JPS6320813B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing DL-serine. More specifically, aziridine-2-carboxylic acid is produced by treating α-halogeno-β-aminopropionitrile or its mineral acid salt with an alkali metal or alkaline earth metal hydroxide in water or a water-containing organic solvent. Then, without isolating this product from the reaction system, the reaction solution was passed through a strongly acidic cation exchange resin to adsorb aziridine-2-carboxylic acid, and the halogen ions were removed by washing with water. , relates to a novel method for producing DL-serine, which comprises heating the ion exchange resin. Serine is a type of α-amino acid, and L-serine is a useful compound as an amino acid infusion, and D-serine is a useful compound as a raw material for the antibiotic cycloserine. Furthermore, serine is a compound useful as a raw material for producing L-tryptophan, which is expected to be used as a feed additive in the future, by an enzymatic method. Conventionally, many methods have been proposed for producing serine, but none of them has been industrially satisfactory, as they have advantages and disadvantages in terms of raw materials, number of reaction steps, yield, etc. The present inventors used α-halogeno-β-aminopropionitrile or its mineral acid salt, which can be easily produced by the reaction of α,β-cyhalogenopropionitrile or α-halogenoacrylonitrile with ammonia, as a raw material, We worked hard to find a method to produce serine from this compound in high yield, and as a result, we found that α-
Heat treatment of an aqueous solution of chloro-β-aminopropionitrile or its mineral acid salt with sodium hydroxide produces sodium aziridine-2-carboxylate, which can be converted into aziridine-2-carboxylate without isolating this product from the reaction solution. By passing the reaction solution containing sodium 2-carboxylate through a strongly acidic cation exchange resin, aziridine-2-carboxylic acid is adsorbed onto the ion exchange resin, chloride produced by the reaction is removed, and the ion exchange is performed. It was discovered that when the resin is heat-treated in a wet state, aziridine-2-carboxylic acid becomes DL-serine in an adsorbed state, and that DL-serine can be obtained in high yield by isolating this, and the present invention has been developed. It was completed. That is, the method of the present invention provides α-halogeno-β
- Aziridine-2-carboxylic acid is produced by treating aminopropionitrile or its mineral acid salt with an alkali metal or alkaline earth metal hydroxide in water or a water-containing organic solvent, optionally with heating. The reaction solution is then passed through a strongly acidic cation exchange resin to adsorb aziridine-2-carboxylic acid without isolating the produced aziridine-2-carboxylic acid and washed with water to remove halogen ions. is removed, and then the ion exchange resin is heated in a wet state, that is, in the presence of water, thereby producing DL-serine in high yield. Conventionally, DL- from aziridine-2-carboxylic acid
The method for producing serine is to heat-treat aziridine-2-carboxylic acid lithium salt synthesized by a hydrolysis reaction of aziridine-2-carboxylic acid ethyl ester with lithium hydroxide in 15% sulfuric acid (KDGundermann, Chem. .Ber., 93 , 1639
(1960)) is known. However, in this method, the amount of sulfuric acid used must be in large excess (approximately 12 molar ratio) to the raw material aziridine-2-carboxylic acid lithium salt, and after the reaction, the generated DL-serine must be separated from the reaction system. In this method, it is necessary to neutralize excess sulfuric acid with calcium hydroxide or barium hydroxide, precipitate it in the form of calcium sulfate or barium sulfate, and separate it separately, which has the disadvantage of complicating the process and reducing the volumetric efficiency of the reaction. Not good either. In addition, in the method for producing serine by hydrolysis of aziridine-2-carboxylic acid in sulfuric acid, if halogen ions coexist in the reaction system, a large amount of α-halogeno-β-
It has the drawback that it is accompanied by by-products such as alanine and β-halogenoalanine, and the yield of DL-serine is reduced. On the other hand, the method of the present invention is a novel production method that has not been previously known, and the process is significantly simplified compared to the above-mentioned hydrolysis method in sulfuric acid. Since the halogen ions produced as by-products during the production of acid salts can be easily removed, there are almost no by-products, and high yields can be obtained for the raw material α-halogeno-β-aminopropionitrile or its mineral acid salts. There is an advantage that DL-serine can be obtained at a lower rate. Furthermore, DL-serine produced by the reaction can be isolated by flowing ammonia water through the ion exchange resin to elute DL-serine, and then concentrating the eluate to dryness, or concentrating the eluate and then concentrating the isoelectric point It can be easily isolated by methods such as crystallization, which is also one of the characteristics of the present invention. In the method of the present invention, α-halogen
β-Aminopropionitrile or its mineral acid salt is treated with an alkali metal or alkaline earth metal hydroxide in water or an aqueous organic solvent to produce an alkali or alkaline earth metal salt of aziridine-2-carboxylic acid. let α-halogeno-β-aminopropionitrile or its mineral acid salt used as a raw material is α-chloro-β-aminopropionitrile, α-bromo-
β-aminopropionitrile, α-chloro-β-
Aminopropionitrile hydrochloride, α-bromo-β
-Aminopropionitrile hydrochloride, α-chloro-
Examples include β-aminopropionitrile sulfate and α-bromo-β-aminopropionitrile sulfate. These α-halogeno-β-
Aminopropionitrile or its mineral acid salt can be produced by the following method. That is, after reacting α,β-dihalogenopropionitrile or α-halogenoacrylonitrile with ammonia in water or an organic solvent, the reaction product is reacted with an organic solvent immiscible with water as necessary. Free α-halogeno-β- can be obtained by distillation under reduced pressure.
