JPH05178802A - Production of n-benzylglycine and its derivative - Google Patents

Abstract

PURPOSE:To readily obtain N-benzylglycine useful as an intermediate for medicines, photographic chemicals, etc., and its derivative in high yield from industrially readily and inexpensively obtainable raw materials. CONSTITUTION:A compound of formula I (R is H, 1-4C alkyl, 7-8C aralkyl, hydroxy-substituted aralkyl or 1-3C hydroxyalkyl and H of the alkyl may be replaced with phenyl) is reacted with a compound of formula II (X is H, halogen, 1-4C alkyl or 1-4C alkoxy; (n) is 1-5 integer) in the presence of a base (preferably NaOH) to give a Schiff base of formula III, which is successively reduced, preferably hydrogenated and catalytically reduced in the presence of a catalyst of Pd or Pd supported on a carrier under <=20kg/cm<2> to give a compound of formula IV in high yield. This compound is further reacted with an alkali metal cyanate (preferably NaCN or KCN) and a mineral acid (preferably hydrochloric acid) to give a compound of formula V in a container.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing N-benzylglycine and its derivatives. Derivatives of N-benzylglycine also include N-benzylhydantoin and its derivatives.

N-benzylglycine and its derivatives are useful compounds as intermediates for medicines, photographic agents and the like.

[0003]

2. Description of the Related Art Conventionally, several methods for producing N-benzylglycine and its derivatives are known. For example, (1) a method of reacting benzylamine and chloroacetic acid in the presence of a base (JP-A-54-14931).

[Chemical 3] (2) Method of reacting benzylamine and glyoxal in the presence of sulfur dioxide (US4684483)

[Chemical 4] (3) A method of reacting a copper complex of glycine and benzyl chloride in a polar solvent (Inorg. Chim. Act)
a 133 , 1, 1987).

[Chemical 5] Etc. are known.

[0004]

However, the above-mentioned known methods have drawbacks such as the use of expensive benzylamine, the production of wastewater containing heavy metals harmful to the human body, and the poor production efficiency. However, it is hard to say that it is an industrially advantageous method.

[0005]

In view of the above situation, the present inventors have earnestly studied to provide a method for producing N-benzylglycine and its derivatives easily and economically.

As a result, as shown by the following reaction formula, the Schiff base obtained by reacting glycine and benzaldehyde in the presence of a base is reduced to give the desired N
-It was found that benzylglycine and its derivatives can be obtained in high yield, and the inventions according to claims 1 to 6 were achieved.

[Chemical 6]

Furthermore, the N-obtained by the above reaction formula
It was found that N-benzylhydantoin and its derivative can be easily obtained by reacting a reaction solution containing benzylglycine and its derivative with an alkali metal cyanate as shown in the following reaction formula and a mineral acid. The invention described in 8 has been reached.

[Chemical 7]

That is, the gist of the invention described in claims 1 to 6 is that N-benzylglycine characterized by reacting a glycine derivative and a benzaldehyde derivative in the presence of a base to form a Schiff base, and subsequently reducing the same. It is a method for producing the derivative.

The method for producing N-benzylglycine and its derivatives according to the present invention is a novel method, which is characterized by the fact that N-benzylglycine and benzaldehyde derivatives, which are industrially easily and inexpensively available, give N-benzylglycine and benzaldehyde derivatives. The point is that benzylglycine and its derivatives are obtained in high yield.

Examples of the glycine derivative include glycine, alanine, phenylalanine, isoleucine, leucine, serine, threonine, tyrosine, valine and phenylserine.

The benzaldehyde derivatives include benzaldehyde, o-, m-, p-chlorobenzaldehyde, o-, m-, p-bromobenzaldehyde, 3,5.
-Dichlorobenzaldehyde, 3,5-dibromobenzaldehyde, o-, m-, p-tolualdehyde, o-,
m-, p-ethylbenzaldehyde, o-, m-, p-
Propylbenzaldehyde, m-, pn-butylbenzaldehyde, m-, pt-butylbenzaldehyde, o-, m-, p-methoxybenzaldehyde, o
-, M-, p-ethoxybenzaldehyde, o-, m
-, P-propoxybenzaldehyde and the like can be mentioned.

When the glycine derivative and the benzaldehyde derivative are reacted to form a Schiff base, a base is usually used. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal alcoholates such as sodium methylate and sodium ethylate. Usually, inexpensive sodium hydroxide is preferably used. Be done. The amount of the base used is usually 0.3-based on the glycine derivative.
It is used in a range of 1.5 times mol, preferably 0.5 to
It is 1.1 times the molar amount. If it is less than 0.3 times by mole, the yield of the target Schiff base will be reduced, and if it exceeds 1.5 times by mole, the yield will be reduced due to a side reaction.

