synthesis of compound 2

[0022] 5.00 g (19.1 mmoL) of 4-[1-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1-methylethyl]phenethyl alcohol (compound 1) and di Add 50 mL of methyl chloride into a 250 mL single-necked bottle, start stirring, add 2.50 g (21.0 mmoL) of thionyl chloride dropwise, and stir for 45 minutes. Add 50 ml of water to wash, separate the layers, and concentrate the organic phase. Compound 2 was obtained, 4.02 g, yield 75.2%.

Embodiment 2

[0023] Embodiment 2: the synthesis of compound 2

[0024] 4-[1-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1-methylethyl]phenethyl alcohol (compound 1) 10.00 g (38.2mmoL) and chloroform Add 100mL into a 250mL single-necked bottle, start stirring, add 5.00 g (42.0mmoL) of thionyl chloride dropwise, and stir for 60 minutes. Add 100 ml of water to wash, separate the layers, and concentrate the organic phase. Compound 2 was obtained, 8.57g, yield 80.1%.

Embodiment 3

[0025] Embodiment 3: the synthesis of compound 3

[0026] Weigh 5.00g (17.9mmoL) of 2-{2-[4-(2-chloroethyl)phenyl]propyl}-4,5-dihydro-4,4-dimethyloxazole (compound 2) , 1-(2-ethoxy-ethyl)-2-piperidin-4-yl-1H-benzimidazole 5.37g (19.6mmoL), K 2 CO 3 Add 3.7 g and 50 mL of DMF into a 250 ml three-necked flask, heat to 90°C, and stir for 3 h. Cool down to room temperature, add 80 mL of water, filter with suction, collect the filter cake and put it in a blast oven for drying to obtain 7.70 g of the target compound 3 with a yield of 83.4%.

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