Preparation method of bilastine

A technology of bilastine and molar ratio, which is applied in the field of preparation of the compound of formula I of bilastine raw material medicine, and can solve the problem of generating quaternary ammonium salt by-products and the like

Pending Publication Date: 2020-04-03
上海天慈中商药业有限公司
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Problems solved by technology

[0005] The alkylation reaction of this method requires the use of flammable and explosive sodium hydrogen, and will generate quaternary ammonium salt by-products

Method used

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  • Preparation method of bilastine
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preparation example Construction

[0054] The preparation method of bilastine,

[0055] The present invention provides a kind of preparation method of bilastine, described method comprises steps:

[0056] (1) Formula II compound (for example, methyl 4-hydroxyethylphenyl tert-butyrate) is dissolved in the first solvent, adding oxidizing agent (for example, 2,2,6,6-tetramethylpiperidine oxide ( TEMPO) and sodium hypochlorite aqueous solution), oxidation to obtain the compound of formula III (such as, 4-acetaldehyde methyl phenyl tert-butyrate);

[0057]

[0058] (2) Formula III compound and 1-(2-ethoxyl-ethyl)-2-piperidin-4-yl-1H-benzimidazole hydrochloride (formula IV) are dissolved in the second solvent, under stirring React for a period of time (such as 1 hour), add a reducing agent (for example, sodium borohydride), and reductively aminate to obtain 4-[2-[1-(2-ethoxyethyl) benzimidazolyl] piperidinyl] Ethyl-phenylmethyl tert-butyrate (Formula V).

[0059]

[0060] (3) 4-[2-[1-(2-ethoxyethyl) benzimid...

Embodiment 1

[0076] 4-Hydroxyethylphenyl methyl tert-butyrate (222g) was dissolved in dichloromethane (1L), added 2,2,6,6-tetramethylpiperidine oxide (TEMPO) (1g), cooled to 0°C, add sodium hypochlorite aqueous solution (13%, 600mL) dropwise, stir for 1h, carry out post-treatment (i.e. liquid separation, the organic phase is successively washed with 10% aqueous sodium bisulfite solution (1L), saturated brine (1L), and concentrated in vacuo dry), to obtain methyl 4-acetaldehyde phenyl tert-butyrate (185 g), with a purity of 95.3%, and a yield of 83.3%.

Embodiment 2

[0078] Methyl 5-acetaldehyde phenyl tert-butyrate (220g) was dissolved in methanol (1.5L), and 1-(2-ethoxy-ethyl)-2-piperidin-4-yl-1H was added in portions - Benzimidazole hydrochloride (340g), stirred at room temperature for 1 hour, cooled to 0°C, added 10% methanolic sodium hydroxide solution (400mL), added sodium borohydride (76g) in batches, and reacted at room temperature for 2 hours, vacuum Concentrate to remove most of the methanol, add water (1.5L) dichloromethane (1.5L) to the residue, extract and separate the liquids, and concentrate the organic phase in vacuo to obtain 4-[2-[1-(2-ethoxyethyl)benzimidazole Base]piperidinyl]ethyl-phenyl-tert-butyric acid methyl ester (421g), purity: 96.2%; yield: 88.2%.

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Abstract

The invention provides a preparation method of bilastine. Specifically the method comprises the following steps: oxidizing 4-hydroxyethyl phenyl methyl tert-butyrate to obtain 4-acetaldehyde phenyl methyl tert-butyrate, and carrying out a reductive amination reaction on the 4-acetaldehyde phenyl methyl tert-butyrate and a compound represented by a formula IV to obtain 4-[2-[1-(2-ethoxyethyl)benzimidazolyl]piperidyl]ethyl-phenyl methyl tert-butyrate (represented by a formula V); and hydrolyzing and acidifying the compound represented by the formula V to obtain bilastine. The method is high in yield, simple to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a bilastine raw material compound of formula I. Background technique [0002] Bilastine is the second generation of histamine H developed by Spanish FAES pharmaceutical company 1 Receptor antagonist is a non-sedating long-acting antihistamine that selectively antagonizes peripheral H1 receptors, has no affinity for muscarinic receptors, and has low affinity for other receptors. For the treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticarial diseases. This product is safe, without the cardiotoxicity and sedative effects of commonly used antihistamines. [0003] Patents ES2151442A1, CN104402773A, Kong Hao, etc. (Chinese Journal of Pharmaceutical Industry, 2015, 46 (7)) reported the synthesis method of bilastine: [0004] [0005] The alkylation reaction of this method needs to use inflammable and explosive sodium...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 李函璞马西来李勇刚池王胄沙飞
Owner 上海天慈中商药业有限公司
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