JPS6257616B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing α-chloro-β-alanine or its mineral acid salt. For more details,
As shown in reaction formula (1), after reacting phthalimide of formula () with α-chloroacrylonitrile of formula () to produce α-chloro-β-phthalimidopropionitrile of formula (), The present invention relates to a method for producing α-chloro-β-alanine or a mineral acid salt thereof by hydrolyzing a compound in a mineral acid.

α-chloro- produced by the method of the present invention
β-alanine or its mineral acid salt is a compound useful as an intermediate for amino acids such as serine or pharmaceuticals.

For example, by heating the compound in an aqueous solution while maintaining the pH at 5 to 6, serine, which is a type of α-amino acid, can be produced according to reaction formula (2).

Conventionally, as a method for producing α-chloro-β-alanine or its mineral acid salt, regarding α-chloro-β-alanine hydrochloride, (1) aqueous ammonia and α-chloroacrylonitrile are reacted, and then treated with benzoyl chloride. A method for producing α-chloro-β-benzoylaminopropionitrile obtained by hydrolyzing it in hydrochloric acid (Japanese Patent Publication No. 39-30152), (2) α
-Production method by hydrolyzing -chloro-β-(2-carbomethoxybenzoylamino)propionitrile in hydrochloric acid (KDGundermann, chem.Ber.
, vol. 91, p. 160 (1958)) is publicly known. However, all of these known methods have problems such as yield when producing the raw material α-chloro-β-benzoylaminopropionitrile or α-chloro-β-[2-carbomethoxybenzoylamino]propionitrile. However, there are problems with this method, and it is difficult to say that it is a satisfactory method.

The present inventors have intensively studied an industrially advantageous method for producing α-chloro-β-alanine or its mineral acid salt, and as a result, have completed the method of the present invention.

The method of the present invention involves stirring phthalimide and a catalytic amount of base in an organic solvent at room temperature or with heating if necessary, and gradually adding α-chloroacrylonitrile at a molar ratio of 1 to 3 to the phthalimide dropwise.
The reaction is carried out at a temperature of 20 to 100°C, and the produced α-chloro-β-phthalimidopropionitrile is isolated from the reaction system or subsequently heated in a mineral acid to hydrolyze it without isolation. This is a method for producing α-chloro-β-alanine mineral salt and further processing this mineral salt to produce α-chloro-β-alanine. If the intermediate α-chloro-β-phthalimidopropionitrile is not isolated by this method, after the intermediate generation reaction, the solvent and unreacted α-chloroacrylonitrile are removed, and then a mineral acid is added to the reaction system. This method involves hydrolysis under acidic conditions. According to the method of the present invention, it is easy to produce the intermediate product α-chloro-β-phthalimidopropionitrile, there is almost no impurity by-product, and the hydrolysis reaction of this product proceeds quantitatively. The yield of α-chloro-β-alanine or its mineral acid salt is significantly superior to that of known methods. In addition, the method of the present invention simplifies the reaction operation, and furthermore, α-
Phthalic acid produced during hydrolysis of chloro-β-phthalimidopropionitrile can be recovered almost quantitatively, and can also be recycled into phthalimide for reuse.

α- produced as an intermediate product in the method of the present invention
Chloro-β-phthalimidopropionitrile is prepared in a known manner, i.e. 1 molar ratio of phthalimide and 7.5
A method (KDGundermann,
chem.Ber., vol. 91, p. 160 (1958)), but this method uses a large excess of α-chloroacrylonitrile, and by-products are produced, resulting in insufficient yield of the target product. This method is not satisfactory, and there are other problems such as the need for special measures for reaction operations. The present inventors investigated an improved method for producing α-chloro-β-phthalimidopropionitrile, and found that by dropping α-chloroacrylonitrile dropwise into an organic solvent containing phthalimide and a base, an excess of α-chloroacrylonitrile can be produced. The present inventors have discovered a method for producing α-chloro-β-phthalimidopropionitrile in high yield without using chloroacrylonitrile, and have completed the method of the present invention.