The amount of the benzaldehyde derivative used is usually 0.6 to 1.5 times, and preferably 0.9 to 1.2 times the mol of the glycine derivative.
If it is less than 0.6 times by mole, the yield of the target Schiff base will be reduced, and even if it is used in excess of 1.5 times by mole, the corresponding effect cannot be obtained, which is economically disadvantageous.

The reaction solvent is not particularly limited,
Water; alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol; ethers such as tetrahydrofuran and dioxane; polar solvents such as N, N-dimethylformamide and N-methyl-2-pyrrolidone; or a mixture thereof. Although it can be used, water is preferably used for economic reasons.

The reaction temperature is usually in the range of 0 to 80 ° C, preferably 10 to 40 ° C. If the reaction temperature exceeds 80 ° C., the yield of the Schiff base decreases due to a side reaction, while if the reaction temperature is less than 0 ° C., the reaction rate is too slow for practical use.

The reaction solution containing the Schiff base thus obtained is subsequently reduced to give the desired N
-Benzylglycine and its derivatives can be easily produced. Examples of the reduction method include catalytic reduction by hydrogenation or a reduction method with a metal hydride compound such as sodium borohydride or lithium aluminum hydride. Of these, the method by hydrogenation catalytic reduction is preferable from the industrial viewpoint. Examples of the catalyst used for the hydrogenation catalytic reduction include commonly used catalysts, and examples thereof include noble metals such as palladium, platinum, rhodium, ruthenium, and rhenium, or oxides thereof, as they are, or alumina, carbon, etc. The thing supported by the carrier can be mentioned. Particularly, when water is used as a solvent, good results are obtained by using palladium-carbon.

Since the amount of the catalyst used varies depending on the type of the catalyst used, it cannot be generally stated, but it is 0.005 in terms of the pure content of the noble metal or its oxide with respect to the glycine derivative.
When it is used in the range of 0.5 wt%, good results are obtained.

The reaction temperature is usually in the range of 0 to 80 ° C, preferably 10 to 40 ° C. When the reaction temperature is higher than 80 ° C, the yield of N-benzylglycine and its derivative is lowered due to a side reaction. On the other hand, when the reaction temperature is lower than 0 ° C, the reaction rate is too slow for practical use.

This reduction reaction is carried out under normal pressure, that is, 1 kg / cm.
² (hereinafter, the unit of pressure is indicated by absolute pressure), but in that case, it takes 10 to 50 hours to complete the reaction. Further, this reaction can be carried out under pressure,
When reacting under pressure, the pressure range is usually 20 kg
/ Cm ² or less, preferably ^{2 to 10} kg / cm ²
Is. In this way, when the reaction is carried out under pressure and the reaction temperature is raised or the amount of catalyst used is increased, the reaction time can be shortened. Therefore, this reaction can be completed in an arbitrary reaction time by selecting the reaction pressure, the amount of catalyst used, etc. within the above-mentioned range, as described in Examples described later.

The N-benzylglycine and its derivatives obtained as described above are obtained by appropriately separating the reaction solution from the catalyst by filtration and then using a known means such as filtration ( Isolation).

Next, the gist of the invention described in claims 2 to 8 is to react N-benzylglycine and its derivative obtained by the above-mentioned method with an alkali metal cyanate and a mineral acid to give N-benzyl. It is a method for easily producing hydantoin and its derivatives.

At this time, it is not necessary to use N-benzylglycine and its derivative isolated in particular, and the reaction liquid containing N-benzylglycine and its derivative described above can be used as it is.

Examples of the alkali metal cyanate include sodium cyanate and potassium cyanate. The amount of the alkali metal cyanate used is in the range of 0.9 to 2.0 times, preferably 1.0 to 1.5 times the mol of the produced N-benzylglycine and its derivative. If it is less than 0.9 times by mole, the yield of N-benzylhydantoin and its derivative decreases, and if it exceeds 2.0 times by mole, the corresponding effect cannot be obtained, which is economically disadvantageous. ..

As the solvent used for the reaction of N-benzylglycine and its derivative with alkali metal cyanate, the same solvent as used for obtaining N-benzylglycine and its derivative can be used.

Examples of the mineral acid used in the present invention include hydrochloric acid, sulfuric acid, phosphoric acid and the like. The amount of the mineral acid used is 0.9-based on the produced N-benzylglycine and its derivative.
It is in the range of 5.0 times mol, preferably 1.0 to 3.0.
It is in the double molar range. If it is less than 0.9 times the molar amount, the yield of N-benzylhydantoin and its derivative decreases,
Even if it is used in an amount exceeding 5.0 times the molar amount, it is economically disadvantageous because the effect corresponding to it cannot be obtained.

The reaction temperature for reacting N-benzylglycine and its derivative with an alkali metal cyanate and a mineral acid is usually 20 to 100 ° C., preferably 30 to 100 ° C. This is because if the temperature is lower than 20 ° C., the reaction rate and the yield decrease. The reaction time is usually in the range of 0.5 to 6 hours.

