JPS6324510B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing substituted nitriles. More specifically, the present invention relates to (A) general formula (In the formula, R ¹ represents hydrogen, a hydrocarbon group, an alkoxyl group, or a halogen, and R ² represents hydrogen, a hydrocarbon group, or an alkoxyl group); and (B) the general formula (In the formula, R ³ and R ⁴ are an alkyl group, R ⁵ is an alkylene group, and X is a halogen)
It is characterized by reacting a dialkylaminoalkyl halide in the coexistence of a strongly alkaline aqueous solution and a quaternary ammonium compound. (C) General formula The present invention relates to a method for producing substituted nitriles shown in the following. The substituted nitriles represented by the above formula (C) are useful as intermediate raw materials for pharmaceuticals, and can be derived, for example, into pharmaceuticals such as disopyramide, which is known as an arrhythmia therapeutic agent, by partial hydrolysis. Such a substituted nitrile represented by the formula (C) is produced by a reaction between an arylpyridylacetonitrile represented by the above formula (A) and an N,N-dialkylaminoalkyl halide represented by the above formula (B). A method for doing so has already been disclosed in US Pat. No. 3,225,054. However, the method disclosed herein uses sodium amide and has disadvantages in that it is expensive, requires careful handling, and is difficult to control the reaction heat. Furthermore, when N,N-dialkylaminoalkyl halide is used in the form of a salt, there is also the drawback that substituted nitriles (C) cannot be obtained in high yields. The present invention improves all of the drawbacks and difficulties of the conventional methods, and produces substituted nitriles (C) in high yields using inexpensive bases and without complicated reaction operations. made it possible. In the general formula of the arylpyridylacetonitriles (A), R ¹ is hydrogen; a hydrocarbon group such as methyl, ethyl, n-propyl, iso-propyl,
Alkyl groups such as n-butyl, cyclopentyl,
Cycloalkyl groups such as cyclohexyl, phenyl, o-tolyl, m-tolyl, p-tolyl, o-
Aryl groups such as anisyl, p-anisyl, o-, m- or p-chlorophenyl; alkoxyl groups such as methoxy, ethoxy, iso-propoxy, n-butoxy, etc.; or halogens such as chlorine, bromine, iodine, fluorine, etc.; It is. Further, R ² is hydrogen; a hydrocarbon group, such as the group exemplified in R ¹ ; or an alkoxyl group, such as the group exemplified in R ¹ . Specific examples of the arylpyridylacetonitrile represented by the above formula (A) include phenyl-2-pyridylacetonitrile, phenyl-4-pyridylacetonitrile, 4-tolyl-2-pyridylacetonitrile, and 2-tolyl-2-pyridylacetonitrile. , 4-methoxyphenyl-2-pyridylacetonitrile, 4-chlorophenyl-4-pyridylacetonitrile, phenyl-2-(4-methylpyridyl)acetonitrile, phenyl-2-(4-
Examples include ethoxypyridyl)acetonitrile. In the general formula of the N,N-dialkylaminoalkyl halide, R ³ and R ⁴ are alkyl groups, such as methyl, ethyl, n-propyl, iso-propyl,
n-butyl, sec-butyl, n-pentyl, n-
hexyl, etc., and R ⁵ is an alkylene group, such as methylene, ethylene, propylene, butylene,
Hexylene, etc. Further, X is a halogen, such as chlorine, bromine, or iodine, and preferably chlorine. Specific examples of the N,N-dialkylaminoalkyl halide represented by formula (B) include, for example, N,N-
Dimethylaminoethyl chloride, N,N-diethylaminoethyl chloride, N,N-di-n-ropylaminoethyl chloride, N,N-diiso-propylaminoethyl chloride, N,N-di-n-butylaminoethyl chloride, Examples include N,N-disec-butylaminoethyl chloride, 3-N,N-dimethylaminopropyl chloride, and 3-N,N-diethylaminopropyl chloride. (B) may be used in the form of a salt and liberated in the reaction system. In the present invention, (A) and (B) are reacted using a strong alkaline aqueous solution and a quaternary ammonium compound. As the strong alkali, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are suitable. It is preferable to use an aqueous solution of about 5 to 70% by weight, particularly about 20 to 40% by weight. In addition, the amount used is (A)1
The amount of strong alkali is preferably in the range of 1 to 20 equivalents, particularly 3 to 10 equivalents, based on the mole. As the quaternary ammonium compound, a quaternary ammonium halide compound, a quaternary ammonium hydroxide compound, or the like is used. Specifically, tetramethylammonium chloride, tetraethylammonium chloride, tetra n-propylammonium chloride, tetraiso-propylammonium chloride, tetrabutylammonium chloride, octadecyltrimethylammonium chloride, dimethylethylcetylammonium chloride, benzyltrimethylammonium chloride,
Benzyltriethylammonium chloride, dimethylphenylbenzylammonium chloride, cetylpyridinium chloride, or similar bromides, iodides, hydroxides, and the like can be used. Although the amount of the quaternary ammonium compound to be used can vary over a wide range, it is usually sufficient in the range of 1 to 1000 mmol, particularly 2 to 20 mmol, per 1 mole of component (A). The reaction of the present invention involves contacting the arylpyridyl acetonitrile (A), the N,N-dialkylaminoalkyl halide (B) (or its salt), an aqueous alkali solution, a quaternary ammonium compound, and, if necessary, a solvent. It is done by folding. When using a solvent, it is preferable to use one that is compatible with (A) and (B) and is water-insoluble. The reaction system is a suspension system of an organic phase and an aqueous phase, and the substituted nitriles (C) are produced exclusively in the organic phase and remain in the organic phase, so after the reaction is completed, it can be easily separated from the aqueous phase by leaving it still. Can be separated. or,
The halogen component desorbed from component (B) is transferred from the organic phase to the aqueous phase by the ammonium compound,
There, it becomes a strong alkali salt and remains in the aqueous phase, so there is no need to separate it from the organic phase. In the reaction of (A) and (B), it is preferable that (B) be used in a ratio of about 1 to 1.1 mol per 1 mol of (A). The reaction temperature is 10 or
A temperature of 100°C, particularly in the range of 30 to 70°C, is preferred.
The reaction time also varies depending on the reaction temperature, but
Usually, a period of 1 to 5 hours is sufficient. After the reaction is completed, the target substituted nitriles can be isolated by removing the aqueous phase, washing with water and drying, and then distilling off the solvent. In the present invention, the reaction operation is simple and the target product (C) can be produced in high yield. In particular, there is an advantage that similarly good results can be obtained even when component (B) is used in the form of a salt. Next, the present invention will be explained in more detail with reference to Examples. Example 1 666.7 wt%, N, N was added to a 300 ml four-necked flask equipped with a stirrer, thermometer, condenser, and dropping funnel.
- Prepare 33.0 g of diisopropylaminoethyl chloride hydrochloride aqueous solution and 19.4 g of toluene, and add
14.7 g of a 30 wt% aqueous sodium hydroxide solution was added dropwise to neutralize. After adding 19.4 g of phenyl-2-pyridylacetonitrile and 0.2 g of benzyltriethylammonium chloride and raising the temperature to 50°C,
Drop 66.7g of 30wt% sodium hydroxide aqueous solution,
The reaction was carried out at 50°C for 3 hours. Toluene 50% to the reaction mixture
ml, the separated oil layer was washed with water, dried, the toluene was distilled off using an evaporator, and gas chromatography analysis revealed that 4-diisopropylamino-2-phenyl-2-(2-pyridyl)butyronitrile was obtained in a yield of 100% (based on nitrile). It was found that it was generated in %. Examples 2 and 3 The reaction was carried out in the same manner as in Example 1, except that the amount of sodium hydroxide was changed. The results are shown in Table 1.

