JPS6320811B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing α-halogeno-β-alanine or its mineral acid salt. More specifically, α-halogenopropionitrile is reacted with ammonia to produce α-halogenopropionitrile.
After producing β-aminopropionitrile,
Without isolating the product from the reaction system, mineral acid is subsequently added to the reaction system, or the reaction mixture is added into mineral acid and hydrolyzed under mineral acid acidity to obtain α.
- A method for producing halogeno-β-alanine or a mineral acid salt thereof is provided.

α-halogeno-β-alanine or its mineral acid salt produced by the method of the present invention is a compound useful as an intermediate for α-amino acids or pharmaceuticals. For example, when α-chloro-β-alanine is maintained at pH 5 to 6 in an aqueous solution and heat-treated, serine, which is a type of α-amino acid, can be produced as shown in the reaction formula below.

Conventionally, as a method for producing α-halogeno-β-alanine or its mineral acid salt, regarding α-chloro-β-alanine hydrochloride, (a) aqueous ammonia and α-chloroacrylonitrile are reacted, and then the reaction mixture is chlorinated. A method of producing α-chloro-β-benzoylaminopropionitrile by treating it with benzoyl, and hydroseparating it in hydrochloric acid (Japanese Patent Publication No. 1973-
30152), (b) A method for producing α-chloro-β-(2-carbomethoxybenzoylamino)propionitrile by hydrolyzing it in hydrochloric acid (KD
Gundermann, Chem. Ber., vol. 91, p. 160 (1958)) is publicly known. However, in all of these known methods, the amino group is protected with an acyl group and the hydrolysis reaction is carried out, so that the benzoic acid or phthalic acid by-produced during the hydrolysis and the target product α-chloro-β-alanine hydrochloride are separated. It is necessary to separate the intermediate α-chloro-β-
There are some problems in terms of yield etc. when producing benzoylaminopropionitrile or α-chloro-β-(2-carbomethoxybenzoylamino)propionitrile, and the production method is not necessarily satisfactory from an industrial perspective. do not have.

The present inventors used α,β-dihalogenopropionitrile as a raw material and investigated the reaction between this and ammonia, and found that α-
α-halogeno-β-alanine is produced in high yield by producing halogeno-β-aminopropionitrile and subsequently hydrolyzing the reaction product in mineral acid without isolating the reaction product from the reaction system. The inventors have also discovered that mineral salts thereof can be obtained, and have completed the present invention.

That is, in the method of the present invention, α,β-dihalogenopropionitrile and ammonia are first reacted in water or/and an organic solvent to produce α-halogeno-β-aminopropionitrile.
Then, without isolating this product from the reaction system, after the completion of the reaction, if necessary, the reaction mixture from which excess ammonia has been removed is hydrolyzed in mineral acid to obtain α-halogeno-β- It produces alanine or its mineral acid salt.

α-halogeno produced by the method of the present invention
The method for producing β-alanine or its mineral salt is a new production method that has not been previously known. Compared to the above-mentioned known production methods, the process can be significantly shortened, and there is no need for separation from by-products. This production method is industrially very advantageous, as it has the advantages of not having any oxidation, and also provides high yields of α-halogeno-β-alanine or its mineral acid salts.

In the method of the present invention, α,β-dihalogenopropionitrile and ammonia are first reacted.

The raw material α,β-dihalogenopropionitrile used may be chlorine, bromine, iodine or a fluorine derivative, but usually α,β-dichloropropionitrile or α,β-dibromopropionitrile is used. Frequently used. All of these raw materials can be easily produced by chlorination or bromination of acrylonitrile. α,β-dichloropropionitrile is particularly preferred from an industrial standpoint.

Further, as ammonia, aqueous ammonia is usually used, but ammonia gas or aqueous ammonia can also be used dissolved in an organic solvent. The organic solvent used is an organic solvent that has the ability to dissolve ammonia, and generally,
Lower alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tertiary butanol, methyl cellosolve or cellosolve, and these may be used alone or in combination of two or more. Furthermore, these organic solvents can also be used in a mixture with water.

The concentration of ammonia can be selected in the range of 5 to 30% by weight when using ammonia water, and 2 to 25% by weight when using ammonia gas (or ammonia water) dissolved in lower alcohol. can.

