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Synthesis method of chiral methyl 5-(4-fluorophenyl)-5-hydroxyvalerate

A technology of methyl hydroxyvalerate and hydroxyvaleric acid, which is applied in the field of synthesis of chiral 5--5-hydroxyvalerate methyl, can solve problems such as difficult control of reaction conditions, achieve low cost, high yield, and method simple and easy effects

Inactive Publication Date: 2020-05-12
ZHENGZHOU INST OF CHIRAL DRUGS RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specifically, at present, chiral 5-(4-fluorophenyl)-5-hydroxyvaleric acid methyl ester is mainly prepared by reducing 5-(4-fluorophenyl)-5-oxoylvaleric acid methyl ester, but carbonyl and The ester group is easy to be reduced at the same time, and the reaction conditions are not easy to control

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] This example provides a synthetic method for chiral methyl 5-(4-fluorophenyl)-5-hydroxyvalerate, including:

[0032] Synthetic Compound IV Dissolve 12.7 g of glutaric anhydride in dichloromethane solution at -5°C to prepare a glutaric anhydride dichloromethane solution, add dropwise to dichloromethane and trichloromethane in this glutaric anhydride dichloromethane solution In the aluminum chloride system, keep stirring at -5 °C for 30 min, then add 9.6 g of fluorobenzene dropwise, control the reaction temperature at 5 °C for 4 h, filter with suction to obtain a filter cake, and use dichloromethane to recrystallize to obtain 20.2 g of compound IV ; Wherein, the quality of the aluminum trichloride in the described dichloromethane and aluminum trichloride system is 21 g;

[0033] Synthesis of compound III Dissolve 20.2 g of compound IV in methanol, add 3.63 g of sodium borohydride in batches at 0°C, keep the temperature at 0°C for 5 h, pour the reaction solution into water...

Embodiment 2

[0037] This example provides a synthetic method for chiral methyl 5-(4-fluorophenyl)-5-hydroxyvalerate, including:

[0038] Synthetic Compound IV Dissolve 12.7 g glutaric anhydride in dichloromethane solution at -20°C to prepare glutaric anhydride dichloromethane solution, add dropwise to dichloromethane and trichloromethane in this glutaric anhydride dichloromethane solution In the aluminum chloride system, keep stirring at -20°C for 30 min, then add 9.6 g of fluorobenzene dropwise, control the reaction temperature at -10°C for 3 h, filter with suction to obtain a filter cake, and use dichloromethane to recrystallize to obtain 19.3 g of compound IV; Wherein, the quality of the aluminum trichloride in the described dichloromethane and aluminum trichloride system is 26 g;

[0039]Synthesis of compound III Dissolve 19.3 g of compound IV in methanol, add 4.2 g of sodium borohydride in batches at -10°C, keep the temperature at -10°C for 5 h, pour the reaction solution into water a...

Embodiment 3

[0043] This example provides a synthetic method for chiral methyl 5-(4-fluorophenyl)-5-hydroxyvalerate, including:

[0044] Synthetic Compound IV Dissolve 12.7 g glutaric anhydride in dichloromethane solution at 0°C to prepare glutaric anhydride dichloromethane solution, add dropwise to dichloromethane and trichloromethane in this glutaric anhydride dichloromethane solution In the aluminum chloride system, keep stirring at 0°C for 30 min, then add 9.6 g of fluorobenzene dropwise, control the reaction temperature at 15°C for 6 h, filter with suction to obtain a filter cake, and use dichloromethane to recrystallize to obtain 20.4 g of compound IV; , the quality of the aluminum chloride in the dichloromethane and aluminum chloride system is 29 g;

[0045] Synthesis of compound III Dissolve 20.4 g of compound IV in methanol, add 4.2 g of sodium borohydride in batches at 20°C, keep the temperature at 20°C for 7 h, pour the reaction solution into water after the reaction, and use et...

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PUM

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Abstract

The invention provides a synthesis method of chiral methyl 5-(4-fluorophenyl)-5-hydroxyvalerate. The method comprises the following steps: fluorobenzene and glutaric anhydride taken as raw materials undergo a Friedel-Crafts acylation reaction to synthesize 5-(4-fluorophenyl)-5-carbonylvaleric acid; the 5-(4-fluorophenyl)-5-carbonylvaleric acid undergoes a reduction reaction to synthesize 5-(4-fluorophenyl)-5-hydroxyvaleric acid; the 5-(4-fluorophenyl)-5-hydroxyvaleric acid undergoes a cyclization reaction to produce 6-(4-fluorophenyl)-tetrahydropyran-2-one; and the 6-(4-fluorophenyl)-tetrahydropyran-2-one undergoes an alcoholysis reaction to obtain the target compound, namely chiral methyl 5-(4-fluorophenyl)-5-hydroxyvalerate. The synthesis method avoids the problem that carbonyl and ester groups are easy to reduce at the same time, has the advantages of solution control of reaction conditions, high yield, mild reaction temperature, simplicity, easiness in implementation and low cost,and can realize industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a synthesis method of chiral 5-(4-fluorophenyl)-5-hydroxyvaleric acid methyl ester. Background technique [0002] Ezetimibe (Ezetimble, chemical name: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -Hydroxyphenyl)-2-propionolactam) is a new type of cholesterol absorption inhibitor developed by Schering-Plough Pharmaceuticals, which binds to the membrane protein on the brush border membrane vesicles of the small intestine, inhibits the intestinal response to food and bile The absorption of cholesterol delivered to the intestinal tract reduces the cholesterol content in serum and liver, and is mainly used for the treatment of hyperlipidemia; the product was first launched in the United States in 2002. Among the many synthetic routes of ezetimibe, chiral (5)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester is an intermediate in its synthesis. T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/03C07C69/732
CPCC07C67/03C07C51/367C07C51/083C07B2200/07C07C69/732C07C59/56C07C59/88
Inventor 邓照西
Owner ZHENGZHOU INST OF CHIRAL DRUGS RES CO LTD