JPH0323538B2 - - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula

The present invention relates to a method for producing 2-arylpropionitrile represented by the formula: [In the formula, Ar is an aromatic group]. By hydrolyzing the above-mentioned 2-arylpropionitrile, the corresponding 2-arylpropionic acid can be obtained. Some 2-arylpropionic acids exhibit pharmacological effects such as anti-inflammatory, analgesic, and antipyretic properties. For example, there are compounds that are widely used as pharmaceuticals, such as m-benzoylphenylpropionic acid (generic name: ketoprofen). Many methods are known for producing 2-arylpropionic acid, and the 2-arylpropionic acid obtained by the present invention
-A method via arylpropionitrile is also an important method. Known methods for producing 2-arylpropionitrile include the following, but all of them have the following drawbacks. Method for methylating arylacetonitrile (see, for example, Japanese Patent Application Laid-Open No. 115452/1983): In this method, it is difficult to limit the number of methyl groups introduced during methylation to one. Reacting 2-halogenopropionitrile with an aromatic compound by Friedel-Crafts reaction,
A method of introducing a 2-propionitrile group into an aromatic ring (see, for example, JP-A No. 51-36432): This method has a low yield and low substitution position selectivity, and it is difficult to obtain the desired compound after the reaction. Not easy to purify. As a result of searching and researching a method for producing 2-arylpropionitrile that can eliminate the difficulties of the above-mentioned known methods, the present inventor discovered that 1-arylethyl halide (

