JPH0466228B2 - - Google Patents

Description

BACKGROUND OF THE INVENTION Technical Field The present invention relates to a method for producing serine derivatives. More specifically, the present invention relates to a method for producing a serine derivative from a dioxane derivative, which has never been isolated as a compound, and hydrocyanic acid. The serine derivative produced according to the present invention is generally obtained as a DL form by a synthetic chemical synthesis method. The serine derivatives produced according to the invention are serine, ie DL-serine, as well as DL-serine in which the hydrogens of the N- and/or methylene groups are substituted. DL-serine derivatives, with or without optical resolution, are useful as physiologically active substances such as medicines or as raw materials thereof, as cosmetics or as raw materials thereof, or as raw materials for α-amino acids such as tryptophan, cysteine, cystine, etc. It is something. Prior art Methods for producing DL-serine using hydrocyanic acid (including free and in situ generated from cyanide salts) as one of the raw materials include Strecker reaction, Zelinsky reaction,
-There are applications of Stadnikoff reaction or Bu¨cherer reaction. For example, a method for producing DL-serine from glycolaldehyde, hydrocyanic acid and ammonia (Fischer, Leuchs: Chemische Berichte,
35, 3787 (1902)), Process for producing DL-serine from alkoxyglycol aldehyde, hydrocyanic acid and ammonia (Leuchs, Geiser: Chemische
Berichte, 39 , 2644 (1906)), from 1,1,2-triacetoxyethane, hydrocyanic acid and ammonia.
Method for producing DL-serine (Geipel, Glo¨de,
Hilgetag, Gross: Chemische Berichte, 98 ,
1677 (1965), and Special Publication No. 56-29652),
A method for producing DL-serine from a compound represented by [Formula] [Formula] or [Formula] (X is a halogen atom or an acyloxy group), hydrocyanic acid, and ammonia (Tokuko Showa)
57-11309), a method for producing DL-serine from alkoxyacetal, hydrocyanic acid and ammonium carbonate (Nadeau, Gaudry, Canadian
Journal of Chemistry, 27 B, 421 (1949)). However, as far as the present inventors know, these known methods have the following problems. 1 The raw material to react with hydrocyanic acid is unstable and difficult to purify, making it not commercially available () 2 Requires several steps to manufacture and the process is complicated (~) 3 Unnecessary groups in DL-serine Because of the binding, the yield of DL-serine per unit weight is small (~) 4 It takes a long time to react with hydrocyanic acid to produce DL-serine in high yield () 5 DL-serine In order to use raw materials with unnecessary groups attached to them, DL-serine must be separated from by-products derived from these groups (e.g. alcohols, carboxylic acids, etc.) from the reaction mixture after hydrolysis. This makes the process complicated (~). SUMMARY OF THE INVENTION The present invention aims to solve the above-mentioned problems and to industrially produce DL-serine or its derivatives at low cost. This is what we are trying to achieve. Therefore, the method for producing a serine derivative according to the present invention involves reacting a dioxane derivative represented by the following formula () with hydrocyanic acid, and then placing the reaction product under aqueous alkaline or acidic conditions to produce a serine derivative represented by the following formula (). The present invention is characterized in that a serine derivative is obtained. (Here, R is a hydrogen atom or a methyl group,
Both R ¹ and R ² represent a hydrogen atom. ) Effect The dioxane derivative of the above formula () is a compound that has not been reported to have been isolated as a conventional compound, and most of it is a new substance that has not been described in any literature.
