JPH0129786B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a 2-amino-4-cyanobutyric acid derivative, which is a type of intermediate for producing amino acids.

Various methods have been proposed to date to produce amino acids, and most of them involve various intermediates. Although these methods have achieved a certain degree of effectiveness, endless improvements are desired in the following respects. That is, (a) the steps for synthesizing intermediates or target products should be simplified;
(b) The yield should be improved; (c) The reaction conditions should be made more relaxed to stabilize the reaction;
Improvements are desired such as (d) simplification of operation, (e) process that can effectively utilize by-products, and (f) resource- or energy-saving process.

Therefore, the present inventors conducted intensive research on the production method of an intermediate for producing amino acids, particularly ornithine, with the aim of making the above improvements, and discovered a very unique production method of the intermediate, resulting in the present invention.

Specifically, the above object of the present invention is as follows: (In the formula, R ¹ represents H, CH ₃ or an aryl group,
φ represents a phenyl group, and U ² has 1 to 4 carbon atoms.
represents an alkyl group. ) by reacting N-(substituted methylene)glycine ester with acrylonitrile to form the following general formula () (In the formula, R ¹ , φ and R ² are the same as above.) It has been found that this can be achieved by obtaining a 2-amino-cyanobutyric acid derivative represented by the following formula.

Further, by hydrolyzing the 2-substituted amino-4-cyanobutyric acid ester obtained by the above method in the presence of an acid or an alkali, an intermediate more advantageous for producing amino acids can be obtained.

The method of the present invention will be explained in detail below.

First, starting materials used in the present invention are prepared.

N-(substituted methylene)glycine ester represented by the above general formula is a dehydration reaction between glycine ester obtained by the reaction of glycine with an alcohol having 1 to 4 carbon atoms, etc., and ketones and/or aldehydes. obtained by.

As the ketones, acetone, methyl ethyl ketone, cyclohexanone, acetophenone, benzophenone, etc. are selected, and as the aldehydes, formaldehyde, acetaldehyde, propionaldehyde, benzaldehyde, etc. are selected, but in order to effectively achieve the object of the present invention, Practically speaking, benzophenone, benzaldehyde, and acetophenone are selected. In particular, these aldehydes and ketones not only allow the by-products produced in the reactions described below to be used again as raw materials, but are also effective in forming a closed system.

Acrylonitrile, on the other hand, is obtained by methods known per se.

Next, these two types of raw materials are reacted. There are two reaction methods: a method in which the reaction is carried out in a homogeneous solvent system and a method in which the reaction is carried out between an aqueous phase and an organic phase, and the latter reaction method is preferred because it is easy to operate and isolate.

When reacting in a homogeneous solvent system, alcohols such as ethanol, halogenated hydrocarbons such as dichloromethane, ethers, hydrocarbons such as benzene, dimethylformamide and dimethyl sulfoxide may be used alone or in combination of two or more. and use it. As the base, an alkali metal oxide such as potassium hydroxide, an alkali alcoholate such as sodium ethylate, an organic base such as 1,8-diazabicyclo(5,4,0)undecene-7, etc. are used. The amount of base added at this time is usually 0.01 to 6 molar equivalents per mole of N-(substituted methylene)glycine ester. This reaction proceeds smoothly if the reaction solution is stirred at a temperature above 0°C and at the boiling point of the solvent, preferably below 50°C.

When the reaction is carried out in a two-phase solvent system, a mixed solvent of water and an organic solvent such as halogenated hydrocarbons, ethers, or hydrocarbons is used as the reaction solvent. In this case, the base used is an alkali metal hydroxide, carbonate, hydrogen carbonate, etc., such as sodium hydroxide, sodium carbonate, or sodium hydrogen carbonate. The amount of base used in this reaction is usually N-
The amount is 0.01 to 6 molar equivalents per mole of (substituted methylene)glycine ester. The reaction temperature at this time varies somewhat depending on the solvent used, but the reaction is generally carried out at 0 to 80°C, usually 0 to 40°C.

When the reaction is carried out in a two-phase solvent system, the reaction proceeds without using a phase transfer catalyst, but it is more preferable to use a phase transfer catalyst in an amount of 0.01 to 1.0 molar equivalent per mole of N-(substituted methylene)glycine ester.
As the phase transfer catalyst, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, benzyltrimethylammonium hydroxide, ceyltrimethylammonium bromide, dodecyltrimethylammonium chloride, and tetraethylammonium hydroxide, more preferably Tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium hydroxide, and tetraethylammonium hydroxide are used.

