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A kind of preparation method of fenofibrate key intermediate 4-chloro-4'-hydroxybenzophenone

A technology of hydroxybenzophenone and methoxybenzophenone, which is applied in the field of preparation of 4-chloro-4'-hydroxybenzophenone, a key intermediate of fenofibrate, can solve the problem that cannot be recycled and reused, The color of the product is deep and difficult to remove, polluting the environment and other issues

Active Publication Date: 2019-02-26
ZHEJIANG YONGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In 2010, Qiao Deyang et al. (Qiao Deyang, Li Gan et al. Research on the improvement of the synthesis process of 4-hydroxy-4'-chlorobenzophenone. Chemical World, 2010,5,295-297.), reported that for Friedel-Crafts After the reaction is completed, the catalyst and the product are not separated, and the post-treatment is directly carried out with water, and the temperature is controlled below 40 ° C to obtain the product directly from the water. The route is shown in the following formula 4, and the reaction yield is relatively high. A large amount of catalyst aluminum trichloride and the dark color of the product are difficult to remove
But there is following shortcoming: (1) anhydrous aluminum trichloride is very easy to form complex compound with reactant, needs to add excessive anhydrous aluminum trichloride for suppressing the generation of by product, thereby caused a large amount of waste of raw material; ( 2) Anhydrous aluminum trichloride is extremely sensitive to water, and will decompose when it encounters water, thereby releasing a large amount of hydrogen chloride gas and polluting the environment; (3) Dilute acid needs to be added, and ketone can be released at low temperature, resulting in a large amount of waste acid And aluminum-containing waste liquid, which is extremely corrosive, produces a large amount of aluminum sludge, which cannot be recycled and reused, causing environmental pollution and does not meet environmental protection requirements
Using anisole and p-chlorobenzoyl chloride as starting materials, using a new type of magnetic nanoparticle-supported Lewis acid as a catalyst, the method for catalytically synthesizing 4-chloro-4'-methoxybenzophenone has not been found in relevant literature and patents. to report

Method used

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  • A kind of preparation method of fenofibrate key intermediate 4-chloro-4'-hydroxybenzophenone
  • A kind of preparation method of fenofibrate key intermediate 4-chloro-4'-hydroxybenzophenone
  • A kind of preparation method of fenofibrate key intermediate 4-chloro-4'-hydroxybenzophenone

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Experimental program
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Embodiment 1

[0048] With formula (II) anisole (10.8g, 0.1mol), formula (III) p-chlorobenzoyl chloride (19.3g, 0.11mol) and catalyst AlCl 3 -IL-SiO 2 @γ-Fe 2 o 3 (20mol%, 27g), and 200mL of dichloromethane were added into a 500mL three-necked flask, mixed uniformly and heated to 60°C in a water bath, stirred, and reacted for 1h. After the reaction was completed (TLC detection), the catalyst was separated with a magnet and washed with ethyl acetate (3×20 mL). Combine the organic phases and wash with anhydrous MgSO 4 Drying and distillation under reduced pressure gave 22.23 g of 4-chloro-4'-methoxybenzophenone of formula (IV), with a yield of 90%. The separated catalyst is used in the next reaction.

Embodiment 2

[0050] With formula (II) anisole (10.8g, 0.1mol), formula (III) p-chlorobenzoyl chloride (19.3g, 0.11mol) and catalyst AlCl 3 -IL-SiO 2 @γ-Fe 2 o 3 (20mol%, 27g), and 200mL of dichloromethane were added into a 500mL three-necked flask, mixed uniformly and heated to 60°C in a water bath, stirred, and reacted for 1.5h. After the reaction was completed (TLC detection), the catalyst was separated with a magnet and washed with ethyl acetate (3×20 mL). Combine the organic phases and wash with anhydrous MgSO 4 Drying and distillation under reduced pressure gave 22.97 g of 4-chloro-4'-methoxybenzophenone of formula (IV), with a yield of 93%. The separated catalyst is used in the next reaction.

Embodiment 3

[0052] With formula (II) anisole (10.8g, 0.1mol), formula (III) p-chlorobenzoyl chloride (19.3g, 0.11mol) and catalyst AlCl 3 -IL-SiO 2 @γ-Fe 2 o 3 (20mol%, 27g), and 200mL of dichloromethane were added into a 500mL three-necked flask, mixed uniformly and heated to 120°C in a water bath, stirred, and reacted for 1.5h. After the reaction was completed (TLC detection), the catalyst was separated with a magnet and washed with ethyl acetate (3×20 mL). Combine the organic phases and wash with anhydrous MgSO 4 Drying and distillation under reduced pressure gave 22.65 g of 4-chloro-4'-methoxybenzophenone of formula (IV), with a yield of 91.7%. The separated catalyst is used in the next reaction.

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Abstract

The invention relates to a method for catalytically synthesizing 4-chloro-4'-methoxybenzophenone using anisole and p-chlorobenzoyl chloride as starting materials and using new magnetic nanoparticles loaded Lewis acid as a catalyst. The present invention uses a new type of magnetic nano-loaded Lewis acid as the catalyst, which has the following advantages: 1) The magnetic nano-loaded Lewis acid catalyst uses less amount and can be reused; 2) The reaction time is greatly shortened and the conversion rate and yield of the reaction are improved; 3 ) Magnetic nano-loaded Lewis acid catalysts are easy to separate and recover quickly, with simple processes and relatively low production costs.

Description

technical field [0001] The invention relates to a preparation method of fenofibrate key intermediate 4-chloro-4'-hydroxybenzophenone. Background technique [0002] 4-chloro-4'-hydroxybenzophenone (4-chloro-4'-hydroxybenzophenone, referred to as CBP, molecular formula C 13 h 9 ClO 2 , with a molecular weight of 232.66, off-white or off-white to reddish-white crystals, with a melting point of 177-181°C and a boiling point of 257°C), which is the key intermediate and pesticide product for the synthesis of the blood lipid-lowering drug Fenofibrate and It is an important raw material for the preparation of heat-resistant polymers, etc., and has a wide range of uses; among them, the application as an intermediate of the blood lipid-lowering drug fenofibrate is particularly important. There are two main methods for the synthesis of 4-chloro-4'-hydroxybenzophenone: one is the Friedel-Crafts acylation method, and the other is the Fries transposition rearrangement reaction method. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C45/46C07C49/84C07C45/61C07C49/83B01J31/28
CPCC07C45/46C07C45/61B01J31/28B01J2231/4205B01J35/33C07C49/84C07C49/83
Inventor 周国斌王莺妹黄锦峰张峰
Owner ZHEJIANG YONGTAI PHARMA
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