KR840000496B1 - Process for the production of alpha-halogeno-beta-aminopropionitrilemineral acid salt - Google Patents

Abstract

α,β-Dihalogenopropionitriles(II)reacted with NH3 to give α-halo-β-aminopropionitriles (I; x=ahlo; x1=HCl, H2SO4, HNO3, H3PO4, etc.). Thus, 62g α,β-dichloropropionitrile was introduced into NH3 at 0-5≰C for 2 hr and reacted for 3 hr. This soln. was treated with 88g isopropyl alcohol contg. 25% HCl to give 60.8g α-chloro-β-aminopropionitrileHCl salt.

Description

Method for preparing α-halogeno-β-aminopropionitrile mineral acid salt

The present invention relates to a method for preparing α-halogeno-β-aminopropionitrile mineral acid salt. More specifically, the present invention provides α-halogeno-β-aminopropionitrile characterized by reacting α, β-dihalogenpropionitrile with ammonia in water and / or an organic solvent. It relates to a process for preparing photoacid salts of α-halogeno-β-aminopropionitrile by reacting photoacids with halogeno-β-aminopropionitrile.

The present invention also relates to α-halogeno-β-aminopropionitrile and sulfates thereof, which are conventionally not isolated novel compounds. α-halogeno-β-piaminopropionitrile and α-halogeno-β-aminopropionitrile sulfate are conventionally not isolated novel compounds. These compounds are useful as intermediates for the manufacture of pharmaceuticals or pesticides and intermediates for general organic synthesis. In addition, these compounds are hydrolyzed to obtain useful compounds that can be converted into α-halogeno-β-alanine, which is useful as an α-amino acid synthetic intermediate such as serine.

Conventionally, α-halogeno-β-aminopropionitrile has been separated in the form of hydrochloride or benzoyl compound of α-chloro-β-aminopropionitrile. For example, a method characterized by separating α-chloro-β-benzoylpropionitrile by treating a product obtained by reacting α-chloroacrylonitrile with ammonia water with benzoyl chloride is disclosed in JP 30152/1964. It is described in In addition, L. Doub and U. Krolls dissolve ammonia gas in methanol, add α-chloroacrylonitrile to it, and distill unreacted ammonia and methanol under reduced pressure, and then -45 to -35. Α-Chloro-β-aminopropionitrile hydrochloride was isolated in a yield of about 55% by the action of 25% methanolic hydrochloric acid and treatment with ether at a low temperature of. However, these methods cannot be said to be industrially satisfactory because the reaction operation is not only complicated, but also the yield of the final target is low. Therefore, there has been a desire for the development of an effective method for separating the α-halogeno-β-aminopropionitrile and α-halogeno-β-aminopropionitrile mineral acid salts, in particular sulfate.

It is an object of the present invention to provide a novel process for preparing α-halogeno-β-aminopropionitrile and photoacid salts thereof. Another object of the present invention is to provide an industrially advantageous method for preparing α-halogeno-β-aminopropionitrile mineral salt.

(식중, X는 할로겐 원자를 나타냄)으로 표시되는 α-할로게노-β-아미노프로피오니트릴 및 일반식

(식중, X는 할로겐 원자임)으로 표시되는 α-할로게노-β-아미노프로피오니트릴 황산염을 제공하는데에 있다.Another object of the present invention is a general formula

Α-halogeno-β-aminopropionitrile represented by the formula (wherein X represents a halogen atom) and a general formula

It is to provide the (alpha)-halogeno- (beta)-amino propionitrile sulfate which is represented by (where X is a halogen atom).

According to the present invention, α, β-dihalogenopropionitrile is reacted with ammonia in water and / or an organic solvent, and the resulting α-halogeno-β-aminopropionitrile is treated with a mine or water [Alpha] -halogeno- [beta] -aminopropionitrile is extracted from the reaction mixture solution using an organic solvent which is not mixed with Can be produced in high yield of 80% or more.

According to the present invention, α, β-dihalogenopropionitrile is reacted with ammonia in water and / or an organic solvent, and the resulting α-halogeno-β-aminopropionitrile-containing reaction mixture is 1 mmHg or less. Α-halogeno-β-aminopropionitrile can be separated by distillation under reduced pressure.

The reaction between α, β-dihalogenopropionitrile and ammonia according to the present invention is a conventionally unknown reaction. In addition, the method of the present invention has the advantage that not only the yield of the desired α-halogeno-β-aminopropionitrile mineral acid salt is significantly improved, but also the reaction operation is greatly simplified, and the industrial significance is significant. Moreover, it is a big feature of this invention that alpha, beta- dihalogeno propionitrile which is a raw material is a raw material which can be manufactured very easily by halogenation of alpha-acrylonitrile.

