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Synthetic method of loxoprofen sodium process impurity

A technology for loxoprofen sodium and process impurities, which is applied in the field of synthesis of loxoprofen sodium process impurities, and can solve the problems of loxoprofen sodium without open literature research

Inactive Publication Date: 2021-09-14
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are no technical impurities specified in the quality standards of loxoprofen sodium in various national pharmacopoeias. The Japanese Pharmacopoeia uses thin-layer chromatography (TLC) technology to control related substances. There is no published literature to study the impurities of loxoprofen sodium, especially the process impurities of loxoprofen sodium. Research

Method used

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  • Synthetic method of loxoprofen sodium process impurity
  • Synthetic method of loxoprofen sodium process impurity
  • Synthetic method of loxoprofen sodium process impurity

Examples

Experimental program
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Embodiment 1

[0032] The preparation of step 1. formula III compound:

[0033] Put 275ml of anhydrous methanol into a 1000ml three-necked flask, add the compound of formula II (2-methoxycarbonylcyclopentanone) (31.93g, 224.6mmol), add sodium methoxide (34.67g, 641.71mmol) at 20~30℃, and stir After 10 minutes, cool down to 0~5°C, add dropwise the mixture of the compound of formula I (methyl p-bromomethylisophenylpropionate) (55.00g, 213.9 mmol) and 100ml of methanol, and keep the temperature at 0~5°C for reaction 5h, TLC spot plate central control (developing solvent: dichloromethane: methanol = 10:1), showed that there is no remaining raw material point, concentrated under reduced pressure and evaporated to dryness at 45°C, added 100ml of dichloromethane to dissolve, and washed with 50ml of water. The dichloromethane layer was obtained, which was concentrated and evaporated to dryness to obtain 66.43 g of a compound of formula III as a yellow oil, with a yield of 88.64% and an HPLC purity o...

Embodiment 2

[0037] The preparation of step 1. formula III compound:

[0038] Put 275ml of anhydrous methanol into a 1000ml three-necked flask, add the compound of formula II (2-methoxycarbonylcyclopentanone) (31.93g, 224.6mmol), add sodium methoxide (23.11g, 427.80mmol) at 20~30℃, and stir 10min, cool down to 0~5°C, add dropwise the mixture of compound of formula I (methyl p-bromomethylisophenylpropionate) (55.00g, 213.9mmol) and 100ml methanol, after dropping, raise the temperature to 45~50°C and keep it warm Reaction for 3 hours, TLC spot plate central control (developing agent: dichloromethane: methanol = 10:1), showing that there is no remaining raw material point, concentrated under reduced pressure and evaporated to dryness at 45°C, added 100ml of dichloromethane to dissolve, washed with 50ml of water Separated to obtain a dichloromethane layer, concentrated and evaporated to dryness to obtain 62.62 g of a compound of formula III as a yellow oil, with a yield of 83.55% and an HPLC p...

Embodiment 3

[0042] The preparation of step 1. formula III compound:

[0043] Put 275ml of anhydrous methanol into a 1000ml three-necked flask, add the compound of formula II (2-methoxycarbonylcyclopentanone) (31.93g, 224.6mmol), add sodium methoxide (40.45g, 748.80mmol) at 20~30℃, and stir 10min, cool down to 0~5°C, add dropwise the mixture of compound of formula I (methyl p-bromomethylisophenylpropionate) (55.00g, 213.9mmol) and 100ml methanol, after dropping, raise the temperature to 5~10°C and keep it warm Reaction for 4 hours, TLC spot plate central control (developing solvent: dichloromethane: methanol = 10:1), showing that there is no remaining raw material point, concentrated under reduced pressure and evaporated to dryness at 45°C, added 100ml of dichloromethane to dissolve, washed with 50ml of water The dichloromethane layer was obtained by separation, and concentrated and evaporated to dryness to obtain 66.30 g of the compound of formula III as a yellow oil, with a yield of 88.4...

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Abstract

The invention relates to a synthetic method of a loxoprofen sodium process impurity. The synthetic method of the loxoprofen sodium process impurity comprises the steps: 1, carrying out a reaction on a compound represented by a formula I and a compound represented by a formula II with sodium methoxide in a methanol solvent to obtain a compound represented by a formula III; and 2, carrying out a hydrolysis reaction on the compound represented by the formula III under the action of an inorganic acid to obtain a compound represented by a formula IV. The invention provides the specific synthetic method of the loxoprofen sodium process impurity compound represented by the formula IV, and provides a standard reference substance for quality control of loxoprofen sodium bulk drugs and preparations.

Description

technical field [0001] The invention relates to a method for synthesizing process impurities of loxoprofen sodium. Background technique [0002] Loxoprofen Sodium (Loxoprofen Sodium), which belongs to the phenylpropionic acid non-steroidal anti-inflammatory drug, was developed by Japan Sankyo Co., Ltd., and was launched in Japan in 1986. Compared with similar drugs, loxoprofen sodium has stronger, faster and safer action characteristics, and its structural formula is as follows: [0003] . [0004] Process impurities in raw materials are the key to the quality control of raw materials at present. Since the chemical structure of impurities is different from that of raw materials and lacks toxicological data, they may affect the human body. Therefore, it is important to identify and perform toxicological evaluation of unknown process impurities. meaning. There are no technical impurities specified in the quality standards of loxoprofen sodium in various national pharmacop...

Claims

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Application Information

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IPC IPC(8): C07C51/09C07C62/32C07C67/343C07C69/757
CPCC07C51/09C07C62/32C07C67/343C07C69/757C07C2601/14
Inventor 刘彦彬吴艳华连迎迎郑学芳张斌王大磊
Owner 迪嘉药业集团股份有限公司
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