JPS6147821B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula

[Formula] (where R is a lower alkylene group, X is a lower alkyl group, lower alkoxy group, carboxylate group, hydroxy group, nitro group, chlorine atom or bromine atom, M is an alkali metal, and n is 0 or (representing an integer from 1 to 3). The glycine derivative of the present invention represented by the above general formula is a substance useful as an intermediate for synthesizing medicines, agricultural chemicals, public health drugs, dyeing aids, and other organic chemicals. Conventional manufacturing methods include, for example, taking N-benzylglycine as an example. 1) A method of reacting benzaldehyde and glycine to form a Schiff base, and reducing this (JACS Vol. 93, 5542).
2) A method for reductively decomposing N,N-dibenzylglycine obtained by reacting benzyl chloride with glycine (French Patent No. 1100016)
3) A method of reacting benzylamine with monochloroacetic acid (Japanese Unexamined Patent Publication No. 54-14931) is known, but all of these methods have low yields and problems in the manufacturing process, and are not suitable for industrial use. When implemented, it is difficult to say that it is necessarily completely satisfactory. The present invention aims to provide a method for producing the above-mentioned glycine derivatives with a very high yield through relatively simple steps. That is, the present invention is based on the general formula

[Formula] (where RXn is the same as above) is reacted with glycolonitrile in an aqueous medium to obtain an N-acetonitrile derivative of the amine, which is then treated with an alkali metal hydroxide. General formula characterized by hydrolysis

The object of the present invention is to provide a method for producing a glycine derivative represented by the formula: The method of the present invention will be explained in more detail below. As is clear from the general formula of the amines used as raw materials in the method of the present invention, a major feature is that the carbon of an alkylene group is interposed between the amino group, which is a reactive group, and the benzene nucleus. A compound in which the amino group is directly bonded to the benzene nucleus,
That is, when aniline or a derivative thereof is used as a raw material amine, the reaction with glycolonitrile according to the method of the present invention hardly progresses, and when the temperature is forcibly raised and the reaction is carried out for a long time, glycolonitrile This will lead to decomposition. In the method of the present invention, the group (R) interposed between the amino group of the raw material amine and the benzene nucleus is a linear or branched lower alkylene group having 1 to 4 carbon atoms. In addition, the substituent (X) bonded to the benzene nucleus is a lower alkyl group,
A group or atom selected from a lower alkoxy group, a carboxylate group, a hydroxy group, a nitro group, a chlorine atom, and a bromine atom. Regarding amines suitably used in the present invention,
Some specific examples include benzylamine, phenethylamine, 3-phenylpropylamine, α-methylbenzylamine, α-methylphenethylamine, α. α-dimethylbenzylamine, α. Typical examples include α-dimethylphenethylamine, m-methylbenzylamine, p-methoxybenzylamine, p-chlorobenzylamine, p-hydroxybenzylamine, p-ethoxycarbonylbenzylamine, m-sodium carboxybenzylamine, etc. It can be given as The raw material glycolonitrile used in the present invention is glycolonitrile produced in advance or an aqueous solution thereof. Glycolonitrile can be produced from hydrocyanic acid and formaldehyde, and one advantageous method thereof is described in Japanese Patent Application No. 142,180/1982. Using hydrocyanic acid and formaldehyde as raw materials instead of glycolonitrile and reacting them directly with the above amines means that even if a small amount of glycolonitrile is produced on the spot from hydrocyanic acid and formaldehyde during the reaction process, glycolonitrile can be used as raw materials. This is not preferable because a diacetonitrile derivative of the amine is produced as a by-product. According to the present invention, when the amine of formula (1) is reacted with glycolonitrile in an aqueous medium, a monoacetonitrile derivative of the amine can be obtained without using a catalyst or requiring special operations.