Aminopropionitrile is obtained. Furthermore, when hydrogen chloride or sulfuric acid is applied to the reaction solution or extraction solution, α-halogeno-β-aminopropionitrile hydrochloride or sulfate can be obtained, respectively. For example, α-chloro-β-aminopropionitrile hydrochloride was prepared by adding α-chloroacrylonitrile dropwise into a solution of ammonia gas dissolved in isopropanol at around 0°C, and reacting at the same temperature for 2 to 4 hours. Afterwards, by charging a solution of hydrogen chloride in isopropanol, it can be isolated with a yield of 80% or more. The hydroxides of alkali metals or alkaline earth metals used in the method of the present invention are hydroxides of alkali metals such as lithium, sodium, potassium, rubidium, or beryllium, magnesium,
It is a hydroxide of alkaline earth metals such as calcium, strontium, and barium. Specifically, lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, etc. are used. In the method of the present invention, the amount of alkali metal or alkaline earth metal hydroxide used is
When using halogeno-β-aminopropionitrile as a raw material, 2 equivalents or more based on the raw material, and α
When using -halogeno-β-aminopropionitrile mineral salt as a raw material, the amount is 3 equivalents or more based on the raw material. The upper limit of the amount to be used is not particularly limited, but it is not necessary to use a significantly excessive amount, and a range of up to 5 equivalents is usually sufficient. The reaction is carried out in water or a water-containing organic solvent.
That is, the reaction is carried out in an aqueous solution or in a solvent containing water and an organic solvent miscible with water. Examples of organic solvents miscible with water include methanol, ethanol, n-propanol, isopropanol,
Examples include alcohols such as tert-butanol, cellosolve, and methyl cellosolve, acetone, dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-diethylformamide, and dimethylsulfoxide.
When water and an organic solvent are used together in the reaction, the ratio of water to organic solvent can be arbitrarily selected. The amount of these solvents used is 3 to 200 times, preferably 5 to 100 times, the amount of α-halogeno-β-aminopropionitrile used as the raw material. The reaction method is to dissolve α-halogeno-β-aminopropionitrile or its mineral acid salt in water, and add the above-mentioned alkali metal or alkaline earth metal hydroxide into the solution in the form of an aqueous solution while stirring. Alternatively, it may be added as a solid and then reacted at 0 to 100°C for 0.5 to 50 hours, preferably at 20 to 80°C for 1 to 30 hours. The charging order of raw materials and alkali is not particularly limited to the above method, and α-halogeno-β-aminopropionitrile or The mineral salts may also be added. The end point of the reaction can be easily determined by means such as thin layer chromatography. Aziridine-2- produced by the above reaction
The carboxylic acid is obtained in solution in the form of an alkali metal or alkaline earth metal salt depending on the alkali used in the reaction. Without isolating the alkali metal or alkaline earth metal salt of aziridine-2-carboxylic acid from the reaction system, the reaction product solution was then passed through a strongly acidic cation exchange resin to produce aziridine-2-carboxylic acid. The acid is adsorbed on an ion exchange resin to remove the halogen ion of the metal halide produced as a by-product in the aziridine-2-carboxylic acid production reaction. Thereafter, by heating the ion exchange resin that has adsorbed aziridine-2-carboxylic acid in a wet state, DL-serine is produced in an adsorbed state. The strongly acidic cation exchange resin used is H
It may be of any type, such as the Na type or the NH ₄ type, but the H type is preferably used. Further, the base of the ion exchange resin can be of any type, such as gel type, porous type, or macroporous type. Therefore, the brand is not particularly limited as long as it is a strongly acidic cation exchange resin.
