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Preparation method of ezetimibe internmediate ketone

A technology for ezetimibe and ketone, applied in the field of preparing ezetimibe intermediate ketone, can solve the problems of increasing production cost, complicated operation, environmental pollution and the like, and achieves the advantages of avoiding danger, safe experimental operation and reducing production cost. Effect

Inactive Publication Date: 2015-07-01
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The chiral prosthetic group mentioned in the literature ( S )-4-phenyl-2-oxazolidinone is commercially available, and the price is higher, greatly improving the production cost
At the same time, in the synthesis of chiral prosthetic groups ( S )-4-phenyl-2-oxazolidinone and ezetimibe intermediate (4 S )-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone should undergo organic solvent extraction, organic layer washing, The organic layer is washed with saturated salt water, dried with anhydrous sodium sulfate, and desolvated under reduced pressure. The operation is cumbersome, and a large amount of organic solvent is used to increase the production cost. If it is not recovered properly, it will pollute the environment.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Step 1, under nitrogen protection, add L-phenylglycine (60g, 0.396mol) into a 1000mL round-bottomed four-neck flask, add 600mL of tetrahydrofuran, cool to 0°C, add sodium borohydride (30g, 0.792mol) in batches, drop Add boron trifluoride diethyl ether (214.4g, 1.512mol), naturally warm up to room temperature, react at room temperature, control in thin layer chromatography (TLC), and react for 5 hours; after the reaction, add 120mL of methanol dropwise, stir for 1h, and concentrate to dryness; The residue was added to 20% NaOH aqueous solution (600mL) and stirred overnight; extracted with chloroform (100mL*5), the organic layer was washed with saturated brine (100mL*5), dried over anhydrous sodium sulfate, and precipitated under reduced pressure. Obtain 46.3g white crystal, namely ( S )-2-phenylglycinol, the yield was 85.1%, and the product was directly used in the next step without purification. Prepared in this step ( S )-2-Phenylglycinol structure detection data are...

Embodiment 2

[0035] Step 1, under nitrogen protection, add lithium aluminum hydride (2.43g, 0.064mol) into a 1000mL round-bottomed four-neck flask, add 125mL of tetrahydrofuran, cool to 0°C, add L-phenylglycine (5g, 0.033mol) in batches, Heated to reflux, controlled by TLC, and reacted for 5 hours. After the reaction finishes, add saturated potassium carbonate solution, suction filtration, extraction with ethyl acetate, desolvation under reduced pressure, obtain 2.2g white crystal ( S )-2-phenylglycinol, the yield was 48.5%, and the product was directly used in the next step without purification. Prepared in this step ( S )-2-Phenylglycinol structure detection data with example 1.

[0036] Step 2 and step 3 are the same as example 1.

Embodiment 3

[0038] Step 1, under nitrogen protection, add L-phenylglycine (60g, 0.396mol) into a 1000mL round-bottomed four-neck flask, add 600mL of tetrahydrofuran, cool to 0°C, add sodium borohydride (30g, 0.792mol) in batches, drop Add boron trifluoride diethyl ether (214.4g, 1.512mol), react at a temperature of 0°C, and control in thin-layer chromatography (TLC). It is found that the reaction is not complete, and after post-processing, ( S )-2-phenylglycinol. The post-processing steps are as follows: after the reaction, 120 mL of methanol was added dropwise, stirred for 1 h, and concentrated to dryness; the residue was added to 20% NaOH aqueous solution (600 mL), and stirred overnight; chloroform extraction (100 mL*5), and the organic layer was washed with saturated salt Washed with water (100mL*5), dried over anhydrous sodium sulfate, and precipitated under reduced pressure to obtain 10.9g white crystals, namely ( S )-2-phenylglycinol, the yield is 20%, and the product is directly u...

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Abstract

The invention belongs to the field of medicinal chemistry and relates to improvement of a preparation method of an important ezetimibe internmediate (4S)-3-[5-(4-fluorophenyl)-1,5-dioxo amyl]-4-phenyl-2- oxazolidinone I. According to the improved method, L-phenylglycine, p-fluorobenzoylbutanoic acid are used as raw materials and are subjected to three steps of reaction to obtain the target intermediate (4S)-3-[5-(4-fluorophenyl)-1,5-dioxo amyl]-4-phenyl-2- oxazolidinone I. The preparation method disclosed by the invention is simple to operate, low in consumption, low in raw material cost and simple and easy in post-treatment and therefore is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the improvement of the method for preparing ezetimibe intermediate ketone. Background technique [0002] Ezetimibe is a new type of cholesterol absorption inhibitor, jointly developed by Merck and Schering-Plough, approved by the US Food and Drug Administration FDA in October 2002, and approved by the US Food and Drug Administration in November 2002 It was listed in Germany for the first time in July, and in the same period in the United States, the United Kingdom, Sweden and other places. It was launched in my country in August 2007. The product name is Yishichun. [0003] The mechanism of action of ezetimibe is to lower blood lipids by inhibiting the absorption of cholesterol in the diet and bile in the intestine, and it will not affect the absorption of triglycerides and fat-soluble vitamins. For patients who cannot tolerate medium and high doses of statins Or patients with ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/26
CPCC07D263/26
Inventor 孙婕汪卫敏汪丽茜肖亚平
Owner NANJING NORMAL UNIVERSITY
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