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A kind of ezetimibe intermediate compound

A technology of ezetimibe and intermediates, which is applied in the field of ezetimibe intermediate compounds, can solve the problems of incomplete reaction, unfavorable industrialized large-scale production, large impurities, etc., and achieve the effect of simple production and operation

Active Publication Date: 2020-08-14
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Compound Ⅰ reacts with substituted 1,3-propanediol to generate compound Ⅱ, which produces a six-membered heterocyclic ring. The six-membered ring is relatively stable and difficult to destroy, so the reaction is not complete, the impurities are large, and the yield is low, which increases the production cost. Facilitate large-scale industrial production
[0012] There are problems in the synthesis method of ezetimibe mentioned above, or the yield is low, the impurities are large, or the technical requirements are high, which increases the production cost. In summary, the cost of the synthesis method of ezetimibe in the prior art is relatively high , not conducive to large-scale industrial production

Method used

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  • A kind of ezetimibe intermediate compound
  • A kind of ezetimibe intermediate compound
  • A kind of ezetimibe intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] step 1:

[0067] Measure 180ml of tetrahydrofuran and dichloromethane mixed solvent (the ratio of the two is 1:3) into a 500ml round bottom flask, add 0.8gZnCl 2 And 2ml HCl, add 32ml trimethylorthoformate, react 4-(4-fluoro-benzoyl)-butyric acid (II) with ethanedithiol at 20°C for 4 hours. Add 5g of sodium bicarbonate to terminate the reaction. The solvent was evaporated, the residue was dissolved in 150ml of methanol, and cooled in an ice-water bath. During the cooling process, 100ml of 10% potassium hydroxide solution was added, the temperature was controlled at 25°C, and stirred for 30 minutes. Concentrate, add 300ml 10% tartaric acid solution to make the pH reach 3-4, extract twice with 200ml+100ml ethyl acetate, wash the organic phase with water until neutral, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and recrystallize from n-hexane to obtain 4-[2-(4-Fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). Yield 94.6%. ...

Embodiment 2

[0077] step 1:

[0078] Measure 180ml of tetrahydrofuran and dichloromethane mixed solvent (the ratio of the two is 1:3) into a 500ml round bottom flask, add 0.8gZnCl 2 And 2ml HCl, add 32ml trimethylorthoformate, react 4-(4-fluoro-benzoyl)-butyric acid (II) with ethanedithiol at 20°C for 4 hours. Add 5g of sodium bicarbonate to terminate the reaction. The solvent was evaporated, the residue was dissolved in 150ml of methanol, and cooled in an ice-water bath. During the cooling process, 100ml of 20% sodium hydroxide solution was added, the temperature was controlled at 25°C, and stirred for 30 minutes. Concentrate, add 300ml 10% tartaric acid solution to make the pH reach 3~4, extract twice with 200ml+100ml dichloromethane, wash the organic phase with water until neutral, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and recrystallize from n-hexane Obtain 4-[2-(4-fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV) . Yield 95.5%.

...

Embodiment 3

[0088] step 1:

[0089] Measure 180ml tetrahydrofuran into a 500ml round bottom flask, add 0.8g ZnCl 2 And 2ml HCl, add 32ml trimethylorthoformate, react 4-(4-fluoro-benzoyl)-butyric acid (II) with ethanedithiol at 20°C for 4 hours. Add 5g of sodium bicarbonate to terminate the reaction. The solvent was evaporated, the residue was dissolved in 150ml of methanol, and cooled in an ice-water bath. During the cooling process, 100ml of 30% lithium hydroxide solution was added, the temperature was controlled at 25°C, and stirred for 30 minutes. Concentrate, add 300ml of 10% tartaric acid solution to make the pH reach 3-4, extract twice with 200ml + 100ml of n-hexane, wash the organic phase with water until neutral, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and recrystallize from n-hexane to obtain 4 -[2-(4-Fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyryl-4-phenyl-oxazolidin-2-one (IV). Yield 93.9%.

[0090] Step 2:

[0091] In an anhydrous and oxygen-free envi...

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Abstract

The invention provides a novel intermediate compound of ezetimibe and a preparation method thereof. The preparation method comprises a step of converting 4-(4-fluoro-benzoyl)-butyric acid into 4-[2-(4-fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyric acid by using an unseparated intermediate compound. The method provided by the invention is simple in route, low in price and high in efficiency; and in order to better protect functional groups, the method employs the selectively removable protective group, so the method has the advantages of few impurities, high product purity and high product yield.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to an ezetimibe intermediate compound. Background technique [0002] Ezetimibe is the first selective cholesterol absorption inhibitor that interferes 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 level of plasma cholesterol. Its combined use with statins can reduce the frequency of high doses of statins, and its drug effect is 8 times that of statins alone in lowering cholesterol. [0003] [0004] Patent US5767115 provides a route for the synthesis of ezetimibe, using (4-benzyloxy-ben...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D339/06
CPCC07D339/06Y02P20/55
Inventor 张贵民臧超夏明军
Owner SHANDONG NEWTIME PHARMA
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