Ezetimible intermediate and synthetic method of ezetimible

A technology of ezetimibe and its intermediates, which is applied in the field of ezetimibe synthesis, and can solve the problems of long synthetic route, high dose of chiral reducing agent, low yield and purity, etc.

Inactive Publication Date: 2009-05-06
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In the route of synthesizing ezetimibe in the patent WO2007072088, the hydroxyl group on the chiral carbon of the 3-position branch is obtained by chiral reduction of the carbonyl group. Before the chiral reduction, the carbonyl group is protected by ethylene glycol for other chemical It is destroyed during the reaction, and the obtained intermediate compound IV and compound VI are relatively fine solid substances. In the process, a small part of the product will flow out with the filtrate, resulting in poor quality of the product, and it is diffi...

Method used

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  • Ezetimible intermediate and synthetic method of ezetimible
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  • Ezetimible intermediate and synthetic method of ezetimible

Examples

Experimental program
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Effect test

Embodiment 1

[0093] The synthetic method of formula II compound (wherein R1=H, R2=H)

[0094] Add 21.0g (0.1mol) of compound I and 50mL of dichloromethane into a 500mL reaction flask, and add 14.3mL (14.81g, 0.195mol) of 1,3-propanediol, 12mL of trimethyl orthoformate and 0.15mL of concentrated Sulfuric acid, the system was stirred and reacted at 40°C for 2 hours, and the reaction was complete by TLC; 25g of sodium bicarbonate solid was added, and after stirring for 15 minutes, 15mL of methanol was added to the residue, and 200mL of 10% sodium hydroxide was slowly added to the reaction system under the condition of ice-water bath cooling The solution was stirred continuously at a temperature of 20-25° C., and the reaction was carried out for 5 hours. TLC detected that the hydrolysis reaction was complete. Slowly add 150 mL of 10% citric acid solution to the reaction solution under cooling in an ice-water bath to make the pH value 1-2. Continue to stir for 30 minutes, add 200mL ethyl aceta...

Embodiment 2

[0096] The synthetic method of formula II compound (wherein R1=H, R2=H)

[0097] Add 21.0g (0.1mol) formula I compound, 50mL dichloromethane to 500mL reaction bottle, under continuous stirring, add 12.47.mL (12.92g, 0.17mol) 1,3-propanediol, 12mL trimethyl orthoformate and 0.15 mL of concentrated sulfuric acid, the system was stirred and reacted at 60°C for 3h, and the reaction was complete by TLC; 25g of sodium bicarbonate solid was added, and after stirring for 15min, 15mL of methanol was added to the residue, and 200mL of 10% The sodium hydroxide solution was stirred continuously at a temperature of 20-25° C., and the reaction was carried out for 5 hours. TLC detected that the hydrolysis reaction was complete. Slowly add 150 mL of 10% citric acid solution to the reaction solution under cooling in an ice-water bath to make the pH value 1-2. Continue to stir for 30 minutes, add 200mL ethyl acetate for extraction, then extract the aqueous solution twice with 50-50mL ethyl ace...

Embodiment 3

[0099] The synthetic method of formula II compound (wherein R1=H, R2=H)

[0100]Add 21.0g (0.1mol) formula I compound, 50mL dichloromethane to 500mL reaction bottle, under continuous stirring, add 18.34.mL (19g, 0.25mol) 1,3-propanediol, 12mL trimethyl orthoformate and 0.15mL Concentrated sulfuric acid, the system was stirred and reacted at 30°C for 4h, and the reaction was complete by TLC; 25g of sodium bicarbonate solid was added, and after stirring for 15min, 15mL of methanol was added to the residue, and 200mL of 10% hydroxide was slowly added to the reaction system under the condition of ice-water bath cooling. The sodium solution was stirred continuously at a temperature of 20-25° C., and the reaction was carried out for 5 hours. TLC detected that the hydrolysis reaction was complete. Slowly add 150 mL of 10% citric acid solution to the reaction solution under cooling in an ice-water bath to make the pH value 1-2. Continue to stir for 30 minutes, add 200mL ethyl acetate...

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Abstract

The invention provides an intermediate for synthesizing ezetimibe and a preparation process thereof, and also provides a method for synthesizing the ezetimibe by the intermediate. The synthesizing method has short route, and comprises the following concrete steps: a compound I and substituted 1, 3-propanediol react to generate a compound II; the compound II and pivalyl chloride react to generate a compound III; the compound III and a compound A react to generate a compound IV; the compound IV and a compound V react to generate a compound VI under the condition of a titanium compound catalyst; the compound VI is re-ringed to generate a compound VII with beta-lactam; the compound VII is hydrolyzed to produce a compound VIII; and the compound VII is reduced to a compound IX ezetimibe by a borane chiral reducing agent. The synthesization has short route and mild reaction condition; and the produced intermediate and final product has high yield and high purity.

Description

technical field [0001] The invention relates to the field of synthesis of ezetimibe, in particular to a method for synthesizing ezetimibe using an intermediate. Background technique [0002] Ezetimibe (Ezetimibe) was developed by Harry Davis, Margaret Van Heek and Kevin Alton at the Schering-Plough Research Center. In October 2002, Ezetimibe (Zetia) was approved by the FDA. It was first launched in Germany in November of the same year under the trade name ezetrol. Ezetimibe is the first selective cholesterol absorption inhibitor, which can interfere with the absorption of dietary cholesterol and cholesterol synthesized by the liver in the enterohepatic circulation without affecting the absorption of other nutrients. Its pharmacology only acts on the small intestine, and reduces the transport of intestinal cholesterol to the liver by inhibiting the absorption of cholesterol, reducing its storage; it can strengthen the removal of cholesterol in the blood, thereby reducing the...

Claims

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Application Information

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IPC IPC(8): C07D319/06C07D205/08A61P3/06
Inventor 黄仲斌戴连华韩勇
Owner ENANTIOTECH CORP
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