In the method of the present invention, α, β-dihalogenopropionitrile is used as the raw material. As the α, β-dihalogenopropionitrile, all of chlorine, cancelled, oxo and fluorine derivatives can be used, and α, β-dichloropropionitrile and α, β-dibromopropionitrile are preferable. In addition, ammonia to be used can usually be used in the form of ammonia water or in the form of a solution in which ammonia gas or ammonia water is dissolved in an organic solvent. The reaction of α, β-dihalogenopropionitrile with ammonia proceeds in water and / or organic solvents. In order to easily separate the product, an organic solvent solution of aqueous ammonia or ammonia is usually used.

When the reaction is carried out in an organic solvent, the organic solvent is an organic solvent capable of dissolving ammonia, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl Lower alcohols such as cellosolve or cellosolve. These are used alone or in the form of a mixture of two or more kinds. These organic solvents may be used in the form of a mixture with water.

The usage-ammonia is 2 mol or more with respect to 1 mol of (alpha), (beta)-dihalogeno propionitrile, and 2.2 mol or more is preferable. When the reaction is carried out in ammonia water, 5 to 30% by weight of ammonia is used, and when the reaction is carried out in an organic solvent, 2 to 25% by weight of ammonia is used. Although the present invention is not particularly limited in the reaction for producing α-halogeno-β-aminopropionitrile in the process, the method and the order of addition of the raw material and the solvent, water and / or usually containing ammonia Preference is given to slowly adding α, β-dihalogenopropionitrile in an organic solvent.

The reaction temperature is usually -40 ° to 30 ° C, preferably -20 ° C to 20 ° C, and the reaction time is usually 0.5 to 20 hours, preferably 1 to 15 hours. The reaction atmosphere is also good in air, but it is preferable because the reaction is carried out under an inert gas, such as nitrogen atmosphere or nitrogen stream, because side reactions are suppressed.

The end point of the reaction can be quickly and easily determined by means such as gas chromatography or high performance liquid chromatography.

In the method of the present invention, for example, to separate α-halogeno-β-aminopropionitrile or a photoacid salt thereof from the reaction mixture obtained by the reaction of α, β-dihalogenopropionitrile and ammonia, The following methods (1) to (4) can be adopted.

(1) When the reaction is carried out in aqueous ammonia, to separate α-halogeno-β-aminopropionitrile from the reaction solution, excess ammonia is removed by injecting nitrogen gas into the reaction solution, followed by mixing with water. Α-halogeno-β-aminopropionitrile, which was produced using an organic solvent, was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate, and then, under vacuum of 1 mmHg or less, α-halogeno-β-aminopropiotrile. Nitrile is distilled off under reduced pressure. Organic solvents that do not mix with the above water include general organic solvents such as aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, trichloro Halogenated hydrocarbons such as roethane, tetrachloroethylene, chlorobenzene and 0-dichlorobenzene; Ketones, such as methyl isobutyl ketone and diisobutyl ketone, and esters, such as methyl acetate, ethyl acetate, butyl acetate, can be mentioned.

(2) When isolating the resulting α-halogeno-β-aminopropionitrile from the reaction solution when the reaction is carried out in an organic solvent, the reaction solution is filtered to remove the by-product ammonium halide, followed by The residue is treated as in the process.

(3) When the above reaction is carried out in ammonia water, to separate α-halogeno-β-aminopropionitrile from the reaction solution, the α-halogeno- is separated from the reaction solution using an organic solvent which is not mixed with water. The β-aminopropionitrile is extracted, and then the acid is applied to the extract to precipitate the α-halogeno-β-aminopropionitrile mineral salt, or by a suitable method such as blowing a nitrogen gas into the reaction solution. A-halogeno- beta -aminopropionitrile mineral acid salt may be precipitated by removing the ammonia of N, followed by mixing the reaction solution with an organic solvent mixed with excess water containing a photoacid. Examples of the organic solvent which does not mix with water used to precipitate α-halogeno-β-aminopropionitrile include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, trichloroethylene, tetrachloroethylene, chlorobenzene and 0-dichlorobenzene; alcohols such as n-butanol and isobutanol; Ketones, such as ethyl isobutyl ketone and diisobutyl ketone, and esters, such as methyl acetate, ethyl acetate, and butyl acetate, can be mentioned.

(4) When separating the α-halogeno-β-aminopropionitrile mineral acid salt from the reaction solution in the case of carrying out the above reaction in an organic solvent, an excess of an excess amount may be used by a suitable method such as injecting nitrogen gas into the reaction solution. After the ammonia was removed, the by-product ammonium halide was removed by filtration, and then the reaction solution was treated with a mine to precipitate α-halogeno-β-aminopropionitrile mineral acid salt. The minerals used to convert α-halogeno-β-aminopropionitrile to their mineral salts in the methods (3) and (4) described above may include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Hydrochloric acid and sulfuric acid are also preferred. Hydrochloric acid may be used in the form of hydrochloric acid, but hydrogen chloride may be used with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, methylcellosolve, cellosolve, tetrahydrofuran or dioxane, and the like. It is preferable to use it as a form of the solution dissolved in the mixed organic solvent.