In the method of the present invention, the reaction between phthalimide and α-chloroacrylonitrile is carried out in the presence of a base. The bases used are alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide. , alkali or alkaline earth metal salts of phthalimide such as sodium phthalimide, potassium phthalimide, lithium phthalimide or calcium phthalimide, sodium carbazole, potassium carbazole or trimethylbenzylammonium hydroxide. Particularly preferred is an alkali or alkaline earth metal salt of phthalimide, since the use of the base can significantly suppress the polymerization or decomposition of α-chloroacrylonitrile or the by-product of ring-opening products of the phthalimide ring. The yield of the product α-chloro-β-phthalimidopropionitrile is high, and it has the advantage of preventing coloring of the reaction solution, which favorably advances the hydrolysis reaction of the intermediate product and achieves the desired purpose with a high yield. can get things. It is also possible to advantageously recover phthalic acid.

The amount of base to be used may be a catalytic amount, specifically 0.005 to 0.4 molar ratio to phthalimide, preferably
The molar ratio is 0.01-0.2.

Furthermore, in the method of the present invention, phthalimide and α
- Organic solvents used in the reaction with chloroacrylonitrile include methanol, ethanol, n-
Propanol, isopropanol, n-butanol, isobutanol, methyl cellosolve, cellosolve, glycerin, or general formula () (In the formula, R ¹ , R ² and R ³ represent lower alkyl groups), aromatic hydrocarbons such as benzene, toluene or xylene, dichloromethane, chloroform, tetrachloride carbon, dichloroethane, trichloroethane,
halogenated hydrocarbons such as trichloroethylene, tetrachloroethane, tetrachloroethylene, chlorobenzene or o-dichlorobenzene, ethers such as dioxane, trioxane or tetrahydrofuran, ketones such as acetone or methyl ethyl ketone, esters such as ethyl acetate or butyl acetate, Acetonitrile, nitrobenzene, N/N-dimethylformamide, N/N
- Nitrogen-containing solvents such as diethylformamide or N-methylpyrrolidone, or dimethyl sulfoxide. Preferably, it is a tertiary alcohol represented by the general formula (), and industrially it is tertiary butanol. When these tertiary alcohols are used as solvents, the by-product of α-chloro-β-[2-carbalkoxybenzoylamino]propionitrile, which is a compound in which the phthalimide ring is opened due to steric hindrance, is almost always observed. The yield of the target product can be improved.
These solvents are usually used alone, but two or more solvents can also be used in combination. The amount of the solvent to be used is at least 1 times the weight of phthalimide, particularly preferably at least 2 times the weight from the viewpoint of 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 1 to 1 mole of phthalimide.
3 molar ratio of α-chloroacrylonitrile, preferably 1.05 to 2 molar ratio, and there is no need to particularly use an excess of α-chloroacrylonitrile.

In the method of the present invention, the reaction of phthalimide and α-chloroacrylonitrile is carried out to form phthalimide,
α-Chloroacrylonitrile was gradually added dropwise to a mixture containing an organic solvent and a base at room temperature or with heating if necessary, and then the mixture was heated at 20 to 100°C.
It is carried out for 1 to 10 hours, preferably at 40 to 85°C for 2 to 8 hours. In some cases, phthalimide, α
- A method may be used in which a base is added to a mixture containing chloroacrylonitrile and an organic solvent.
In particular, there are no restrictions on the addition method, order, etc. of reaction raw materials, reaction additives, and reaction medium.

By carrying out the reaction between phthalimide and α-chloroacrylonitrile under the above conditions, the reaction proceeds rapidly with almost no impurity by-products produced. The end point of the reaction can be easily and quickly determined by thin layer chromatography.