[Formula] is generated selectively and almost quantitatively. The quantitative ratio of both raw materials used is not particularly limited, but may be a stoichiometric amount, that is, a molar ratio of amine to glycolonitrile of 1:1. It is okay to use an excess of one of the raw materials, but
There are no particular advantages. Most of the excess amount remains unreacted, which is uneconomical, and may also cause coloration or contamination with impurities due to its own decomposition. In order to cause the two to react, it is preferable to gradually add the glycolonitrile aqueous solution to the amine in the aqueous medium while stirring, or to mix equivalent amounts of both in small portions. When the raw material amine or the reaction product aminoacetonitrile derivative is insoluble or poorly soluble in water, it is dissolved in the presence of an inert organic solvent that can dissolve the amine, such as methanol, ethanol, hydrofuran, dioxane, etc. Alternatively, when carried out in the form of a suspension, the reaction can proceed smoothly. The reaction does not require particularly high temperatures, and room temperature to slight heating is sufficient. If the reaction temperature is high, the reaction rate will be high, but there is also a risk of decomposition and coloring, so a temperature in the range of 10 to 60°C is usually preferred. The reaction is generally completed in a short time, within 30 minutes to about 3 hours. The reaction solution thus obtained contains the aminoacetonitrile derivative in high purity, does not require any purification step, and can be used in the next hydrolysis step. Furthermore, if particularly necessary, this aminomonoacetonitrile derivative can be isolated and used as an intermediate in the synthesis of various compounds. As the alkali metal hydroxide used in the next hydrolysis step, sodium hydroxide and potassium hydroxide are used. These alkalis are usually
Used as a 20-50% by weight aqueous solution. The amount to be used is not particularly limited when used in excess, but it is usually preferable to add the stoichiometric amount to a slight excess, that is, the molar ratio of glycolonitrile to alkali is about 1:1 to 1.5. Excessive amount of alkali suppresses side reactions and helps to expel by-produced ammonia. In order to cause the two to react, it is preferable to add the reaction solution of the amine and glycolonitrile to the aqueous alkali metal hydroxide solution while stirring, or to mix the two in small amounts. The reaction temperature is not necessarily limited, but if it is too low, the reaction time will be longer, so it is usually 60℃~
A range of boiling points is preferably applied. The reaction is generally completed in about 1 to about 3 hours. In addition, in practical terms, it is desirable to boil the reaction solution at least once before the end of the reaction in order to remove ammonia as a by-product of the reaction. From the alkali metal salt of the phenyl-substituted glycine derivative thus obtained, free phenyl-substituted glycine can be obtained in high yield by means such as neutralization, fractional crystallization, or ion exchange treatment, if necessary. Hereinafter, typical examples of the method of the present invention will be shown and explained in more detail, but these are merely examples for explanation, and it goes without saying that the present invention is not limited to these. Needless to say, there are no restrictions whatsoever. Example 1 Hard glass 3 equipped with thermometer and stirrer
The neck flask was placed in a constant temperature water bath. Benzylamine 107g (1.00mol), 50% by weight ethanol 300
g, glycolonitrile (50% by weight aqueous solution) 114g
(1.00 mol) was charged, heated, and reacted at 50°C for 1 hour with stirring. 1 separately equipped with a thermometer, stirrer, and reflux condenser
A three-neck flask made of hard glass was placed in a constant temperature oil bath. Caustic soda (40% by weight aqueous solution) 150g
(1.50 mol) was added thereto, and the above reaction solution was added thereto, heated and reacted under reflux for 2 hours. After the reaction was completed, the liquid was almost colorless and transparent, and analysis revealed that 181 g of N-benzylglycine soda had been produced. The reaction yield is 97%. This reaction solution was mixed with H-type ion exchange resin Amberlite.
After treatment with 600ml of IRC-84 and a small amount of powdered activated carbon to remove trace amounts of colored substances, it was concentrated and N-
139 g of benzylglycine crystals were obtained. The yield from benzylamine is 92%. When this product was analyzed, the purity was found to be 98%. Comparative Example 107 g of benzylamine was placed in the same apparatus as in Example 1.
(1.00 mol), and a 30% wt solution of soda cyanide 163
g (1 mol) was added thereto and dissolved with stirring, and 81 g (1 mol) of a 37% by weight formalin solution was added dropwise thereto at 40° C. or lower over 1 hour. After the dropwise addition was completed, the mixture was heated and reacted at 50° C. for 1 hour with stirring. Then 40 g of a 50% by weight solution of caustic soda was added at once. The mixture was heated and reacted at boiling point for 2 hours. The liquid after the reaction was colored brown, and as a result of analysis,
75g of N-benzylglycine soda and 67g of N-benzyliminodiacetic acid soda were produced. Examples 2 to 5 Various amines were reacted in the same manner as in Example 1. Table 1 shows the reaction conditions of the first stage reaction and the yield of the obtained phenyl-substituted glycine. The hydrolysis in the second stage reaction is the same as in Example 1.

【table】

Claims (1)

[Scope of Claims] 1 General formula [Formula] (where R represents a lower alkylene group, X represents a lower alkyl group, an alkali metal oxycarbonyl group, a hydroxy group, a nitro group, a chlorine atom or a bromine atom, and n is 0
Or represents an integer from 1 to 3. ) is reacted with glycolonitrile in an aqueous medium to obtain an N-acetonitrile derivative of the amine, which is then hydrolyzed with an alkali metal hydroxide [Formula] (However, R, X, and n are the same as above, and M represents an alkali metal.) A method for producing a glycine derivative represented by: