JPS5936653A - Preparation of 2-arylpropionitrile - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a pharmaceutical, in high yield, by reacting 1-arylethyl halide with sodium cyanide or potassium cyanide in the presence of effective amounts of water and a quaternary ammonium salt. CONSTITUTION:The objective compound of formula II can be prepared by reacting the 1-arylethyl halide of formula I (Ar is aromatic group; X is Cl, Br of I ) with sodium cyanide or potassium cyanide without using a polar solvent in the presence of effective amounts of a quaternary ammonium salt and water. The amount of water is preferably 2-0.16pts.wt. per 1pt.wt. of sodium cyanide or potassium cyanide. When the amount of water is out of the above range, the yield becomes low. The reaction temperature is preferably 40-150 deg.C. EFFECT:The generation of hydrogen cyanide gas can be suppressed remarkably.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula A r OH"""\cN (wherein,
Ar is an aromatic group. ) This relates to a method for producing 2-arylpropionitrile represented by:

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.

There are some that are widely used as pharmaceuticals, such as 4i1ULId and m-benzoylphenylpropionic acid (generic name: ketoprofen).

Many methods are known for producing 2-arylpropionic acid, and the method via 2-arylpropionitrile obtained by the present invention is also an important method.

Known methods for producing 2-arylpropionitrile include:
The following are listed, but all of them have some drawbacks.

1) Method of methylating arylacetonitrile (see, for example, Japanese Patent Application Laid-Open No. 115452/1982): In this method, it is not easy to limit the number of methyl groups introduced during methylation to one.

II) React 2-halogenopropionitrile with an aromatic compound by a Friedelta raft reaction to form a 2-
A method of introducing a propionitrile group (for example, JP-A-51
-56432): This method has a low yield;
Furthermore, the substitution position selectivity is low, making it difficult to purify the target compound after one reaction.

As a result of searching and researching a method for producing 2-arylpropionitrile that can eliminate the drawbacks of the above-mentioned known methods, the present inventor discovered that 1
-Complete-ruethyl halide (ArcH<””: A in the formula
r is an aromatic group, and X is chlorine.

Represents a halogen such as bromine or chloride. ) with water and the fourth
We have found a new method for producing 2-arylpropionitriles, which overcomes the drawbacks of the above-mentioned known methods, by reacting them with sodium cyanide or potassium cyanide in the presence of ammonium salts.

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 case of 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.

(Reference: Comparative Example 1) Furthermore, there was a safety and health problem in that the reaction between the by-produced hydrogen halide and the cyanide generated highly toxic cyanide gas.

As a way to solve the problem of styrene-type compound by-products, this cyanation reaction is carried out using anhydrous dimethylformamide (D
MF) A method of reacting in a polar solvent such as dimethyl sulfoxide (DMSO) (for example, JP-A-52-1115
36), but these solvents are expensive compared to water, benzenetoluene, or inexpensive helogenated hydrocarbons, and are water-soluble and have a high boiling point, making post-treatment difficult and difficult to recover. The problem was that it was easy and bulky.

In the method of the present invention, the desired 2-arylprobionitrile 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 two methods of the present invention will be explained in detail. Examples of the aryl group of 1-arylether halide, which is a raw material in the present invention, include phenyl, tolyl, isobutylphenyl,
te% t-butylphenyl, cyclohexylphenyl, anisyl 1m-phenoxyphenyl, naphthyl, 6
-Medoxy 2-naphthyl, m-benzoylphenyl.

Examples include diphenyl and the like, and aromatic nucleus substituted products of these aryl groups with fluorine or chlorine.

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, it is not trioctylmethylammonium 5-monicum chloride, trimethylbenzylammonium chloride, or triethylbenzylammonium chloride.

