JPS62896B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 2-(3-benzoylphenyl)propionic acid. It is already well known that the compounds produced by the method of the present invention are useful as pharmaceuticals, especially as anti-inflammatory analgesics. However, known methods for synthesizing propionic acids of this type generally require 5 to 10 steps and require isolation of intermediate products, and therefore cannot be said to be advantageous from an industrial standpoint. The object of the present invention is therefore to provide a process for the preparation of 2-(3-benzoylphenyl)propionic acid, which can be carried out starting from easily and inexpensively available compounds and without isolating most of the intermediate products. Our goal is to provide the following. According to the invention, this purpose is achieved by reacting 3'-(α-hydroxybenzyl)propiophenone with a secondary amine in the presence of a dehydrating agent to produce diphenylphosphoric azide without isolating the enamine formed. The generated amidine is hydrolyzed without isolation, and then the generated 2-[3-(α
This is achieved by a method for producing 2-(3-benzoylphenyl)propionic acid, which is characterized by subjecting 2-(hydroxybenzyl)phenyl]propionic acid to a dionez oxidation reaction. The method of the present invention is shown in the following reaction formula. reaction formula In each step shown in the above reaction formula,
Since enamine and amidine compounds are not isolated, industrial implementation is extremely advantageous, and furthermore, the final step, Diones oxidation reaction, can be carried out at room temperature, and the end point of the reaction can be confirmed by a change in the color tone of the reaction solution. This also facilitates the industrial implementation of the process of the invention. The synthesis reaction adopted in the method of the present invention can be carried out in a suitable inert solvent, for example, benzene or toluene solvent is used for the synthesis of enamine compounds, and ethyl acetate, tetrahydrofuran is used for the synthesis of amine compounds. , cyclohexane,
Good results can be obtained by using N,N-dimethylformamide, N,N-dimethylsulfoxide or the like, or by using ethylene glycol or the like when hydrolyzing amidine. Note that 3'-(α-hydroxybenzyl)propiophenone, which is the raw material for the method of the present invention, was obtained by patent application.
53-35134 (Japanese Unexamined Patent Publication No. 54-128553), it can be synthesized starting from 3'-bromopropiofenone according to the following reaction formula. reaction formula The invention will now be explained in more detail with reference to examples. Example a Synthesis of 2-[3-(α-hydroxybenzyl)phenyl]propionic acid 24g (0.1mol) of 3'-(2-hydroxybenzyl)propiophenone and 25.5g of piperidine
(0.3mol) and 1.4g of boron trifluoride etherate
(0.01 mol) is dissolved in 450 ml of toluene and reacted for 25 hours in a Cope apparatus using Monocular Sieve 4A as a dehydrating agent to produce the corresponding enamine. To the residue obtained by distilling off the solvent under reduced pressure, 300 ml of tetrahydrofuran and 30.25 g (0.11 mol) of diphenylphosphoric azide were added under an argon stream, and the mixture was stirred at room temperature for 1 hour and at 40°C for 1 hour, and then stirred for 3 hours at 40°C. The corresponding amidine is formed by refluxing for a period of time. Next, the solvent was distilled off, the crude product was dissolved in 1300 ml of ethylene glycol, 85 g (1.52 mol) of potassium hydroxide was added, and then 7
Reflux for an hour. Reaction mixture with water 9000 ml
ml, dilute with carbon dioxide gas and adjust the pH to approximately 9.
Next, wash with ethyl ether. The aqueous layer is separated and acidified with hydrochloric acid, extracted with ethyl acetate, the organic layer is washed with water and saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. 2-[3-(α-hydroxybenzyl)phenyl]propionic acid 17.4g
(0.068mol) is obtained. Yield from raw material ketone: 68% Melting point: 114-115℃ b Synthesis of 2-(3-benzoylphenyl)propionic acid 2-[3- obtained by the method described in a above
52 mg of (α-hydroxybenzyl)phenyl]propionic acid is dissolved in 2 ml of acetone, and Johns reagent is added dropwise to this until the color of the solution changes from blue-yellow to red-yellow. Next, a small amount of isopropanol was added until the color of the reaction solution changed from reddish-yellow to colorless, and then 70 ml of chloroform was added, the formed precipitate was filtered off, the filtrate was washed with water, and the mixture was diluted with anhydrous magnesium sulfate. After drying and distilling off the solvent under reduced pressure, the desired 2
-(3-Benzoylphenyl)propionic acid 45mg
is obtained (yield 89.2%). IR spectrum (ν ^cap _nax cm ^-1 ): 1730, 1705 (-COOH), 1655

[Formula] NMR spectrum (CDCL ₃ ) δppm: 1.50 (3H, d, J=6.6,

【formula】) 3.76 (1H, q, J=6.6,

[Formula]) 7.2 -7.75 (9H, m, Ar-H) 11.29 (1H, br, -COOH, +D ₂ O disappearance)

Claims (1)

[Claims] 1 3′-(α-hydroxybenzyl)propiophenone and a secondary amine are reacted in the presence of a dehydrating agent, and the resulting enamine is reacted with diphenylphosphoric azide without isolating the resulting amidine. Hydrolyzes without isolation and then produces 2-[3-(α-hydroxybenzyl)
A method for producing 2-(3-benzoylphenyl)propionic acid, which comprises subjecting phenyl]propionic acid to a dionez oxidation reaction.