α-Chloro-β-phthalimidopropionitrile produced by the reaction of phthalimide and α-chloroacrylonitrile is isolated from the reaction system, then added to mineral acid and heated under acidic conditions for hydrolysis. Thus, α-chloro-β-alanine or its mineral acid salt can be obtained. It is also possible to continue the hydrolysis without isolating α-chloro-β-phthalimidopropionitrile from the reaction system. In particular, when the reaction between phthalimide and α-chloroacrylonitrile is carried out in the presence of an alkali or alkaline earth metal salt of phthalimide in a tertiary alcohol solvent represented by the general formula (), polymerization of α-chloroacrylonitrile occurs. Alternatively, since side reactions such as decomposition can be effectively suppressed and the reaction proceeds quantitatively, there is no problem even if this method is adopted. In this case, there is no particular problem if a solvent coexists during the hydrolysis, but it is preferable to distill off the solvent under reduced pressure after the reaction, and then add the residue to a mineral acid or add a mineral acid to the residue. hand,
Hydrolyze under heat.

Examples of mineral acids used for hydrolyzing α-chloro-β-phthalimidopropionitrile include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, with hydrochloric acid or sulfuric acid being industrially preferred.

The concentration of the mineral acid used can be appropriately selected within the range of 3 to 80% by weight, but preferably 8 to 30% by weight in the case of hydrochloric acid, and preferably 8 to 30% by weight in the case of sulfuric acid.
It is 15-60% by weight. The amount of mineral acid used varies somewhat depending on the mineral acid concentration, but usually α-chloro-β
- Phthalimido The amount is 2 parts by weight or more per 1 part by weight of propionitrile, and preferably 3 parts by weight or more from the viewpoint of reaction operation.

The hydrolysis reaction of α-chloro-β-phthalimidopropionitrile is carried out in the above mineral acid at 50-150°C for 2-15 hours, preferably at 80-130°C for 3-10 hours.
Take your time and do it. The end point of the reaction can be quickly and easily determined by thin layer chromatography.

In the method of the present invention, either the α-chloro-β-alanine mineral salt or the free α-chloro-β-alanine can be extracted depending on the treatment method after the hydrolysis reaction. For example, after hydrolysis is carried out in hydrochloric acid, the reaction solution is cooled, the by-produced phthalic acid is separated, the solution is concentrated to dryness, the residue is extracted with a lower alcohol, and ether is added to this extract. Then α-chloro-β-alanine hydrochloride is obtained. In addition, hydrolysis is performed in sulfuric acid, the by-produced phthalic acid is separated, the liquid is neutralized with an alkali such as calcium hydroxide or barium hydroxide, and the resulting aqueous solution is removed under reduced pressure. The free α-chloro-
β-alanine is obtained.

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

Example 1 29.4 phthalimides in 90 g of tertiary butanol
g, 2.2 g of potassium phthalimide and 0.15 g of hydroquinone, and heated to 80°C. Then α
- 21.0 g of chloroacrylonitrile was added dropwise at 80°C over a period of about 2 hours, and then heated under reflux for 3 hours. After the reaction, the mixture is cooled to 25°C, the precipitated crystals are separated, and the mass is washed with a small amount of methanol and water. The obtained lump of α-chloro-β-phthalimidopropionitrile was added to 346 g of 20% hydrochloric acid, and
Heat to reflux for an hour. Thereafter, the reaction solution is cooled to 0° C., and the precipitated phthalic acid is separated and washed with a small amount of cold water.

Amount of phthalic acid recovered: 30.5g (92% recovery rate vs. phthalimide).

The washing liquids were combined and concentrated to dryness under reduced pressure, and then extracted with 250 ml of hot isopropanol. The extract is concentrated under reduced pressure to about one-third of its liquid volume and then ether is added to form α-chloro-β.
-Alanine hydrochloride is precipitated.

Separate the crystals, wash with a small amount of ether, and dry at 40°C.