Furthermore, there is no problem in using two or more brands of strongly acidic cation exchange resins together. The amount of the ion exchange resin used is determined based on the amount of the alkali metal or alkaline earth in the aqueous solution of α-halogeno-β-aminopropionitrile or its mineral acid salt and aziridine-2-carboxylic acid produced from the compound, which is the starting material of the present invention. The exchange capacity in a wet state is 1 equivalent or more, preferably 1.2 equivalents or more, based on the total amount of the cation of the similar metal and ammonia produced by the reaction. For example, aziridine-2-carboxylic acid is prepared by treating 1 mol of α-chloro-β-aminopropionitrile hydrochloride with 3 mol of sodium hydroxide in water, and the strong acid has a total exchange capacity of 2.2 meq/ml. When a sex-type cation exchange resin is used, the amount of the resin is 2.3 or more, preferably 2.7 or more. When the amount of resin is small, leakage of aziridine-2-carboxylic acid occurs. Furthermore, it is possible to reduce the amount of ion exchange resin used by concentrating the reaction product solution of aziridine-2-carboxylic acid salt under reduced pressure and using an aqueous solution from which the precipitated metal halide is separately removed. In the present invention, in order to adsorb aziridine-2-carboxylic acid produced from α-halogeno-β-aminopropionitrile or its mineral acid salt onto the above-mentioned strongly acidic cation exchange resin, the ion exchange resin is usually Aziridine-2-
Either the method is to pass the carboxylic acid production solution as it is alkaline, or to neutralize the reaction solution with a mineral acid such as sulfuric acid or hydrochloric acid to make the pH of the reaction solution neutral or weakly acidic. But that's fine. At this time, aziridine-2 in the aziridine-2-carboxylic acid aqueous solution
- There is no particular limitation on the concentration of carboxylic acid. When an organic solvent miscible with water is used in the reaction, the organic solvent may remain contained, but it is preferable to distill off the organic solvent and then pass it through an ion exchange resin in the form of an aqueous solution. After passing the aqueous solution of aziridine-2-carboxylic acid through an ion exchange resin,
Wash with water until no halogen ions are detected in the distillate. If halogen ions coexist in the ion exchange resin column adsorbed with aziridine-2-carboxylic acid, in the subsequent serine production process by heating the ion exchange resin, in addition to the target serine, α-halogeno-β-alanine Alternatively, the yield of serine decreases due to the by-production of β-halogenoalanine. In the method of the present invention, a strongly acidic cation exchange resin that has adsorbed aziridine-2-carboxylic acid and removed halogen ions is heated in a wet state, that is, in the presence of water. There is no particular limitation on the method of heating the ion exchange resin; for example, heated water may be continuously passed through a column packed with an ion exchange resin, or a column filled with an ion exchange resin may be heated from the outside. Alternatively, the ion exchange resin adsorbed with aziridine-2-carboxylic acid can be transferred to another heating container and heated while stirring. The heating conditions are 40 to 120°C for 1 to 100 hours, preferably 50 to 100°C for 2 to 50 hours. reaction is 40
Although the reaction can proceed at temperatures below .degree. C., for example at room temperature, it takes an extremely long time to complete the reaction, which is not practical. In the method of the present invention, the produced DL-serine is in a state of adsorption on the ion exchange resin. Therefore, in order to separate and isolate DL-serine from an ion exchange resin, for example, DL-serine adsorbed with aqueous ammonia is eluted using a conventional method.
After concentrating the eluate to dryness or concentrating the eluate, the isoelectric point 1=PH may be adjusted as necessary and crystallization may be performed. The present invention will be explained below with reference to Examples. Example 1 After adding and dissolving 14.1 g of α-chloro-β-aminopropionitrile hydrochloride in 160 g of water, an aqueous solution of 12.8 g of sodium hydroxide dissolved in 90 g of water was gradually added dropwise while stirring. Then, the reaction mixture is heated to 60°C and reacted at 60-65°C for 4 hours. Next, this reaction solution was cooled and neutralized with a 5% sulfuric acid aqueous solution, and the strongly acidic cation exchange resin Lewatit S-100 was used.
(H type) Passed through a column packed with 600 ml. Further, purified water was passed through the column until no chloride ions were detected in the distillate from the column. Thereafter, hot water heated to 90 to 95° C. is circulated for 6 hours through the ion exchange resin column adsorbing aziridine-2-carboxylic acid to cause a reaction. After the reaction, the ion exchange resin column was cooled, the reaction product was eluted with 1 part of 3N ammonia water and 1 part of distilled water, and the eluate was concentrated to dryness to obtain 10.2 g (90% purity) of DL-serine.