[Formula]: In the formula, Ar represents an aromatic group, and X represents a halogen such as chlorine, bromine or iodine. )
The disadvantages of the above known methods were overcome by reacting with sodium cyanide or potassium cyanide in the presence of water and a quaternary ammonium salt.
-Discovered a new method for producing arylpropionitriles. It is generally known that the cyanation reaction of benzyl halide proceeds relatively easily. On the other hand, when a methyl group is present in the methylene group of the benzyl group as in the 1-arylethyl halide of the present invention, hydrogen halide is eliminated during the cyanation reaction, producing a styrene-type compound and reducing the yield. There is a disadvantage that this method tends to produce styrene-type compounds, especially when water is used as a solvent.
(See Comparative Example 1) Furthermore, there was a safety and health problem in that the reaction between the by-produced hydrogen halide and cyanide generated highly toxic cyanide gas. As a method to solve this problem of by-product of styrene-type compounds, the cyanation reaction is carried out in a polar solvent such as anhydrous dimethylformamide, (DMF) and dimethyl sulfoxide (DMSO) (for example, see JP-A-52-111536). ), but these solvents are expensive compared to water, benzene-toluene, or inexpensive halogenated hydrocarbons, and are water-soluble and have high boiling points, making post-treatment difficult and not easy to recover. There was a problem. In the method of the present invention, the desired 2-arylpropionitrile can be obtained in high yield simply by coexisting an effective amount of quaternary ammonium salt and water without using these polar solvents, resulting in the generation of cyanide gas. It has become clear that this can be suppressed to a large extent. The above method of the present invention will be explained in detail. Examples of the aryl group of 1-arylethyl halide, which is a raw material in the present invention, include phenyl, tolyl,
Isobutylphenyl, tert-butylphenyl, cyclohexylphenyl, anisyl, m-phenoxyphenyl, naphthyl, 6-methoxy-2-naphthyl, m-benzoylphenyl, diphenyl, etc., and aromas caused by fluorine or chlorine of these aryl groups Examples include nuclear substitutes. Further, the halogen group in 1-arylethyl halide means chlorine, bromine or iodine. The quaternary ammonium salt used in the present invention is used in an effective amount as a phase transfer catalyst, and examples thereof include the following quaternary ammonium salts. That is, examples include trioctylmethylammonium chloride, trimethylbenzylammonium chloride, triethylbenzylammonium chloride, tetrabutylammonium hydrogen sulfate, and the like, but are not limited to these. In particular, relatively highly lipophilic quaternary ammonium salts such as trioctylmethylammonium chloride are preferred. The amount of these quaternary ammonium salts used is 0.1 mol% or more based on the 1-arylethyl halide, and increasing this amount tends to shorten the reaction time, but increasing the amount used increases costs. Therefore, it is preferable to use 1 to 10 mol%. Furthermore, water is necessary for the reaction of the present invention, and as a result of studies conducted by the present inventors, it was surprisingly found that the yield significantly changes depending on the amount of water. That is, the amount of water used is preferably 2 times to 0.16 times the weight of sodium cyanide or potassium cyanide, and if the amount of water used is more or less than this preferred amount, the yield of the target compound will decrease. Reference Examples 8-9 The use of organic solvents in the process of the invention also affects the yield, and in some systems it may be preferable to use them in small amounts or not at all. When using an organic solvent, examples of organic solvents used in ordinary phase transfer catalytic reactions include aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform. The reaction temperature is 40 to 150°C, preferably 80 to 110°C. The reaction time is carried out until the reaction is completed, and is usually 30 minutes to 20 hours. The raw material 1-arylethyl halide is (i)
1 obtained by addition reaction of hydrogen halide to styrenes, (ii) reduction of acetylated aromatic compound
It can be synthesized by converting the hydroxyl group of -arylethyl alcohol into a halogen group, (iii) converting the hydroxyl group of 1-arylethyl alcohol obtained with an aromatic aldehyde and a methyl Grignard reagent into a halogen group, etc. In addition, the hydrolysis reaction of the nitriles obtained in the present invention to carboxylic acids can be carried out using conventional nitrile hydrolysis reactions, such as acidic hydrolysis or alkaline hydrolysis (see: Org. Syntheses Coll. vol. 1, 321,
346 pages, conducted by Jnhn Wiley & Sons,
The yield of carboxylic acid is almost quantitative. Next, the method of the present invention will be explained in more detail using comparative examples and examples. Example 1 Production of 2-phenylpropionitrile Sodium cyanide was added to a 50 ml glass reaction vessel.
2.94g (60mmol), water 0.59g, trioctylmethylammonium chloride (90% aqueous solution)
1.02 g (2.5 mmol) and 7.04 g (50 mmol) of 1-phenylethyl chloride are added to the mixture. A reflux condenser was attached to this glass reaction vessel, and the heated oil bath temperature was gradually increased in an oil bath.
The reaction was carried out for 5 hours while maintaining the temperature at 120°C and stirring the reaction solution vigorously. Analysis by gas chromatography showed a yield of 89.6%. Water was added to the reaction solution, extracted with toluene, the toluene layer was washed with water, and then distilled under reduced pressure to obtain 2-phenylpropionitrile. Yield 81.0%. bp115~6℃/20mmHg. NMR (CDCl ₃ ) δ1.6 (3H, d, JH=7Hz), 3.9
(1H, q, JH = 7Hz), 7.4 (5H, s). IR (neat) 2200, 1590, 1480, 1440, 750, 690cm
^-1 . MSm/e (intensity ratio) 131 (M ⁺ , 71), 89(7), 104(11),
116 (100). In addition, the styrene production ratio after the completion of the reaction

[Formula] was 0.03. Comparative Example 1 When the quaternary ammonium salt was not used in Example 1 Same as Example 1 except that trioctylammonium chloride (91% aqueous solution) was not used and the reaction time was extended to 11 hours. Reaction and post-treatment. The yield of 2-phenylpropionitrile was 1.1%. In addition, the styrene production ratio

[Formula] was 6.3. Examples 2 to 6 Synthesis of 2-phenylpropionitrile Reactions and post-treatments were carried out in the same manner as in Example 1, except as described in the table below. Amount of 1-phenylethyl chloride used
7.04g (50 mmol) Amount of sodium cyanide used
2.94g (60 mmol) Usage amount of TOMAC (trioctylmethylammonium chloride 90% aqueous solution)
1.02g (2.5 mmol) Oil bath temperature 120℃