Yield 27.5g (yield 86% vs. phthalimide), melting point (℃): 134-135 Elemental analysis value: C ₃ H ₆ ClNO ₂ HCl C H Cl N Calculated value (%) 22.52 4.41 44.31 8.75 Analytical value (%) 22.28 4.35 44.65 8.76 Example 2 29.4 g of phthalimide and 0.15 g of hydroquinone are added to 90 g of methanol in which 0.65 g of sodium hydroxide is dissolved and heated to 45°C. Then α-
19.3 g of chloroacrylonitrile was added dropwise at 45 to 50°C over about 2 hours, and the mixture was further reacted at the same temperature for 5 hours. After the reaction, the mixture is cooled to 20°C, and the precipitated crystals of α-chloro-β-phthalimidopropionitrile are separated and washed with a small amount of methanol and water. The lump was added to 300 g of 25% hydrochloric acid, and the same hydrolysis reaction and post-treatment as in Example 1 were carried out to obtain α-
Chloro-β-alanine hydrochloride is obtained. Yield 25.6g
(yield 80% vs. phthalimide), melting point 133-135° C. Example 3 α-chloro-β-phthalimidopropionitrile is prepared in the same manner as in Example 1. The obtained α
-chloro-β-phthalimidopropionitrile
Add to 350 g of 60% sulfuric acid and heat at 110-115°C for 6 hours. The reaction solution is cooled to 0°C, precipitated phthalic acid is separated, and the mixture is washed with a small amount of cold water. Amount of recovered phthalic acid: 30.2g (91% recovery rate vs. phthalimide).
Combine the washing solutions and neutralize by gradually adding calcium hydroxide at below 25°C until the pH reaches 6.5. Separate the generated calcium sulfate precipitate and wash with water.
The washing liquids are combined and concentrated under reduced pressure until the liquid volume becomes about 100 g. When ethanol is added to the concentrate, a white precipitate is deposited. After separating and washing with ethanol,
19.3 g dry and free α-chloro-β-alanine
(yield 78% vs. phthalimide).

Melting point (°C): 165-166 Elemental analysis value: C ₃ H ₆ ClNO ₂ Calculated value (%) 29.16 4.90 28.70 11.34 Analysis value (%) 28.87 4.79 28.53 11.07 Example 4 In 90 g of tertiary butanol Phthalimide 29.4
g, 2.2 g of potassium phthalimide and 0.15 g of hydroquinone, and heated to 80°C. Then α
- 21.0 g of chloroacrylonitrile was added dropwise at 80°C over a period of about 2 hours, and then heated under reflux for 3 hours. Thereafter, the solvent and excess α-chloroacrylonitrile are distilled off under reduced pressure. Then to the residue
Add 350 g of 20% hydrochloric acid and heat under reflux for 5 hours. Thereafter, the reaction solution was cooled to 0° C., and the precipitated phthalic acid was separated and washed with a small amount of cold water.

Amount of phthalic acid recovered: 32.5g (98% recovery rate vs. phthalimide).

The washing liquids were combined and concentrated to dryness under reduced pressure, and then extracted with 250 ml of hot isopropanol. The extract was concentrated under reduced pressure until the liquid volume was reduced to about one-third, and then ether was added to obtain α-chloro-
β-alanine hydrochloride precipitates. Separate the crystals,
After washing with a small amount of ether, dry at 40°C.

Yield 28.8g (90% yield vs. phthalimide), melting point 133
~134℃

Claims (1)

[Claims] 1. Phthalimide and a catalytic amount of base are mixed in an organic solvent with stirring, and α
-dropping chloroacrylonitrile to react;
α-chloro-β-, which is characterized in that the produced α-chloro-β-phthalimidopropionitrile is isolated from the production system and then subsequently heated and hydrolyzed in a mineral acid without isolation. A method for producing alanine or its mineral acid salt. 2. The method according to claim 1, wherein the organic solvent is a tertiary alcohol. 3. The method according to claim 1, wherein the base is an alkali metal salt or alkaline earth metal salt of phthalimide.