JPS6032753A - Production of beta-phenylserine compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound, by reacting glycine with benzaldehyde in a mixed solvent of water and a hydrophobic organic solvent in the presence of an alkali, treating the reaction mixture with an acid to separate the titled compound in almost pure form the aqueous layer in high yield, and recycling the organic solvent layer containing benzaldehyde. CONSTITUTION:Glycine is made to react with a benzaldehyde compound in a mixed solvent composed of (A) water and (B) a hydrophobic organic solvent capable of dissolving the benzaldehyde compound and inert to the reaction (e.g. hydrocarbon, alcohol, ether, etc.) in the presence of an alkali, optionally using 0.01-2.0g, based on 100g of glycine, of a phase-transfer catalyst to obtain a salt of N-benzylidene-beta-phenylserine compound. The reaction mixture is added with a mineral acid to dissolve the produced beta-phenyl-serine compound as a mineral acid salt in the aqueous layer and the by-produced benzaldehyde compound in the organic solvent layer. Both layers are separated from each other, and the aqueous layer is neutralized to obtain the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing β-phenylserines. The β-phenylserines of the present invention are themselves a type of α-amino acid, and are not only useful as physiologically active substances, but also compounds useful as intermediates in the production of β-phenylalanine derivatives.

Conventionally, the methods for producing β-phenylserine are 1) copper complex of glycine and penzua? A method of producing by reacting redehydes (for example, West German Patent No. 960, 722)
There is. However, this method uses copper salts, which poses problems in terms of industrial pollution, makes wastewater treatment troublesome, and is generally a production method that has drawbacks such as low yields.

In addition, 2) a method of reacting glycine and benzaldehydes in the presence of Phulkali and then treating with acid to produce β-phenylserine is also one of the well-known production methods. For example, KerIneth N, F, Sha-w
and 5idney W, Fox, Journa
l of AmerIcan Chemical 5
Society, 75, 3419 (1953), glinone and benzaldehyde are reacted in water in the presence of thorium hydroxide, and then treated with hydrochloric acid to form β-
Phenylserine is obtained with a yield of 70%. However, as described in the above-mentioned literature, in this method, the sodium salt of N-benzylidene-β-phenylserine, which is a reaction product of piglycine and benzaldehyde, is precipitated at once, and the reaction mixture as a whole is A major problem is that it solidifies, making mechanical stirring impossible. In addition, in terms of reaction mechanism, as shown in reaction formula (1), 1 mol of benzaldehyde is first condensed with 1 mol of glycine to form N-penzylidene glycine, which is then further condensed with 1 mol of benzaldehyde. Add N-
Benzylidene-β-phenylserine is produced. The desired β-phenylserine is produced by acid-treating this I-benozylidene-β-phenylserine.

Therefore, the reaction requires 2 moles of benzaldehyde per 1 mole of glycine, and 1 mole of this is regenerated as benzaldehyde during the acid treatment of the intermediate product N-benzylidene-β-phenylserine. In the conventional method, in order to separate this regenerated benzaldehyde from the product l-terphenylserine, the adhered benzaldehyde is removed by washing the β-phenylserine crystals with alcohol. Therefore, it also has the disadvantage that recovery of benzaldehyde from the sap from which β-phenylserine has been separated is complicated.

As described above, the conventionally known production methods have various drawbacks, and the current situation is that they are not necessarily satisfactory for industrial production.

The present inventors have conducted extensive studies on industrial methods for producing 9-phenylserines based on the problems of the prior art, such as the following: . That is, in the method of the present invention, glycine and benzaldehydes are reacted in the presence of an alkali, and then treated with an acid to produce β-hue, -lucerine, and the reaction is carried out in a mixed solvent of water and a hydrophobic organic solvent. The main feature is that it is done in 1~.

The raw material benzaldehyde used in the method of the present invention is unsubstituted or substituted benzaldehyde, and has a substituted benzaldehyde holder, nitro group, cyano group, or phenyl group, and its substitution position There is also no particular limitation on the number of substituents.

Examples of benzaldehydes include 0-tolualdehyde, m-)lualdehyde, p-tolualdehyde, p'-
Ethylbenzaldehyde, 0-anisaldehyde, m-
Anisaldehyde, p-anisaldehyde, 6,4-methylenedioxybenzaldehyde, m-phenothousandibenzaldehyde, m-benzyloxybenzaldehyde,
p-benzyloxybenzaldehyde, 3,4-dibenzyloxybenzaldehyde, 0-chlorobenzaldehyde, m-chlorobenzaldehyde v I) -rio
/l/benzaldehyde m--bromobenzaldehyde, p-bromobenzaldehyde, 2,4-dichlorobenzaldehyde, 3,4-
Examples include dichlorobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, p-nitrobenzaldehyde, p-cyanobenzaldehyde, p-diphenylaldehyde, etc.

The amount of these benzaldehydes to be used is 2 moles or more, preferably in a range of 20 to 30 moles relative to green.

