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Preparation method of flurbiprofen

A technology of flurbiprofen and o-fluoroaniline, which is applied in the field of preparation of flurbiprofen, can solve the problems of many by-products, unsatisfactory amplification, harsh reaction conditions, etc., achieve high yield and purity of intermediate products, and improve overall Safe operation and mild reaction conditions

Pending Publication Date: 2021-02-09
浙江东亚药业股份有限公司
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Problems solved by technology

But, the main problem of this route is: 1) although, the starting material of producing 2-fluoro-4-bromobiphenyl is o-fluoroaniline, yet, it uses expensive metal palladium catalyst, brominated reagent and organoboron Reagents and other raw materials, and will produce a large number of by-products, heavy metal residues and increase the cost of three wastes treatment, which makes the starting materials more expensive; 2) The anhydrous and oxygen-free reaction conditions of the Grignard reaction are demanding, and the stability is very poor, and it is very easy to hydrolyze Coupling with itself, it is difficult to accurately measure its effective content
Another example is flurbiprofen synthesis process research [D], Qingdao University of Science and Technology, reported in 2012 with o-fluoroaniline as raw material, through 7 steps such as bromination, diazotization, coupling, Grignard reaction, using bromine or The bromination reaction of N-bromosuccinimide (NBS) is poor in selectivity and produces more by-products, which brings great pressure to separation and purification and waste treatment; while using 1,5-dibromo-3,3 - In the case of dimethyl hydantoin (DBDMH), although its selectivity is high, the operation is loaded down with trivial details, and the raw material price is very expensive
In summary, in the synthesis methods reported in the existing literature, there are generally problems such as long routes, harsh reaction conditions, many by-products, and difficulties in separation and purification, which make the total yield of the final product very low and cannot meet the needs of scale-up. Suitable for industrial production

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  • Preparation method of flurbiprofen
  • Preparation method of flurbiprofen
  • Preparation method of flurbiprofen

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preparation example Construction

[0049] The preparation method of this flurbiprofen comprises the following steps:

[0050] Under the action of Lewis acid, the acylation reaction of o-fluoroaniline or N-substituted o-fluoroaniline and 2-halopropionyl halide is preferably carried out in a water-insoluble organic solvent to obtain the corresponding intermediate compound of formula II;

[0051]

[0052] In the above formula II, R 1 Selected from acetyl, propionyl, H or Boc group; said X is the corresponding halogen in 2-halopropionyl halide; the halogen here can be chlorine, bromine or iodine, and the halogen of two corresponding halogen substitution positions They can be the same or different, preferably they are all chlorine, preferably chloropropionyl chloride. The above-mentioned water-insoluble organic solvent is preferably selected from one or more of cyclohexane, petroleum ether, n-heptane, methylene chloride and ethylene dichloride, preferably o-fluoroaniline or N-substituted o-fluoroaniline The mol...

Embodiment 1

[0077] Preparation of the first step intermediate formula II compound

[0078]

[0079] In a clean reactor, disperse 168g of aluminum trichloride (1.26mol) in 400mL of dichloromethane solvent, stir until dissolved, under the protection of nitrogen, lower the temperature to 10-15°C, and dropwise add 80g of 2 - Chloropropionyl chloride (0.63mol), control the temperature and carry out heat preservation and stirring for 1h, then, to the reaction solution of the above reaction system, slowly dropwise add 200mL of dichloromethylene chloride prepared in advance with 92g o-fluoroacetanilide (0.6mol) Methane clarifies the solution. After the dropwise addition, heat up to reflux and stir for 18-20h. After the reaction is over, cool down the reaction system by 0-5°C, and then add 300mL of 5% dilute hydrochloric acid solution dropwise. After the dropwise addition, fully stir 1h, standing for stratification, collecting the organic phase, and extracting the water phase once with dichloro...

Embodiment 2

[0082]

[0083] 98g (0.4mol) of the formula II compound (intermediate 2) obtained according to the above-mentioned method was dissolved in 500mL of anhydrous methanol solvent, and then 53g of trimethyl orthoformate (0.5mol) and p-toluenesulfonic acid (0.02mol) were added, Then, the temperature was raised to 50-60° C. for 2 h. After the reaction is over, carry out vacuum distillation to recover methanol and trimethyl orthoformate, distill until no liquid flows out, then add 600mL of dichloromethane and 200mL of water to the solid concentrate, stir well, let stand to separate and collect After the organic phase was distilled under normal pressure to recover the solvent, 200 mL of isopropanol was added to the residue for sufficient beating treatment, and the filter cake was obtained by filtration. The filter cake was rinsed with a little isopropanol, and the obtained wet product was placed in a 50°C refrigerator. Drying under vacuum condition for 5-6h gave 99g of intermediate ...

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Abstract

The invention relates to a preparation method of flurbiprofen, and belongs to the technical field of medicine synthesis. In order to solve the problems of poor safety and low yield of the existing route, the invention provides a preparation method of flurbiprofen. The method comprises the following steps: under the action of Lewis acid, carrying out acylation reaction on o-fluoroaniline or N-substituted o-fluoroaniline and 2-halogenated propionyl halide to obtain an intermediate compound as shown in formula II; under the action of a ketal catalyst, carrying out ketal reaction on the compound as shown in the formula II and a carbonyl protection reagent to obtain a ketal substance; in the presence of an acidic catalyst, carrying out a rearrangement reaction on the ketal to obtain a compoundas shown in a formula IV; under an acidic or alkaline condition, carrying out hydrolysis reaction to obtain a compound as shown in a formula V; under the action of a diazotization catalyst and a phasetransfer catalyst, mixing a compound as shown in a formula V, benzene and nitrite under an acid condition, carrying out diazotization reaction, and carrying out hydrolysis reaction after the diazotization reaction is finished, so as to obtain the corresponding product flurbiprofen as shown in a formula I. The method has the effects of high reaction safety and high yield.

Description

technical field [0001] The invention relates to a preparation method of flurbiprofen, which belongs to the technical field of medicine synthesis. Background technique [0002] Flurbiprofen (flurbiprofen) belongs to propionic acid non-steroidal anti-inflammatory drugs, its chemical name is (±)-2-(2-fluoro-4-biphenyl)-propionic acid, and its structural formula is as follows: [0003] [0004] Flurbiprofen is currently known as propionic acid non-steroidal anti-inflammatory drugs with the best curative effect, and it is mainly used clinically to treat rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc. Flurbiprofen has become an excellent variety of non-steroidal anti-inflammatory analgesics with its high-efficiency antipyretic, anti-inflammatory and analgesic effects, low toxicity and small side effects, and has broad market competitiveness and development prospects. [0005] The flurbiprofen reported both at home and abroad is mainly represented by the biph...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/33C07C233/25C07C233/49C07C227/20C07C229/42C07C51/377C07C57/58C07D319/06
CPCC07C231/12C07C227/20C07C51/377C07D319/06C07C233/33C07C233/25C07C233/49C07C229/42C07C57/58
Inventor 池骋张道明王佃龙刚丽霞池正明
Owner 浙江东亚药业股份有限公司
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