This compound reacts very efficiently with hydrocyanic acid to give serine derivatives. This fact must be said to have been unexpected. According to the method of the present invention, since a specific dioxane derivative is used as one of the raw materials, the reaction time with hydrocyanic acid can be shortened, and this dioxane derivative does not contain unnecessary groups for the target serine derivative. Since there are no by-products based on unnecessary groups, the yield of the target product per unit weight is high, and the isolation and purification of the target product is easy because there are no by-products based on unnecessary groups. Furthermore, the dioxane derivatives in which R corresponds to a hydrogen atom or a phenyl group can be easily recrystallized from water, alcohols, etc., so the dioxane of high purity can be used as a raw material, and it is possible to eliminate impurities or by-products based on impurities. Many advantages can be enjoyed in industrial production of DL-serine or its derivatives, such as no worries. Detailed Description of the Invention Dioxane Derivative The dioxane derivative used in the present invention has the formula ()
It is expressed as Here, R is a hydrogen atom or a methyl group, with a hydrogen atom being particularly preferred. Hydrocyanic acid Hydrocyanic acid may be a free form produced separately, or it may be generated in situ from a cyanide salt and an organic acid, an inorganic acid, or an inorganic salt in the reaction system when reacting with a dioxane derivative. It's okay to be hot. Examples of cyanates include ammonium cyanide,
Lithium cyanide, sodium cyanide, potassium cyanide, beryllium cyanide, magnesium cyanide, calcium cyanide, etc. can be mentioned, and among these cyanates, sodium cyanide and potassium cyanide are preferred,
Particularly preferred is sodium cyanide. When generating hydrocyanic acid in situ, organic acids such as formic acid, acetic acid, butyric acid, benzoic acid, toluic acid, phthalic acid, benzenesulfonic acid, and toluenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid are used as compounds to be reacted with cyanide. Examples include inorganic acids such as ammonium chloride, ammonium sulfate, ammonium hydrogen sulfate, sodium hydrogen sulfate, ammonium carbonate, ammonium hydrogen carbonate, ammonium phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, and other inorganic salts. I can do it. Preferred among these salts are ammonium salts, with ammonium chloride and ammonium sulfate being particularly preferred. Optional Compounds for Use in Combination During the reaction between the dioxane derivative and hydrocyanic acid, various compounds can be used in combination as long as they do not inhibit the reaction. For example, ammonia, carbon dioxide gas, and ammonium salts and carbonates other than those mentioned above can be used. Reaction - First Step This step mainly concerns the reaction of the dioxane derivative with hydrocyanic acid. A solvent is usually used in the reaction. for example,
Water, alcohols such as methanol and ethanol are preferably used, and water is particularly preferably used. The reaction temperature is usually -10 to 100℃, preferably 0
The temperature range is from 10 to 50°C, particularly preferably from 10 to 50°C. The reaction time is usually 10 minutes or more, preferably 30 minutes or more. There is no upper limit to the reaction time, but usually
24 hours is sufficient, and the reaction is often completed in about 5 hours. The ratio of hydrocyanic acid to dioxane derivative (theoretically generated amount when generated in situ) is usually 1.0 to 10 mol, preferably 1.6 to 5 mol, of hydrocyanic acid per mol of dioxane derivative. The nature of the compound produced by the reaction between dioxane derivatives and hydrocyanic acid has not yet been confirmed. However, according to one assumption, this compound is a precursor with respect to the carboxyl group of the desired serine derivative, i.e. in the case of serine.
It is believed to be HOCH ₂ CH(NH ₂ )CN (however, the present invention is not restricted in any way by such estimation). Reaction - Second Step This step involves placing the reaction product of the first step (i.e. the process product with or without isolation of the intermediate compound described above) under aqueous alkaline or acidic conditions. It is primarily concerned with producing serine derivatives. Aqueous alkaline or acidic conditions are conditions that cause hydrolysis, and if the intermediate compound from the first step is a nitrile, it is hydrolyzed to form a serine derivative in which the cyano group is a carboxyl group. I will do it. Regardless of the intermediate compound from the first step, the "aqueous alkaline or acidic conditions" in the second step of the present invention are known conditions used in the alkali or acid hydrolysis of organic nitrile compounds or hydantoins. The following conditions are sufficient. Isolation of the produced serine derivative The DL-serine derivative is usually present in the salt form in the reaction product from the second step, but the free DL-serine derivative can be isolated according to a conventional method. . For example, a method may be used in which the reaction mixture is neutralized with an acid or base to an isoelectric point and then subjected to fractional crystallization, or a method in which the reaction mixture is passed through a cation or anion exchange resin and then eluted. Experimental Examples In the following Examples and Comparative Examples, the yield of DL-serine or N-substituted-DL-serine was calculated based on the high performance liquid chromatography described below. Model: Shimadzu LC-5A high performance liquid chromatography column: Shimadzu Shim-pack ISC-07/S1504 Detector: Shimadzu SPD-2A UV detector (195nm) Mobile phase: 0.1N-NaH ₂ PO ₄ /0.25%H ₃ PO ₄ aqueous solution temperature: 55°C Pressure: 45 Kg/cm ² Flow rate: 5 ml/min Example 1 1.18 g (10 mmol) of 2,5-diamino-1,4-dioxane and cyanide were added to 10 ml of water. 0.98 g (20 mmol) of sodium and 2.15 g (40 mmol) of ammonium chloride were added and reacted at 25° C. for 3 hours. Add sodium hydroxide to this reaction mixture.
