JPH026344B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing phenylacetonitrile derivatives. More specifically, the present invention relates to the general formula [In the formula, R represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R' represents an alkyl group, an alkenyl group, or an aryl group or an aralkyl group having a nitro group as a substituent. ] Phenylacetonitrile derivatives and general formula [In the formula, R′ is the same as above. This invention relates to a novel method for producing a phenylacetonitrile derivative represented by the following. The phenylacetonitrile derivatives represented by the above general formulas (1) and (2) are compounds useful as synthetic raw materials for pharmaceuticals, dye intermediates, and various chemicals, and various methods have been developed to date. For example, general formula [In the formula, R is the same as above. ] Phenylacetonitrile derivative or formula represented by Phenylacetonitrile represented by the general formula R'X (5) [wherein X represents a halogen atom]. R' is the same as above. ] in the presence of a base such as sodium amide, sodium metal, or sodium alkoxide in an appropriate solvent [ACCope, HLHolmes, and HOHouse,
Org.React., 9, 107 (1957)], the compound of general formula (3) or the compound of formula (4) and the compound of general formula (5) in an aqueous alkali hydroxide solution in the presence of a quaternary ammonium salt. How to react below [M. Makosza, B.
Serafin, Rocz.Chem., 39, 1223, 1401 (1965)
Reference] etc. are known. However, all of these methods are industrially disadvantageous. That is, in the former method, the base is expensive and difficult to handle, the solvent used must be completely dehydrated, and the yield of the target compound is only about 70 to 80% at most. In addition, in the latter method, the quaternary ammonium salt used as a catalyst is unstable in an aqueous alkali hydroxide solution and is decomposed as the reaction progresses, so it is not possible to quantitatively recover the quaternary ammonium salt after the reaction is completed. Moreover, since such decomposition products are mixed into the target compound, the purity of the target compound is insufficient, and the yield is only 80%.
It stops at about %. In view of the current situation, the present inventor has conducted extensive research in order to obtain phenylacetonitrile derivatives in high yield and purity through simple operations. As a result, when reacting the phenylacetonitrile derivative represented by the above general formula (3) or the phenylacetonitrile represented by the formula (4) with the halogen compound represented by the general formula (5), the general formula R ₁ O(C ₂ H ₄ O) _n R ₂ (6) [In the formula, R ₁ and R ₂ are the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or an aralkyl group, and m is 4 to Each represents 460 integers. ] It has been found that when a compound represented by the following is present, the above reaction proceeds suitably and the intended object of the present invention can be achieved. The present invention was completed based on this knowledge. According to the method of the present invention, the desired phenylacetonitrile derivative can be produced in a high yield of 90% or more, in some cases 95% or more, and with a high purity of 95% or more, under mild conditions and with simple operations. Obtainable. In addition, in the method of the present invention, the compound represented by the general formula (6) used is inexpensive, has almost no toxicity, is easy to handle, is stable in the reaction system, can be quantitatively recovered, and can be recycled. It is also possible to use Therefore, the method of the present invention can be said to be industrially extremely advantageous. The phenylacetonitrile derivative represented by general formula (3) and the phenylacetonitrile represented by formula (4) used as starting materials in the present invention are both known compounds. In general formula (3), R
The alkyl group represented by is methyl, ethyl, n-
propyl, iso-propyl, n-butyl, tert-
Butyl, n-amyl, iso-amyl, n-hexyl, n-heptyl, n-octyl groups, etc. are included, and aryl groups include phenyl, o-methylphenyl, p-methylphenyl, chlorophenyl, dichlorophenyl, nitrophenyl, nitro Chlorophenyl, etc. are included, and the aralkyl group includes benzyl, α-methylbenzyl, diphenylmethyl, α
-chlorobenzyl, 2-phenylethyl, 3-phenylpropyl, and the like. Specific examples of the phenylacetonitrile derivative of general formula (3) include phenylacetonitrile, 2-phenylpropionitrile, 2-phenylbutyronitrile, 2-phenylhexanenitrile, 2-phenyldecanenitrile, 2-phenyl-3-methylpentanenitrile, 2,3-diphenylpropionitrile, 2,
3-diphenylbutyronitrile, diphenylacetonitrile, naphthylacetonitrile, 2,6-
Examples include dichlorophenylacetonitrile and o-methylphenylacetonitrile. The halogen compounds represented by general formula (5) used as the other starting material in the present invention are all known compounds. In general formula (5)
The alkyl group represented by R′ includes methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec
-Butyl, n-amyl, iso-amyl, n-hexyl, n-heptyl, n-octyl groups, etc. are included, alkenyl groups include allyl, metaallyl, crotyl groups, etc., and aryl groups include 2-nitrophenyl groups. , 4-nitrophenyl, 2,4-dinitrophenyl, 3-chloro-4-nitrophenyl,
2-nitro-4-chlorophenyl, 3-bromo-
4-nitrophenyl, 3-methyl-4-nitrophenyl, 2-nitro-4-methoxyphenyl groups, etc. are included, and the aralkyl group includes benzyl, 2-nitrophenyl, etc.
-phenylethyl, p-methylbenzyl, 3-phenylpropyl, naphthylmethyl groups, and the like. Specifically, the halogen compound of general formula (5) includes methyl chloride, ethyl chloride, n-propyl chloride,
iso-propyl chloride, n-butyl chloride, n-chloride
amyl, iso-amyl chloride, n-hexyl chloride,
n-heptyl chloride, n-pentyl chloride, n-chloride
