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Preparation method of loxoprofen sodium degradation impurity

A technology for loxoprofen sodium and impurities is applied in the field of preparation of loxoprofen sodium oxidative degradation impurities, can solve problems such as no reports on the preparation of impurities, and achieve the effects of less side reactions, simple operation and high conversion rate

Pending Publication Date: 2022-05-06
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, there is no report on the preparation of this impurity

Method used

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  • Preparation method of loxoprofen sodium degradation impurity
  • Preparation method of loxoprofen sodium degradation impurity
  • Preparation method of loxoprofen sodium degradation impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Put 13g of 2-(4-((2-cyclopentanonyl)methyl)phenyl)propionic acid (compound I), 16.35g of acetic anhydride, and 150ml of tetrahydrofuran into a 250ml three-necked flask, stir and add 2mL of concentrated sulfuric acid, 10~ React at 20°C for 4 hours and monitor the reaction by sampling TLC (ethyl acetate:n-hexane=2:1). After the reaction of the raw materials was complete, sodium bicarbonate solution was added to adjust the pH to 5-6, and the layers were separated. The organic phase was concentrated under reduced pressure until there was no distillate, and 14.3 g of the concentrate was obtained. The reaction was directly carried out to the next step without purification.

[0049] Put 14g of the concentrate from the previous step and 200ml of dichloromethane into a 500ml three-necked bottle, add 44g of 50% hydrogen peroxide dropwise at a temperature of 20-30°C, and react for 20 hours at 20-30°C after dropping. Sample TLC (ethyl acetate:n-hexane=2:1) ​​was used to monitor the...

Embodiment 2

[0053] Put 13g of 2-(4-((2-cyclopentanonyl)methyl)phenyl)propionic acid (compound I), 16.35g of acetic anhydride, and 150mL of dioxane into a 250ml three-necked flask, stir and add 3mL of hydrochloric acid, React at 30-40°C for 6 hours, and monitor the reaction by sampling TLC (ethyl acetate:n-hexane=2:1). After the reaction of the raw materials was complete, sodium bicarbonate solution was added to adjust the pH to 5-6, and the layers were separated. The organic phase was concentrated under reduced pressure until there was no distillate, and 15.4 g of the concentrate was obtained. The reaction was directly carried out to the next step without purification.

[0054] Put 15g of the concentrate from the previous step and 200ml of dichloromethane into a 500ml three-necked bottle, add 10g of m-chloroperoxybenzoic acid at a temperature of 20-30°C, and react for 10 hours at 20-30°C. Sample TLC (ethyl acetate:n-hexane=2:1) ​​was used to monitor the reaction. After the raw material r...

Embodiment 3

[0057] Put 13g of 2-(4-((2-cyclopentanonyl)methyl)phenyl)propionic acid (Compound I), 16.35g of acetic anhydride, 50ml of dichloromethane into a 250mL reaction flask, stir and add 3mL of perchloric acid , react at 10-20° C. for 2 hours and monitor the reaction by sampling TLC (ethyl acetate:n-hexane=2:1). After the reaction of the raw materials was complete, sodium bicarbonate solution was added to adjust the pH to 5-6, and the layers were separated. The organic phase was concentrated under reduced pressure until there was no distillate, and 16.3 g of the concentrate was obtained. The reaction was directly carried out to the next step without purification.

[0058] Put 16g of the concentrate from the previous step and 200ml of toluene into a 500mL reaction bottle, add 44g of peracetic acid dropwise at a temperature of 20-30°C, and react for 10 hours at 20-30°C after dropping. Sample TLC (ethyl acetate:n-hexane=2:1) ​​was used to monitor the reaction. After the reaction of the...

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Abstract

The invention discloses a method for synthesizing loxoprofen sodium degradation impurities, and belongs to the field of pharmaceutical chemicals. The method comprises the following steps: by taking 2-(4-((2-cyclopentanone) methyl) phenyl) propionic acid (compound I) as a starting material, carrying out enolization, epoxidation and epoxy ring-opening reaction, and purifying by column chromatography to obtain 2-(4-((1-hydroxy-2-cyclopentanone) methyl) phenyl) propionic acid (compound IV). The synthesis route is simple and efficient, the reaction yield is high, and the used materials, solvents and reagents are cheap and easy to obtain. The loxoprofen sodium impurity can be used for quality control of loxoprofen sodium bulk drugs or used as an impurity reference substance.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method for loxoprofen sodium to oxidize and degrade impurities. Background technique [0002] Loxoprofen sodium is a non-steroidal anti-inflammatory drug, used for anti-inflammatory analgesia of rheumatoid arthritis, low back pain, frozen shoulder, neck, shoulder and wrist syndrome, etc. Antipyretic and analgesic for pain reduction and acute upper respiratory tract inflammation. [0003] In the literature (Journal of Chromatography A, 2008, 1208, 164), the degradation impurities of loxoprofen sodium are reported, as shown in formula IV. [0004] [0005] So far, there is no report on the preparation of this impurity. Therefore, synthesizing this impurity is of great significance to the quality and impurity research of loxoprofen sodium, and can be used for the qualitative and quantitative analysis of impurities in the production of loxopro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/90C07C51/373C07D303/48C07D301/12C07C69/157C07C67/08
CPCC07C51/373C07D303/48C07D301/12C07C67/08C07C2601/10C07C2601/08C07C59/90C07C69/157
Inventor 徐新良庄江海庄程翰郭国天杨张艳李晓黎吕能李炫锋
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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