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Preparation method of fexofenadine intermediate

A technology of fexofenadine and intermediates, which is applied in the field of medicine and fine chemical industry, can solve the problems of short synthesis route, difficulty in separating and purifying product isomers, high price and the like

Inactive Publication Date: 2012-02-15
浙江华纳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the preparation of the catalyst and its expensive price limit its application in industrial production
[0012] 4. U.S. Patent US2011071295 discloses a method for synthesizing formula (I), which combines different fragments to form formula (I), which solves the problem of meta-isomer control, but uses expensive Pd catalyst, and in some reaction steps, HgO is used to oxidize the triple bond to obtain a carbonyl group, there are many by-products, and industrialization is difficult
[0013] 5. U.S. patents US4254129 and US6348597 have relatively short synthetic routes, and the disadvantage is that the products of the Friedel-Crafts reaction and the compounds of subsequent reactions have the problem of meta-isomers, and it is difficult to separate and purify product isomers

Method used

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  • Preparation method of fexofenadine intermediate
  • Preparation method of fexofenadine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1. Preparation of methyl α,α-dimethylphenylacetate (II).

[0038] Add 480kg of methanol into a 1000L reactor, add 100kg of α,α-dimethylphenylacetic acid under stirring, and stir to dissolve. Pass ice brine to cool down, and cool to -5°C to 0°C. Slowly add 15kg of concentrated sulfuric acid dropwise, after the addition is complete, stir for 30 minutes. Slowly raise the temperature and reflux for 4-5 hours, then distill off excess methanol. Cool down, dissolve the residue with 320kg of dichloromethane, wash with 160kg of 10% aqueous sodium bicarbonate solution twice (80kg each), wash twice with 160kg of water (80kg each), and dry with 5kg of anhydrous sodium sulfate 6 hours. Suction filtration, concentration and recovery of dichloromethane to obtain 94kg of oily product α,α-dimethylphenylacetic acid methyl ester (II).

Embodiment 2、4

[0039] Example 2, Preparation of 4-[4-chloro-1-butyryl]-α,α-dimethylphenylacetic acid methyl ester (Ⅲ).

[0040] Add 950kg of dried dichloromethane (dried with anhydrous calcium chloride or molecular sieves) into a 2000L reactor, add 172kg of anhydrous aluminum trichloride under stirring, and stir for 3 hours. Cool to -5°C ~ 0°C. Control the temperature at -10°C to -5°C, and slowly add 90kg of 4-chlorobutyryl chloride dropwise. After the dropwise addition was completed, the mixture was incubated and stirred for 3 hours.

[0041] Control the temperature of the system at -10 to 0°C, and slowly add 94kg of methyl α,α-dimethylphenylacetate (II). After the feeding is completed, keep stirring for 2 hours, then raise the temperature to 20-25°C and react for 24 hours, and the raw material point basically disappears as monitored by TLC.

[0042]Mix 380kg of water and 170kg of concentrated hydrochloric acid to prepare dilute hydrochloric acid, pass cooling brine to cool down to 0-5°C...

Embodiment 3

[0045] Example 3. Preparation of 4-[4-chloro-1-butyryl]-α,α-dimethylphenylacetic acid (IV).

[0046] Add 140kg of 4-[4-chloro-1-butyryl]-α,α-dimethylphenylacetic acid methyl ester (Ⅲ), 350kg of concentrated hydrochloric acid, 180kg of water and 700kg of glacial acetic acid into a 1000L reactor, and heat to reflux for about 40- 45 hours.

[0047] The reaction was terminated, and the glacial acetic acid was evaporated under reduced pressure. After most of the glacial acetic acid was evaporated, 150kg of water was added.

[0048] The reaction solution was extracted 3 times with dichloromethane (200kg for the first time, 160kg for the second time, and 160kg for the third time). Combine the extracted organic phases, wash 3 times with drinking water, each 150kg. The organic phase was stirred and dried with 8 kg of anhydrous sodium sulfate, filtered with suction, and dichloromethane was recovered from the filtrate, and the oily product 4-[4-chloro-1-butyryl]-α,α-dimethylphenylaceti...

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Abstract

The invention provides a preparation method of a fexofenadine intermediate 2-[4-[4-[4-(hydroxy diphenylmethyl)-1-piperidyl]-1-oxobutyl] phenyl]-2,2-dimethyl acetate, and belongs to the technical field of fexofenadine intermediate synthesis. Alpha-alpha-dimethyl phenylacetic acid is used as a raw material in the method; and the intermediate I is synthesized by the steps of esterification, Friedel-Crafts reaction, acid hydrolysis, purification, esterification, condensation and the like. The preparation method has the advantages that: the raw materials and the auxiliary materials are cheap and easily obtained, the process is smooth, the cost is low, the quality is high, the method is suitable for industrial scale production of medicines and the like.

Description

Technical field: [0001] The invention belongs to the field of pharmaceutical fine chemicals, in particular to a fexofenadine intermediate 2-[4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxo The synthetic method of substituted butyl] phenyl] -2,2-dimethyl acetate. Background technique: [0002] Fexofenadine (fexofenadine), chemical name (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α -Dimethylphenylacetic acid hydrochloride is a new generation of H1-receptor type antihistamine without sedative side effects, suitable for seasonal allergic rhinitis. This product is developed by Hoechst Marcon Roussel Company. Compared with similar products, it has good curative effect and extremely low toxic and side effects. It is produced from the key intermediate 2-[4-[4-[4-(hydroxybenzhydryl)-1-piperidinyl]-1-oxobutyl]phenyl]-2,2-dimethyl Acetate (formula Ⅰ) is obtained by hydrolysis, reduction, and salt formation. Its structural formula is as follows: [0003] ...

Claims

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Application Information

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IPC IPC(8): C07D211/22
Inventor 黄本东段新方王诗宏
Owner 浙江华纳药业有限公司
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