Octyl, benzyl chloride, p-methylbenzyl chloride, 2-phenylethyl chloride, 3-phenylpropyl chloride, naphthylmethyl chloride, 2,4-dinitrochlorobenzene, 2-nitrochlorobenzene,
4-nitrochlorobenzene, 3,4-dichloronitrobenzene, 2,5-dichloronitrobenzene, 2-methoxy-3-chloronitrobenzene,
Examples include chlorides such as 2-methyl-3-chloronitrobenzene, and compounds in which the chlorine atom of these compounds is replaced with a fluorine atom, bromine atom, or iodine atom. In the present invention, the reaction of the phenylacetonitrile derivative represented by the general formula (3) or the phenylacetonitrile represented by the formula (4) with the halogen compound represented by the general formula (5) is carried out using a compound represented by the general formula (6). must be carried out in the presence of General formula (6)
The alkyl groups represented by R ₁ and R ₂ include methyl, ethyl, n-propyl, iso-propyl,
n-butyl, tert-butyl, n-amyl, iso-
amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-lauryl,
n-cetyl, n-stearyl, etc., alkenyl groups include n-oleyl, aryl groups include phenyl, n-octylphenyl, n-nonylphenyl, naphthyl, etc., and aralkyl groups include benzyl, 2-phenylethyl, 3-phenylpropyl groups, etc. are included, respectively. Specifically, the compounds represented by the general formula (6) include polyethylene glycol-200, -300, -400, -600, -1000, -1500,
-1540, -2000, -4000, -6000, -20000, mono or dimethyl ether, mono or diethyl ether, mono or dipropyl ether,
mono or dibutyl ether, mono or dipentyl ether, mono or dihexyl ether,
mono or diheptyl ether, mono or dioctyl ether, mono or dinonyl ether,
Mono or didecyl ether, monolauryl ether, monocetyl ether, monostearyl ether, monooleyl ether, monooctyl phenyl ether, monononyl phenyl ether, monophenyl ether, mononaphthyl ether, monobenzyl ether, monophenyl ethyl ether , lauryl methyl ether, lauryl ethyl ether, lauryl propyl ether, lauryl butyl ether, cetyl methyl ether, cetyl ethyl ether, cetyl propyl ether, cetyl butyl ether, stearyl methyl ether, stearyl ethyl ether, stearyl propyl ether, stearyl butyl ether, oleyl methyl ether, Oleyl ethyl ether, oleyl propyl ether, oleyl butyl ether,
Octylphenyl methyl ether, octylphenyl ethyl ether, octylphenyl propyl ether, octylphenyl butyl ether, nonylphenyl methyl ether, nonylphenyl ethyl ether, nonylphenyl propyl ether, nonylphenyl butyl ether, diphenyl ether, dinaphthyl ether,
Examples include dibenzyl ether and diphenylethyl ether. Among these, polyethylene glycol (PEG)-400-dimethyl ether,
PEG-400-diethyl ether, PEG-400-di-n-propyl ether, PEG-400-di-n-
Butyl ether, PEG-600-dimethyl ether, PEG-600-diethyl ether, PEG-600
-di-n-propyl ether, PEG-600-di-
Particularly preferred are n-butyl ether, PEG-1000-dimethyl ether and PEG-1000-diethyl ether. The amount of the compound of general formula (6) to be used is not particularly limited and may be selected appropriately depending on the type of compound used, but generally, the compound of general formula (3) or the compound of formula (4) is used. It is sufficient that it is present in the reaction system in an amount of 1 mol % or more. The phenylacetonitrile derivative of general formula (3) and the halogen compound of general formula (5) are reacted to form the general formula (1).
In the reaction to obtain the phenylacetonitrile derivative, the ratio of the two to be used is not particularly limited, but it is generally advisable to use the latter in an amount of 0.1 to 1.5 times the former, preferably an equimolar to 1.1 times the amount of the former. In addition, in the reaction of reacting the phenylacetonitrile of formula (4) with the halogen compound of general formula (5) to obtain the phenylacetonitrile derivative of general formula (2), the proportion of the two used is not particularly limited, but usually It is preferable to use the latter in a molar amount 2 to 5 times that of the former, preferably 2 to 2.5 times the molar amount. The reaction of the phenylacetonitrile derivative of the general formula (3) or the phenylacetonitrile of the formula (4) with the halogen compound of the general formula (5) is generally carried out in an aqueous alkali hydroxide solution. Such alkali hydroxides include, for example, sodium hydroxide, potassium hydroxide, etc., and the alkali hydroxide concentration in the aqueous solution should normally be in the range of 40 to 65%. The reaction is usually carried out at a temperature of about 30 to 100°C, preferably 30 to 70°C.
The reaction is generally completed in about 2 to 8 hours. In this way, the desired compounds of general formulas (1) and (2) are produced. The target compound thus obtained can be easily isolated and purified from the reaction mixture by conventional separation means such as distillation and recrystallization. Examples are given below. Example 1 As shown in Table 1 below, the compound of general formula (3) 0.2
While vigorously stirring a mixture of a predetermined amount of the compound of general formula (6), 66 g (1 mole) of 85% potassium hydroxide, and 28 g of water at a predetermined temperature, the compound of general formula (5) is added.
A mixed solution of 0.21 mol and 40 ml of benzene was added dropwise over a period of 2 hours, and after further stirring at the same temperature for a predetermined time, the mixture was cooled to room temperature. Add 50 ml of benzene, and after separation, extract the benzene layer with approximately 5% aqueous hydrochloric acid solution (50 ml x 4 times).
Next, the benzene layer is washed with water and then dried with sodium sulfate. Benzene is distilled off and the residue is distilled under reduced pressure to obtain the desired compound of general formula (1). The results (yield and purity) are shown in Table 2. Note that the symbols indicating the types of compounds of general formula (6) in Table 1 mean the following compounds. :PEG-600-Bu ₂ :PEG-1000-Et ₂