The hydrophobic organic solvent used in the method of the present invention is one that dissolves benzaldehydes and is inert to the reaction.
It may have some degree of mutual solubility with water, but the two layers, the aqueous layer and the organic layer.
There is no particular restriction as long as it forms a layer. Specifically, hydrocarbon solvents such as benzene, toluene, xylene or ethylbenzene, methylene chloride, dichloromethane,
Chloroform, carbon tetrachloride, dichloroethane, dichloro[
Coethylene, trichloroethylene, chlorobenzene, 6
- dichlorobenzene t7'vU. ) Halogenated hydrocarbon doublers such as dichlorobenzene, 1-butanol, 2-
Butanol, imbutanol, 1-pentanol, 2-
pentanol, 3-pentanol, 1-heptatool,
Alcoholic solvents such as 2-heptatool or ro-heptanol1. Examples include ether solvents such as diethyl ether, dipropyl ether, butyl ether, ketone solvents such as methyl isobutyl ketone or diimbutyl ketone, and ester solvents such as acetate ester or phosphate ester. However, it is not limited to these examples. These solvents are usually used alone, but there is no problem in the reaction when two or more of them are used in combination.

The amount of these organic solvents used is not particularly limited as long as it is at least the amount that can dissolve the raw material benzaldehyde at the reaction temperature, but for the sake of reaction operation, it is usually 05 to 20 times the weight of the benzaldehyde, preferably 1. It is used in a range of 0.05 to 10 times the weight.

In the method of the present invention, the reaction is carried out in a mixed solvent of at least one of the above hydrophobic organic solvents and water. Although there is no particular restriction on the ratio of water and organic solvent in this mixed solvent, it is preferably 17 to 100 parts by weight of water and 20 to 500 parts by weight of organic solvent.

In the method of the invention, the reaction is also carried out in the presence of an alkali. The alkali used is preferably an alkali metal or alkaline earth metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide. There is no problem if the amount of barking is greater than the theoretical amount, but preferably 12
It is used in the range of ~30 equivalents. Of course, even if the amount of O equivalent is exceeded, there is no problem in reaction 1 (reaction 1), but the amount of acid used in the acid treatment after the reaction increases, which is not very practical in 2.

Furthermore, in the method of the present invention, a phase transfer catalyst can be used for the reaction if necessary. Phase transfer catalysts include quaternary ammonium salts such as tetramethylammonium chloride 2, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benfurtributylammonium chloride, tetrabutylammonium hydrogen sulfate or trioctylmethylammonium floride; and tetrabutylphosphonium chloride, tetrabutylphosphonium bromide 1. Mention may be made of quaternary phosphonium salts such as hexadecyltributylphosphonium chloride or ethyltrioctylphosphonium bromide. Any tfd or catalytic amount of these phase transfer catalysts may be used, and specifically, an amount of 001 to 20 grams per glycine 1001i' as a raw material is sufficient.

By adding these phase transfer catalysts as necessary, the reaction is promoted and the yield of β-phenylserines is improved. The effect of adding this phase transfer catalyst is particularly remarkable when the amount of alkali used is 15 equivalents or less relative to the raw material glycine.

In the method of the present invention, there is no particular limitation on the order in which raw materials and solvents are charged, and the reaction may be carried out in any order. - For example, after charging glycino, water, an organic solvent in which an aldehyde is dissolved, and if necessary a phase transfer catalyst, the reaction is carried out by charging or dropping an alkali in the form of a solid or aqueous solution while stirring. Reaction temperature and time are 0-80℃, 3
-50 hours, preferably 10-60°C, 5-30 hours. In this way, an alkali salt of N-benzylidene-β-phenylserine is produced.

In the method of the present invention, the alkali metal or alkaline earth metal salt of N-benzyritine-β-phenylserine produced by the above reaction is not isolated from the reaction system, but is treated with the following acid treatment. It can be easily isolated as β-phenylserine. That is, when the reaction mass of 1-benzylidene-β-phenylserine is added with a mineral acid having an amount of 1 or more of the total light of the glycine and alkali used in the reaction and treated at 0 to 80°C, preferably 10 to 60°C, N- Benzylidene-β-phenylserine is easily hydrolyzed to produce the corresponding β-phenylserine, which is further converted into a mineral acid salt by the excess acid and dissolved in water. The acid used is a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or boric acid, and the amount used is sufficient to convert the produced β-phenylserine to a mineral salt, that is, a mineral acid such as glycine. This is more than the total equivalent of the alkali and glycine used in the reaction with benzaldehyde. On the other hand, by this acid treatment operation, the N-benzylidene group is hydrolyzed and benzaldehydes produced as by-products are dissolved in the organic solvent. After the acid treatment, the aqueous layer and the organic solvent layer are separated by a liquid separation operation, and the aqueous layer is neutralized with an alkali such as sodium hydroxide to precipitate β-phenylserine crystals, which are isolated by filtration. . In this way, β-phenylserine can be produced almost pure and in good yield. On the other hand, it is not necessary to recover the benzaldehyde dissolved therein, and the organic solvent layer can be used for X-cycle as it is by simply replenishing the amount consumed in the reaction.