The DL-serine yield was 87.4%/(vs. α-chloro-β
-aminopropionitrile hydrochloride). In addition, the isoserine by-product rate is 4%/(vs. α-chloro-β
-aminopropionitrile). As a result of analysis of sodium aziridine-2-carboxylate produced in the intermediate stage using high performance liquid chromatography, the production rate was 95.8%/(relative to α).
chloro-β-aminopropionitrile hydrochloride). Examples 2 to 5 The reaction was carried out in the same manner as in Example 1, except that Lewatit S-100 was replaced with another resin as the strongly acidic cation exchange resin, and the results shown in Table 1 were obtained.

[Table] Example 6 In Example 1, α-chloro-β-aminopropionitrile hydrochloride was replaced with α-chloro-β-aminopropionitrile hydrochloride.
- Using 15.4 g of aminopropionitrile sulfate,
Also, instead of sodium hydroxide, potassium hydroxide
Using 22.4 g, the reaction was carried out in the same manner as in Example 1 except that 10.3 g (purity 90.3%) of DL-serine was obtained.
Yield 88.6%/(vs. α-chloro-β-aminopropionitrile sulfate) Example 7 10.5 g of free α-chloro-β-aminopropionitrile was added to 100 g of water, and further 8.8 g of lithium hydroxide was added. An aqueous solution of 80g of water was added dropwise, and the mixture was allowed to react at room temperature for 24 hours. The resulting reaction solution is treated with a strongly acidic cation exchange resin.
Pass through 400 ml of Lewatit S-100 (H type) and wash with distilled water until no chlorine ions are detected in the distillate. Then, add 500ml of the ion exchange resin.
Transfer to a flask and react at 50-60°C for 20 hours with stirring. After the reaction, the ion exchange resin was filled into a dropping funnel, eluted with 800 ml of 3N ammonia water and 800 ml of distilled water, and the eluate was concentrated to dryness to obtain 10.2 g (purity 92%) of DL-serine.
Yield 89.4%/vs α-chloro-β-aminopropionitrile. Example 8 Add 14.1 g of α-chloro-β-aminopropionitrile hydrochloride to 160 g of water, dissolve, and then gradually add 12 g of calcium hydroxide while stirring. Then, the temperature was raised to 60°C and the reaction was carried out at 60-65°C for 8 hours.
After the reaction, excess calcium hydroxide was separately removed, and the reaction solution was adsorbed onto 600 ml of strongly acidic cation exchange resin Lewatit S-100 (H type) in the same manner as in Example 1. After removing chlorine ions, the reaction solution was heated at 80 to 90°C. Circulate hot water for 10 hours. After that, 10.4 g (purity 90.5%) of DL
- Obtained serine. Yield 89.6%/vs α-chloro-β
-Aminopropionitrile hydrochloride Example 9 After adding and dissolving 14.1 g of α-chloro-3-aminopropionitrile hydrochloride in 160 g of water, an aqueous solution of 12.8 g of sodium hydroxide dissolved in 90 g of water was added with stirring. It was dripped gradually. Then the reaction mixture was
The temperature was raised to 60-65°C and the mixture was reacted for 4 hours. Next, this reaction solution was cooled and passed through a column packed with 600 ml of strongly acidic cation exchange resin Lewatit S-100 (H type), and 600 ml of pure water was passed through it to adsorb aziridine-2-carvone onto the ion exchange resin. . Thereafter, hot water heated to 70 to 75°C was circulated through the ion exchange resin column for 8 hours to cause a reaction.
After the reaction, the ion exchange resin column was cooled, and the reaction product was eluted with 1 part of 3N ammonia water and 1 part of distilled water, and the eluate was concentrated under reduced pressure until the liquid amount became about 30 g. After that, adjust the pH to 5.6 with concentrated hydrochloric acid.
℃, filter the precipitated crystals, wash with a small amount of cold water, and vacuum dry.
7.8 g of white crystals of DL-serine were obtained. As a result of purity analysis using high performance liquid chromatography, purity
It was 98.8%.

Claims (1)

[Claims] 1. Aziridine-2-carboxylic acid adsorbed on a strongly acidic cation exchange resin is heated in the presence of water.
In the method for producing DL-serine, α-halogeno-β-aminopropionitrile or its mineral acid salt is treated with an alkali metal or alkaline earth metal hydroxide in water or a water-containing organic solvent to produce aziridine-2. - Generate an alkali metal or alkaline earth metal salt of carboxylic acid, then pass water through a strongly acidic cation exchange resin to adsorb aziridine-2-carboxylic acid, remove halogen ions, and then ion exchange A method for producing DL-serine, which comprises heating a resin in the presence of water.