JPS58955A - Preparation of butyric acid derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate of amino acid, with simplified process, under mild conditions, in high yield, by reacting N-(diphenylmethylene)glycinonitrile with acrylamide. CONSTITUTION:The 4-cyano-4-(diphenylmethylene)aminobutyric acid amide of formula II can be prepared by reacting N-(diphenylmethylene)glycinonitrile of formulaIwith acrylamide in a solvent, preferably in a binary-phase solvent system containing a phase-transfer catalyst, in the presence of a base, at 0-80 deg.C, preferably at 0-40 deg.C. The compound of formula II can be converted to 4-amino- 4-cyanobutyric acid amide of formula III and benzophenone by hydrolyzing in the presence of an acid, and glutamic acid of formula IV can be obtained by heating the compound of formula III in the presence of an acid or base. The by-produced benzophenone is recycled and reused as a raw material of the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a butyric 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. In other words, (a) the synthesis steps of intermediates or target products should be simplified; 6: I) the yield should be improved; (n) to be easy to operate; (e)) to be a process that allows effective use of by-products; and (f)
Improvements such as resource-saving and energy-saving processes are desired.

Therefore, the present inventors conducted intensive research on the production method of amino acids for the purpose of the above-mentioned improvement, and discovered a method using a very specific intermediate, resulting in the present invention.

The above-mentioned object of the present invention is, specifically, to obtain a compound having the general formula (1) obtained by reacting N-(diphenylmethylene)glycinonitrile represented by the formula (1) with acrylamide. (2) Obtaining a butyric acid derivative represented by formula (3) (hereinafter referred to as derivative (3)) by hydrolyzing the butyric acid derivative represented by formula (hereinafter referred to as derivative (2)) in the presence of an acid. achieved by.

The above object of the present invention can also be achieved by heating the derivative (3) in the presence of an acid or a base to obtain a butyric acid derivative represented by formula (4) (hereinafter referred to as derivative (4)). .

Furthermore, the above object of the present invention can also be achieved by obtaining a butyric acid derivative represented by formula (5) (hereinafter referred to as derivative (5)) by hydrolyzing derivative (3) in the presence of ketones and an alkaline aqueous solution. achieved.

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

First, derivative (2) is produced.

The starting material at that time, N-(
57 phenymu methylene) glycinonitrile is obtained by the dehydration reaction of glycinonitrile with benzophenone (Tezrahebron Let, t.

4625 (1978)).

Benzophenone not only allows by-products produced in the reaction described below to be used again as a raw material, but is also effective in forming a closed system.

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

Next, these two types of raw materials are reacted. There are two types of 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 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, hydrogen chloride such as benzene, dimethylformamide and dimethyl sulfoxide, etc. may be used alone or in combination as a solvent. Use by mixing more than one species. As a base, an alkali metal hydroxide such as potassium hydroxide, an alkali metal acolate such as sodium ethylate, 1.8
An organic base such as -diazabicyclo(5,4,O)undecene-7 is used.

The amount of base added at this time is usually α01 to 6 molar equivalents per mole of N-(diphenylmethylene)glycinonitrile. In this case, the temperature is below the boiling point of the solvent, preferably 50°C.
If the reaction solution is stirred in the following steps, the reaction will proceed smoothly.

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 suboxide, etc., such as sodium hydroxide, sodium carbonate, or sodium hydrogen carbonate. The amount of base used in this reaction is usually
u-<ep 0.01 to 6 molar equivalents per 1 mol of diphenylmethyleneglycinonitrile. 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 +! N-(
101 to 1.0 molar equivalents of phase transfer catalyst are used per mole of diphenylmethylene)grinnod')k'. Examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate, penzyltriethylammonium chloride, benzyltrimethylammonium hydroxide,
Quaternary trimethylammonium salts such as ceyltrimethylammonium bromide, dodecyltrimethylammonium chloride, and natophethylammonium hydroxide are used, more preferably tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium hydroxide, and natophethylammonium hydroxide.