According to the method of the present invention, it is possible not only to solve the problem of stirring in an aqueous solvent in the known method, but also to solve the problem of separation of β-phenylserine and benzaldehyde. One advantage is that benzaldehydes can be dissolved in the aqueous layer and the organic solvent layer, respectively, and easily separated by a liquid separation operation. ! The benzaldehyde recovered in the organic solvent layer does not need to be recovered from the organic solvent layer again, and the organic solvent layer can be recycled and used as is by simply replenishing the amount of benzaldehyde consumed in the reaction. The dog of the present invention is also characterized by its ability to As described above, the method of the present invention can solve the problems of the prior art at once and simplify the manufacturing process, and has great significance compared to the industrial manufacturing method.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Glycine 607, water 400 fl, benzaldehyde 21
21 and 120 g of toluene were charged. While stirring at 1°C to 15°C, 177.8f of 45% sodium hydroxide was added dropwise over about 2 hours. Then gradually increase the reaction temperature to 2
The temperature was raised to 0°C and the reaction was carried out at 20-25°C for 20 hours. After the reaction, 292 og of 65% hydrochloric acid was added dropwise over 45 minutes at a temperature of 40° C. or lower, and the mixture was further stirred at room temperature for 1 hour. After standing still, the lower aqueous layer was separated in 2 portions and analyzed by high performance liquid chromatography. The θ-phenylserine production rate was 6 ± 926 = 4 (,:
(glycine). The aqueous layer was neutralized to pH=6 with 45% sodium hydroxide at room temperature, cooled to 0-5℃, stirred at the same temperature for 1 hour, filtered, washed with cold water, and then heated to 50℃.
By drying under reduced pressure, white crystals of β-phenylserine with a fi of 131.41 were obtained. Purity analysis of this product by high performance liquid chromatography was 905%, and differential thermal analysis confirmed that it had one molecule of water of crystallization. Yield 820% (relative to glycine) Melting point: 198-200
°C (decomposition) elemental analysis value (%) CHN Calculated value as COH□3NO4 54,266.57
703 Measured value 54,186,377.15 Example 2 The reaction was carried out in the same manner as in Example 1 except that 890v of benzaldehyde was newly added to the toluene layer of recovered benzaldehyde obtained in Example 1. β-phenylserine was obtained.

6 Example 2 In Example 1, dichloroethane 2 was used instead of toluene.
00f, 50% potassium hydroxide 2241Ft instead of 45% thorium hydroxide. Reaction temperature, time 60-65
18 hours in the same manner as in Example 1.
29.51i' of β-phenylserine was obtained. Purity 90
9%, yield 81.2% (based on glycine).

Example 4 Water 500? Glycine 602 and sodium hydroxide 48'y are added and dissolved therein. Next, after adding 0.5 f of trioctylmethylammonium chloride,
A solution of benzaldehyde 169.6f dissolved in toluene 1502 was added dropwise over approximately 1 hour while stirring at 60°C, and the reaction was further carried out at 25 to 35°C for 20 hours. After the reaction, 209 g of 35-thihydrochloric acid was added dropwise at a temperature of 40°C or lower, and the mixture was stirred at room temperature for 1 hour. After standing still, the lower aqueous layer was separated, and the aqueous layer was purified with 45% sodium hydroxide at room temperature.
The mixture was neutralized to H=6, stirred at 0-5°C for 1 hour, filtered, washed with cold water and dried to obtain 125.5ii' of β-phenylserine. Purity: 906%, Yield: 7B, 3% (based on glycine) Examples 5 to B A reaction for synthesizing β-phenylserine from glycine and benzaldehyde was carried out in the same manner as in Example 1, using various organic solvents. The results are shown in Table-1.

Examples 9 to 13 Reactions were conducted according to the method of Example 1 using various substituted benzaldehydes instead of benzaldehyde. The results are shown in Table-2.

/',,,/'' 5 Example 14 In Example 1, the amount of sodium hydroxide used was 15 and 21 equivalents to glycine, and trioctylbenzylammonium chloride was used as a phase transfer catalyst at 0.0.
Table 3 shows the results of a comparison of the β-phenylserine production rate in the aqueous layer obtained by adding 5f and performing the in-situ acid treatment after the reaction with the case in which no phase transfer catalyst was added.

Table-6 15 Yes 25-35720 F36.8 No 776 21 Yes 90.5 None 896 8 306-

Claims (1)

[Claims] 1) Glycine and benzaldehydes are reacted in the presence of an alkali, and then treated with an acid to produce β-phenylserines in a mixed solvent of water and a hydrophobic organic solvent. 2) A method for producing β-phenylserines, characterized in that the reaction is carried out in the presence of a phase transfer catalyst.