JPH0150221B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing 2-phenylpropionitrile. 2-phenylpropionic acid and its salts, esters, amides, and other derivatives obtained by hydrolyzing 2-phenylpropionitrile in a conventional manner are useful in pharmaceuticals, etc. It is useful as an intermediate for active substances. Known methods for producing 2-phenylpropionitrile include (i) methylation of the α-position of phenylacetonitrile [Journal of the Americas;
Chemical Society (J.Am.Chem.Soc.)
55, 2851 (1933), 64, 150 (1942), etc.] (ii) Methods based on indirect methylation of phenylacetonitrile (see JP-A-56-15258) are known. However, method (i) above
The selectivity of limiting the number of methyl groups to be introduced to 1 was poor, resulting in unreacted acetonitrile and α, α
-Dimethyl-phenylacetonitrile contamination made it difficult to separate and purify the desired product, 2-phenylpropionitrile. In addition, method (i) above has the disadvantage that an alkylthio group or a carbalkoxy group is introduced as a protecting group in advance, and this protecting group is removed after methylation, which requires an extra step and an extra raw material. . As a result of research to overcome these drawbacks and develop a method for producing 2-phenylpropionitrile that is preferable for industrial and economical implementation, the present inventors have developed a method for producing 2-phenylpropionitrile according to the following reaction flow. I found a way to synthesize it. That is, in step 1, styrene and hydrochloric acid are reacted in the presence of a quaternary ammonium salt effective as a phase transfer catalyst. This step 1 is known [see Journal of Organ Chemistry (J, Org. Chem.), 45, 3527 (1980)]. , the presence of an effective amount of quaternary ammonium salt as a phase transfer catalyst is essential. Step 2 is mainly based on the method invented by the present inventors (see "Production of 2-arylpropionitrile: Application filed by the present applicant dated August 24, 1982"). , in the presence of an effective amount of a quaternary ammonium salt as a phase transfer catalyst and water 1
- A method for producing 2-phenylpropionitrile, which is characterized by reacting phenylethyl chloride with sodium cyanide or potassium cyanide. In other words, as is clear from the reaction flow, the method of the present invention reuses the expensive quaternary ammonium salt in Step 2, which is essential for proceeding with both Step 1 and Step 2 in high yield. This is an industrially very easy and economical method characterized by combining Step 1 and Step 2 for the purpose of. Furthermore, the features of step 2 will be explained. 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 Reference Examples 1 and 2) Furthermore, there was a safety and health problem in that highly toxic cyanide gas was generated due to the reaction between the by-produced hydrogen halide and cyanide. 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) dimethyl sulfoxide (DMSO), etc. However, 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. Next, the present invention will be explained in detail. The quaternary ammonium salt used in the present invention is used in an effective amount as a phase transfer catalyst.
In order to prevent the quaternary ammonium salt from migrating to the aqueous layer and being lost during the process of removing excess hydrochloric acid by washing with water, it is necessary to use a lipophilic quaternary ammonium salt. desirable. Examples thereof include, but are not limited to, trioctylmethylammonium chloride, trimethylbenzylammonium chloride, triethylbenzylammonium chloride, tetrabutylammonium hydrogen sulfate, and the like.
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 styrene, and increasing this amount tends to shorten the reaction time, but increasing the amount used also increases costs. Therefore, it is preferable to use 1 to 10 mol%. Next, process 1 will be explained. The hydrochloric acid used may be commercially available industrial hydrochloric acid; the higher the concentration of hydrogen chloride, the faster the reaction will be completed. Although the reaction proceeds even if the amount of hydrochloric acid is equimolar to styrene, it is preferably used at least 3 times by mole to complete the reaction quickly. The reaction temperature in step 1 is 20°C to reflux temperature,
