Novel synthetic method of high-purity fexofenadine and intermediate

A fexofenadine, high-purity technology, applied in the field of chemical pharmacy, can solve the problems of difficulty in obtaining high-purity fexofenadine, affecting the quality of finished products, and high cost of raw materials, achieving mild conditions, convenient operation, and simple operation. Effect

Active Publication Date: 2015-04-29
CHIZHOU DONGSHENG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent CN102070512 uses p-cyanobenzoate as raw material to prepare fexofenadine through methylation, condensation, bromination or esterification, coupling and reductive hydrolysis. This method also avoids 3,4-position isomerism Body problem, but the route is long, the cost of raw materials is high, and a lot of waste is generated
[0006] Literature Synthetic Communications, 2011, 2296, reported a new route, using cumene as raw material, through Friedel-Crafts acylation, condensation, reduction, etherification, bromine Grignard reaction and deetherification to obtain fexofenadine, this route is shorter, but expensive protection reagents are used, and the cost is very high
All routes use the condensation reaction between the intermediate of amine heterocyclic alcohol and the halogenated intermediate. There are some unknown impurities in this step, which will affect the quality of the finished product. It is difficult to obtain high-purity fexofenadine.

Method used

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  • Novel synthetic method of high-purity fexofenadine and intermediate
  • Novel synthetic method of high-purity fexofenadine and intermediate
  • Novel synthetic method of high-purity fexofenadine and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] (1) Add 166.7 g (1.25 mol) of aluminum trichloride and 450 ml of dichloromethane to a 2-liter three-necked flask equipped with a mechanical stirrer and under the protection of nitrogen. After cooling to 0-5°C, add 140 ml dropwise (1.25mol) 4-Chlorobutyryl chloride (B), add dropwise within 30 minutes. Then 143g (1.19mol) cumene (A) was added dropwise within 40 minutes, keeping the internal temperature at 5-10°C. After continuing the reaction for 30 minutes, the reaction solution was carefully poured into 1 kg of ice water, slowly returned to room temperature under stirring, and the phases were separated, and the aqueous phase was extracted with 400 ml of dichloromethane. Combine the organic phases and wash once with 500 ml saturated sodium bicarbonate. Revolve the dichloromethane below 30℃ to obtain 280 g of yellow oil, crystallize it with a mixed solvent of isopropanol and water at -10℃, filter, wash the filter cake with isopropanol and water, and dry under vacuum to ob...

Embodiment 2

[0063] The 4-(4-chlorobutyryl)-α,α-dimethylbenzyl bromide (III) prepared in Example 1 above was used as the raw material. Add 300 ml of concentrated sulfuric acid, 60 g (0.2 mol) of raw material (III) into a 1L three-necked flask equipped with a mechanical stirrer and nitrogen protection, and then slowly add 55 g of anhydrous formic acid (D) dropwise at 20°C. Add time for about 3 hours and continue to react at room temperature for 2 hours. The reaction solution was slowly poured into 3L ice water, adjusted to pH 2.5 with 20% sodium hydroxide, extracted twice with 500 ml of toluene, combined the organic phases and washed once with 300 ml of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated Most of the toluene was distilled off, leaving about 300 ml of toluene solution, cooled and crystallized, filtered, the filter cake was washed with a small amount of cold toluene, and dried under vacuum to obtain 45 g of compound (IV) with a...

Embodiment 3

[0065] The 4-(4-chlorobutyryl)-α,α-dimethylbenzyl bromide (III) prepared in Example 1 above was used as the raw material. Add 300 ml of concentrated sulfuric acid into a 1L three-necked flask equipped with a mechanical stirrer and under the protection of nitrogen, and then slowly and dropwise add 55 g of anhydrous formic acid (D) and 60 g (0.2 mol) of raw material (III) at 20°C. 200 ml of carbon tetrachloride solution, dripped for about 3 hours, and continued to react at room temperature for 2 hours. The reaction solution was slowly poured into 3L ice water, adjusted to pH 2.5 with 20% sodium hydroxide, extracted twice with 500 ml of toluene, combined the organic phases and washed once with 300 ml of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated Distill out most of the toluene and carbon tetrachloride, leaving about 300 ml of mixed solution, cooling and crystallization, filtration, the filter cake is washed with a small a...

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PUM

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Abstract

The invention relates to a simple and efficient synthetic method of fexofenadine (chemical name: 4-{1-hydroxyl-4-[4-(hydroxyl benzhydryl)-1-piperidyl]-butyl}-alpha, alpha-dimethyl-phenylacetic acid (I)) and its intermediate. According to the method, isopropyl benzene is used as a raw material. Through a Friedel-Crafts acylation reaction, a halogenation reaction and a carbonyl insertion reaction, a key intermediate 4-(4-chloro-1-butyryl)-alpha, alpha-dimethyl phenylacetic acid (IV) is obtained; the key intermediate reacts with another raw material dibenzyl-(4-pyridyl)-methanol (E) to obtain a key pyridinium intermediate 4-{4-chloro-[4-hydroxydiphenylmethyl]-1-pyridinium]-1-butyryl}-alpha, alpha-dimethyl phenylacetic acid (V); and through catalytic hydrogenation and metallic hydrogen reduction, high-purity fexofenadine is obtained. The synthetic method provided by the invention has advantages of smooth process, simple reaction, short route, convenient post-treatment, high yield and low cost, and is a very ideal preparation method of fexofenadine and industrialization feasible route.

Description

technical field [0001] The present invention relates to fexofenadine, chemical name: 4-[1-hydroxyl-4-[4-(hydroxybenzhydryl)-1-piperidinyl]-butyl]-α,α-dimethyl -The synthetic method of phenylacetic acid and its intermediate, belongs to the technical field of chemical pharmacy. Background technique [0002] Fexofenadine (fexofenadine), chemical name (±) 4-[1-hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]-butyl]-α,α- Dimethyl-phenylacetic acid (I) is a histamine H1 receptor antagonist developed by Hoechest Marion Roussel in Germany. Its hydrochloride was first launched in the United States in 1996 under the trade name Allegra. It is mainly used clinically to treat seasonal Allergic rhinitis and chronic idiopathic urticaria. This product has no central nervous sedative effect, mild cardiac adverse reactions, compared with the first generation of antihistamines such as diphenhydramine (diphenhydramine) and chlorphenamine (chlorphenamine), it has stronger anti-allergic effect a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
CPCC07D211/22
Inventor 不公告发明人
Owner CHIZHOU DONGSHENG PHARMA
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