Preparation method of flurbiprofen axetil

A technology of flurbiprofen axetil and synthesis method, which is applied in the field of preparation of flurbiprofen axetil, can solve problems such as short synthesis route, and achieve the effects of convenient operation, environment-friendly, and rich synthesis process

Inactive Publication Date: 2015-05-27
SHANDONG WEIGAO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The present invention is a supplement to the existing method for synthesizing flurbiprofen axetil, which solves the drawback that the synthesis of flurbiprofen axetil mainly relies on flurbiprofen as a raw material, the synthesis route is short, and the last step is to synthesize flurbip

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  • Preparation method of flurbiprofen axetil

Examples

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Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of 2-(4-nitro-3-fluorophenyl)propionic acid-1-acetoxyethyl ester (intermediate I)

[0029] Add 2-(4-nitro-3-fluorophenyl) propionic acid (213.0 g, 1.000 mol) and anhydrous acetonitrile (2000 ml) into the reactor, replace the air with nitrogen three times, slowly heat up to 35-40 ° C, Further anhydrous potassium carbonate (276.4 g, 2.000 mol) was added. 1-Chloroethyl acetate (245.1 g, 2.000 mol) was added dropwise to the system. After completion, control the internal temperature of the reaction system at 35-40°C for 5.0 hours. The reaction solution was concentrated under reduced pressure until no liquid flowed out. After cooling to 15-25°C, ethyl acetate (2000ml) and water (2000ml) were added, and the layers were separated. The organic phase was concentrated under reduced pressure to obtain 242.4g of a light yellow oil. Yield 81.00%.

Embodiment 2

[0030] Example 2 Preparation of 2-(4-amino-3-fluorophenyl)propionic acid-1-acetoxyethyl ester (intermediate II)

[0031] After diluting 2-(2-fluoro-4-nitro)propionic acid-1-acetoxyethyl ester (149.6g, 0.500mol) with absolute ethanol (900.0ml), add 10% wet palladium carbon (15.00g ), nitrogen replacement for three times, then pass through hydrogen with a pressure of 0.3-0.4 MPa to carry out the reduction reaction, stir at 50-60° C. for 16 h, and then filter off palladium-carbon. The organic phase was concentrated under reduced pressure to obtain 128.0 g of brown oil with a yield of 95.10%.

Embodiment 3

[0032] Example 3 Preparation of 2-(3-fluoro-4-iodophenyl)propionic acid-1-acetoxyethyl ester (intermediate III)

[0033] 2-(4-Amino-3-fluorophenyl)propionic acid-1-acetoxyethyl ester (107.7, 0.400mol), 40% hydrobromic acid (0.440mol) and water (200ml) were added to the reactor, Cool down to 0-5°C, which is system I; control the temperature at 0-5°C, add sodium nitrite (0.440mol) aqueous solution dropwise to system I; make a solution of potassium iodide (0.800mol) and water and cool down to 0-5°C is system II; control the temperature at 0-10°C, add the mixed solution of system I to system II dropwise, slowly raise the temperature to 60-70°C after the dropwise addition, and react for 2-3 hours. After cooling down to 20-30°C, extract twice with dichloromethane, discard the water phase, combine the organic phases, wash the organic phase twice with 10% sodium thiosulfate solution, discard the water phase, and concentrate the organic phase to obtain a brown oil The product was 109....

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Abstract

The invention relates to a preparation method of flurbiprofen axetil. The method comprises the following steps: condensing 2-(4-nitro-3-fluorophenyl) propionic and 1-chloroethyl acetate so as to generate 1-acetoxyl ethyl 2-(4-nitro-3-fluorophenyl) propionate, carrying out hydrogenation reduction on 1-acetoxyl ethyl 2-(4-nitro-3-fluorophenyl) propionate under the catalysis of palladium-carbon so as to generate 1-acetoxyl ethyl 2-(4-amino-3-fluorophenyl) propionate, carrying out diazotization and iodination on 1-acetoxyl ethyl 2-(4-amino-3-fluorophenyl) propionate so as to obtain 1-acetoxyl ethyl 2-(3-fluoro-4-iodophenyl) propionate, carrying out Suzuki coupling reaction on the intermediate and a phenylboronic acid in water by taking palladium-carbon as a catalyst so as to obtain a target product flurbiprofen axetil crude product, carrying out silica gel column chromatography on the crude product so as to obtain a flurbiprofen axetil finished product. The method disclosed by the invention enriches the synthesis methods of flurbiprofen axetil, a synthetic process is simple in operation, environment-friendly and low in cost, and the purity of obtained flurbiprofen axetil is over 99.3%, therefore, the method has a good industrial application prospect.

Description

Technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of flurbiprofen axetil. Background technique [0002] Flurbiprofen Axetil (Flurbiprofen Axetil) chemical name: (±) 2-(2-fluoro-4-biphenyl)propionic acid-1-acetoxyethyl ester, molecular formula: C 19 h 19 FO 4 , molecular weight: 330.4. [0003] Flurbiprofen axetil is a new type of non-steroidal anti-inflammatory analgesic drug, which is the prodrug of flurbiprofen and the first non-steroidal targeted analgesic drug approved by SFDA. Flurbiprofen axetil has a certain lipophilicity, and its targeting effect and fat-soluble characteristics make it easy to cross cells. After entering the human body, it can target and gather at surgical incisions and inflammatory sites, and is rapidly hydrolyzed under the action of carboxylesterase. Flurbiprofen reduces prostaglandin synthesis by inhibiting cyclooxygenase (COX) in the spinal cord and periphery, while reducing...

Claims

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Application Information

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IPC IPC(8): C07C69/65C07C67/343C07C67/56
CPCC07C201/12C07C67/307C07C67/343C07C67/56C07C227/04
Inventor 黄显峰毕建伟郭凯韩江升曲华平张丽静张帅彦
Owner SHANDONG WEIGAO PHARM CO LTD
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