In all of the above reactions, stoichiometric amounts of starting materials are used in principle, preferably in a ratio of 19 to 1.1 moles of acrylonitrile per mole of N-(diphenylmethylene)glycinonitrile.

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, usually 5 to
The reaction is completed in 60 minutes.

After the reaction is completed, the product is collected using a known method, and the following formula (
The derivative (2) shown in 2) is obtained.

After the completion of the reaction, 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 separated organic phase after the reaction, and the residue is passed through a cuff filled with silica or gel. In this case, some impurities including the phase transfer catalyst are adsorbed by the cuff, so after development with a solvent, the solvent is removed from the effluent under reduced pressure to obtain purified derivative (2).

In the present invention, the purified derivative (2) further fractionated is
Alternatively, the reaction mixture containing the derivative (2) obtained in the above reaction is subjected to a hydrolysis reaction in the presence of an acid.

In the presence of water, select mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, organic carboxylic acids such as acetic acid, propionic acid, citric acid, oxalic acid, or ion exchange resins having sulfonic acid groups as acids. Temperature 0-50℃ preferably 20-30℃
The reaction is allowed to proceed for 15 to 10 hours, preferably for 1 to 3 hours. At this time, at least 1 mol or more of acid is used per 1 mol of derivative (2).

Thus, when the hydrolysis reaction is carried out in the presence of an acid, a derivative (3) represented by the following formula (3) and benzophenone are obtained.

Derivative (3) and benzophenone are separated from the hydrolysis reaction product by a known method, such as extraction.

The by-product benzophenone can be recycled as a raw material for the production of N-(diphenylmethylene)glycinonitrile using known methods.

In addition, when the hydrolysis reaction is performed without using the derivative (2) alone as a raw material, in other words, when the mixture produced by the addition reaction of acrylamide to N-(diphenylmethylene)glycinonitrile is directly subjected to the hydrolysis reaction, the K humidity temperature is It is necessary to remove the aqueous layer from the liquid and add acid to the organic layer.

Further, the separated spun conductor (3) or the reaction mixture containing the derivative (3) obtained by hydrolysis is further subjected to hydrolysis by heating in the presence of an acid or #ILl&.

As acid H,80,,Er01,H□po4,aH,'
cooa.

C*”*C00FK, citric acid, (OOOH), etc. as a base, NaOH1, OH, N11I401T,
Na, 00. ．． 0400. , OH, 0OONa etc. in the presence of water at a temperature of 50 to 150°C, preferably 70°C.
Incubate at ~105°C for 1 to 10 hours, preferably 3 to 5 hours.

At this time, at least 2 mol or more of the acid or base is used per 1 mol of derivative (3).

When the reaction is completed, the derivative (4) shown by the following formula (4)
is obtained.

J The derivative (4) is separated and purified from the reaction product using a known method, for example, using an ion exchange resin.

Further, in the present invention, the separated spun conductor (3) or a reaction mixture containing the derivative (3) is subjected to hydrolysis in a ketone and aqueous alkaline solution.

NaOH, OH, NEr4011r as alkali
.

Na, Coj, 0aOO,%OF! , 0OONa, etc., and react in a two-phase solvent of ketones such as acetone, methyl ethyl ketone, and water at a temperature of 0 to 50°C, preferably 20 to 40°C, for 1 to 10 hours, preferably 3 to 5 hours.

At this time, at least 1 mol or more of alkali is used per 1 mol of derivative (3).

When the reaction is completed, the following formula (5) A derivative (5) represented by is obtained.

The derivative (
5) is separated and purified.

As described above, according to the method of the present invention, derivatives (2), (3), (4) or (
S) can be obtained in high yields through simplified steps.

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

! l! Example Convention 1 ($7 phenylmethylene) cridinonitrile 44g
(11112 mol), acrylic acid amide t4g (102
mole), tetragutylammonium hydrogen sulfate [13g
((101 mol), dichloromethane 50s/and 35
Sodium hydroxide aqueous solution! Log was placed in an Erlenmeyer flask and stirred at room temperature for 1 hour.