In particular, relatively highly lipophilic quaternary ammonium salts such as trioctylmethylammonium chloride are preferred. The amount of these quaternary ammonium salts used is 1-A1
7 + If the amount used is increased by 0.1 mol% or more based on ethyl halide, the reaction time tends to be shortened, but since increasing the amount used is delayed by an increase in cost, it is preferably 1 to 1. It is preferable to use 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 has surprisingly been found that the yield changes significantly depending on the amount of water.

In other words, the amount of water used is preferably 2x to 0.16 times the weight of sodium cyanide or potassium cyanide, and even if the amount of water used is greater or less than this preferred amount, the amount of 6- Yield decreases. (Reference Examples 8-9) The use of organic solvents in the uninvented process also affects the yield, and depending on the system, there are cases where it is preferable to use small amounts or not to use them at all.

When using an organic solvent, organic solvents used in ordinary phase transfer catalytic reactions, such as aromatic hydrocarbons such as benzene and toluene, dichloromethane, dichloroethane,
Examples include halogenated hydrocarbons such as chloroform.

Reaction temperature is 40-150°C, preferably 80-110°C
It is done by heating. The reaction time is usually 30 minutes to 20 hours (2) until the reaction is completed.

The raw material 1-arylethyl halide is produced by (1) addition reaction of hydrogen halide to styrenes.

(11) Conversion of 1-arylethyl alcohols obtained by reduction of acetylated aromatic compounds to halogen groups, (ii) 1-arylethyl alcohols obtained by using aromatic aldehydes and methyl Grignard reagent It can be synthesized by converting the hydroxyl group of into a halogen group.

The hydrolysis reaction of the nitriles obtained in the present invention to carboxylic acid can be carried out using 9 conventional hydrolysis reactions of nitriles. 2 For example, acidic hydrolysis or alkaline hydrolysis (see: Or
g, 5ynth% ses Co11. votl.

321.546 pages, Jnhn Wiley & 5o
The yield of carboxylic acid is quantitative.

Next, the method of the present invention will be explained in more detail with reference to comparative examples and examples.

Example, 2-7z-: #9fo=8. Ya. Generation 50.
6 Sodium cyanide 2.94P (
60 mmol), water 0.59F, trioctylmethylammonium chloride (90X aqueous solution) 1.02 r
(2.5 mmol) and 1-phenylethyl chloride 7041F (50 mmol) is added to the mixture. A reflux condenser was attached to this glass reaction vessel, and the temperature of the heated oil bath was gradually increased and maintained at 120°C.

The reaction was carried out for 5 hours while 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%. bp 115~6℃/20IIIH
g.

NMR (CD04) δ 1.6 (5H, d,
J day = 7Hz), A9 (IH, q, JH = 7Hz), 7
．． 4 (5H, s).

Engineering R (neat) 2200, 1590, 1480, 14
40°750.690 country-1 M5ζ (intensity ratio) 131 (M, 71), 89 (7).

104(11), 116(100).

In addition, the styrene production ratio after the completion of the two reactions (0, T (,0H=
C.B.

/C, H, <”) (d, 0.03 te afc.

Comparative Example 1 When quaternary ammonium salt was not used in Example 1 Trioctylammonium chloride (91% aqueous solution)
The reaction and post-treatment were carried out in the same manner as in Example 1, except that the reaction time was not used and the reaction time was extended to 11 hours. The yield of 2-phenylpropionitrile was 1.1%. In addition, the styrene production ratio (C・H1cH=CH110・HI
Hello, there was one N9 at 3.

Examples 2 to 9 2-7 Synthesis of enylpropionitrile 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: 7.04t
(50 mmol) Amount of sodium cyanide used 2
．． Usage amount of 94t (60ml70TOMAC()IJ octylmethylammonium chloride 90% aqueous solution)
1.029 (2.5 mmol) Oil bath temperature 1
20℃ 10- *Amount of water used: Weight of water contained in the TOMAO (IJ octylammonium chloride 90% aqueous solution) used (equivalent to 10% of TOMAC)
is added.

