JPS6126903B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved process for producing α-chloro-β-phthalimidopropionitrile. More specifically, when producing α-chloro-β-phthalimidopropionitrile from phthalimide and α-chloroacrylonitrile, α-chloroacrylonitrile is produced by reacting with a tertiary alcohol as a solvent in the presence of a base. - This is a significantly improved method for producing β-phthalimidopropionitrile.

Compound α-chloro-β obtained by the method of the present invention
- Phthalimidopropionitrile is a compound useful as an intermediate for amino acids or pharmaceuticals.

Conventionally, α-chloro-β-phthalimidopropionitrile has been produced by dropping a methanol solution of sodium methoxy into a mixture of 1 molar ratio of phthalimide and 7.5 molar ratio of α-chloroacrylonitrile (KDGundermann ，
Chem. Ber., vol. 91, p. 160 (1958)). However, in this method, α-chloroacrylonitrile must be used in large excess relative to phthalimide, and during the reaction, the phthalimide ring is opened due to the action of the base and methanol. The yield of α-chloro-β-phthalimidopropionitrile decreases due to the formation of some by-products of benzoylamino]propionitrile, and the use of a base to suppress the polymerization and decomposition reactions of α-chloroacrylonitrile. This method is not necessarily satisfactory because of various problems, such as the need to devise a method for adding the base dropwise into the liquid. Furthermore, according to the method described in the above literature, when α-chloroacrylonitrile is used in an approximately equimolar amount to phthalimide, α-chloro-β-[2-carbomethoxybenzoylamino]propionitrile becomes the main product. Become.

The present inventors have found that α-chloroacrylonitrile is industrially advantageously produced from phthalimide and α-chloroacrylonitrile.
As a result of research on a method for producing β-phthalimidopropionitrile, the method of the present invention was arrived at.

That is, in the method of the present invention, phthalimide and α
- A method characterized by using a tertiary alcohol as a solvent in the presence of a base during the reaction with chloroacrylonitrile.

According to the method of the present invention, the formation of a compound in which the phthalimide ring is opened due to the steric hindrance of the tertiary alcohol is hardly observed, and therefore the target α-chloro-β-phthalimidopropionitrile can be selectively extracted. It has the advantage that it can be produced in high yield, that the amount of α-chloroacrylonitrile used relative to phthalimide can be significantly reduced, and that no special measures are required for the reaction operation.

In the method of the present invention, α-chloroacrylonitrile and phthalimide are used as raw materials, and the amount of these raw materials used is 1 to 3 mol, preferably 1.05 to 2.0 mol, of α-chloroacrylonitrile per 1 mol of phthalimide.

Bases used in the method of the present invention include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or calcium hydroxide, sodium methoxide, sodium ethoxide, etc. or an alkali metal alkoxide such as potassium tert-butoxide, an alkali metal salt of phthalimide such as sodium phthalimide, potassium phthalimide or lithium phthalimide, a sodium or potassium salt of carbazole, or trimethylbenzylammonium hydroxide. The amount of these bases used is 0.005 to 0.4 molar ratio, preferably 0.01 to 0.2 molar ratio to phthalimide.

Furthermore, the solvent used in the method of the invention has the general formula () (wherein R ¹ , R ² and R ³ each independently represent a lower alkyl group), preferably tertiary butanol, tertiary pentyl alcohol or tertiary hexyl alcohol. Alcohol, etc., and industrially, it is preferable to use tertiary butanol.

The amount of tertiary alcohol to be used as a solvent is at least 1 times the weight of phthalimide, preferably at least 2 times the weight, particularly from the viewpoint of reaction operation.

In the method of the present invention, the reaction is carried out by gradually adding α-chloroacrylonitrile dropwise into a mixture containing phthalimide, a tertiary alcohol, and a base at room temperature or with heating if necessary.
20-100℃, 1-10 hours, preferably 40-85℃,
Perform for 2 to 8 hours. Alternatively, a method may be employed in which a base is added to a mixture containing phthalimide, α-chloroacrylonitrile, and a tertiary alcohol.

The end point of the reaction between phthalimide and α-chloroacrylonitrile can be easily and quickly determined by thin layer chromatography.

To isolate α-chloro-β-phthalimidopropionitrile obtained by the method of the present invention from the reaction solution, if the product has precipitated outside the system, the reaction solution can be isolated as is, or after concentrating the reaction solution. , and when the product is partially or completely dissolved in the reaction solution, add an organic solvent that hardly dissolves the product, or remove the solvent by a method such as steam distillation, It can also be isolated by separating it into two.

The method for producing α-chloro-β-phthalimidopropionitrile according to the method of the present invention achieves the desired purpose in a high yield with almost no by-product of a compound with an opened phthalimide ring, compared to the known method using methanol as a solvent. This is a manufacturing method with great industrial value as it has the advantage of producing a large amount of product.

Hereinafter, the present invention will be explained with reference to Examples.

Example 1 2.2 g of potassium phthalimide, 29.4 g of phthalimide and 0.15 g of hydroquinone are added to 90 g of tertiary butyl alcohol and heated to 80°C.

Next, add 21.0g of α-chloroacrylonitrile.
The dropwise addition takes approximately 2 hours at 80°C. After the addition, the mixture was further heated under reflux for 3 hours.

After the reaction, the precipitated crystals were separated by cooling to 25°C, washed with a small amount of methanol and water, and dried to obtain 43.2 g of white α-chloro-β-phthalimidopropionitrile (yield 92%). against phthalimide).

Melting point 142-143℃.

At the end of the reaction, the reaction solution was subjected to thin layer chromatography (thin layer plate: Tokyo Kasei Spot Film Silica Gel-F, developing solvent: benzene:acetone=
8:2 (volume ratio)) until the point where the phthalimide spot disappears.

Example 2 29.4 g of phthalimide, 0.3 g of sodium methoxide and 0.15 g of hydroquinone are added to 120 g of tertiary butyl alcohol and heated to 50°C. Next, 21.0 g of α-chloroacrylonitrile was heated at 50 to 55°C.
It takes about 2 hours to drop the solution. Thereafter, the mixture was reacted at the same temperature for 5 hours, and then cooled to 25°C to separate the precipitated crystals. After washing with methanol and water, the mixture was dried to obtain 41.3 g of white α-chloro-β-phthalimidopropionitrile (88% yield vs. phthalimide).

Melting point 141-142.5℃.

Example 3 α-chloro-β-
Phthalimidopropionitrile 40.4g (yield 86%)
against phthalimide).

Example 4 The same procedure as in Example 2 was carried out except that 0.4 g of sodium hydroxide was used instead of sodium methoxide, and 40.8 g of α-chloro-β-phthalimidopropionitrile (yield: 87%) was obtained. phthalimide) was obtained.

Claims (1)

[Claims] 1. A method for producing α-chloro-β-phthalimidopropionitrile, which comprises reacting phthalimide and α-chloroacrylonitrile in the presence of a base in a tertiary alcohol solvent.