JPH0134218B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing β-hydroxyamino acids. For more details, see 3-
The present invention relates to a method for producing a β-substituted β-hydroxyamino acid by adsorbing substituted aziridine-2-carboxylic acid or a derivative thereof onto a strongly acidic cation exchange resin and heating it in the presence of water. As β-substituted-β-hydroxy amino acids,
For example, threonine, phenylserine or β
-Hydroxyvaline etc. Threonine is a type of essential amino acid and is expected to have potential as a feed additive, while β-substituted β-hydroxy amino acids such as phenylserine and β-hydroxyvaline are expected to have physiological activity on their own. It is also a useful compound as an intermediate for various agricultural medicines. Conventionally, in a method for producing β-substituted β-hydroxy amino acids from 3-substituted aziridine-2-carboxylic acid and its derivatives, a mixture of 3-methylaziridine-2-carboxylic acid methyl ester and ethyl ester was treated with perchloric acid. and then further treatment with hydrochloric acid to produce threonine. After ring hydrolysis,
A method for producing phenylserine by reduction under a Pd/C catalyst is known (Heterocycles, 9 , 473 (1978)). However, in the former method, in order to isolate threonine from the solution containing threonine produced, it is necessary to concentrate the reaction solution, adjust the pH with aqueous ammonia, and then purify it using an ion exchange resin, making the process extremely complicated. It has the disadvantage of becoming. In addition, in the latter method, it is necessary to isolate N-benzylphenylserine after treatment with perchloric acid, and then reduce it under a Pd/C catalyst to remove the benzyl group, making the process extremely complicated. , is not an industrially useful method. Also,
In the ring-opening reaction of 3-substituted aziridine-2-carboxylic acid or its derivatives, if anions with higher nucleophilic ability than water, such as halogen ions, coexist in the reaction system, these ions may be added as by-products. It also has the disadvantage that compounds are formed and the yield of β-substituted β-hydroxy amino acids is reduced. As described above, several methods have been proposed for producing β-substituted β-hydroxyamino acids, but each has advantages and disadvantages, and no industrially satisfactory production method has been found. The present inventors have intensively studied methods for industrially producing β-substituted β-hydroxy amino acids from 3-substituted aziridine-2-carboxylic acids or derivatives thereof, and as a result, have arrived at the method of the present invention. That is, the present invention provides the general formula () (In the formula, R ₁ is a methyl group, a substituted or unsubstituted phenyl group, or a pyridyl group, R ₂ is a hydrogen atom or a methyl group, and X is -CO ₂ H, -CO ₂ M
(Here, M is an alkali metal or alkaline earth metal), -CO ₂ R ₃ (Here, R ₃ is a lower alkyl group having 1 to 5 carbon atoms or a benzyl group), -CO 3-Substituted aziridine-2-carboxylic acid or its derivatives represented by ₂ NH ₂ or -CN) is adsorbed onto a strongly acidic cation exchange resin and heated in the presence of water to form β-substituted -β- This is a method for producing hydroxyamino acids. The method of the present invention is a novel method that has not been previously known. Compared to conventionally known methods, the process is significantly simplified, almost no by-products are produced, and the corresponding β-hydroxy It has the advantage that amino acids can be obtained in high yield. Furthermore,
The β-substituted β-hydroxy amino acid produced by the reaction is isolated by flowing aqueous ammonia through the heated ion exchange resin to elute the β-substituted β-hydroxy amino acid, and concentrating the eluate to dryness. Alternatively, it can be performed by a simple operation of concentration and crystallization, and one of the major features of the method of the present invention is that reaction, purification, and isolation can be performed simultaneously in this way. The raw material used in the method of the present invention is a 3-substituted aziridine-2-carboxylic acid represented by the above general formula () or a derivative thereof, and these raw material compounds are β-substituted-α,β-dihalogenated Reaction of propionic acid or its derivatives or β-substituted-α-halogenoacrylic acid derivatives with ammonia (JP-A-54-157555; E. Kyburz, Helv. Chim.
acta, 49, 359 (1966); G. Szeimies, Chem. Ber.
110, 1792 (1977); EPStyhgach, Khim.
Geterotsikl. Soedin, 1973, 1523; Y. Yukawa,
Mem.Inst.Sci.and Ind.Research，Osaka
Univ., 14, 191 (1957); EPStyngack, Izv.
Akad.Nauk.Mold.SSR.Ser.Biol.Khim.Nank,
1975, 62), or thermal decomposition reaction of 3-substituted acrylic acid ester and azidocarboxylic acid ester,
(MPSamnes, J.Chem.Soc., Perkin Trans.1,
1972, 344), and furthermore, 3-substituted aziridine-2
-Alkali metal or alkaline earth metal salts of carboxylic acids can be prepared by treating a 3-substituted aziridine-2-carboxylic acid ester with an equal amount of alkali metal or alkaline earth metal hydroxide, or by treating β-
Substituted α-amino-β-halogenopropionic acid or its derivatives (esters, amides, nitriles) or β-substituted α-halogeno-β-aminopropionic acid or its derivatives by hydroxylation of alkali metals or alkaline earth metals. It can be manufactured by a known technique such as treatment with a substance, or a method similar thereto. The strongly acidic cation exchange resin used in the method of the present invention may be of any type, such as H type, Na type, or NH ⁺ ₄ type, but it is usually preferable to use H type.
Further, as the base of the ion exchange resin, any type of base such as gel type, porous type, or macroporous type can be used. 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. When using an alkali metal or alkaline earth metal salt of 3-substituted aziridine-2-carboxylic acid as a raw material, the amount of ion exchange resin used is the amount of 3-substituted aziridine-2-carboxylic acid and its salt. 1 equivalent or more based on the exchange capacity in a wet state based on the total amount of metal ions, preferably,
It is 1.2 equivalent or more. For example, when using 1 mol of 3-substituted aziridine-2-carboxylic acid potassium salt as a raw material and using a strongly acidic cation exchange resin with a total exchange capacity of 2 equivalents, the amount of resin used is 1
The above value is preferably 1.2 or more. Also, 3-
When using a substituted aziridine-2-carboxylic acid or a derivative thereof such as an ester, amide, or nitrile, the exchange capacity in a wet state is 1 equivalent or more relative to the 3-substituted aziridine-2-carboxylic acid or its derivative itself. , preferably 1.2 equivalents or more. For example, 1 mole of 3-substituted aziridine-2
- When using a strongly acidic cation exchange resin using carboxylic acid ethyl ester as a raw material and having a total exchange capacity of 2 equivalents, the amount of the resin used is 0.5 or more, preferably 0.6 or more. Inorganic salts such as sodium chloride and ammonium bromide in the aqueous solution of raw materials,
When substances that are easily adsorbed by strongly acidic cation exchange resins, such as compounds containing amino groups, are included, it is necessary to increase the amount of resin by more than the amount corresponding to these substances. In the method of the present invention, the 3-substituted aziridine-2-carboxylic acid represented by the general formula () or its derivative contains an aqueous solution or an organic solvent miscible with water, such as alcohols such as methanol, ethanol, and isopropanol. an aqueous solution of
These aqueous solutions are poured into a resin column filled with a strongly acidic cation exchange resin, and then washed with water, or the strongly acidic cation exchange resin is added to and mixed with these aqueous solutions, so that the ion exchange resin adsorbs them. . In particular, when the aqueous solution of the raw material compound contains a compound such as sodium chloride or ammonium bromide that generates oxygen substances such as hydrochloric acid or hydrobromic acid through ion exchange, the raw material compound may be ionized. Since there is a possibility that the halogen ions may be desorbed from the exchange resin or react with the raw material compound, the raw material aqueous solution is poured into the ion exchange resin tower, and then thoroughly washed with water to remove the 3-substituted aziridine-2-carboxylic acid or its derivative. A method of adsorbing the compound to a strongly acidic cation exchange resin is preferred. In this way, the strongly acidic cation exchange resin adsorbed with 3-substituted aziridine-2-carboxylic acid or its derivative is heated in the presence of water. There are no particular limitations on the heating method, but it is necessary to maintain a moist state, and heated water may be continuously passed through a column filled with ion exchange resin, or a column filled with ion exchange resin may be used. It may be heated externally. Alternatively, the ion exchange resin can be transferred to a separate container and heated while stirring in the presence of water. The heating conditions are 40 to 120°C for 1 to 100 hours, preferably 50 to 100°C for 2 to 50 hours. Although the reaction proceeds at temperatures below 40° C., for example at room temperature, it takes an extremely long time to complete the reaction, which is not practical. The β-substituted-β-hydroxy amino acid produced by heating the 3-substituted aziridine-2-carboxylic acid or derivative adsorbed on the ion exchange resin is adsorbed on the ion exchange resin after the reaction, and this β- Substituted β-hydroxy amino acids can be isolated by elution from an ion exchange resin according to conventional methods.
