Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof

A fexofenadine, high-purity technology, used in the field of chemical pharmacy, can solve problems such as poor reaction selectivity

Active Publication Date: 2011-05-25
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The first method can conveniently construct the para-substi...

Method used

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  • Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof
  • Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof
  • Synthesizing route and preparation method of high-purity fexofenadine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] At 20°C, add 30 g (0.75 mol) of sodium hydroxide and 140 ml of water into 2 g of tetra-n-butylammonium bromide and 21 g (0.12 mol) of methyl p-cyanomethylbenzoate, drop Add 53 g of dimethyl sulfate (0.42 mol), and drop it in about 1 hour. The reaction was continued for 4 hours. Add 100 milliliters of toluene and stir for 20 minutes, let stand, separate layers, extract the water liquid twice with 30×2 milliliters of toluene to combine the organic liquid, wash with water until neutral and recover the toluene under reduced pressure, and recover the toluene under reduced pressure (the recovered toluene continues to be applied to (2) and the resulting solid was recrystallized in isopropanol with a yield of 85%.

Embodiment 2

[0064] At 20°C, add 2 grams of tetra-n-butylammonium bromide and 23 g (0.12 mol) of ethyl p-cyanomethylbenzoate into 2 grams of tetra-n-butylammonium bromide and 23 g (0.12 mol) of ethyl p-cyanomethylbenzoate, drop Add 53 g of dimethyl sulfate (0.42 mol) in DMF, and drop it in about 1 hour. The reaction was continued for 4 hours, DMF was evaporated under reduced pressure, 100 ml of toluene was added and stirred for 20 minutes, allowed to stand, separated into layers, the aqueous liquid was extracted twice with 30×2 ml toluene to combine the organic liquid, washed with water until neutral and the toluene was recovered under reduced pressure, Toluene was recovered under reduced pressure (the recovered toluene was continuously used here), and the obtained solid was recrystallized in isopropanol with a yield of 88%.

Embodiment 3

[0066] At 5°C, add 2 grams of tetra-n-butylammonium bromide and 21 g (0.12 mol) of methyl p-cyanomethylbenzoate to 2 grams of tetra-n-butylammonium bromide and 21 g (0.12 mol) of methyl p-cyanomethylbenzoate, drop Add 53 g of dimethyl sulfate (0.42 mol), and drop it in about 1 hour. The reaction was continued for 4 hours. Add 100 ml of toluene and stir for 20 minutes (the original temperature is still maintained at this time), stand still, separate layers, extract the water liquid twice with 30×2 ml toluene to combine the organic liquid, wash with water until neutral and recover the toluene under reduced pressure, and recover under reduced pressure Toluene (recovered toluene continues to be used here), and the obtained solid is recrystallized in isopropanol with a yield of 90%.

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Abstract

The invention relates to a preparation method of high-purity fexofenadine (chemical name (+/-)-4-[1-hydroxyl-4-[4-(hydroxyldiphenylmethyl)-1-piperidyl]butyl]-alpha, alpha-dimethylphenylacetic acid) and an intermediate thereof and a novel synthesizing route. The method comprises the following steps of: with p-cyanomethylbenzoate (II) as a raw material, and with a new compound (Va) or salt (Vb) thereof as a key intermediate, hydrolyzing, esterifying or halogenating to obtain a compound (VII); and condensing, hydrolyzing and reducing with a piperdinol compound (VIII) to obtain a high-purity fexofenadine type compound (I) without para-position substitution. The invention has the advantages of simple reaction, convenience for postprocessing, higher yield and high purity of generated products and is a more ideal preparation method of fexofenadine.

Description

technical field [0001] The present invention relates to fexofenadine, chemical name: (±)-4-[1-hydroxyl-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]-α,α- The invention discloses a preparation method of dimethylphenylacetic acid and an intermediate thereof, belonging to the field of chemical pharmacy. Background technique [0002] Fexofenadine, chemical name (±)-4-[1-hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]butyl]-α,α-dimethyl Phenylacetic acid, the active ingredient in a non-sedating antihistamine sold in the United States under the trade name "Allegra". The drug has good antihistamine activity and belongs to the third-generation antihistamine without sedative effect. Compared with similar products such as astemizole, cetirizine and loratadine, it has good efficacy and extremely Low toxicity and side effects. [0003] US patent 4254129 discloses the synthesis method of fexofenadine for the first time. In this route, fexofenadine is obtained by the Friedel-Crafts ac...

Claims

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Application Information

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IPC IPC(8): C07D211/22C07C255/40C07C255/41C07C253/30C07C309/73C07C309/66C07C303/28C07D307/58
Inventor 王立新王文徐小英甘立新黄俊田芳贺光云
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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