Add 35 ml of an aqueous solution containing 4.0 g (100 mmol),
The hydrolysis reaction was carried out under reflux for 2 hours. A small amount of this reaction mixture was taken out and evaporated to dryness, and the infrared absorption spectrum revealed that it contained a large amount of sodium salt of DL-serine. DL
-The yield of serine was measured by high performance liquid chromatography and was 81%. Example 2 2.64 g of ammonium chloride and ammonium sulfate
Example 1 was repeated substituting (20 mmol).
The yield of DL-serine was 81%. Example 3 Example 1 was repeated under all the same conditions except that the hydrolysis reaction was carried out using 15 ml of 35% hydrochloric acid for 3 hours.
The yield of DL-serine was 87%. Example 4 2,5-diamino-1,4-dioxane 1.18g
(10 mmol) and ammonium carbonate 4.81 g
(50 mmol) in 30 ml of an aqueous solution containing 0.55 g of hydrocyanic acid.
10 ml of an aqueous solution containing (20 mmol) was added dropwise over 30 minutes. During this time, the reaction mixture was kept at 25°C.
After the dropwise addition was completed, the reaction was further continued at 25°C for 4 hours.
Next, this reaction mixture was transferred to a stainless steel pressure-resistant reaction tube with an internal capacity of 100 ml, 4 g (100 mmol) of sodium hydroxide was added, the mixture was sealed, and hydrolysis was carried out at 180°C for 3 hours with shaking. Summer. DL
-The yield of serine was 42%. Example 5 2,5-diamino-1,4-dioxane was converted into 2,
5-bis(methylamino)-1,4-dioxane
Example 1 was repeated using 1.46 g (10 mmol). The yield of N-methyl-DL-serine was 80%. Example 6 2.5-diamino-1,4-dioxane was converted into 2,
Example 1 was repeated using 2.7 g (10 mmol) of 5-bis(phenylamino)-1,4-dioxane and 20 ml of water instead of 10 ml. The yield of N-phenyl-DL-serine was 75%. Comparative Example 1 Example 1 was repeated, replacing 2,5-diamino-1,4-dioxane with 1.20 g (20 mmol) of glycolaldehyde. The yield of DL-serine was only 47%. Comparative Example 2 2,5-diamino-1,4-dioxane was replaced with 1.20 g (20 mmol) of glycolaldehyde,
1.5 ml of 25% aqueous ammonia ( _NH3 as 22
Example 1 under the same conditions except that 1 mmol) was added.
repeated. Yield of DL-serine is only 61%
It was hot. In this comparative example, the yield of DL-serine was reduced to 75
% required a long reaction time of 25 hours with glycolaldehyde, sodium cyanide, ammonium chloride, and ammonia.

Claims (1)

[Claims] 1. After reacting a dioxane derivative represented by the following formula () with hydrocyanic acid, the reaction product is placed under aqueous alkaline or acidic conditions to produce a serine derivative represented by the following formula () or a salt thereof. A method for producing a serine derivative, the method comprising: obtaining a serine derivative; (Here, R is a hydrogen atom or a methyl group,
Both R ¹ and R ² represent a hydrogen atom. )