【table】

【table】

[Table] In the above reaction, in order to recover the compound of general formula (6), the hydrochloric acid extract is extracted once with 20 ml of benzene, then 60 g of sodium hydroxide is added to the aqueous layer, and extracted with benzene ( 50ml x 3 times). After drying, the benzene was distilled off under reduced pressure under a nitrogen stream, and the
When treated with Hg at 110 to 120°C for 1 hour, the compound of general formula (6) can be recovered as a residue with a recovery rate of 99% or more. Example 2 As shown in Table 3 below, the compound of general formula (4) 0.2
Mol, prescribed amount of compound of general formula (6), 0.5 mol of compound of general formula (5), 198 g (3 mol) of 85% potassium hydroxide
A mixed solution of 84 g of water was vigorously stirred at a predetermined temperature for a predetermined time and then cooled to room temperature. Add 50 ml of benzene, and after separation, extract the benzene layer with approximately 5% aqueous hydrochloric acid solution (50 ml x 4 times). Next, the benzene layer is washed with water and then dried with sodium sulfate. Benzene is distilled off and the residue is distilled under reduced pressure to obtain the desired compound of general formula (2). The results (yield and purity) are shown in Table 4. In addition, the symbols indicating the types of compounds of general formula (6) in Table 3 mean the following compounds. :PEG-600-Bu ₂ :PEG-1000-Et ₂ :PEG-1000

【table】

[Table] In the above reaction, in order to recover the compound of general formula (6), the hydrochloric acid extract is extracted once with 20 ml of benzene, then 60 g of sodium hydroxide is added to the aqueous layer, and extracted with benzene ( 50ml x 3 times). After drying, the benzene was distilled off under reduced pressure under a nitrogen stream, and the
When treated with Hg at 110 to 120°C for 1 hour, the compound of general formula (6) can be recovered as a residue with a recovery rate of 99% or more. Example 3 Compound of general formula (3) and general formula (5) listed in Table 5 below
Using the compound of formula (6) and the compound of general formula (6), Example 1
The desired compound of general formula (1) is obtained in the same manner as above. The results are shown in Table 6.

【table】

【table】

[Table] Example 4 Compound of general formula (3) where R is a hydrogen atom (0.2 mol), 4 mmol of compound of general formula (6) shown in Table 7 below, 66 g (1 mol) of 85% potassium hydroxide and water
While vigorously stirring 38 g of the mixture at 30°C, a mixture of 0.21 mol of isopropyl bromide and 40 ml of benzene was added dropwise over 2 hours, and after further stirring at the same temperature for 4 hours, it was cooled to room temperature. Thereafter, the same treatment as in Example 1 is carried out to obtain the desired compound of general formula (1) (R: hydrogen atom, R': isopropyl group). The results (yield and purity) are also shown in Table 7.

[Table] Comparative Example 1 23.4g of compound of general formula (3) where R is a hydrogen atom
(0.2 mol), 85% potassium hydroxide 66g (1 mol),
40ml ethylene glycol and 22.9g ethyl bromide
(0.21 mol) was stirred at 30°C for 24 hours.
After cooling, the yield of the resulting compound of general formula (1) (R: hydrogen atom, R': ethyl group) was determined to be 13% by gas chromatography analysis. Further, only trace amounts of the compound of general formula (2) (R': ethyl group) were produced. Comparative Example 2 23.4g of compound of general formula (3) where R is a hydrogen atom
(0.2 mol), 85% potassium hydroxide 66g (1 mol),
28g water, 40ml dioxane and 22.9g ethyl bromide
(0.21 mol) was stirred at 30°C for 24 hours.
After cooling, the yield of the compound of general formula (1) (R: hydrogen atom, R': ethyl group) was determined to be 10% by gas chromatography analysis. Further, only trace amounts of the compound of general formula (2) (R': ethyl group) were produced.

Claims (1)

[Claims] 1 General formula R ₁ O(C ₂ H ₄ O) _n R ₂ [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or an aralkyl group. , m represents an integer from 4 to 460, respectively. ] In the presence of a compound represented by the general formula [In the formula, R represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. Phenylacetonitrile derivatives represented by the general formula R'X [wherein R' represents an alkyl group, an alkenyl group, an aryl group or an aralkyl group having a nitro group as a substituent, and X represents a halogen atom, respectively. ]
By reacting with a halogen compound represented by the general formula [In the formula, R and R' are the same as above. A method for producing a phenylacetonitrile derivative, the method comprising obtaining a phenylacetonitrile derivative represented by the formula: General formula R ₁ O(C ₂ H ₄ O) _n R ₂ [In the formula, R ₁ and R ₂ are the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or an aralkyl group, and m is 4 to 460 Indicate each integer. ] In the presence of a compound represented by the general formula Phenylacetonitrile represented by the general formula R'X [wherein R' represents an alkyl group, an alkenyl group, an aryl group or an aralkyl group having a nitro group as a substituent, and X represents a halogen atom, respectively. ]
By reacting with a halogen compound represented by the general formula [In the formula, R′ is the same as above. A method for producing a phenylacetonitrile derivative, the method comprising obtaining a phenylacetonitrile derivative represented by the formula: