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Method for synthesizing ezetimibe

A technology of ezetimibe and compounds, which is applied in the field of ezetimibe synthesis, can solve the problems of large-scale industrial production and high production cost, harsh reaction conditions, and complex operation in the process, so as to avoid the use of chiral reagents , Reduction of reaction steps, beneficial to the effect of industrial production

Active Publication Date: 2014-10-01
HENAN ACADEMY OF SCI CHEM RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0026] During the synthesis of this route, air-sensitive metal compounds Li, LDA, and TiCl were involved many times. 4 etc., and the low temperature reaction at -78°C, and the use of Pd / C under high pressure to catalyze the hydrogenation of olefinic bonds, the process is complex and the reaction conditions are harsh
[0027] Each of the existing ezetimibe synthesis routes has its own advantages and disadvantages, but it is not suitable for large-scale industrial production and the high production cost is the main problem

Method used

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  • Method for synthesizing ezetimibe

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Experimental program
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Effect test

Embodiment 1

[0041] (1) Add 0.72g of aluminum trichloride (0.0054mol) to 0.90mL (0.0092mol) of fluorobenzene and mix well, add glutaric anhydride (0.3g, 0.0025mol) and fluorobenzene (1.1ml, 0.012 mol) of the mixed solution, after dropping, react at room temperature for 5 hours. After the reaction, cool in an ice bath, add 1.5mL of 1mol / L hydrochloric acid dropwise, then pour into ice water, a large amount of white solid precipitates, filter, wash the filter cake with ice water, then put the filter cake into 8mL of 10% sodium hydroxide React in the solution at 60°C for 1 hour, filter while hot, adjust the pH value of the filtrate to 1 with hydrochloric acid, place the solution at 0°C for 1-2 hours, filter, heat the filter cake with ethyl acetate to dissolve, filter while hot, and spin the filtrate to dry A white solid was obtained, which was dried to yield 0.7 g of compound 4 as a white solid.

[0042](2) Dissolve 0.7 g of compound 4 in dichloromethane, reflux at 50°C, slowly add 25 mL of ...

Embodiment 2

[0049] (1) Add 3.6g of aluminum trichloride (0.027mol) into 4.5mL (0.046mol) of fluorobenzene and mix well, add glutaric anhydride (1.5g, 0.0125mol) and fluorobenzene (5.5ml, 0.06 mol) of the mixed solution, after dropping, react at room temperature for 5 hours. Cool in an ice bath after the reaction, add 10mL of 1mol / L hydrochloric acid dropwise, then pour into ice water, a large amount of white solid precipitates, filter, wash the filter cake with ice water, then put the filter cake into 50mL of 10% sodium hydroxide solution React at 60°C for 1 hour, filter while hot, adjust the pH value of the filtrate to 1 with hydrochloric acid, place the solution at 0°C for 1 to 2 hours, filter, heat the filter cake with ethyl acetate to dissolve, filter while hot, and spin the filtrate to obtain The white solid was dried to obtain 3.06 g of compound 4 as a white solid.

[0050] (2) Dissolve 3.06g of compound 4 in dichloromethane, reflux at 70°C, slowly add 2.35mL of thionyl chloride dr...

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Abstract

The invention discloses a novel technical method for synthesizing ezetimibe (a compound 1), and belongs to the field of organic chemical medical synthesis. The method comprises the following steps: synthesizing a (3R, 4S)beta-lactam ring of a key intermediate (a compound 9) by taking p-anisaldehyde, 4-fluoroaniline and glutaric anhydride as main raw materials; and reducing and hydrolyzing the compound to obtain ezetimibe. The method disclosed by the invention adopts simply and easily-available materials, and is less in synthesis steps, and stable in process; a chiral four-membered ring of the key intermediate is directly constructed by virtue of one-step reaction to obtain an important intermediate (3R, 4S)-1-(4- fluorophenyl)-3-[(3S)-3-]4-fluorophenyl)-3-carbonyl propyl]-4-(4-methoxypheyl)-2-azetidinone (a compound 9); a target enantiomer proportion in the product is high, post-treatment operation is simple, and industrial large-scale production is easy to realize.

Description

technical field [0001] The invention relates to a synthesis method of ezetimibe, which belongs to the field of organic chemical medicine synthesis. Background technique [0002] Ezetimibe is a breakthrough in the research of blood lipid-lowering drugs. It was approved by the US FDA in 2002 and became the first lipid-lowering drug with a completely innovative mechanism of action since statins. The drug inhibits the absorption of cholesterol and phytosterols in food and bile at the brush border of the small intestine, reduces the transport of cholesterol from the intestine to the liver, reduces the storage of cholesterol in the liver, and increases the clearance of cholesterol in the blood, thereby reducing plasma cholesterol Level. [0003] As of 2011, ezetimibe's original single tablet and compound tablet have been approved by SFDA and launched in China. As people pay more and more attention to health, cholesterol-lowering drugs will have more and more potential for develo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08C07D201/02
CPCC07D205/08
Inventor 樊燕鸽李文锋赵俊宏薛宝玉段显英徐晓冰
Owner HENAN ACADEMY OF SCI CHEM RES INST CO LTD
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