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Preparation method of bilastine oxide impurity

A technology for oxidizing impurities and bilastine, which is applied in the direction of organic chemistry, can solve problems affecting product quality and difficult removal, and achieve the effect of simple operation and high yield

Inactive Publication Date: 2017-01-18
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oxidation easily occurs during preparation and storage to produce 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-oxide-piperidine] Ethyl]-α,α-dimethylphenylacetic acid, the polarity of this impurity is close to that of bilastine, and both are relatively large, so it is difficult to remove by conventional methods, thus affecting the quality of the entire product

Method used

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  • Preparation method of bilastine oxide impurity
  • Preparation method of bilastine oxide impurity
  • Preparation method of bilastine oxide impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] 10g bilastine 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α- Dissolve dimethylphenylacetic acid in 80mL n-butanol, heat and stir until dissolved, add 12g hydrogen peroxide aqueous solution (30%) dropwise, after the dropwise addition, reflux for 11 hours, cool to room temperature, slowly crystallize, filter , washed, and recrystallized from methanol to obtain 8.7 g of a white solid, with a yield of 84%. 1 H NMR (d 6 -DMSO,500MH z , TMS), δ: 0.9935-1.0203 (t, 3H), 1.4220 (s, 6H), 1.9313-1.9567 (m, 2H), 2.5791-2.6543 (m, 2H), 3.1181 (m, 2H), 3.3400-3.3670 (m,3H),3.4775-3.5239(m,2H),3.6778-3.6859(m,4H),3.8485-3.8690(m,2H),4.4304(t,2H),7.0378-7.0528(m,2H),7.1744 -7.2034 (m, 2H), 7.2934-7.3086 (m, 2H), 7.5319-7.5959 (dd, 2H).

Embodiment 2

[0020] 10g bilastine 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α- Dissolve dimethylphenylacetic acid in 80mL of isopropanol, heat and stir until dissolved, add 11.2g of m-chloroperoxybenzoic acid in batches, reflux for 10 hours, cool to room temperature, slowly crystallize, filter, wash, and reconstitute with methanol After crystallization, 8 g of white solids were obtained with a yield of 78%. 1 H NMR (d 6 -DMSO,500MH z , TMS), δ: 0.9935-1.0203 (t, 3H), 1.4220 (s, 6H), 1.9313-1.9567 (m, 2H), 2.5791-2.6543 (m, 2H), 3.1181 (m, 2H), 3.3400-3.3670 (m,3H),3.4775-3.5239(m,2H),3.6778-3.6859(m,4H),3.8485-3.8690(m,2H),4.4304(t,2H),7.0378-7.0528(m,2H),7.1744 -7.2034(m,2H),7.2934-7.3086(m,2H),7.5319-7.5959(dd,2H)

Embodiment 3

[0022] 10g bilastine 4-[2-[4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidine]ethyl]-α,α- Dissolve dimethylphenylacetic acid in 80mL of n-butanol, heat and stir until dissolved, add 11g of manganese dioxide in batches, reflux for 9 hours, filter while hot, slowly crystallize the filtrate, wash, and obtain a white solid after methanol recrystallization 8.3 g, 80% yield. 1 H NMR (d 6 -DMSO,500MH z , TMS), δ: 0.9935-1.0203 (t, 3H), 1.4220 (s, 6H), 1.9313-1.9567 (m, 2H), 2.5791-2.6543 (m, 2H), 3.1181 (m, 2H), 3.3400-3.3670 (m,3H),3.4775-3.5239(m,2H),3.6778-3.6859(m,4H),3.8485-3.8690(m,2H),4.4304(t,2H),7.0378-7.0528(m,2H),7.1744 -7.2034(m,2H),7.2934-7.3086(m,2H),7.5319-7.5959(dd,2H)

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Abstract

The invention discloses a preparation method of a bilastine oxide impurity. The preparation method comprises that bilastine undergoes a reaction in an alcohol solvent in the presence of an oxidizing agent to produce a bilastine oxide impurity in a high yield. The bilastine oxide impurity can be used for quality control of a bilastine bulk drug or its preparation and can be used as an impurity contrast.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of oxidized impurities of bilastine. Background technique [0002] Bilastine is a second-generation oral non-sedative histamine H1 receptor antagonist, developed by Spanish FAES pharmaceutical company, approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria . The required dose of this product is small, the safety range is large, and it does not have the sedative effect on the central nervous system and the toxic and side effects on the cardiovascular system that commonly used antihistamines have. Its chemical structure is shown in formula II: [0003] [0004] Because bilastine contains a piperidine ring structure, the electron cloud density on the nitrogen is relatively large, and it is easily oxidized in the presence of an oxidizing agent. Oxidation easily occurs during preparat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 赵磊王晓林辉王正泽张丽林谢少斐李纬
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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