In any of the above reactions, a stoichiometric amount of starting material is used in principle, preferably 0.9 per mole of N-(substituted methylene)glycine ester.
Acrylonitrile is used in a proportion of ˜1·1 mol.

The reaction can be carried out under various pressures such as normal pressure, increased pressure, and reduced pressure, but is preferably carried out under normal pressure.

Any system such as batch, continuous or semi-continuous can be used for the reaction. When the reaction is carried out batchwise, the reaction is usually completed in 5 to 60 minutes.

After the reaction is completed, the product is collected using a known method to obtain α-(substituted methylene)amino-4-
A cyanolac acid ester (hereinafter simply referred to as a derivative ()) is obtained.

After the reaction is completed, a known method is employed to separate the product.

For example, when a phase transfer catalyst is used to cause a reaction between two phases, the solvent is removed from the aqueous phase and the separated organic phase after the reaction, and the residue is passed through a column packed with silica gel. In this case, some impurities including phase transfer catalyst are adsorbed on the column, so after washing with solvent,
Removal of the solvent from the total effluent under reduced pressure yields the purified derivative ().

In the present invention, the fractionated purified derivative () or a reaction mixture containing the derivative () obtained in the above reaction is further subjected to a hydrolysis reaction in the presence of an acid or an alkali.

When hydrolyzing with an acid, select mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, etc., organic carboxylic acids such as acetic acid, propionic acid, citric acid, oxalic acid, or ion exchange resins having sulfonic acid groups as the acid. 0.5 at a temperature of 0-50℃, preferably 20-30℃ in the presence of
Allow to react for ~10 hours, preferably 1-3 hours. At this time, at least 1 mol or more of the acid is used per 1 mol of the derivative ().

Thus, when the hydrolysis reaction is carried out in the presence of an acid, 2-amino-4-cyanobutyric acid ester and aldehydes or ketones represented by the following formula are obtained. (hereinafter referred to as derivative ()) The second objective product and by-product of the present invention can be obtained by separating the derivative () and ketone or aldehyde from the hydrolysis reaction product by a known method, such as an extraction method.

The by-product is converted into N-(substituted methylene) by a known method.
It can be recycled as a raw material for producing glycine ester, which is another feature of the present invention.

On the other hand, when hydrolyzed in the presence of an alkali, the alkalis include NaOH, KOH, NH ₄ , OH,
Select Na ₂ CO ₃ , CaCO ₃ , CH ₃ COONa, etc. in the presence of water at a temperature of 0 to 50°C, preferably 20 to 30°C, 1
Allow to react for ~10 hours, preferably 3-5 hours.

At this time, at least 1 mol or more of the alkali is used per 1 mol of the derivative ().

Upon completion of the reaction, 2-(substituted methylene)-4-cyanobutyric acid (hereinafter simply a derivative ()) shown by the following formula
) is obtained.

The derivative (2) can be separated and obtained from the reaction product mixture by a known method, for example, an extraction method.

In addition, instead of using the derivative () alone as a raw material for the hydrolysis reaction, in other words, N-(substituted methylene)
When the mixture produced by the addition reaction of acrylonitrile to glycine ester is subjected to the hydrolysis reaction as it is, the following formulation must be considered.

First, acid hydrolysis removes the aqueous layer from the reaction mixture and adds acid to the organic layer. The acid in this case is the same as above.

Further, for hydrolysis with an alkali, it is only necessary to continue the reaction for an additional 3 to 5 hours after the completion of the addition reaction.

The reaction conditions and separation method are the same as described above.

As described above, according to the method of the present invention, the derivative ()() or () can be obtained in high yield through simplified steps using industrially advantageously obtained starting materials, and the by-product can be recovered again. It can be reused as a raw material for producing starting materials.

The derivative ()() of the present invention can be advantageously converted into an amino acid such as ornithine by further subjecting it to a necessary reaction.

The following method of the present invention will be explained using examples.

Example 1 2.7 g of N-(diphenylmethylene)glycine ethyl ester (10
20 ml of dichloromethane (mmol), 0.5 g (10 mmol) of allylonitrile, 0.3 g (1 mmol) of tetrabutylammonium hydrogen sulfate, and 1.1 g of a 35% aqueous sodium hydroxide solution were charged, and reacted for 30 minutes at room temperature. The reaction solution was separated into layers, the organic layer was washed once with water, and then the solvent was removed. The concentrated solution was separated using a silica gel column to obtain 2.9 g of ethyl 2-(diphenylmethyleneamino)-4-cyanobutyrate. The yield was 90.5%.

