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Preparation method of flurbiprofen axetil

A technology of flurbiprofen axetil and flurbiprofen, which is applied in the field of preparation of flurbiprofen axetil, can solve the problems of complex post-treatment operation, high reaction temperature, high purification cost, etc., achieve short reaction time, high purity, low cost effect

Active Publication Date: 2021-01-08
SHANGHAI ZHONGXI SUNVE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem solved by the present invention is to optimize and improve the synthesis and purification method of existing flurbiprofen axetil, overcome the high reaction temperature in the prior art, the time is long, the post-treatment operation is complicated, and the purification cost is high. Defects such as low yield

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  • Preparation method of flurbiprofen axetil
  • Preparation method of flurbiprofen axetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Add 2.0kg of flurbiprofen and 15.6kg of acetone in a 50L reaction kettle equipped with a thermometer and a constant pressure dropping funnel, stir at room temperature (20-25°C), and dissolve the reaction solution, add 1.36kg of anhydrous potassium carbonate, and stir From 0.5 hour to 1 hour, 1.64 kg of 1-bromoethyl acetate was added dropwise, and the addition was completed in 5 to 15 minutes. Raise the temperature to an internal temperature of 55-60°C, and keep the reaction for 3 hours.

[0054] The reaction solution is concentrated under reduced pressure. When the vacuum degree reaches above 0.09Mpa and no liquid drops out, it is regarded as the end point of concentration. Add 18kg of ethyl acetate and 20kg of purified water to the reaction solution, stir for 30min, then let it stand for 15min, then remove the lower layer of water. Phase, the organic phase was washed with purified water (10kg × 3), added anhydrous magnesium sulfate 4kg and dried for 2 hours, filtered, ...

Embodiment 2

[0057] Add 2.0kg of flurbiprofen, 15.6kg of acetone and 2.35kg of N,N-dimethylformamide into a 50L reactor equipped with a thermometer and a constant pressure dropping funnel, at room temperature (20-25°C) Stir to dissolve the liquid, add 1.36 kg of anhydrous potassium carbonate, stir for 0.5 to 1 hour, add 1.64 kg of 1-bromoethyl acetate dropwise, and complete the dropwise addition in 5 to 15 minutes. React at 20-25°C for 4 hours.

[0058] The reaction solution is concentrated under reduced pressure. When the vacuum degree reaches above 0.09Mpa and no liquid drops out, it is regarded as the end point of concentration. Add 18kg of ethyl acetate and 20kg of purified water to the reaction solution, stir for 30min, then let it stand for 15min, then remove the lower layer of water. Phase, the organic phase was washed with purified water (10kg × 3), added anhydrous magnesium sulfate 4kg and dried for 12 hours, filtered, and concentrated to obtain 2.61kg of crude product flurbiprofe...

Embodiment 3

[0061] Add 2.0kg of flurbiprofen and 15.6kg of acetone and 3.76kg of N,N-dimethylformamide into a 50L reaction kettle equipped with a thermometer and a constant pressure dropping funnel, at room temperature (20-25°C) Stir to dissolve the liquid, add 1.36 kg of anhydrous sodium carbonate, stir for 0.5 to 1 hour, cool down to 10°C, add 2.05 kg of 1-bromoethyl acetate dropwise, and complete the dropwise addition in 5 to 15 minutes. Keep the reaction at 10-15°C for 8 hours.

[0062] The reaction solution is concentrated under reduced pressure. When the vacuum degree reaches above 0.09Mpa and no liquid drops out, it is regarded as the end point of concentration. Add 20kg of ethyl acetate and 20kg of purified water to the reaction solution, stir for 30min, then let it stand for 15min, and then remove the lower layer of water. Phase, the organic phase was washed with purified water (10kg × 3), added anhydrous sodium sulfate 4kg and dried for 12 hours, filtered, and concentrated to dr...

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Abstract

The invention discloses a preparation method of flurbiprofen axetil. The purification method of flurbiprofen axetil comprises the steps of carrying out first molecular distillation on a flurbiprofen axetil crude product, and collecting a heavy component sample; and carrying out secondary molecular distillation on the heavy component sample collected by the primary molecular distillation, and collecting a light component sample to obtain a flurbiprofen axetil finished product. In the first molecular distillation, the temperature of a built-in condenser is 20-30 DEG C; in the first molecular distillation, the heating temperature of a jacket is 50-60 DEG C; the vacuum degree of the first molecular distillation is not higher than 100pa; in the second molecular distillation, the temperature ofa built-in condenser is 50-60 DEG C; in the second molecule, the heating temperature of a distillation jacket is 150-160 DEG C; and the vacuum degree of the second molecular distillation is not higherthan 40 pa. The crude product is purified by adopting a molecular distillation technology, the cost is low, the purity is high, the total impurity content does not exceed 0.1%, and the single impurity content does not exceed 0.05%.

Description

technical field [0001] The invention relates to a preparation method of flurbiprofen axetil. Background technique [0002] Flurbiprofen axetil is a non-steroidal intravenous injection targeted analgesic drug, which is an ester prodrug of flurbiprofen. It was launched in Japan in 1992 and in China in 2004. Compared with flurbiprofen, flurbiprofen axetil can avoid adverse reactions such as gastric mucosal damage caused by oral administration through intravenous injection. It has the advantages of long-lasting effect, strong selectivity, short onset time, and does not affect the recovery of patients. It is widely used It is used in the treatment of clinical inflammatory pain, cancer pain and postoperative pain. At present, the synthetic route of flurbiprofen axetil is basically to first synthesize flurbiprofen, and then react with 1-bromoethyl acetate or 1-chloroethyl acetate for esterification. [0003] In the periodical "Qilu Pharmaceutical Affairs" No. 26, No. 26, Volume 9...

Claims

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Application Information

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IPC IPC(8): C07C69/65C07C67/11C07C67/58C07C67/54
CPCC07C67/11C07C67/58C07C67/54C07C69/65
Inventor 李杰徐俊颜国明尹超衷盛王梦林陈颖源石岩
Owner SHANGHAI ZHONGXI SUNVE PHARMA
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