A preparing method of flurbiprofen

A technology of flurbiprofen and molar ratio, which is applied in the field of preparation of flurbiprofen, can solve the problems of great harm to the environment and operators, high cost, low yield, etc., and achieve high atom utilization rate, less three wastes, and low yield. high rate effect

Active Publication Date: 2017-03-15
MAISON CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Among them, methods 1 and 3 both use a diazotization reaction with a large amount of waste water, and far excessive and highly toxic benzene, which is extremely harmful to the environment and operators; method 2 uses an efficient Suzuki coupling reaction, but the arranged The construction sequence requires the use of expensive 2-fluoro-4-bromoiodobenzene, and the Suzuki reaction using a noble metal catalyst is arranged first, resulting in high cost and low yield

Method used

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  • A preparing method of flurbiprofen
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Examples

Experimental program
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Effect test

Embodiment 1

[0033] A, preparation of 2-(3-fluoro-4-chlorophenyl) propionic acid (4)

[0034] In a 1000ml dry four-neck flask, add 14.4g (0.6mol) of magnesium chips, 50ml of THF, and two iodine pellets, stir and heat to 50°C in a nitrogen atmosphere. Dissolve 105g (0.5mol) of 3-fluoro-4-chlorobromobenzene (2) in 370ml of THF and drop it into 20ml. After confirming the trigger and the reaction is stable, add the remaining solution dropwise at 50-60°C, and keep it warm after dropping Stir for 1h.

[0035] Cool the reaction liquid to 0°C, add 96.3g (0.55mol) sodium 2-bromopropionate (3) at a temperature not exceeding 10°C, and gradually heat to reflux for 1 hour after the addition is complete, and the reaction ends.

[0036] Cool the reaction solution to 0°C, slowly add 400ml of 5mol / L hydrochloric acid, the temperature does not exceed 20°C, stir naturally for 30min after the addition, then heat to 50°C and stir for 1h.

[0037] Separate the liquid, keep the organic phase, and extract the a...

Embodiment 2

[0043] Preparation of 2-(2-fluoro-biphenyl-4-yl)propionic acid——flurbiprofen (1)

[0044] In a 1000ml three-necked flask, add 85g (0.42mol) of the product 2-(3-fluoro-4-chlorophenyl)propionic acid (4) and 89.7g of phenylboronic acid pinacol ester (5) in step A of Example 1 (0.44mol), ethanol 200ml, toluene 300ml, potassium carbonate 121g (0.88mol) dissolved in 200ml of water solution. After stirring evenly, add PdCl under the protection of nitrogen 2 (Amphos) 2 155mg (0.05mol%). Heating to reflux for 4h, TLC showed no raw material (4), and the reaction was over.

[0045]The solvent was distilled off, cooled to 0°C, and filtered with suction. The resulting solid was washed with 200 ml of cold water. Then the solid was dissolved in hot water, and hydrochloric acid was added dropwise until the pH value was less than 3, and a large amount of solid was precipitated, which was dried by suction filtration at room temperature to obtain 95.5 g of white flurbiprofen (1), with a yie...

Embodiment 3

[0048] A, preparation of 2-(3-fluoro-4-chlorophenyl) propionic acid (4)

[0049] In a 1000ml dry four-neck flask, add 14.4g (0.6mol) of magnesium chips, 50ml of THF, and two iodine pellets, stir and heat to 50°C in a nitrogen atmosphere. Dissolve 105g (0.5mol) of 3-fluoro-4-chlorobromobenzene (2) in 370ml of THF and drop it into 20ml. After confirming the trigger and the reaction is stable, add the remaining solution dropwise at 50-60°C, and keep it warm after dropping Stir for 1h.

[0050] Cool the reaction solution to 0°C, add 105g (0.6mol) sodium 2-bromopropionate (3) at a temperature not exceeding 10°C, and gradually heat to maintain 50-60°C for 2 hours after the addition, and the reaction is completed.

[0051] Cool the reaction solution to 0°C, slowly add 400ml of 5mol / L hydrochloric acid, the temperature does not exceed 20°C, stir naturally for 30min after the addition, then heat to 50°C and stir for 1h.

[0052] Separate the liquid, keep the organic phase, and extrac...

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Abstract

A preparing method of flurbiprofen is disclosed and belongs to the technical field of medicine preparation. A Suzuki coupling reaction is adopted. 2-(3-fluoro-4-chloro-phenyl)-propionic acid and a phenylboronic acid reagent are subjected to the palladium catalyzed Suzuki coupling reaction in an organic solvent under existence of an alkali to obtain the flurbiprofen, wherein the mole ratio of the 2-(3-fluoro-4-chloro-phenyl)-propionic acid to the phenylboronic acid reagent is 1:(0.9-1.1). The method is simple. The prepared flurbiprofen is high in yield and high in purity.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, relates to the preparation of non-steroidal anti-inflammatory analgesics, in particular to a preparation method of flurbiprofen, the preparation method of the invention is simple, and the obtained flurbiprofen has high yield and high purity . Background technique [0002] Flurbiprofen 1 (Flurbiprofen), the chemical name is 2-(2-fluorobiphenyl-4-yl)propionic acid, and the English name is 2-(2-fluoro-4-biphenylyl)propionic acid. Its structure is shown in the figure below: [0003] [0004] Flurbiprofen is a non-steroidal anti-inflammatory analgesic developed by British Boots Company. The drug was launched in the UK in 1976. It is a powerful phenylpropionic acid antipyretic, anti-inflammatory and analgesic drug, which can inhibit the production of cyclooxygenase by prostaglandins and play an analgesic, anti-inflammatory and antipyretic role. Its anti-inflammatory and analgesic eff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/353C07C57/58C07F3/02
CPCC07C51/353C07F3/02C07C57/58
Inventor 岳刚王志强黄印全禹凯关登仕符永冠
Owner MAISON CHEM
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