The amounts of α,β-dihalogenopropionitrile and ammonia used as the raw materials are at least 2 molar ratio, preferably at least 2.2 molar ratio, of ammonia per 1 mole of α,β-dihalogenopropionitrile.

In the method of the present invention, the reaction for producing α-halogeno-β-aminopropionitrile is not particularly limited in the reaction raw materials, the method of adding solvents, the order, etc., but usually ammonia water, ammonia gas, or ammonia water is A suitable method is to gradually drop α,β-dihalogenopropionitrile into a solution dissolved in alcohol, and in this case, the α-halogeno- Side reactions such as decomposition of β-aminopropionitrile can be significantly suppressed. In the reaction of α,β-dihalogenopropionitrile and ammonia, the reaction temperature and reaction time are -40 to 30°C for 0.5 to 20 hours, preferably -20 to 20°C for 1 to 15 hours.

The end point of the reaction between α,β-dihalogenopropionitrile and ammonia can be determined quickly and easily using means such as gas chromatography, high performance liquid chromatography, or thin layer chromatography. can.

Then, the method of the present invention uses α, β as described above.
-Produced by the reaction of dihalogenopropionitrile with ammonia. The mineral acid is subsequently added to the reaction mixture without isolating the α-halogeno-β-aminopropionitrile from the reaction system, or
Alternatively, the reaction mixture is added to a mineral acid to make the reaction system acidic, and the mixture is heated and hydrolyzed.

Examples of mineral acids used for hydrolysis of α-halogeno-β-aminopropionitrile include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, with hydrochloric acid and sulfuric acid being industrially preferred. The concentration of mineral acid in the reaction system during hydrolysis can be appropriately selected within the range of 3 to 80% by weight, preferably 8 to 30% by weight in the case of hydrochloric acid, and 15 to 60% in the case of sulfuric acid. Weight%. Therefore, when adding mineral acid to make the reaction system acidic after the reaction between α,β-dihalogenopropionitrile and ammonia, the reaction system should be adjusted to take into account the water remaining in the reaction system and the excess ammonia content. Make sure that the mineral acid concentration falls within the above concentration range. Excess ammonia remaining in the reaction system may be removed in advance by blowing nitrogen gas or the like, and such treatment makes it easy to adjust the mineral acid concentration.

The amount of mineral acid used varies depending on the mineral acid concentration, but is usually at least 2 parts by weight, preferably at least 3 parts by weight, per 1 part by weight of the α-halogeno-β-aminopropionitrile produced. It is advantageous in terms of reaction operation to make it so that

After the reaction of α,β-dihalogenopropionitrile with ammonia to form α-halogeno-β-aminopropionitrile, the reaction mixture is prepared by adding the reaction mixture into a mineral acid or adding the reaction mixture to a mineral acid. Add mineral acid to or make the reaction mixture mineral acidic by any method, raise the temperature while stirring, and heat at 50-150℃ for 0.5-10 hours, preferably 80-150℃.
Hydrolysis is carried out by holding at 120°C for 1 to 6 hours.

During this hydrolysis, methanol, ethanol,
There is no problem in using organic solvents such as n-propanol, isopropanol, n-butanol, isobutanol or tertiary butanol, methyl cellosolve or cellosolve in combination. Therefore, α,β-dihalogenopropionitrile and ammonia When the reaction is carried out in a lower alcohol solvent, the alcohol may be removed by distillation during the subsequent hydrolysis, or may be left in the reaction system.

The end point of the hydrolysis reaction can be quickly and easily determined using means such as thin layer chromatography or high performance liquid chromatography.

The target product obtained by the method of the present invention can be taken out in the form of either α-halogeno-β-alanine mineral salt or free α-halogeno-β-alanine by a post-hydrolysis treatment method. .
For example, α-chloro-β-aminopropionitrile is produced from α,β-dichloropropionitrile and aqueous ammonia, followed by hydrolysis in hydrochloric acid, and then the reaction solution is concentrated to dryness under reduced pressure. Then, the residue is extracted with a lower alcohol, and ether is added to the extract to obtain α-chloro-β-alanine hydrochloride. After hydrolysis in sulfuric acid, the aqueous solution is neutralized with calcium hydroxide or barium hydroxide and the resulting calcium sulfate or barium sulfate is separately removed, and the aqueous solution is concentrated to dryness under reduced pressure, or after concentration, methanol, Addition of a lower alcohol such as ethanol, n-propanol or isopropanol provides free α-chloro-β-alanine.