For example, the adsorbed β-substituted β-hydroxyamino acid is eluted with aqueous ammonia, the eluate is concentrated to dryness, or the eluate is concentrated to below the solubility of the β-substituted β-hydroxyamino acid, and then crystallized. isolated by The method of the present invention will be explained below by way of examples. Note that the 3-substituted aziridine-2-carboxylic acid salts or 3-substituted aziridine-2-carboxylic acid derivatives used as raw materials in Examples 1 to 8 and 10 and 11 are a mixture of cis and trans forms,
The resulting β-hydroxyamino acid is also a mixture of threo and erythro forms. In addition, in the Examples, purity analysis and yield were determined by methods such as high performance liquid chromatography and nuclear magnetic resonance spectroscopy. Example 1 160 ml of an aqueous solution of 12.9 g of 3-methylaziridine-2-carboxylic acid ethyl ester was passed through 60 ml of strongly acidic cation exchange resin Lewatit S-100 (H type) (manufactured by Bayer), and further washed with 60 ml of distilled water. te3
-Methylaziridine-2-carboxylic acid ethyl ester is adsorbed. After that, this ion exchange resin was transferred to a 100ml flask and reacted at 80-85℃ for 7 hours, then transferred to the column again and 5% ammonia water was added.
eluted with 90 ml and 60 ml of distilled water. This eluate was concentrated to dryness to obtain 11.4 g of threonine. The obtained threonine had a purity of 92.5% and a yield of 88.6%. In addition, as a raw material, 3-methylaziridine-2
- When a mixture of carboxylic acid ethyl ester with a ratio of cis isomer to trans isomer at 66:34 was used, the threonine produced was a mixture of threo isomer and allo isomer at 70:30. Furthermore, when only the cis isomer was used as a raw material, most of the compounds were the threo isomer. Example 2 136 ml of an aqueous solution of 8.2 g of 3-methylaziridine-2-nitrile is passed through 60 ml of Lewatit S-100 (H type) and washed with 60 ml of distilled water to adsorb 3-methylaziridine-2-nitrile. Thereafter, hot water heated to 80 to 85°C is circulated through the ion exchange resin for 8 hours. After the reaction, the ion exchange column was cooled and eluted with 90 ml of 5% aqueous ammonia and 60 ml of distilled water, and the eluate was concentrated to dryness to yield 4.9 g of threonine.
7.6 g of solid containing . The obtained threonine had a purity of 64.5% and a yield of 41.2%. Example 3 To 160 g of an aqueous solution of 15.5 g of α-chloro-β-amino-n-butyronitrile hydrochloride is gradually added dropwise, with stirring, an aqueous solution of 12.8 g of sodium hydroxide dissolved in 90 g of water. The reaction mixture is then heated to 60°C and reacted at 60-65°C for 6 hours. Next, this reaction solution was cooled, neutralized with a 5% aqueous sulfuric acid solution, and passed through a column packed with 400 ml of Lewatit S-100 (H type). Further, distilled water was allowed to flow through the column until no chloride ions were detected in the distillate from the column. Then, the 3-methylaziridine-2-carboxylic acid was adsorbed on an ion exchange column at 85-90°C.
The reaction is carried out by circulating hot water heated to
After the reaction, the ion exchange column was cooled and eluted with 600 ml of 5% aqueous ammonia and 400 ml of distilled water. This eluate was concentrated to dryness to obtain 11.0 g of threonine. The obtained threonine has a purity of 88.7% and a yield of 82%.