After the K reaction, the K reaction solution was separated, and the dichloromethane layer was washed with water and then dried. After removing the solvent, the crude cow-Vyj-4-, (<Phenylme-ft'y')71 all! jL 7 turtle F! Obtained L 5 g. The yield was 914%.

This crude product was purified by high performance liquid chromatography using 5/Lica gel as a filler and a mixed solvent of ethyl acetate and cyclohexane as an eluent, and the solvent was removed from the resulting eluate under reduced pressure. Recrystallization was performed from a mixed solvent of ethyl acetate and cyclohexane to obtain 47 g of white crystals.

The analysis results of this compound were as follows.

Melting point 131~2℃ Elemental analysis (as a,, H,, w, o) 0% 11
% 111 Calculated value 74.20 5.88 1 hair 42 Estimated value 7599 5.76 14!2 Infrared absorption spec) N (rock plate for liquid) (on') 5450, 51
50, 2250, 1700.1620, 145
0, 1420, 1310.1i500 1180 I'H nuclear magnetic resonance spectrum/I/(in deuterium-substituted chloroform solution) δ(PP) 1.9-14 (4N 42,45 (11i 53-5B) 2y)y, o~7.7 (11r)!l!Koji Example 2 In a flask equipped with a stirrer, add 4-cyano-4'-(
Shifu Engineering/Nirumeko [N) Ami/11t y = Do 2
．． ? g(rLo 1-eJv), r, j'/-le 5G,
z and 12 d of 1N sananic acid were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the liquid was removed under reduced pressure, extracted twice with 20 ml of benzene, the aqueous layer was neutralized with ammonia, and extracted twice with 50 ml of chloroform. After dehydration, it is concentrated to obtain crude 4-amino-4yanoJl [amide t
2g was obtained. The yield was 945%. Then, the benzene layer was concentrated to obtain 1.8 g of benzophenone.

! JI example 3 0 N also MFI.

Add 4-amino- to a flask equipped with a reflux tube and a stirrer.
1.27 g of 4-cyanobuty-amide ([1 mol of LO) and 40 d of 2N aqueous sodium hydroxide solution were charged, and 2
The mixture was heated to reflux for an hour.

After the reaction is completed, the ion exchange resin DIArON PA 51
4 (Mitsubishi Kasei) to obtain 1.3 g of glutamic acid. The yield was 8114%.

Add 4-amino- to a flask equipped with a stirrer and reflux tube.
4-cyanobutyric acid amide 1.27 g (α01), acetone 10 d and 1N sodium hydroxide aqueous solution 1 d
was added and reacted at room temperature for 2 hours. After the reaction was completed, acetone was removed under reduced pressure, and the residue was washed with cold water for 20 seconds to obtain 1.2 g of crude 4-amino-4-carbamoylbutyric acid amide. The yield was 816:@.

Claims (1)

[Scope of Claims] 1 Formula (1) characterized by reacting N-(diphenylmethylene)glycinonitrile represented by the following formula with acrylamide:
2) A method for producing a butyric acid derivative shown in the following. 2 A method characterized by reacting N-(diphenylmethylene)glycinonitrile represented by formula (1) with acrylamide to obtain a butyric acid derivative represented by formula (2), and then hydrolyzing the derivative in the presence of an acid. A method for producing a butyric acid derivative represented by formula (3). 3 N-(diphenylmethylene)glycinonitrile represented by formula (1) and acrylamide are reacted to obtain a butyric acid derivative represented by formula (2), and then (in step 1) the derivative is hydrated in the presence of an acid. A method for producing a butyric acid derivative represented by formula (4), which comprises decomposing it to obtain a butyric acid derivative represented by formula (3), and finally heating the derivative in the presence of an acid or a base. 1) N-(diphenylmethylene)glycinonitrile represented by the formula (2) is reacted with acrylamide to obtain a butyric acid derivative represented by the formula (2), and then the derivative is hydrolyzed in the presence of an acid to obtain the formula (3) % A method for producing a butyric acid derivative represented by the formula (5), which comprises obtaining a butyric acid derivative represented by the formula (%) and finally hydrolyzing the derivative in the presence of a ketone and an alkaline aqueous solution.