[Table] Examples 4 and 5 The reaction was carried out in the same manner as in Example 1 except that the reaction temperature was changed. The results are shown in Table 2.

[Table] Examples 6 and 7 The reaction was carried out in the same manner as in Example 1 except that the amount of N,N-diisopropylaminoethyl chloride hydrochloride and the amount of sodium hydroxide required for its neutralization was changed. . The results are shown in Table 3.

[Table] Example 8 When the reaction was carried out in the same manner as in Example 1 except that an equimolar amount of potassium hydroxide was used instead of sodium hydroxide, 4-diisopropylamino-2-phenyl -2-(2-
pyridyl)butyronitrile was produced quantitatively. Example 9 When the reaction was carried out in the same manner as in Example 1 except that benzyltrimethylammonium chloride was used instead of benzyltriethylammonium chloride, 4-diisopropylamino-2-phenyl-2-(2- pyridyl)butyronitrile was produced quantitatively. Example 10 The same procedure as in Example 1 was carried out except that phenyl-4-pyridylacetonitrile was used instead of phenyl-2-pyridylacetonitrile, and 4-diisopropylamino-2-
Phenyl-2-(4-pyridyl)butyronitrile was obtained in a yield of 98%. Example 11 In Example 1, 33.0 g of 66.7 wt% N,N-diisopropylaminoethyl chloride hydrochloride aqueous solution
Except that 23.8 g of 66.7 wt% N,N-dimethylaminoethyl chloride hydrochloride aqueous solution was used instead of
When the same procedure as in Example 1 was carried out, 4-dimethylamino-2-phenyl-2-(2-pyridyl)butyronitrile was quantitatively produced.

Claims (1)

[Claims] 1 (A) General formula (In the formula, R ¹ represents hydrogen, a hydrocarbon group, an alkoxyl group, or a halogen, and R ² represents hydrogen, a hydrocarbon group, or an alkoxyl group); and (B) the general formula (In the formula, R ³ and R ⁴ are an alkyl group, R ⁵ is an alkylene group, and X is a halogen)
-It is characterized by reacting a dialkylaminoalkyl halide in the coexistence of a strongly alkaline aqueous solution and a quaternary ammonium compound. (C) General formula A method for producing a substituted nitrile represented by