Flurbiprofen synthesis method

A technology of flurbiprofen and its synthesis method, which is applied in the field of drug synthesis, can solve the problems of high cost, great harm to the environment and operators, and low yield, and achieve the effects of less three wastes, high atom utilization rate, and high yield

Active Publication Date: 2017-03-15
MAISON CHEM
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  • Abstract
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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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preparation example Construction

[0035] ① Preparation of Grignard reagent: It is prepared by reacting 3-fluorobromobenzene and magnesium chips in THF, wherein the molar ratio of 3-fluorobromobenzene and magnesium chips is 1: (1-2).

[0036] ②Coupling reaction: Add sodium 2-bromopropionate to the Grignard reagent of 3-fluorobromobenzene under the condition of -10~70℃, gradually heat to reflux after adding, react for 1-1.5h, react Finish.

[0037] ③Acidification reaction: Cool the reaction solution of the coupling reaction to 0°C, slowly add hydrochloric acid, the temperature does not exceed 20°C, stir naturally for 30-40min after adding, then heat to 50-60°C and stir for 1-1.5h, then Separate the liquid, extract the aqueous layer twice with ethyl acetate, combine the organic phase and the extract, evaporate the solvent in a water bath under reduced pressure until solids appear, add toluene, stir and cool down to -10°C, and filter the resulting white solid with suction Drying affords 2-(3-fluorophenyl)propanoi...

Embodiment 1

[0042] (1) Preparation of 2-(3-fluorophenyl) propionic acid (4)

[0043] 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, and mix 87.5g (0.5mol) of 3-fluorobromobenzene with 370ml of THF , and then drop 20ml of the mixed solution first. After the initiation is confirmed and the reaction is stable, the remaining mixed solution is added dropwise at 50-60°C. After the dropping, keep stirring for 1 hour.

[0044] Cool the reaction solution to 0°C, add 96.3g (0.55mol) of sodium 2-bromopropionate at a temperature not exceeding 10°C, and gradually heat to reflux for 1 hour after the addition, and the reaction ends.

[0045]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.

[0046] Separate the liquid, extract the aqueous layer twi...

Embodiment 2

[0054] (1) Preparation of 2-(3-fluorophenyl) propionic acid (4)

[0055] 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. Mix 87.5g (0.5mol) of 3-fluorobromobenzene with 370ml THF, and then drop 20ml of the mixed solution first. After confirming the trigger and the reaction is stable, add the remaining mixed solution dropwise at 52-58°C, and keep stirring for 1 hour after dropping. .

[0056] Cool the reaction solution to 0°C, add 105g (0.6mol) sodium 2-bromopropionate at a temperature not exceeding 10°C, and gradually heat to reflux for 1 hour after the addition, and the reaction ends.

[0057] 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 32min after the addition, then heat to 52°C and stir for 1h.

[0058] Separate the liquid, extract the aqueous layer twice with 200ml of eth...

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Abstract

The invention relates to a flurbiprofen synthesis method and belongs to the technical field of pharmaceutical synthesis. According to the flurbiprofen synthesis method, Suzuki coupling reaction is utilized, the flurbiprofen can be obtained from 2-(3-fluoro-4-bromophenyl) propionic acid and phenyl boron reagent in organic solvent in the alkali condition through palladium catalytic Suzuki coupling reaction; the mole ratio between the 2-(3-fluoro-4-bromophenyl) propionic acid and the phenyl boron reagent is 1: (0.9 to 1.1). The synthesis method is simple, and the obtained flurbiprofen is high in yield and high in purity.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis and relates to the preparation of non-steroidal anti-inflammatory analgesics, in particular to a method for synthesizing flurbiprofen. The synthesis 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 synthesis of prostaglandin cyclooxygenase and play an analgesic, anti-inflammatory and antipyretic role. Its anti-inflammatory and analgesic effects are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/353C07C57/58
CPCC07C51/353C07C51/363C07F3/02C07C57/58
Inventor 岳刚王志强黄印全禹凯关登仕符永冠
Owner MAISON CHEM
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