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

Example 1 Concentrated ammonia water (ammonia concentration 28% by weight)
60.8g of α,β-dichloropropionitrile was heated at 0°C and stirred under a gentle nitrogen stream.
24.8g is added dropwise over approximately 2 hours. after that,
After reacting for an additional 3 hours at 0-5°C, the reaction mixture is sparged with nitrogen to remove excess ammonia. Then, add 20% hydrochloric acid to the reaction solution at below 10℃.
184 g was added dropwise and heated under reflux for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was extracted with 250 ml of hot isopropanol. When the obtained extract is concentrated and ether is added, white crystals are precipitated. Separate the precipitated crystals and wash with ether at 40°C.
to obtain 26.6 g (83.1% yield vs. α,β-dichloropropionitrile) of α-chloro-β-alanine hydrochloride. Melting point 133-134.5℃ Elemental analysis value (%): C ₃ H ₆ ClNO _2.HCl Calculated value 22.52 4.41 8.75 44.31 Actual value 22.42 4.43 8.80 44.05 Example 2 300 g of isopropanol solution with ammonia concentration of 5.36% by weight Maintained at -5℃ under a gentle nitrogen stream.
α,β-Dichloropropionitrile 24.8 under stirring
g is added dropwise over a period of approximately 2 hours. After that -5~
After reacting at 0° C. for 2 hours, unreacted ammonia was removed by blowing in nitrogen. Then add 20% to the reaction solution.
% hydrochloric acid was added dropwise at a temperature below 10°C, the temperature was gradually raised, and the isopropanol was distilled off until the liquid temperature reached 106°C, followed by a reaction at the same temperature for 2 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 27.8
g (87% yield vs. α,β-dichloropropionitrile) of α-chloro-β-alanine hydrochloride is obtained.
Melting point: 133.5-134.5°C Example 3 60.8 g of concentrated ammonia water (ammonia concentration 28% by weight) was added to 250 g of methanol, and while stirring at -5°C, 24.8 g of α,β-dichloropropionitrile was added.
g is added dropwise over a period of approximately 2 hours. After that -5~
After reacting at 0° C. for 3 hours, unreacted ammonia was removed by blowing in nitrogen. Then add 10 to the reaction solution.
Example 2: 146 g of 25% hydrochloric acid was added dropwise to
React in the same way. The liquid after hydrolysis was treated in the same manner as in Example 1 to obtain 26.6 g (yield: 83
% versus α,β-dichloropropionitrile)
Chloro-β-alanine hydrochloride is obtained. Melting point 133
~134.5% Example 4 Concentrated ammonia water (ammonia concentration 28% by weight)
60.8g of α,β-dichloropropionitrile 24.8g was kept at 0°C and stirred under a gentle nitrogen stream.
g is added dropwise over a period of approximately 2 hours. Thereafter, the reaction mixture is further reacted for 3 hours at 0 to 5°C, and then unreacted ammonia is removed by blowing nitrogen into the reaction mixture. Next, add 200g of 60% sulfuric acid to the reaction solution at 10℃ or below.
was added dropwise, the temperature was gradually raised, and the mixture was hydrolyzed at 100 to 105°C for 5 hours. The hydrolyzed solution is neutralized to pH=6.5 by adding calcium hydroxide little by little at below 20℃. Separate the formed calcium sulfate precipitate and wash with water. The washing liquids are combined and concentrated under reduced pressure to a volume of approximately 100 ml, and then ethanol is added to this concentrated liquid to precipitate α-chloro-β-alanine. After separating, washing with ethanol, and drying under reduced pressure, white free α-chloro-
18.5 g of β-alanine (75% yield vs. α,β-dichloropropionitrile) are obtained.

Melting point: 166-167.5℃ (decomposition) Elemental analysis value (%): C H N Cl calculated value as C ₃ H ₆ ClNO ₂ 29.16 4.90 11.34 28.70 Actual value 28.85 4.78 11.12 28.97

Claims (1)

[Claims] 1. After reacting α,β-dihalogenopropionitrile and ammonia in water or/and an organic solvent to produce α-halogeno-β-aminopropionitrile, this compound is isolated from the reaction system. A method for producing α-halogeno-β-alanine or its mineral acid salt by subsequent hydrolysis in a mineral acid.