The N-benzylhydantoin and its derivative thus obtained can usually be easily isolated by cooling, crystallization and filtration.

[0028]

According to the present invention, the Schiff base obtained by reacting a glycine derivative and a benzaldehyde derivative in the presence of a base is reduced to easily and highly yield the desired N-benzylglycine and The derivative can be obtained.

Further, by reacting the N-benzylglycine and its derivative obtained above with an alkali metal cyanate and a mineral acid, N-benzylhydantoin and its derivative can be easily obtained.

[0030]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 In a 1 liter autoclave equipped with a stirrer and a thermometer,
Glycine 75.3 g (1.00 mol), sodium hydroxide 36 g (0.90 mol), and water 350 g were charged, and the mixture was stirred and dissolved at room temperature, and then benzaldehyde 111.7 g.
(1.05 mol) was injected. Furthermore, 0.47 g of 5% palladium-carbon was added, the inside of the autoclave was replaced with nitrogen, and then the mixture was stirred for about 30 minutes. After confirming that the internal temperature of the autoclave was 30 ° C. or lower, the inside of the autoclave was replaced with hydrogen, and the hydrogen pressure was about 5 kg / cm ² ,
The mixture was stirred at an internal temperature of 30 ° C for about 5 hours. After confirming that hydrogen absorption had stopped, hydrogen in the autoclave was evacuated, the reaction liquid was taken out, and the catalyst was filtered off. The reaction mixture was quantified by high performance liquid chromatography to find that it was 156.8.
g of N-benzylglycine had been produced. The reaction production rate was 90.4% with respect to the raw material glycine. 35% Hydrochloric acid was added dropwise to this reaction solution to acidify the pH of the reaction solution to 1 or less, and the precipitated crystals were collected by filtration to obtain 126 g of N-benzylglycine hydrochloride crystals.

Examples 2 to 5 In the same manner as in Example 1 except that the reaction was carried out at the reaction pressure (hydrogen pressure), the amount of catalyst and the reaction time shown in Table 1,
N-benzylglycine was obtained. The results are shown in Table 1.

[0033]

[Table 1]

Examples 6 to 12 N-benzylglycine derivatives were prepared in the same manner as in Example 1 except that the raw materials shown in Table 2 were used and the amount of the catalyst used in terms of pure palladium was set to the value shown in Table 2. Obtained. The results are shown in Table 2.

[0035]

[Table 2]

Example 13 A 1 liter four-necked flask equipped with a stirrer, a thermometer and a condenser was charged with the reaction solution containing N-benzylglycine obtained in the same manner as in Example 1, and then sodium cyanate was added. 68 g (0.949 mol) was added and heated to 40 ° C. While keeping the reaction solution at 40 to 45 ° C,
94% (0.904 mol) of hydrochloric acid was added dropwise. After completion of the dropping, the reaction solution was heated to 75 ° C. and kept at that temperature for about 1 hour. Furthermore, 149 g of 35% hydrochloric acid (1.424 mol)
Was added dropwise and then heated to 95 ° C. Heating was continued for about 1 hour to complete the reaction. The reaction solution was cooled to room temperature, filtered, washed with water, and dried to obtain 168 g (0.885 mol) of N-benzylhydantoin as white powder. The yield based on N-benzylglycine was 97.8%.

Example 14 The reaction was carried out in the same manner as in Example 9 except that potassium cyanate was used instead of sodium cyanate to obtain 167 g of N-benzylhydantoin. The yield based on N-benzylglycine was 97.2%.

Claims (8)

[Claims] 1. A glycine derivative represented by the following general formula (I) and a benzaldehyde derivative represented by the following general formula (II) are reacted in the presence of a base to form a Schiff's base, and subsequently reduced. A method for producing N-benzylglycine and a derivative thereof. [Chemical 1] 2. A N obtained by reacting a glycine derivative represented by the following general formula (I) with a benzaldehyde derivative represented by the following general formula (II) in the presence of a base to form a Schiff base, followed by reduction. -A method for producing N-benzylhydantoin and its derivatives, which comprises reacting benzylglycine and its derivatives with an alkali metal cyanate and a mineral acid. [Chemical 2] 3. The base is sodium hydroxide.
Or the method described in 2. 4. The reduction is a hydrogenation catalytic reduction.
4. The method according to any one of 3 to 3. 5. The method according to claim 4, wherein the catalyst for catalytic reduction is palladium or palladium supported on a carrier. 6. The method according to claim 4, wherein the catalytic reduction is performed under a pressure of 20 kg / cm ² or less. 7. The method according to claim 2, wherein the alkali metal cyanate is sodium cyanate or potassium cyanate. 8. The method according to claim 2, wherein the mineral acid is hydrochloric acid.