Example 2 Into the same apparatus as in Example 1, 2.5 g (10 mmol) of N-(diphenylmethylene)glycine methyl ester, 20 ml of dichloromethane, and 0.5 acrylonitrile were added.
(10 mmol), 1.7 g (5 mmol) of tetrabutylammonium hydrogen sulfate, and 5.6 g of a 30% aqueous potassium hydroxide solution, and the mixture was reacted for 1 hour while cooling in ice water. The reaction solution was treated in the same manner as in Example 1, and 2-(diphenylmethyleneamino)
2.7 g of methyl 4-cyanobutyrate was obtained. Yield is 87.3%
It was hot.

Example 3 Into the same apparatus as in Example 1, 2.7 g (10 mmol) of N-(diphenylmethylene)glycine ethyl ester, 30 ml of benzene, and 0.5 g (10 mmol) of acrylonitrile were added.
mmol) and 35% aqueous sodium hydroxide solution
3.3g was charged and reacted at 50°C for 3 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 1.7 g of ethyl 2-(diphenylmethyleneamino)-4-cyanobutyrate. The yield was 53.1%.

Example 4 In an apparatus similar to Example 1, 2.1 g (10 mmol) of N-(phenylmethylmethylene)glycine ethyl ester, 20 ml of dichloromethane, 0.5 g (10 mmol) of acrylonitrile, 0.5 g of benzyltriethylammonium chloride, and 10% water were added. 2 g of an aqueous sodium oxide solution was charged, and the mixture was reacted at room temperature for 1 hour. The reaction solution was treated in the same manner as in Example 1, and 2-
1.8 g of ethyl (diphenylmethylmethyleneamino)4-cyanobutyrate was obtained. The yield was 69.7%.

Example 5 Into the same apparatus as in Example 1, 1.9 g (10 mmol) of N-(monophenylmethylene)glycine ethyl ester, 20 ml of dichloromethane, and acrylonitrile were added.
0.5 g (10 mmol), benzyltrimethylammonium chloride, 0.5 g, and 5 g of a 10% aqueous sodium hydroxide solution were charged and reacted in ice water for 1 hour. The reaction solution was treated in the same manner as in Example 1, and 2-
1.2 g of ethyl (monophenylmethyleneamino)-4-cyanobutyrate was obtained. The yield was 49.1%.

Example 6 In a device similar to Example 1, 2.7 g (10 mmol) of N-(diphenylmethylene)glycine ethyl ester, 20 ml of ethanol, and 0.5 sodium ethyl ester were added.
g (10 mmol) and acrylonitrile 0.5 g
(10 mmol) and reacted at room temperature for 1 hour. The reaction solution was treated in the same manner as in Example 1, and 2-
2.7 g of ethyl (diphenylmethyleneamino)-4-cyanobutyrate was obtained. The yield was 84.3%.

Example 7 Into the same apparatus as in Example 1, 1.0 g (3.3
mmol) and 10 ml of ethanol. While stirring at room temperature, 6 ml of 1N hydrochloric acid was added, and the mixture was allowed to react for 1 hour. Ethanol was removed under reduced pressure while cooling, and cyclomethane was added to the concentrate to extract benzophenone. The aqueous layer was diluted with 0.1N sodium hydroxide.
The pH was adjusted to 8-9 and extracted with dichloromethane.
Removal of the solvent yielded 0.39 g of ethyl 2-amino-4-cyanobutyrate. The yield was 82.0%.

Example 8 Into the same apparatus as in Example 1, 1.0 g (3.3
mmol) and 1 ml of ethanol.
20% aqueous potassium hydroxide solution with stirring at room temperature
1.5 g was added and reacted for 3 hours. After removing ethanol under reduced pressure, add 30 ml of dichloromethane to the concentrate.
After adjusting the pH to 6 to 7 with 0.1N hydrochloric acid, the mixture was stirred for 5 minutes. After separating the dichloromethane layer, the solvent was removed to obtain 0.76 g of 2-(diphenylmethyleneamino)-4-cyanobutyric acid. The yield was 82.7%.

Claims (1)

[Claims] First-order general formula () (In the formula, R ¹ represents H, CH ₃ or an aryl group,
φ represents a phenyl group, and R ² has 1 to 4 carbon atoms.
represents an alkyl group. ) The following general formula () is characterized by reacting the N-(substituted methylene)glycine ester represented by () with acrylonitrile. (In the formula, R ¹ , φ and R ² are the same as above.) A method for producing a 2-amino-4-cyanobutyric acid derivative represented by the following.