Example 10 Synthesis of 2-phenylpropionitrile Phase transfer catalyst trioctylmethylammonium chloride (90% aqueous solution) in Example 1 1.02 F
The reaction and post-treatment were carried out in the same manner as in Example 1, except that 0.85 t (2,5<lmol) of tetrabutylammonium hydrogen sulfate was used for 2-phenylpropionitrile (2.5 mmol). A yield of 6% was obtained.

Example 11 Synthesis of 2-phenylpropionitrile The amount of trioctylmethylammonium chloride (90% water bath solution) used in Example 1 was changed to 0.22 t (0.55 mmol), which is the amount of Example 4, and the procedure was carried out. When the reaction was carried out in the same manner as in Example 1, the yield was 5 (19N) at a reaction time of 5 hours, and the yield was 71.1% at a reaction time of 10 hours.

Example 12 Synthesis of 2-(2-(6-methoxy)naphthyl)propionitrile.

1-(2-(6-methoxy)naphthyl)ethyl chloride 1.1? (4,98 mmol), toluene α27
9. ) Lioctylmethylammonium chloride (90
% aqueous solution) 0.1F, sodium cyanide α29t
(5.92 mmol), water α06F mixture in Example 1
Heat in an oil bath in the same manner as above, bring the temperature of the oil bath to 120°C, and stir vigorously.

The reaction product after 5 hours of reaction was analyzed by gas chromatography. The yield was 86.5X.

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.

mp　51-53℃.

NMR (ODO4) δ1.7 (BE, d, ,T
=7.2Hz), A9(3H,s)4.0(IH,q
, ,T-7,2T(z), 71-7.9(6B,
m).

IR (Br) 2250.1600.1480.13
90.1260°196 (100).

Example x3 Synthesis of 2-(m-benzoylphenyl)propionitrile 1-(m-benzoylphenyl)ethyl chloride 0.
51 t (1,27 mmol), toluene 11042
1 trioctylmethylammonium chloride (9o
X aqueous solution) 0.03? , sodium cyanide αloa t
(1,52 mmol), water n04p was heated as in Example 1.

Made it react. Oil bath temperature 120℃. Reaction time: 5 hours. Analysis by gas chromatography showed a yield of 76.5X.

The product was post-treated in the same manner as in Example 12, and a portion was purified and fractionated using thin layer chromatography.

NMR (CD04) δ165(3) (, d, J=7.
2Hz), 4.0 (1H, q, J) 1=7.2H
z), 7.2-7.9 (9H, m).

Engineering R (neat) 2250.1660.1600.1
450.1280°760c! n0 13- (100), 158 (40).

Example 14 Synthesis of 2-(p-tolyl)propionitrile 1-(p-tolyl)ethyl chloride 1.339 (&6
mmol), trioctylmethylammonium chloride (90% aqueous solution) α222° Sodium cyanide 0.
5f (10 mmol).

Water 01? The mixture was heated and reacted in the same manner as in Example 1. The oil bath temperature was 120° C., the reaction time was 5 hours, and the yield was 75.5 N as analyzed by gas chromatography. Work-up was carried out in the same manner as in Example 12, and the product was confirmed to be the title compound by gas chromatography.

M8% (strength ratio)・14s ('M+, 45), 77(
3), 91(6).

103(12), 130(100).

Patent applicant: Nissan Chemical Industries, Ltd. -14 completed-

Claims (1)

[Claims] OH. (1) Effective amounts of 1-arylethyl halide, water and quaternary ammonium salt represented by the general formula AreH< (wherein, Ar is an aromatic group, and X is chlorine, bromine or iodine) General formula A, characterized in that it is reacted with sodium cyanide or potassium cyanide in the presence of
A method for producing 2-arylpropionitrile represented by r0H70B"'ON (in the formula, Ar has the same meaning as above). (2) The weight of water is 2 to 116 times the weight of sodium cyanide or potassium cyanide. 2. The method according to claim 1, wherein the method is: