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Synthesis method of flurbiprofen

A technology of flurbiprofen and a synthetic method, which is applied in the field of synthesis of medicinal flurbiprofen, can solve the problems of increasing industrial production operation steps and costs, higher requirements for organic solvents, unfavorable industrial production, etc., and achieves a total yield Good, low solvent requirement, short reaction route

Inactive Publication Date: 2018-06-29
HEBEI YIPIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the relevant synthetic methods of flurbiprofen published in domestic literature mainly include Chinese Journal of Pharmaceutical Industry 1990,21(6), 285, Chinese Journal of Pharmaceutical Industry 1991,22(1), 2, Qilu Pharmaceutical Affairs 2005,24(11 ), 687, Chinese Journal of Medicinal Chemistry 2013, 23(6), 473, Qingdao University of Science and Technology Master's Thesis 2012, Bi Fengyun and Chinese patent CN201610934843, etc. Among them, Chinese Journal of Pharmaceutical Industry 1990, 21(6), 285 has a lower yield, no conducive to industrial production
Other synthetic routes involve the Grignard reaction for the synthesis of intermediates. This reaction has high requirements for organic solvents and must reach anhydrous level; materials and other dangers, there are certain safety hazards
While the synthetic route of CN201010530223 is relatively simple, but the product needs to be purified by column chromatography, which increases the operation steps and cost of industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A. Synthesis of ethyl 2-(4-nitro-3-fluorophenyl)propionate (3)

[0038] Add 700ml DMF, 40g (0.28mol) o-fluoronitrobenzene and 44.8g (0.33mol) ethyl 2-chloropropionate to a 2L four-neck flask, stir and cool down to -10°C, slowly add 37g (0.33mol) ) DMF solution of potassium tert-butoxide into the system, and control the temperature to continue the reaction for 2 to 3 hours. After TLC detected that the reaction was complete, the pH of the system was adjusted to 3-4 with concentrated hydrochloric acid.

[0039] DMF was recovered under reduced pressure, and the residue was added to ethyl acetate for stirring, so that the residue was completely loosely distributed in ethyl acetate. Filter, wash the filter cake with ethyl acetate, combine the organic phases, wash with saturated brine, discard the water phase, and collect the organic phase. The organic phase was dried and concentrated, the organic phase was recovered, and then the temperature was raised, and 57.8 g of the pr...

Embodiment 2

[0047] A. Synthesis of ethyl 2-(4-nitro-3-fluorophenyl)propionate (3)

[0048] Add 700ml of ethanol, 40g (0.28mol) of o-fluoronitrobenzene and 44.8g (0.33mol) of ethyl 2-chloropropionate into a 2L four-necked flask, stir and cool down to -10°C, and slowly dropwise add 30.6g (0.45 mol) ethanol solution of sodium ethoxide into the system, and after TLC detected that the reaction was complete, the pH of the system was adjusted to 3-4 with concentrated hydrochloric acid.

[0049] Concentrate under reduced pressure, filter, and wash the filter cake with ethyl acetate. The organic phases were combined, washed with saturated brine, the aqueous phase was discarded, and the organic phase was collected. The organic phase was dried and then distilled under reduced pressure to obtain 60.3 g of the product with a molar yield of 88.1%.

[0050] B. Synthesis of ethyl 2-(2-fluoro-4-biphenyl)propionate (4)

[0051] Add 700ml of dioxane to a 2L four-neck flask, add 60.3g (0.25mol) of ethyl 2...

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Abstract

The invention relates to a synthesis method of flurbiprofen. The synthesis method of the flurbiprofen belongs to the technical field of drug synthesis, and comprises the steps of adopting o-fluoronitrobenzene as a starting material; carrying out substitution reaction, coupled reaction and hydrolysis reaction in an organic solvent to obtain the target product flurbiprofen. According to the synthesis method of the flurbiprofen provided by the invention, the raw material source is wide, the used organic solvent has no need to be subjected to nonaqueous treatment, the reaction safety coefficient is high, the process operation is simple, three wastes are less, and the obtained flurbiprofen has high yield and high purity.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a method for synthesizing medicinal flurbiprofen. The synthesis method of the present invention is simple and convenient, does not require anhydrous treatment of organic solvents, and is simple to operate; the discharge of industrial waste water is less, and is environmentally friendly; the obtained flurbiprofen has high yield and high purity, and meets the requirements of the State Food and Drug Administration reporting requirements. Background technique [0002] The chemical name of flurbiprofen (Flurbiprofen, 1) is 2-(2-fluorobiphenyl-4-yl)-propionic acid, and its English name is (2-[2-fluoro-4-biph-enylyl]-propionic acid). It is a non-steroidal anti-inflammatory analgesic drug developed by the British Boots company. Launched in the UK in 1976, it has been sold in many countries around the world, and has been included in the Chinese, British, and American pharmacopoeias. It...

Claims

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Application Information

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IPC IPC(8): C07C27/02C07C57/58
CPCC07C51/09C07C67/343C07C201/12C07C57/58C07C205/56C07C69/65
Inventor 刘慧杰赵翠然啜振华张晓倩李莉娜刘玉强李珠牛彬彬许亚利
Owner HEBEI YIPIN PHARMA
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