【table】

[Table] Example 7 Synthesis of 2-phenylpropionitrile Trioctylmethylammonium chloride (90% aqueous solution) as the phase transfer catalyst in Example 1
The reaction and post-treatment were carried out in the same manner as in Example 1, except that 1.02 g (2.5 mmol) was replaced with 0.85 g (2.5 mmol) of tetrabutylammonium hydrogen sulfate.
-Phenylpropionitrile was obtained with a yield of 78.6%. Example 8 Synthesis of 2-phenylpropionitrile The amount of trioctylmethylammonium chloride (90% aqueous solution) used in Example 1 was changed to 0.22 g (0.55 mmol), which is 1/5 of the amount of Example.
When the reaction was carried out in the same manner as in Example 1, the reaction time was 5.
Yield is 50.9% in time, yield is 50.9% in reaction time 10 hours.
It was 71.1%. Example 9 Synthesis of 2-(2-(6-methoxy)naphthyl)propionitrile 1.1 g (4.98 mmol) of 1-(2-(6-methoxy)naphthyl)ethyl chloride, 0.27 g of toluene,
trioctylmethylammonium chloride (90
% aqueous solution) 0.1g, sodium cyanide 0.29g
(5.92 mmol) and 0.06 g of water was heated in an oil bath in the same manner as in Example 1, the temperature of the oil bath was raised to 120°C, and the mixture was vigorously stirred. After 5 hours of reaction, the reaction product was analyzed by gas chromatography. . The yield was 86.5%. Water was added to this reaction solution and extracted with toluene. After washing the toluene layer with water, a portion was taken, the toluene was distilled off, and the mixture was purified and fractionated using thin layer chromatography. mp51~53℃. NMR (CDCl ₃ ) δ1.7 (3H, d, J = 7.2Hz), 3.9
(3H, s) 4.0 (1H, q, J=7.2Hz), 7.1~7.9
(6H, m). IR (KBr) 2250, 1600, 1480, 1390, 1260,
1030, 860, 820 cm ^-1 . MSm/e (intensity ratio) 211 (M ⁺ , 70), 104(4), 153
(15) 196 (100). Example 10 Synthesis of 2-(m-benzoylphenyl)propionitrile 1-(m-benzoylphenyl)ethyl chloride 0.31 g (1.27 mmol), toluene 0.04 g, trioctylmethylammonium chloride (90%
aqueous solution) 0.03g, sodium cyanide 0.07g
(1.52 mmol) and 0.04 g of water was heated and reacted in the same manner as in Example 1. Oil bath temperature 120℃.
Reaction time: 5 hours. Analysis by gas chromatography showed a yield of 76.5%. The product was post-treated in the same manner as in Example 9, and a portion was purified and fractionated using thin layer chromatography. NMR (CDCl ₃ ) δ1.65 (3H, d, J = 7.2Hz), 4.0
(1H, q, JH = 7.2Hz), 7.2-7.9 (9H, m). IR (neat) 2250, 1660, 1600, 1450, 1280, 760
cm ^-1 . MSm/e (intensity ratio) 235 (M ⁺ , 34), 77 (33), 105
(100), 1580(40). Example 11 Synthesis of 2-(p-tolyl)propionitrile 1.33 g of 1-(p-tolyl)ethyl chloride
(8.6 mmol), 0.22 g of trioctylmethylammonium chloride (90% aqueous solution), 0.5 g (10 mmol) of sodium cyanide, and 0.1 g of water were heated and reacted in the same manner as in Example 1. The oil bath temperature was 120°C, the reaction time was 3 hours, and the yield was 75.5% when analyzed by gas chromatography. Example 9
The product was worked up in the same manner as above, and the product was confirmed to be the title compound by gas chromatography. MSm/e (intensity ratio) 145 (M ⁺ , 45), 77(3), 91(6),
103(12), 130(100).

Claims (1)

[Claims] 1. General formula (In the formula, Ar is an aromatic group and X is chlorine, bromine or iodine.) A 1-arylethyl halide represented by: sodium cyanide or General formula characterized in that when reacting with potassium cyanide, the weight of water is 0.2 to 1.03 times the weight of sodium cyanide or potassium cyanide. (In the formula, Ar has the same meaning as above.) A method for producing 2-arylpropionitrile represented by: