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Method for preparing flurbiprofen axetil compound

A technology for flurbiprofen axetil and compounds, which is applied in the field of preparation of flurbiprofen axetil compounds, can solve the problems of high production cost, large amount of solvent, complicated operation, etc., and achieve good product quality, high product quality, and simple operation Effect

Active Publication Date: 2012-03-21
NANJING YOKO PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the industrial production process, the method of passing through the silica gel column has a long purification period and requires a large amount of solvent, resulting in high production costs and aggravating the burden on patients; vacuum distillation will lead to product decomposition and complicated operations

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add 2-fluoro-α-methyl(1,1'-diphenyl)-4-acetic acid (0.5mol), DMF (1000ml), potassium carbonate (0.6mol) into a 2L reaction flask, stir and heat up for 70~ 75°C, reacted for 2h, lowered to 20°C, added dropwise 1-bromoethyl acetate (0.75mol), reacted for 5h. Then transfer to a separatory funnel, add 2L of ethyl acetate and 1.5L of water, separate the organic phase and continue to wash 2L with water twice, continue to wash the organic phase with 500ml of saturated sodium carbonate solution once, then wash with 2L twice, and finally use 1.5L Wash twice with saturated saline. The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a reddish-brown oil, which was evacuated at 80° C. for 2 h using an oil pump. Dissolve the obtained oil with 2400ml of ethyl acetate:petroleum ether=1:20 (volume ratio), add 84g of silica gel, 84g of activated carbon, heat up and reflux for 30min, cool slightly and suction filter, then add 42g of silica gel, 84g of activ...

Embodiment 2

[0017] Add 2-fluoro-α-methyl(1,1'-diphenyl)-4-acetic acid (0.5mol), DMF (1000ml), potassium carbonate (0.7mol) into a 2L reaction flask, stir and heat up for 70~ 75°C, reacted for 2h, lowered to 20°C, added dropwise 1-bromoethyl acetate (0.85mol), reacted for 5h. Then transfer to a separatory funnel, add 2.5L ethyl acetate, 2L water, separate the organic phase and continue to wash 2.5L twice with water, continue to wash the organic phase once with 700ml of saturated sodium carbonate solution, then wash 2L with water twice, and finally use 1.8 Wash twice with L saturated saline. The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a reddish-brown oil, which was evacuated at 80° C. for 3 h using an oil pump. Dissolve the obtained oil with 3000ml of ethyl acetate:petroleum ether=1:15 (volume ratio), add 84g of silica gel, 84g of activated carbon, heat up and reflux for 35min, cool slightly and suction filter, then add 42g of silica gel, 84g of activ...

Embodiment 3

[0019] Add 2-fluoro-α-methyl(1,1'-diphenyl)-4-acetic acid (0.5mol), DMF (1000ml), potassium carbonate (0.7mol) into a 2L reaction flask, stir and heat up for 70~ 75°C, reacted for 2h, lowered to 20°C, added dropwise 1-bromoethyl acetate (0.85mol), reacted for 5h. Then transfer to a separatory funnel, add 2.5L ethyl acetate, 2L water, separate the organic phase and continue to wash 2.5L twice with water, continue to wash the organic phase once with 700ml of saturated sodium carbonate solution, then wash 2L with water twice, and finally use 1.8 Wash twice with L saturated saline. The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a reddish-brown oil, which was evacuated at 90° C. for 1 h using an oil pump. Dissolve the obtained oil with 3000ml of ethyl acetate:petroleum ether=1:30 (volume ratio), add 84g of silica gel, 84g of activated carbon, heat up and reflux for 30min, cool slightly and suction filter, then add 42g of silica gel, 84g of activ...

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Abstract

The invention discloses a method for preparing a flurbiprofen axetil compound. The method comprises the following steps: adding 1.0mol of 2-fluoro-alpha-methyl(1,1'-diphenyl)-4-acetic acid and 1L of solvent in a reaction container, stirring and heating to 70-75 DEG C, reacting for 2h, cooling to 20 DEG C, dropping 1.5-1.7mol of 1-bromoethyl acetate, reacting for 5h, and cooling; adding ethyl acetate and water, then separating out the organic phase, washing with water, washing with a saturated sodium carbonate solution, then washing with water, and finally washing with saturated salt water; and carrying out rotary evaporation on the organic phase to be dry, and vacuumizing to remove the solvent and obtain a crude product; and then dissolving the crude product with an organic solvent, adding silica gel and activated carbon, heating to reflux for 20-40min, cooling, performing suction filtering, and vacuumizing to obtain flurbiprofen axetil, wherein the solvent is N, N-dimethylformamide or potassium carbonate; and the organic solvent is a mixture of an ester solvent and an ether solvent, the volume ratio of the ester solvent to the ether solvent is 1:(5-30) and the addition amount of the organic solvent is 1-2 times that the mass of the crude product. By adopting the preparation method of the flurbiprofen axetil compound, the problems of the existing purification method can be well solved; the method has low cost, simpleness in operations and good product quality; and the quality of the product obtained through the experiment is higher than the import standard.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, in particular to a method for preparing flurbiprofen axetil compounds. Background technique [0002] Flurbiprofen axetil is a prodrug of the non-steroidal anti-inflammatory drug flurbiprofen. Since flurbiprofen is insoluble in water, flurbiprofen axetil was jointly developed by Japan Research Pharmaceutical Co., Ltd. and Green Cross Pharmaceutical Co., Ltd. and has been used for intravenous injection. It was launched in Japan in 1992 and is widely used clinically to treat postoperative pain. or pain caused by cancer. In 2004, my country approved the listing of flurbiprofen axetil injection of Beijing Tide Pharmaceutical Co., Ltd., which is the only one in the domestic market so far. At present, domestic enterprises have begun to pay attention to the development of this variety. Through a large number of public literature investigations, it has been found that the synthetic r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/65C07C67/10
Inventor 高建兴张峰陆修涛马艳芳曹燕锋姜东成
Owner NANJING YOKO PHARMA GRP CO LTD
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