Sulfuric acid is used in 80-100% concentration and mixed with water such as methanol, ethanol, r-propanol, isopropanol, r-butanol, isobutanol, methyl cellosolve, cellosolve, tetrahydrofuran or dioxane It is preferable to use in the form of a solution in which sulfuric acid is dissolved in a solvent. The amount of mine used may be slightly higher than the theoretical amount, and does not need to be used in excess. The organic solvent used to dissolve the photo acid is usually used in an amount of 0.5 to 10 times the amount of the photo acid, and preferably 1 to 5 times.

As an operation for treating α-halogeno-β-aminopropionitrile with a mine to precipitate its mineral acid salt, for example, an organic solvent solution of the mine is a reaction solution containing α-halogeno-β-aminopropionitrile or It is possible to adopt a method of slowly adding dropwise to the above-described extraction solution or slowly adding an extract or a reaction solution containing α-halogeno-β-aminopropionitrile to an organic solvent solution of the mine.

At this time, it is preferable to process and hold | maintain reaction temperature below 50 degreeC, More specifically, below 30 degreeC. In this way, very high purity α-halogeno-β-aminopropionitrile mineral acid salt can be separated with a high yield of 80% or more. The present invention will be described in more detail with reference to the following examples. The percentages in the examples all represent weight percent.

Example 1

Ammonia gas was dissolved so that the ammonia concentration was 6.4% in isopropanol. 500 g of this isopropanol solution of ammonia was cooled to 0 degreeC, 62 g of (alpha), (beta)-dichloropropionitriles were added dropwise over about 2 hours, stirring in nitrogen atmosphere, and it was made to react at 0-5 degreeC for 3 hours. Nitrogen gas was injected into the reaction solution at the same temperature to remove excess ammonia, and then by-product ammonium chloride was filtered off. 88 g of isopropanol solution in which hydrogen chloride was dissolved at 25% concentration was slowly added dropwise to the filtrate. The precipitated crystals were filtered, washed with isopropanol, and dried to give 60.8 g of α-chloro-β-aminopropionitrile hydrochloride (yield: 86.2% based on α, β-dichloropropionitrile). Melting Point: 154 ~ 155 ℃ (Decomposition)

Elemental Analysis Value (%): C ₃ H ₅ N ₂ Cl.HCl

Found: C 25.34 H 4.35 N 19.98 Cl 50.42

Calculation: 25.55 4.29 19.87 50.29

Example 2

The operation of Example 1 was repeated except that an isopropanol solution of hydrogen chloride was used instead of 58 g of an isopropanol solution of concentrated sulfuric acid prepared at a sulfuric acid concentration of 50%. That is, an isopropanol solution of sulfuric acid in which 29 g of 98% sulfuric acid was dissolved in 29 g of isopropanol at 10 ° C. or lower was slowly added dropwise to the reaction solution. The precipitated white crystals were filtered off, washed with isopropanol, and dried to 65.3 g of α-chloro-β-aminopropionitrile sulfate (yield: α-chloroacrylonitrile) having a melting point of 181 ° to 182 ° C (decomposition). 85%). This was recrystallized from a mixed solvent of water and isopropanol to obtain α-chloro-β-aminopropionitrile sulfate pure at a melting point of 182 ° to 183 ° C (decomposition).

Elemental Analysis Value (%): C ₃ H ₅ N ₂ Cl.1 / 2H ₂ SO ₄

Found: C 23.38 H 3.92 N 18.38 Cl 23.21 S 10.21

Calculation: 23.46 3.94 18.24 23.08 10.44

Infrared absorption spectrum (cm ^-1 ): 2250, 1580, 1485, 1441, 1398, 1240, 1110, 1038, 900

Proton NMR spectrum (D ₂ O, measurement temperature: room temperature): δ value (ppm) 3.76 (2H, doublet), 5.36 (1H, triplet)

Example 3

243 g of concentrated ammonia water (ammonia concentration 28%) was cooled to 0 ° C, and 124 g of α, β-dichloropropionitrile was added dropwise over about 2 hours while reacting vigorously under a nitrogen atmosphere, and reacted at the same temperature for 4 hours. Nitrogen gas was injected into the reaction solution to remove excess ammonia, and the reaction solution was filtered to remove ammonium chloride as a byproduct. The filtrate was extracted three times with 300 ml of 1,2-dichloroethane to separate α-chloro-β-aminopropionitrile. The total extracts were combined, dried over anhydrous sodium sulfate and filtered. While the filtrate was cooled to 10 ° C. or lower, an isopropanol solution of sulfuric acid in which 62 g of 100% sulfuric acid was dissolved in 125 g of isopropanol was slowly added dropwise thereto. The precipitated crystals were filtered off, washed with isopropanol and dried to yield 122.9 g of α-chloro-β-aminopropionitrile sulfate having a melting point of 180 ° to 181 ° C (decomposition) (yield: 80% relative to α-chloroacrylonitrile). ) This product showed the same infrared absorption spectrum as the product obtained in Example 1.