Preferably the temperature is 50°C to reflux temperature. Next, step 2 will be further explained. As mentioned above, the presence of water is necessary in step 2, but the inventors of the present invention have investigated this point in detail and surprisingly found that the yield changes significantly 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 (see Reference Examples 3 to 10) The use of an organic solvent in step 2 of the method of the present invention also affects the yield, and depending on the system, it may be preferable to use a small amount or not to use it at all. When using an organic solvent, organic solvents used in ordinary phase transfer catalytic reactions, such as benzyl,
Aromatic hydrocarbons such as toluene, dichloromethane,
Examples include halogenated hydrocarbons such as dichloroethane and chloroform. The reaction temperature in step 2 is 40-150°C, preferably
This is done by heating to 80-130℃. The reaction time is carried out until the reaction is completed, and is usually 30 minutes to 20 hours. In addition, after the reaction in step 2 is completed, it is also possible to reuse the quaternary ammonium salt in the distillation residue after obtaining 2-phenylpropionitrile by distillation. (See Example 3) 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: Organic Synthesis (see Example 3). Org.Syntheses) Coll.vol1, pages 321, 346, John
Wiley & Sons) and the yield of carboxylic acid is almost quantitative. Next, the method of the present invention will be explained in more detail using Examples and Reference Examples. Example 1 Synthesis of 1-phenylethyl chloride 72.9 g of styrene, 365 g of 35% HCl water,
trioctylmethylammonium chloride (80
% aqueous solution) was added, mixed, and heated in an oil bath. Reflux begins at a reaction temperature of 87°C, then 100°C.
The reaction solution temperature rose to ℃. Stop heating after 30 minutes,
After cooling, the organic layer was left to stand and separated, and the organic layer was washed with 10% Na ₂ CO ₃ and then with saturated saline, leaving a light yellow oil (108.6).
I got g. Comparative analysis (NMR, GC, etc.) between this product and a commercially available standard product confirmed that it was 1-phenylethyl chloride. Purity 84.9% yield
It was 94.2%. Example 2 Synthesis of 2-phenylpropionitrile In a 100 ml glass reaction vessel equipped with a Dimroth condenser, 18.7 g of sodium cyanide and 3.7 g of water were added.
Then, 52.7 g of 1-phenylethyl chloride containing trioctylmethylammonium chloride obtained in Example 1 was charged and heated in an oil bath to bring the temperature of the oil bath to 120°C. After 3 and a half hours, heating was stopped, the mixture was cooled, water was added thereto, and the mixture was stirred and allowed to stand still for liquid separation. The organic layer was washed with water to obtain 50.5 g of crude 2-phenylpropionitrile as a pale yellow oil. As a result of internal standard analysis by gas chromatography, the yield was 76% (based on styrene). The obtained crude 2-phenylpropionitrile was purified by distillation to obtain 2-phenylpropionitrile as a colorless oil. boiling point
115−116℃/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, 690
cm ^-1 MSm/e (intensity ratio) 131 (M. ⁺ 71), 89(7), 104
(11), 116(100). Example 3 Recycling of quaternary ammonium salts 2-phenylpropylene containing 1.19 g (24 mmol) of sodium cyanide, 0.50 g of water, and 0.40 g of trioctylmethylammonium chloride in a 50 ml glass reaction vessel fitted with a Dimroth condenser. 1.0 g of distillation residue of pionitrile and 2.81 g (20 mmol) of 1-phenylethyl chloride were charged, heated in an oil bath, the oil bath temperature was raised to 120°, and the reaction was monitored by gas chromatography. The rate is 75.6%
showed that. Reference example 1 Synthesis of 2-phenylpropionitrile Sodium cyanide in a 50ml 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, styrene production ratio after reaction completion

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

[Formula] was 6.3. Reference Examples 3 to 10 Synthesis of 2-phenylpropionitrile Reactions and post-treatments were carried out in the same manner as in Reference Example 1, except as described below. Amount of 1-phenylethyl chloride used 7.04
g (50 mmol) Amount of sodium cyanide used: 2.94 g (60 mmol) Amount of TOMAC (trioctylmethylammonium chloride 90% aqueous solution) used: 1.02 g (2.5 mmol) Oil bath temperature: 120°C

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Claims (1)

[Scope of Claims] 1. 1-phenylethyl chloride containing the above quaternary ammonium salt obtained by reacting styrene and hydrochloric acid in the presence of a quaternary ammonium salt in the presence of an effective amount of water. A method for producing 2-phenylpropionitrile, which comprises reacting sodium cyanide or potassium cyanide. 2. The manufacturing method according to claim 1, wherein the amount of water used is 2 to 0.16 times the weight of sodium cyanide or potassium cyanide.