It was hot. Example 4 The same reaction as in Example 3 was carried out except that 20.2 g of α-chloro-β-aminobutyric acid ethyl ester hydrochloride was used to obtain 10.5 g of threonine. The obtained threonine had a purity of 93.0% and a yield of 82.0%. Example 5 100 ml of an aqueous solution of 7.2 g of 3-methylaziridine-2-carboxylic acid isopropyl ester was added to Lewatit S
Pass through 30 ml of -100 (H type) and wash with 30 ml of distilled water to adsorb 3-methyl-aziridine-2-carboxylic acid isopropyl ester. after that,
Hot water heated to 80 to 85°C is circulated through this ion exchange resin for 8 hours. After the reaction, the ion exchange column was cooled and eluted with 45 ml of 5% aqueous ammonia and 30 ml of distilled water, and the eluate was concentrated to dryness to yield 11.2 g of threonine.
I got it. The obtained threonine has a purity of 95.9% and a yield of
It was 90.3%. Examples 6 to 8 Strongly acidic cation exchange resin Lewatit S-100
The reaction was carried out in the same manner as in Example 5 except that other resins were used instead, and the results shown in Table 1 were obtained. [Table] Example 9 3,3-dimethylaziridine-2-carboxylic acid
Add 72 ml of 5.8 g aqueous solution to Lewatit S-100 (H type) 30
ml, and then rinse with 30 ml of distilled water.
Adsorb dimethylaziridine-2-carboxylic acid. After that, this ion exchange resin was transferred to a 100ml flask and reacted at 80-85℃ for 7 hours, then transferred to the column again and mixed with 45ml of 5% ammonia water and 30ml of distilled water.
eluted with ml. This eluate was concentrated to dryness to obtain 6.4 g of β-hydroxyvaline. The β-hydroxyvaline obtained had a purity of 91.3% and a yield of 88.5%. Example 10 150 ml of an aqueous solution containing 10.3 g of 3-phenylaziridine-2-carboxylic acid isopropyl ester
Suitable for Lewatit S-100 (H type) 40ml, distilled water
Wash with 40 ml of water to adsorb 3-phenylaziridine-2-carboxylic acid isopropyl ester. Thereafter, hot water heated to 80 to 85°C is circulated through the ion exchange resin for 8 hours. After the reaction, cool the ion exchange column and add 60ml of 5% ammonia water and 90ml of distilled water.
This eluate was concentrated to dryness to give a product of 9.0 ml.
I got g. The product contained 83.3% phenylserine, and the yield as phenylserine was 82.9%. Example 11 160 ml of an aqueous solution of 8.1 g of 3-phenylaziridine-2-carboxylic acid amide was treated in exactly the same manner as in Example 10 to obtain 8.7 g of product. The product is 56.3
% of phenylserine, and the yield of phenylserine was 54.1%. Example 12 160 ml of an aqueous solution of 10.3 g of 3-(2-pyridyl)aziridine-2-carboxylic acid isopropyl ester
was treated as in Example 10 to give product 9.2
I got g. The product contained 80.4% 2-pyridylserine, and the yield of 2-pyridylserine was 81.3%. Example 13 The same method as in Example 1 was performed, except that 19.1 g of 3-methylaziridine-2-carboxylic acid benzyl ester was used instead of aziridine-2-carboxylic acid methyl ester.
It was carried out using 11.8 g of threonine was obtained. Purity 91.7%,
The yield was 91.3%.

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ is a methyl group, a substituted or unsubstituted phenyl group, or a pyridyl group, R ₂ is a hydrogen atom or a methyl group, and X is -CO ₂ H, -CO ₂ M
(wherein M is an alkali metal or alkaline earth metal), —CO ₂ R ₃ (wherein R ₃ is a lower alkyl group having 1 to 5 carbon atoms or a benzyl group), —CONH ₂ or β-, which is characterized by adsorbing 3-substituted aziridine-2-carboxylic acid represented by -CN) or its derivative on a strongly acidic cation exchange resin and heating it in the presence of water.
Substituted method for producing β-hydroxy amino acids.