Example 4

In Example 3, after removing the excess ammonia, the remaining reaction solution was added to 2000 g of isopropanol solution containing 60 g of concentrated sulfuric acid at 20 ° C. or lower, and the precipitate precipitated was filtered and α having a melting point of 108 ° to 181 ° C. (decomposition). 126 g of -chloro-β-aminopropionitrile sulfate (yield: 82% relative to α-chloroacrylonitrile) were obtained.

Example 5

122 g of concentrated ammonia water (28% ammonia concentration) was cooled to 0 ° C, and 62 g of α, β-dichloropropionitrile was added dropwise over 2 hours with vigorous stirring under a nitrogen atmosphere, and reacted at the same temperature for another 4 hours. Nitrogen gas was injected into the reaction solution to remove excess ammonia, and the reaction solution was extracted three times with 200 ml of 1,2-dichloroethane. The extracts were combined, dried over anhydrous sodium sulfate, and sodium sulfate was filtered off. While stirring the filtrate at 10 DEG C or lower, 90 g of an isopropanol solution of hydrogen chloride prepared at 25% hydrochloric acid concentration was slowly added dropwise thereto. The precipitated crystals were filtered, washed with isopropanol and dried to give 57.8 g of α-chloro-β-aminopropionitrile hydrochloride having a melting point of 153 ° to 154.5 ° C. (decomposition) (yield: α, β-dichloropropionitrile). 82%).

Example 6

Α-chloro having a melting point of 179 ° to 181 ° C. (decomposition) as in Example 5, except that 60 g of a concentrated sulfuric acid isopropanol solution prepared at 50% sulfuric acid concentration instead of an isopropanol solution of hydrogen chloride was used. 62.2 g of-?-aminopropionitrile (yield: 81% relative to?,? -dichloropropionitrile) were obtained.

Example 7

243 g of concentrated ammonia water (ammonia concentration 28%) was cooled to 0 ° C., and 124 g of α, β-dichlor-propionitrile was added dropwise over about 2 hours with vigorous stirring under a nitrogen atmosphere, at 0 ° to 5 ° C. The reaction was further carried out for 4 hours. Nitrogen gas was injected into the reaction solution to remove excess ammonia. The resulting α-chloro-β-aminopropionitrile was extracted three times with 300 ml of 1,2-dichloroethane, and the extracts were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure to obtain 62 g of α-chloro-β-aminopropionitrile. Boiling Point: 53 ~ 54 ℃ / 08mmHg

Elemental Analysis Value (%): C ₃ H ₅ N ₂ Cl

Found: C 34.35 H 4.96 N 26.78 Cl 33.86

Calculation: 34.47 4.82 26.80 33.91

Infrared absorption spectrum: 3395 cm ^-1 and 3305 cm ^-1 (νNH ₂ ), 2240 cm ^-1 (νC≡N) proton NMR spectrum (acetone-D ₆ , measuring temperature: room temperature) δ value (ppm): 3.71 (2H, doublet ), 5.98 (1H, triplet)

Mass spectrum (measurement temperature 60 ° C): m / e: 103, 76, 69, 42, 30.

Example 8

After cooling 500 g of isopropanol solution of ammonia in which ammonia was dissolved in isopropanol so that the ammonia concentration was 6.4% at 0 ° C., 62 g of α and β-dichloropropionitrile were added dropwise over 2 hours while stirring under nitrogen atmosphere. It was made to react at 5 degreeC for 3 hours. Nitrogen was injected into the reaction solution at the same temperature, and ammonium chloride, a byproduct of removing excess ammonia, was filtered off. The filtrate was distilled under reduced pressure to obtain 29 g of α-chloro-β-aminopropionitrile as an oil fraction having a boiling point of 52 to 53 ° C / 0.75 mmHg.

Claims (1)

Next, the α, β-dihalogenopropionitrile of the general formula (II) and ammonia are reacted at -40 ° to 38 ° C in the presence of water or an organic solvent, and then a photo acid is reacted with the reaction product. A method for producing α-halogeno-β-aminopropionitrile mineral acid salt of general formula (I).

(Wherein X is a halogen atom and X ₁ represents a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.)