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The synthetic method of ciprofibrate

A synthesis method and technology of dichlorocyclopropyl, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of easy polymerization, low yield of key intermediates, low yield and quality of compounds, etc. problems, to achieve the effect of low environmental pollution, cheap and easy-to-obtain raw materials, and convenient operation

Active Publication Date: 2017-12-01
HANGZHOU LUPU BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing synthetic method uses 1-phenyl-2,2-dichlorocyclopropane, 1-phenyl-2,2-dichlorocyclopropane or 4-methoxystyrene as the starting material, and there is a key intermediate The yield of the compound is low, and there is a great risk of operational safety in the scale-up production of the nitration reaction; the yield and quality of the compound are low; the starting material is expensive and hard to supply in the market, and its stability is poor, and it is prone to problems such as polymerization

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Alcoholysis reaction: Put 1mol of 4-(2,2-dichlorocyclopropyl)phenyl acetate, 300g of methanol, and 0.3mol of potassium carbonate into a 1L reaction bottle, and react at 20°C for 10 hours. There is no raw material in the HPLC control. Concentrate under pressure to obtain about 250 g of oil.

[0016] Alkylation reaction: put 1.8mol ethyl bromoisobutyrate, 2mol potassium carbonate, and 600g alcoholysis product into a 2L clean reaction bottle, heat up and reflux for 24 hours, control raw materials in HPLC <1%, cool down to 50°C, add Water 900g, separate the organic layer.

[0017] Alkaline hydrolysis reaction: add 400g of water to the organic layer, dropwise add 400g of 30% liquid caustic soda, keep the reaction at 15°C for 1.5 hours, no raw materials are controlled in the HPLC, add 500g of dilute sulfuric acid dropwise at 30°C, adjust the pH to 2.0, separate the organic layer, Concentrate under reduced pressure, add 300 g of petroleum ether, precipitate, filter with sucti...

Embodiment 2

[0019] Alcoholysis reaction: Put 1mol of 4-(2,2-dichlorocyclopropyl)phenyl acetate, 300g of methanol, and 0.5mol of potassium carbonate into a 1L reaction bottle, and react at 30°C for 11 hours. There is no raw material in the HPLC control. Concentrate under pressure to obtain about 255 g of oil.

[0020] Alkylation reaction: put 2mol ethyl bromoisobutyrate, 2.5mol potassium carbonate, and 600g alcoholysis product into a 2L clean reaction bottle, heat up and reflux for 24 hours, control raw materials in HPLC <1%, cool down to 50°C, add Water 900g, separate the organic layer.

[0021] Alkaline hydrolysis reaction: add 400g of water to the organic layer, dropwise add 400g of 30% liquid caustic soda, keep the temperature at 25°C for 2 hours, no raw materials are controlled in the HPLC, add 500g of dilute sulfuric acid dropwise at 40°C, adjust the pH to 2.0, separate the organic layer, Concentrate under reduced pressure, add 300 g of petroleum ether, precipitate, filter with suct...

Embodiment 3

[0023] Alcoholysis reaction: Put 1mol of 4-(2,2-dichlorocyclopropyl)phenyl acetate, 300g of methanol, and 0.6mol of potassium carbonate into a 1L reaction bottle, and react at 40°C for 12 hours. There is no raw material in the HPLC control. Concentrate under pressure to obtain about 250 g of oil.

[0024] Alkylation reaction: put 2.2mol ethyl bromoisobutyrate, 3mol potassium carbonate, and 600g alcoholysis product into a 2L clean reaction bottle, heat up and reflux for 24 hours, control raw materials in HPLC <1%, cool down to 50°C, add Water 900g, separate the organic layer.

[0025] Alkaline hydrolysis reaction: add 400g of water to the organic layer, dropwise add 400g of 30% liquid caustic soda, keep the reaction at 30°C for 3 hours, no raw materials are controlled in the HPLC, add 500g of dilute sulfuric acid dropwise at 50°C, adjust the pH to 2.0, separate the organic layer, Concentrate under reduced pressure, add 300 g of petroleum ether, precipitate, filter with suction...

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PUM

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Abstract

The invention relates to a synthesis method of ciprofibrate. In the synthesis method, acetic acid-4-(2,2-dichlorocyclopropyl) phenyl ester is adopted as a raw material, and 2-[4-(2,2-dichlorocyclopropyl) phenoxy]-2-methylpropanoic acid is obtained through alcoholysis, alkylation and alkaline hydrolysis processes. The synthesis method of ciprofibrate, provided by the invention, has the benefits that the raw materials used in the whole reaction are inexpensive and easy to get, the reaction conditions are mild, the operation is convenient, the yield is good, all solvents used in the reaction can be recycled, and the environmental pollution degree is low.

Description

technical field [0001] The invention relates to a synthesis method of ciprofibrate. Background technique [0002] Ciprofibrate is a phenoxyacetic acid hypolipidemic drug with a chemical name of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropionic acid, developed by Synthelabo in France. It is clinically used for type Ⅱ and type Ⅳ hyperlipoproteinemia that cannot be controlled by diet therapy. [0003] The existing synthetic method uses 1-phenyl-2,2-dichlorocyclopropane, 1-phenyl-2,2-dichlorocyclopropane or 4-methoxystyrene as the starting material, and there is a key intermediate The yield of the compound is low, and there is a great risk of operational safety in the scale-up production of the nitration reaction; the yield and quality of the compound are low; the starting material is expensive and the market supply is rare, and its stability is poor, and it is prone to problems such as polymerization . [0004] Therefore, it is necessary to improve the existing synthe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/31C07C69/712C07C51/09C07C59/72C07C37/055C07C39/42
CPCC07C37/0555C07C51/09C07C67/31C07C69/712C07C59/72C07C39/42
Inventor 唐保清徐国平秦国宏张邦礼傅志明
Owner HANGZHOU LUPU BIOTECH CO LTD
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